Poster Session 1

Multiple Sclerosis Journal 2015; 21: (S11) 76–653

Abstracts

Poster Session 1 Diagnosis and differential diagnosis P239 NMDA receptor antibodies are a rare condition in inflammatory demyelinating diseases M. Ramberger1, G. Bsteh1, K. Schanda1, R. Höftberger2, K. Rostasy3,4, M. Baumann3, F. Aboulenein-Djamshidian5, A. Lutterotti1,6, F. Deisenhammer1, T. Berger1, M. Reindl1 1Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, 2Institute of Neurology, Medical University of Vienna, Vienna, 3Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria, 4Pediatric Neurology, Witten/Herdecke University, Children’s Hospital Datteln, Datteln, Germany, 5Department of Neurology, Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Sozialmedizinisches Zentrum Ost Donauspital, Vienna, Austria, 6Neuroimmunology and Multiple Sclerosis Research, Department of Neurology, University ‘Hospital Zürich and University of Zürich, Zürich, Switzerland Background: NMDA receptor (NMDAR) encephalitis is characterized by the presence of IgG anti-NMDAR auto-antibodies in affected patients. NMDAR antibodies were also found in a few cases with NMDAR encephalitis and overlapping central nervous system (CNS) demyelinating diseases, but so far there are no studies systematically investigating the seroprevalence of NMDAR antibodies in patients with acute disseminated encephalomyelitis (ADEM), neuromyelitis optica spectrum disorders (NMOSD), clinically isolated syndrome (CIS) or multiple sclerosis (MS). The aim of this study was to analyze the frequency of NMDAR antibodies in patients with these inflammatory demyelinating CNS diseases and to determine their clinical correlates. Methods: Retrospective case-control study from 2005 to 2014 with the detection of IgG antibodies to NMDAR, aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) by recombinant live cell-based immunofluorescence assays. Fiftyone patients with ADEM, 41 patients with NMOSD, 34 with CIS and 89 with MS were included. Due to a known association of NMDAR antibodies with seizures and behavioral symptoms, patients with those clinical manifestations were preferably included and are therefore overrepresented in our cohort. Nine patients with NMDAR encephalitis, 94 patients with other neurological diseases and 48 healthy individuals were used as controls. Results: NMDAR antibodies were found in all (9/9) patients with NMDAR encephalitis but only in one of 215 (0.5%) patients with inflammatory demyelination and in none of the controls. This patient had relapsing-remitting MS with NMDAR antibodies present already at disease onset, with an increase in NMDAR antibody titer with the onset of psychiatric symptoms and cognitive deficits. The presence of NMDAR antibodies was confirmed in the cerebrospinal fluid using immunohistochemistry. Among 81 patients with

demyelinating disorders who had seizures and/or behavioral symptoms, this one patient had NMDAR antibodies, 22 MOG antibodies (all ADEM), 2 AQP4 antibodies (all NMOSD) and 56 had no antibodies (15 ADEM, 1 NMOSD, 1 CIS and 39 MS). Conclusions: NMDAR antibodies are rarely present in demyelinating diseases, even when focusing on patients with symptoms suggestive of NMDAR encephalitis. However, if present NMDAR antibodies could have a diagnostic value for an overlapping NMDAR encephalitis related disease course in patients with demyelinating diseases. Disclosure This study was supported by research grants from the Fonds zur Förderung der wissenschaftlichen Forschung, Austria (FWF graduate program W1206 SPIN) and the Austrian Federal Ministery of Science and Economy (grant BIG WIG MS). The Medical Universities of Innsbruck (Florian Deisenhammer and Markus Reindl) and Vienna (Romana Höftberger) receive payments for antibody assays (NMDA receptor and other anti-neuronal and anti-glial autoantibodies). Melanie Ramberger, Gabriel Bsteh, Kathrin Schanda, Kevin Rostasy, Matthias Baumann, Fahmy Aboulenein-Djamshidian, Andreas Lutterotti and Thomas Berger have no potential conflicts of interest.

P240 Diagnostic value of enhancing lesions on postcontrast T1-weighted magnetic resonance images in clinically isolated syndromes M. Díaz-Sánchez, N. Cerdá-Fuertes, M. Prieto-León, L. LebratoHernández, J.L. Casado-Chocán, A.J. Uclés-Sánchez Neurology, University Hospital Virgen del Rocio, Sevilla, Spain The magnetic resonance imaging (MRI) criterion for dissemination in time (DIT) based on a single scan requires the simultaneous detection of asymptomatic enhancing and non-enhancing lesions on post-contrast T1-weighted scan. Although this criterion is highly specific for predicting early conversion to clinically definite multiple sclerosis (CDMS), its sensitivity is rather low. We aim to analyze the value of the simultaneous presence of enhancing and non-enhancing lesions, regardless of whether the enhancing ones are symptomatic or not, for predicting conversion to CDMS as an alternative criterion for demonstrating DIT in patients with clinically isolated syndromes (CIS). We also evaluate the accuracy of this alternative DIT criterion for the diagnosis of multiple sclerosis according to the McDonald 2010 criteria. Inclusion criteria: 1) CIS suggestive of central nervous system demyelination (since 2008); 2) clinical assessment and baseline brain MRI within 8 weeks of CIS onset; 3) clinical follow-up of at least 12 months.

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Poster Session I, 21(S11) We included 102 CIS patients, 70 women (68.62%), with a mean age at onset of 32 years. After a mean follow-up of 39 months, 58 (56.86%) patients were diagnosed as having MS according to the McDonald 2010 criteria. The overall conversion rate to CDMS was 39.21%. In 24 patients (23.52%) baseline MRI simultaneously showed asymptomatic enhancing and non-enhancing lesions, whereas in 33 patients (32.35%) simultaneously detected enhancing (symptomatic or not) and non-enhancing lesions. The alternative DIT criterion proposed, based on a single MRI scan, was more sensitive (53.44% v 39.65%) maintaining a high specificity (95.45% v 97.72%). Both DIT criteria identified a subset of patients with CIS who were at high early risk of developing CDMS (hazard ratio: 3.34 and 4.46, p< 0.001; respectively). The proposed alternative DIT criterion, based on a single scan, is more sensitive that the original one with a slight decrease in specificity. This modified criterion should be evaluated in other CIS cohorts.

to generate the predicted probability of being early SPMS for the late RRMS patients. This analysis is part of developing a screening tool that can help physicians to identify SPMS early. Results: Positive non-zero coefficients (indicating higher likelihood of being early SPMS) were obtained for age (0.04, CI [0.01, 0.07]), unemployment (0.86, [0.17, 1.72]), requirement for assistance in daily living (2.34, [1.71, 3.21]), number of T2 lesions (0.06, [0.03, 0.10]), and the presence of motor (1.18, [0.46, 2.20]), paraesthesia/sensory (0.10, [-0.19, 0.79]), ataxia/coordination (0.95, [0.34, 1.63]), and micturition/bladder (0.68, [0.02, 1.34]) symptoms. Predicted probabilities for the late RRMS population indicated that 58% would be classified as early SPMS. Conclusion: These analyses highlight significant differences between RRMS and SPMS populations. The variables that proved significant could be useful parameters for physicians to consider when assessing the transition from RRMS to SPMS. The results indicate potential misclassification of late RRMS patients.

Disclosure

Disclosure Funding source

Maria Díaz Sanchez: Nothing to disclose Nuria Cerdá Fuertes: Nothing to disclose María Prieto León: Nothing to disclose Lucia Lebrato Hernández: Nothing to disclose José Luis Casado Chocán: Nothing to disclose Antonio José Uclés Sánchez: Nothing to disclose

This study is supported by Novartis Pharma AG, Basel, Switzerland. Deniz Simsek is an employee of Novartis Pharma AG, Basel, Switzerland. Elisabetta Verdun Di Cantogno is an employee of Novartis Pharma AG, Basel, Switzerland. Raquel Lahoz is an employee of Novartis Pharma AG, Basel, Switzerland. James Pike is a paid employee of Adelphi Real World, Macclesfield, United Kingdom. Eddie Jones is a paid employee of Adelphi Real World, Macclesfield, United Kingdom.

P241 Understanding the characteristics of secondary progressive multiple sclerosis to facilitate early identification D. Simsek1, E. Verdun Di Cantogno1, R. Lahoz1, J. Pike2, E. Jones2 1Novartis Pharma AG, Basel, Switzerland, 2Adelphi Real World, Macclesfield, United Kingdom Background: The transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) can be difficult to define. Objective: To assess the difference between early RRMS and early SPMS patients on sociodemographics, daily activities and clinical characteristics including symptoms and MRI parameters and quantify the likelihood of late stage RRMS patients being classified as early SPMS. Methods: Data were drawn from the Adelphi Multiple Sclerosis Disease Specific Program, a cross-sectional study of 250 neurologists and 3294 patients in the US. Patients with at least 4 years with MS diagnosis and EDSS⩾3 were analysed; 188 were defined as late RRMS (physician designation of RRMS, EDSS between 3 and 6) and 67 as early SPMS (physician designation of SPMS less than 3 years). Additionally, 1010 early RRMS patients (physician designation of RRMS, EDSS< 3, EDSS also scored one year previously) were analysed. Lasso penalised logistic regression was used to determine variables associated with being early RRMS or early SPMS. Covariates included in the regression were age, unemployment, requirement for assistance in daily living, number of T2 lesions, and the presence of motor, parathesia/sensory, ataxia/coordination, micturition/bladder, mood/depression, and concentration/cognition symptoms. Bootstrap-based 95% confidence intervals were produced. Regression coefficients were used

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P242 Corpus callosum lesions in patients with a clinical isolated syndrome N.A. Cerdá-Fuertes, M. Díaz-Sánchez, M. Prieto-León, L. Lebrato-Hernández, A.J. Uclés-Sánchez, J.L. Casado-Chocán Neurology, University Hospital Virgen del Rocio, Sevilla, Spain Corpus callosum (CC) lesions are frequently detected in patients with multiple sclerosis (MS), but are rare in healthy aging and cerebrovascular patients. However they are not included as an isolated typical location in the McDonald 2010 diagnostic criteria for dissemination in space (DIS), but rather as a part of periventricular lesions. We aim to analyze the diagnostic precision of the appearance of CC lesions in patients with a clinically isolated syndrome (CIS) in diagnosing MS according to the McDonald 2010 criteria and in predicting conversion to clinically definite MS (CDMS). Inclusion criteria: 1) CIS suggestive of central nervous system demyelination (since 2008); 2) clinical assessment and baseline brain magnetic resonance imaging (MRI) within 3 months of CIS onset; 3) clinical follow-up of at least 12 months. We included 77 patients, 55 women (71.43%), with a mean age at onset of 34 years. After a mean follow-up of 36 months, 44 patients (57.14%) were diagnosed as having MS according to McDonald 2010 criteria and the overall conversion rate to CDMS was 38.96%.

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Poster Session I, 21(S11)

In 30 patients (38.96%) baseline MRI showed lesions in CC, of whom 28 patients (93.33%) were diagnosed of MS. The presence of lesions in CC showed a high specificity and positive predictive value (PPV) for the diagnosis of EM (93.93% y 93.33%, respectively). The presence of lesions in CC was related to a higher and faster risk of conversion to a CDMS (hazard ratio: 4.80; p < 0,001). Our results confirm the high specificity and PPV of lesions in CC for the diagnosis of MS in patients with CIS, helping to exclude other alternative diseases. In addition, this radiologic finding has pronounced prognostic value identifying a subset of CIS patients who were at high early risk of developing CDMS. Disclosure Nuria Alicia Cerdá-Fuertes: Nothing to disclose. María Díaz-Sánchez: Nothing to disclose. María Prieto-León: Nothing to disclose. Lucía Lebrato-Hernández: Nothing to disclose. Antonio José Uclés-Sánchez: Nothing to disclose. José Luis Casado-Chocán: Nothing to disclose.

MS Variants

Clinically 59% (n=13/22) of patients had paraparesis (mostly) or tetraparesis. The decrease in visual acuity and even blindness were found in 27% (n=6/22). AQP4 Ab-seropositive patient’s average EDSS were 6.0. Radiological finding showed optic neuritis (ON) and transverse myelitis (TM) - 59% (n=13/22); isolated TM of the cervical and thoracic spinal cord - 22,7% (n=5/22); brain lesion- 81,8% (n=18/22). Subcortical and periventricular lesions predominated in patient group with ON and TM - 84,6% (n=11/13). ON was detected in 63,6% (n=14/22) - in 5/14 (35,7%) cases were bilateral ON; 9/14 (64,3%) patients had unilateral ON. Conclusions: 1. It was found that there are 12,76% unidentified NMO/NMOSD patients in MS patients group. 2. AQP4 Ab-seropositive group had no clinical and radiological differences from AQP4 Ab-seronegative group or compared to literature data. 3. Most common clinical symptom in NMO/NMOSD patients group were lower paraparesis and unilateral blindness. 4. Average EDSS in NMO patients were 6.0. Disclosure Nothing to disclose

P243 Property of neuromyelitis optica spectrum disorder S. Svilpe1, D. Volčeka2,3, J. Ignatjeva1,4, T. Muravska4,5, L. Vainšteine1,6, G. Karelis1,7, V. Ķēniņa5,7, A. Platkājis1,8, L. Elsone6, A. Gudreniece1 1Neurology, Eastern Clinical University Hospital „Gaiļezers’, 2Riga Stradins University, Institute of Anatomy and Anthropology, 3Latvijas Juras Medicinas Centrs, Multiple Sclerosis Center, 4Riga Stradins University, Faculty of Continuing Education, Residency of Neurology, 5Pauls Stradins Clinical University Hospital, Department of Neurology, 6Riga Stradins University, Doctoral Studies, 7Riga Stradins University, Department of Neurology and Neurosurgery, 8Riga Stradins University, Department of Radiology, Riga, Latvia Background: Neuromyelitis optica (NMO) is an uncommon, autoimmune inflammatory disorder of the central nervous system (CNS) characterized by attacks of predominantly optic neuritis and/or longitudinally extensive transverse myelitis - leading to disability. It was once thought of as a variant of Multiple Sclerosis (MS), and is still oftentimes misdiagnosed as MS. Patients with limited forms of the disease such as monophasic or recurrent LETM or severe bilateral or recurrent optic neuritis are said to have NMO spectrum disorder (NMOSD). Aquaporin-4 antibodies (AQP4-Ab) are highly specific for NMO/NMOSD. Despite NMO diagnostic criteria there is overlap between MS and NMOSD. Methods: The retrospective-prospective research was done in Riga Eastern Clinical University hospital “Gaiļezers” during the period from 01/01/2005 to 01/01/2014. All patients were tested for AQP4-Ab, performed neurological and radiological examination to identify NMO patients in MS group. Results: From all CNS demyelinating disorders patients (n=564) were included 72 patients (12,76%) with NMO/NMOSD where 30% (n=22/72) consented to participate; 4,17% (n=3/72) were dead. Female to male sex ratio were 3:1; the average age - 32,5 years; AQP4 Ab-seropositive patients were 13,9% (n=10/72).

P244 Efficacy of rituximab in refractory neuromyelitis optica N. Collongues1, D. Brassat2, E. Maillart3, P. Labauge4, J.-C. Ouallet5, C. Carra-Dalliere4, T. Moreau6, B. Bourre7, C. Papeix3, B. Audoin8, B. Brochet5, S. Vukusic9, J. De Seze1, R. Marignier9, OFSEP and CFSEP 1CHU Strasbourg, Strasbourg, 2CHU Toulouse, Toulouse, 3CHU Pitié-Salpétrière, Paris, 4CHU Montpellier, Montpellier, 5CHU Bordeaux, Bordeaux, 6CHU Dijon, Dijon, 7CHU Rouen, Rouen, 8CHU Marseille, Marseille, 9CHU Lyon, Lyon, France Background: Few data are available on patient with neuromyelitis optica refractory to immunosuppressors (RNMO). Objective: To assess the treatment effect of rituximab (RTX) as a maintenance therapy in RNMO patients and to identify predictive factors of therapeutic response. Methods: Data on RNMO patients treated chronically with RTX were collected and follow-up prospectively from a populationbased cohort. A random subject effect and a fixed time effect were used to identify predictive factors of disability. Results: Out of a total of 305 cases, we identified 21 patients (19 females/2males, mean age at onset 37.7 years) that received RTX as rescue therapy during a mean follow-up of 31 months. Antibodies against aquaporin-4 were found in 19/21 patients. After RTX treatment, RNMO patients experienced a decrease in mean AAR (from 1.3 to 0.4; p< 0.001), and median EDSS score (from 5 to 3; p=0.02). Mean annualized infusion rate was 2.3±1.6 and for a mean annualized dose of 1664±1002 mg. The body mass index was significantly predictive of disability as assessed on the EDSS. No side effects were reported at the end of the study. Conclusions: RTX is an effective and well tolerated treatment in RNMO. Our study indicated that BMI could drive a dose-effect response in these patients.


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Poster Session I, 21(S11) Disclosure Dr. Collongues serves on scientific advisory boards for and has received honoraria from Biogen Idec, Merck Serono, sanofigenzyme, Bayer Schering Pharma and Alexion Pharmaceutical. Dr. Brochet serves on scientific advisory boards for and has received honoraria or research support from Biogen Idec, Merck Serono, sanofi-genzyme, Bayer Schering Pharma, teva. Dr. De Seze serves on scientific advisory boards for and has received honoraria from Biogen Idec, Merck Serono, sanofi-genzyme, Bayer Schering Pharma, Chugai and Alexion Pharmaceutical. Dr JC Ouallet has received consultancy fees, speaker fees, research grants (non-personal), and honoraria from Novartis, Biogen-Idec, Merck-Serono, Bayer Schering, Roche, Almirall, Teva and Genzyme. Dr. Marignier serves on scientific advisory board for MedImmune and has received honoraria from Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme. Drs. Brassat, Vukusic, Maillart, Labauge, Carra Dalliere, Moreau, Bourre and Audoin report no disclosures. P245 Autologous hematopoietic stem cell transplant in patients with neuromyelitis optica - four year update J.M. Burton1, J. Storek2, P. Duggan2, F. Costello1, R. Bell1, L. Metz1 1Department of Clinical Neurosciences, 2Faculty of Medicine, Department of Hematology, University of Calgary, Calgary, AB, Canada Background: Neuromyelitis Optica (NMO) is an immune-mediated astrocytopathy characterized by frequent demyelinating/ necrotizing attacks of optic nerves and spinal cord. Treatments are highly toxic and incompletely effective. Fifty percent of patients are blind in one eye or require a mobility aide within 5 years. The immunological features of NMO, coupled with its severity make it an ideal candidate for a trial of AHSCT with the goal of disease remission and freedom from immunosuppressive medications. Objectives: We have undertaken a trial of autologous non-ablative stem cell transplantation (AHSCT) in NMO to determine if such treatment leads to disease remission and freedom from immunosuppressive medication. We hypothesize a 50% reduction in the proportion of patients experiencing relapse events over a three-year period. Secondary outcomes include relapse rate, EDSS, vision measures and survival. Methods: This open-label single centre trial was approved by the Calgary Conjoint Health and Research Ethics Board and Health Canada. Eligible patients have confirmed NMO, ages 18-65 and EDSS < =6.5 with =>1 relapse in 12 months or =>2 relapses in 24 months despite maintenance therapy. Using a cyclophosphamide/ rituximab/ATG protocol, patients undergo mobilization/harvesting of stem cells followed by a conditioning/stem cell infusion 4-8 weeks later. Results: Three NMO patients have undergone transplantation thus far. A 28F was transplanted in May 2011 with pre-transplant annualized relapse rate (ARR) of 5 and EDSS 4.5, now 0 and 2.0 at month 48 respectively. A 36F was transplanted in April 2012 with pre-transplant ARR of 5, now 0.33 and 3.0 at month 36 respectively, who started on mycophenolate mofetil at her request

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in 2014. A 39M was transplanted in January 2014 with pre-transplant ARR of 1.3 and EDSS 3.5 who remains stable with improved motor and sensory FSS scores with a stable EDSS at 17 months. Despite clinical improvement in all patients, the latter two patients, both NMO-IgG seropositive pre-transplant, remain seropositive. Conclusions: This transplant regimen appears tolerable in relatively young and healthy patients with active NMO and is associated with a significant to complete reduction in relapses and EDSS. If these results persist over a longer time period and in subsequent patients, AHSCT may prove to be an effective and tolerable option for NMO patients. Disclosure Dr. Burton has nothing to disclose. Dr. Storek has nothing to disclose. Dr. Duggan has nothing to disclose. Dr. Bell has nothing to disclose. Dr. Costello has nothing to disclose. Dr. Metz has nothing to disclose. P246 Genetic variation within miR-146a predicts disease onset & relapse in multiple sclerosis Y. Zhou1, M. Chen2, S. Simpson,Jr.1, J.C. Charlesworth1, I. Van der Mei1, R. Lucas3, A.-L. Ponsonby4, B.V. Taylor1 1Menzies Institute for Medical Research, Hobart, TAS, Australia, 2Xinqiao Hospital, Chongqing, China, 3National Centre for Epidemiology and Population Health, Canberra, 4Murdoch Children’s Research Institute, Melbourne, VIC, Australia Background: Despite extensive studies focusing on the expression changes of microRNAs (miRNAs) in multiple sclerosis (MS) compared to healthy controls, no studies have evaluated the association of miRNAs with MS clinical course. MiR-146a is primarily involved in the regulation of inflammation and it was up-regulated in active MS brain lesions. Additionally, miR-146a’s expression is altered by Epstein-Barr virus (EBV), smoking and low-density lipoprotein (LDL), which are well-defined independent risk factors for MS, thus making miR-146a a strong candidate gene to study in MS clinical course. Methods: We investigated whether polymorphisms in the miR146a gene predicted clinical course (conversion to MS after a first demyelinating event, relapse rate and disability) using a longitudinal cohort study of persons with a first demyelinating event now followed for over 9 years. CDMS and relapse were monitored by annual interview and medical record review. Disability was measured by EDSS at face-to-face reviews at baseline and 5-yr review, and annualised disability progression calculated. Results: We found the genotype (GC+CC) of rs2910164 predicted relapse comparing with GG genotype (HR=1.54 (95% CI: 1.08, 2.20), p=0.02). A similar result was seen for CDMS as an outcome (HR: 1.64 (95% CI: 1.03, 2.59), p=0.04). We also found a significant interaction of rs2910164 (pinteraction=0.02) with baseline anti-EBNA-1 IgG level and LDL (pinteraction< 0.001) as a predictor of relapse. Carriers of the (GC+CC) genotype showed a significantly increased risk of relapse from increased baseline anti-EBNA-1 IgG titers (HR=1.68, p=0.01). The results were


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similar for rs2910164 interacting with baseline anti-EBNA-1 IgG level predicting CDMS, although this interaction did not reach statistical significance (pinteraction=0.06). Carriers of the GG genotype showed a significant increased risk of relapse from increased LDL levels (HR=1.61, p< 0.001). The results were still similar for rs2910164 interacting with LDL level predicting CDMS (pinteraction=0.05). We did not observe any significant interaction between rs2910164 with baseline anti-EBNA-2 IgG or smoking to predict relapse, CDMS or EDSS. Conclusion: Our findings suggest miR-146a and its target genes as potential therapeutic targets for preventing relapse in MS. Disclosure The authors have nothing to disclose. P247 Variation within myelin basic protein gene predicts disease course in multiple sclerosis Y. Zhou1, S. Simpson,Jr.1, J.C. Charlesworth1, I. Van der Mei1, R. Lucas2, A.-L. Ponsonby3, B.V. Taylor1 1Menzies Institute for Medical Research, Hobart, TAS, 2National Centre for Epidemiology and Population Health, Canberra, 3Murdoch Children’s Research Institute, Melbourne, VIC, Australia Background: Myelin basic protein (MBP) is a major component of the myelin sheath ofcentral nervous system neurons and is believed to play an important role in the process of myelination. The molecular mimicry hypothesis suggests that T-cells may recognize epitopes on MBP as human herpersvirus-6 (HHV6) or Epstein-Barr virus (EBV) epitopes resulting in an autoimmune response against myelin. Despite significant interest, none of the large GWAS studies of MS have found any variations within the MBP gene that predict MS risk or clinical course. Methods: We investigated whether variations in the MBP gene act either directly or via interaction with HHV6 or EBV to predict clinical course (conversion to MS after a first demyelinating event, relapse rate and disability) using a longitudinal cohort study of persons with a first demyelinating event now followed for over 9 years. CDMS and relapse were monitored by annual interview and medical record review. Disability was measured by EDSS at face-to-face reviews at baseline and 5-yr review, and annualised disability progression calculated. Results: We found one variant in MBP, predicted outcomes, with the risk genotype: significantly predicting CDMS with HR=1.66, 95% 1) CI=1.05-2.63, p=0.030; 2) significantly predicting relapse with HR=1.63, 95% CI=1.16-2.30, p=0.005; 3) significantly predicting EDSS with β=1.93, 95% CI=0.423.44, p=0.050. We also found this SNP’s risk genotype significantly interacted with baseline-measured anti-HHV6 IgG levels, such that those with the risk genotype showed a potent positive association of HHV6 IgG with CDMS (HR: 5.17, p=0.13; pinteraction=0.16) and relapse (HR: 2.85, p=0.010; pinteraction=0.01), whereas the non-risk allele carriers showed no association.

Functional prediction analysis showed this variant is the target of many transcription binding factors and the binding sites of miR218 and miR-188-3p. Conclusion: Our results provide a novel insight into the potentially important role of genetic variation within the MBP gene in the development and progression of MS. Disclosure The authors have nothing to disclose. P248 Short myelitis as a first manifestation of neuromyelitis optica spectrum disorder S.-Y. Huh1, S.-H. Kim2, J.-W. Hyun2, C.H. Bin3, M.S. Park3, D.W. Bae4, H.J. Kim2 1Neurology, Kosin University College of Medicine, Busan, 2Neurology, Research Institute and Hospital of National Cancer Center, Ilsan, 3Neurology, Yeungnam University College of Medicine, Daegu, 4Neurology, The Catholic University of Korea, Seoul, Republic of Korea Background: Longitudinally extensive transverse myelitis (LETM, extending ⩾3 contiguous vertebral segments) is one of the most characteristic features supporting the diagnosis of neuromyelitis optica spectrum disorder (NMOSD). However, some NMOSD patients present with non-LETM (NLETM, < 3 segments), resulting in a diagnostic challenge. Objective: We investigated the frequency, clinical and imaging characteristics of NLETM among the NMOSD patients who presented with myelitis as their first manifestation. Methods: Patients who met the following inclusion criteria, from June 2005 to March 2015, were recruited and reviewed from three referral hospitals in Korea: (1) seropositivity for aquaporin-4 antibody, (2) initial presentation with myelitis, and (3) spinal cord MRI performed within 3 months of initial myelitis onset. Results: Of the 76 enrolled patients, 65 patients (85.5%) had 69 LETM lesions (median length 7, range 3~16) and the remaining 11 patients (14.5%) showed 15 NLETM lesions (median length 2, range 1~2.5). Of the 15 NLETM lesions, 6 lesions (40%) had a length of 2 vertebral segments, 5 lesions (33.3%) had a length of 2.5 segments, 3 lesions (20%) showed a length of the 1.5 segments and 1 lesion (6.7%) had a length of the 1 segment. Gadolinium-enhanced images were available in 13 NLETM lesions, of which 9 lesions showed enhancement (5 diffuse and 4 nodular pattern) and 4 NLETM lesions had no enhancement. On axial images, 11 NLETM lesions (73.3%) were mainly located in the central gray matter, while 4 NLETM lesions (26.7%) exhibited peripheral involvement which is undifferentiated from typical multiple sclerosis lesions. Of the 8 patients who had initial brain MRI, 6 patients showed no brain lesions and 2 patients had brain lesions characteristic of NMOSD. Of the 11 patients with NLETM, 5 patients (45.5%) had no relapse with immunosuppressants for 26 months (mean) and the remaining 6 patients (54.5%) had relapses, 3 of whom exhibited recurrent NLETM. Conclusion: A considerable number of NMOSD patients (14.5%) who presented initially with myelitis show NLETM lesions. This


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Poster Session I, 21(S11) result indicates that NLETM does not exclude the possibility of NMOSD diagnosis. Serologic test for aquaporin-4 antibody and brain MRI findings are essential to make an accurate and timely diagnosis in patients presented with NLETM. Disclosure Dr. Huh SY reports no disclosures. Dr. Kim SH reports no disclosures. Dr. Hyun JW reports no disclosures. Dr. Bin CH reports no disclosures. Dr. Park MS reports no disclosures. Dr. Bae DW reports no disclosures. Dr. Kim HJ has received honoraria for speaking or consulting from Bayer Schering Pharma, Biogen Idec, Genzyme, Merck Serono, and Novartis. P249 Age and gender effects on neuromyelitis optica spectrum disorder phenotypes D.K. Sato1,2, P.Z. Melo1, L.M. Oliveira1, F.M.H. Jorge1, R.F. Simm1, G.E.S. Linhares1, S.L. Apostolos-Pereira1, K. Fujihara2, D. Callegaro1 1University of Sao Paulo, Sao Paulo, Brazil, 2Tohoku University School of Medicine, Sendai, Japan Background: Neuromyelitis Optica Spectrum Disorders (NMOSD) are characterized by severe optic neuritis (ON) and transverse myelitis (TM), and positivity to aquaporin-4 (AQP4) antibodies. NMOSD onset is concentrated during the fourth decade of life, and females are more affected. However, the influence of onset age or gender on the clinical phenotype has not been extensively analysed. Methods: Consecutive anti-AQP4 positive NMOSD patients followed at Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HC-FMUSP NMO database, Sao Paulo, Brazil). Serum anti-AQP4 was tested using a cell-based assay with live transfected cells. Results: Among the 140 anti-AQP4 positive NMOSD, 14.3% (20/140) had onset age < 18 years, 70.7% (99/140) between 18 - 50 years and 15% (21/140) > 50 years. The female:male (F:M) ratio was 3:1 in paediatric cases, 11:1 between 18 - 50 years and 4:1 in patients > 50 years. Eighty-four patients had both ON and TM, and 24.3% (34/140) had simultaneous ON and TM. ON attacks were present in 95% (19/20) of paediatric cases, but 57.1% (12/21) of patients > 50 years experienced only TM attacks. Brainstem symptoms like vomiting and hiccups were present in 55% (11/20) of paediatric group, while only 14.3% (3/21) of patients > 50 years had similar symptoms. Males represented only 12% (17/140) of total, but they had more frequently disease restricted to ON attacks than females (29.4% vs. 9.8%). Conclusions: In our series of anti-AQP4 positive NMOSD, the F:M ratio was lower in paediatric and > 50 years onset. Patients with onset age > 50 years had more frequently a disease limited to spinal cord, contrasting with paediatric patients who usually have attacks in multiple regions. Our data indicates a close connection between age/gender and NMOSD phenotypes.

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Disclosure This study was partially supported by grant-in-aid for scientific research from the Japan Society for the Promotion of Science (KAKENHI 15K19472), the Health and Labour Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labour and Welfare of Japan, and CAPES/Ministry of Education Brazil (88881.068012/2014). Dr Sato has received scholarship from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, grant-in-aid for scientific research from the Japan Society for the Promotion of Science (KAKENHI 15K19472), research support from CAPES/Brasil (88881.068012/2014) and speaker honoraria from Novartis. Dr Melo has no disclosures Dr Oliveira has no disclosures Dr Jorge has no disclosures Dr Simm has no disclosures Dr Linhares has no disclosures Dr Apostolos-Pereira has no disclosures Dr. Fujihara serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, Medimmune and Medical Review; has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical; serve as an editorial board member of Clinical and Experimental Neuroimmunology (2009-present) and a advisory board member of Sri Lanka journal of Neurology; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The ChemoSero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical,Ono Pharmaceutical, Nihon Pharmaceutical, and Genzyme Japan; is funded as the secondary investigator (#22229008, 2010-2015) by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan and as the secondary investigator by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfre and Labor of Japan (2010-present). Dr Callegaro has no disclosures P250 Longitudinal analysis of autoantibodies, IFNgamma, and IL-17 in the serum of patients with concomitant NMO and SLE K.T. Kovacs1, S.R. Kalluri2, A.B. Serrano3, T. Deierborg3, T. Csepany4, M. Simo5, L. Rokusz6, L. Czirjak1, T. Berki1, T. Molnar1, B. Hemmer2, Z. Illes7 1University of Pecs, Pecs, Hungary, 2Technische Universität München, Munich, Germany, 3Lund University, Lund, Sweden, 4University of Debrecen, Debrecen, 5Semmelweis University, 6Military Hospital - State Health Centre, Budapest, Hungary, 7Institute of Clinical Research and Department of Neurology, University of Southern Denmark, Odense, Denmark


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Background: Association of neuromyelitis optica (NMO) with SLE has been recognized, but the relationship between serological and clinical activities is not well established. Objectives: To examine polyclonal B cell activation, appearance of myelin oligodendrocyte glycoprotein (MOG)-antibodies and cytokines reflecting T cell function during the course of NMO in patients with SLE. Methods: In 19 samples of 6 patients, who developed NMO during SLE, we examined correlation of AQP4-IgG1 and IgM antibodies with (i) anti-MOG IgG and IgM antibodies; anti-nuclear, anti-nucleosoma and anti-dsDNA IgG (ii) antibodies; (iii) cytokines and chemokines in the serum reflecting T-cell function; (iv) longitudinal relation to NMO disease activity. Results: AQP4-IgG1 were present 2-5 years before the first NMO relapse. We found correlation between AQP4-IgG1 and IgM (P=0.02), AQP4-IgG1 and anti-nucleosoma (P=0.04), AQP4-IgM and anti-nucleosoma (P=0.001), AQP4-IgM and ANA (P=0.009). During relapse, AQP4-IgG1 and IgM ANA, anti-dsDNA and antinucleosoma were elevated. AQP4 antibodies correlated with IFNgamma (P=0.01), IL-17 (P=0.01) and IP-10 (P=0.03). MOG antibodies were not detected. Conclusions: In patients with SLE, AQP4-IgG1 antibodies are present in the sera years before the first NMO attack; polyclonal B cell response and antibody production characterize NMO relapses; despite of multiple autoantibodies in the serum, MOG antibodies were not present; Th1 and Th17 responses may correlate with autoantibody responses. Disclosure Z. Illes has received research support from Biogen Idec and travel grants and speaking fees from Bayer Healthcare, Biogen Idec, Merck Serono, Sanofi-aventis/Genzyme, Teva Pharmaceuticals, and Novartis, research grants from Biogen Idec, Lundbeckfonden and Scleroseforeningen (Denmark). Hemmer has served on scientific advisory boards for Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GSK, Chugai Pharmaceuticals, Micromet, Genentech and Genzyme Corporation; serves on the international advisory board of Archives of Neurology and Experimental Neurology; has received speaker honoraria from Bayer Schering, Novartis, Biogen Idec, Merck Serono, Roche, and Teva Pharmaceutical Industries Ltd; and has received research support from Biogen Idec, Bayer Schering, Merck Serono, Five prime, Metanomics, Chugai Pharmaceuticals and Novartis. He has been filed a patent for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and genetic determinants of neutralizing antibodies to interferon-beta. SRK, ABS, TD, TC, MS, LR, LC, TB, TM have nothing to disclose. P251 Do vaccinations trigger relapses in neuromyelitis optica? M.A. Mealy1, L.J. Cook2, F. Pache3, D.I. Velez4, D.J. Kimbrough5, D. Becker1, J.A. Jimenez Arango4, F. Paul3, M. Levy1 1Neurology, Johns Hopkins University, Baltimore, MD, 2Pediatrics, University of Utah, Salt Lake City, UT, United

States, 3Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany, 4Neurology, Universidad de Antioquia, Medellin, Colombia, 5Neurology, Brigham & Women’s Hospital, Partners MS Center, Harvard Medical School, Boston, MA, United States Objective: To determine if vaccinations chronologically correlate with relapses in neuromyelitis optica (NMO) or are associated with a higher relapse rate. Background: Neuromyelitis optica (NMO) is a relapsing autoimmune disease of the central nervous system that preferentially attacks the optic nerve and spinal cord. Vaccines activate the immune system and can potentially increase the risk of relapse in NMO. Across all demyelinating diseases of the central nervous system, a review of the literature suggests the risk of vaccine-associated relapses occurring within 30 days from vaccination is low. However, the majority of reported cases feature a clinical syndrome of optic neuritis and/or transverse myelitis similar to NMO raising the concern that NMO patients may be more susceptible. Design and methods: We conducted a retrospective analysis on 90 patients with relapsing NMO and NMO Spectrum Disorder (NMOSD) who have received a total of 180 vaccinations over the duration of their disease course. Subjects were included from three NMO Clinics at Johns Hopkins Hospital (Baltimore, MD, USA), Charité Hospital (Berlin, Germany) and Universidad de Antioquia (Medellín, Colombia). We compared the likelihood of a relapse occurring within 30 days of a vaccine to the likelihood of a relapse occurring within 30 days of a random date. We also compared the relapse rate between patients who received vaccinations during their disease course to those who did not. Results: We identified six NMO/NMOSD patients who relapsed within 30 days of a vaccination. Three of the events were at the onset of disease and three occurred later in the disease course. Three vaccines included the tetanus and diphtheria immunizations, two were influenza and one was a hepatitis B vaccination. The rate of vaccine associated relapses in this patient population was approximately 3%. The likelihood of a spontaneous relapse occurring with 30 days of random date was 2%. Conclusions: There is a small risk of vaccine associated relapses in NMO/NMOSD. Further studies on risk stratification are necessary to assist in patient care decisions. Disclosure Maureen Mealy: nothing to disclose Lawrence Cook: nothing to disclose Florence Pache: nothing to disclose Diego Velez: nothing to disclose Dorlan Kimbrough: nothing to disclose Daniel Becker: nothing to disclose Jorge Jimenez Arango: nothing to disclose Friedemann Paul: nothing to disclose Michael Levy: nothing to disclose P252 Neuromyelitis optica in Spain: a multicenter study of 178 patients M. Sepúlveda, T. Armangué, N. Solà-Valls, F. Graus, A. Saiz, NMO Spanish Group


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Poster Session I, 21(S11) Neurology, Hospital Clinic and Institut d Investigació August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain Introduction: The available epidemiological information, clinical characteristics and outcome on neuromyelitis optica (NMO) is limited. Most studies were performed before the introduction of the 2006 NMO criteria, the implementation of more sensitive methods of aquaporin-4 antibodies (AQP4-ab) detection, and the analysis of antibodies to myelin-oligodendrocyte glycoprotein (MOG-ab). We aimed to describe the demographic, clinical, disease course and serologic characteristics of a Spanish cohort. Methods: We performed a retrospective, multicenter study. Data were collected from January 2013 through January 2015, using hospital files and a specific clinical questionnaire for NMO. We identified 178 patients who fulfilled the 2006 NMO criteria or were NMO spectrum disorders (NMOsd) associated with AQP4-ab. Samples were tested for AQP4-ab and MOG-ab using cell-based assays. Results: Mean age at onset was 40.2 years (range 10-77) with a mean (SD) disease duration of 94.4 (100.4) months. Patients were mainly (86.5%) Caucasian, with a female:male ratio of 6.4:1. Fifty-seven patients (32%) were NMOsd. Optic neuritis was the most frequent initial event in NMO, and extensive myelitis in NMOsd. The course was monophasic in 26 patients (14%). Eightyone percent of patients were treated. In total, 145 patients (81.5%) had AQP4-ab, 8 (4.5%) MOG-ab, 2 (1%) both and 23 (13%) were double seronegative. Older age at onset (hazard ratio, HR, 1.05, 95% CI 1.02-1.07, p< 0.001), higher Expanded Disability Status Scale (EDSS) after the first relapse (HR 1.27, 95% CI 1.09-1.48, p=0.003) and a longer spinal cord lesion (HR 1.07,95% CI 1.021.13, p=0.009) were predictors to faster progression to EDSS score of 4, 6 and 7. NMO patients with MOG-ab exhibited a male predominance, a more frequent onset with simultaneous optic neuritis and myelitis, a higher CSF pleocytosis, and a lower disability at the end of a similar follow-up period (EDSS 1.8 vs 4.0 in AQP4-ab positive and 4.8 in seronegative patients, p=0.006). Conclusions: Our study provides new demographic, clinical and prognostic data on a large cohort of NMO patients. The frequency of MOG-ab is low but their identification has clinical and prognosis implications. Disclosure M Sepúlveda, T. Armangué, N. Solà-Valls, F. Graus: nothing to disclose A. Saiz: had received compensation for consulting services and speaking from Bayern-Schering, Merck-Serono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceuticals Industries Ltd and Novartis. Filiations of all the authors of the NMO Spanish group will be provided

Paediatric MS P253 Comorbid conditions and medication utilization among pediatric-onset multiple sclerosis patients in the United States M. Wenten, S. Richman, N. Everage, T. Soman Biogen, Cambridge, MA, United States

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Background: Pediatric-onset MS (POMS) is a well-recognized but relatively uncommon entity. As such, information on co-morbid conditions and drug utilization are limited. The goal of this study was to describe the demographic, comorbid conditions, and drug utilization among POMS patients in a sample of the insured US population. Methods: POMS patients were selected from a large US insurance-claims database from January 1, 2004 to June 31, 2011. POMS patients were defined as those with two or more International Classification of Disease 9th Revision (ICD-9) codes for MS with a first claim before age 18. Controls were selected and matched on year of birth, gender, time in the database, and pharmacy benefit eligibility. Comorbidities and medications were classified using a system which groups ICD-9 codes and National Drug Codes (NDC) into meaningful categories. Comparisons of comorbidities between cases and controls were estimated using odds ratios (OR) and 95% confidence intervals. Results: Among the 110,349 MS patients in the database, 916 (0.83%) were less than age 18 with a mean age of diagnosis of 14 years, and 59% were females. Common comorbid conditions in cases with increased odds compared to controls include: connective tissue disease (31%, OR: 5.5); headache, including migraines (28%, OR: 9.4); metabolic disorder (19%, OR: 4.8); diseases of the heart (17%, OR: 6.1); non-traumatic joint disorder (17%, OR: 2.3); and gastrointestinal disorder (17%, OR: 5.5). The majority of patients (90%) were not prescribed any MS disease-modifying treatment. Conclusions: POMS occurs in less than 1% of the MS population and appears to be associated with substantial comorbidity. The relative increase in comorbid conditions observed within this pediatric population merits further investigation. Disclosure Madé Wenten is a full-time employee of Biogen and holds stock in Biogen. Sandra Richman is a full-time employee of Biogen and holds stock in Biogen. Nicholas Everage is a full-time employee of Biogen and holds stock in Biogen. Teesta Soman is a full-time employee of Biogen and holds stock in Biogen. P254 Acquisition of early developmental milestones and need for special education services in paediatric-onset multiple sclerosis G.S. Aaen1, M. Waltz2, T. Casper2, J. Ness3, M. Gorman4, N. Makhani5, W. Vargas6, E. Waubant7, T. Chitnis4, T. Lotze8, J. Graves7, L. Benson4, J.-M. Tillema9, M. Rodriguez9, J. Rose2, B. Weinstock-Guttman10, L. Krupp11, A. Belman11, US Network of Paediatric Multiple Sclerosis Centers 1Paediatrics, Loma Linda University, Loma Linda, CA, 2University of Utah, Salt Lake City, UT, 3University of Alabama at Birmingham, Birmingham, AL, 4Harvard Medical School, Boston, MA, 5Yale University, New Haven, CT, 6Columbia University, New York, NY, 7University of California San Francisco, San Francisco, CA, 8Baylor College of Medicine, Houston, TX, 9Mayo Clinic, Rochester, MN, 10University of Buffalo, Buffalo, 11Stony Brook University, Stony Brook, NY, United States


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Intro: Paediatric-onset multiple sclerosis (POMS) is associated with cognitive impairment in up to one third of patients. Here we describe acquisition of early developmental milestones and the need for special education services, topics not previously reported in children with MS. Goals: To report the proportion of patients with POMS who were delayed in meeting early developmental milestones and the proportion of patients requiring special education services. Methods: A retrospective analysis of patients and controls prospectively enrolled in a study of POMS was performed examining developmental milestone acquisition and the need for special education services. Results: A total of 467 POMS (308 female and 153 male, age range: 1.9 -19.2 years, median 14.7, SD 3.8) with mean disease duration of 11.5 months and 428 healthy controls were enrolled from 2011 to 2014. Controls were enrolled from general paediatric clinics at participating institutions. Those with MS onset prior to age 11 (n=89) were compared to those with onset after 11 (n=369). Control participants had more delays in walking than children with POMS (5.7 % vs 2.2%, p=0.0143) and a trend in delay for development of two word phrases after 24 months (5.2% vs 2.4%, p=0.07). No differences in these parameters was observed among those with MS onset prior to or after age 11. In contrast, those with MS onset prior to age 11 vs. after age 11 were more likely to need an Individualized Education Plan (28.1% versus 13%, p=0.002), occupational therapy (11% versus 3.3%, p=0.008), reading assistance (18.3% versus 5.1%, p=0.0003) and math assistance (18.3% versus 5.7%, p=0.001). Discussion: Children with POMS do not have delayed walking or language acquisition as compared to controls. Children with MS onset prior to age 11 vs. after age 11 years are more likely to receive special education services. Disclosure G Aaen: Nothing to disclose M Waltz: Nothing to disclose T Casper: Nothing to disclose M Gorman: Nothing to disclose N Makhani: Nothing to disclose W Vargas: Nothing to disclose E Waubant: Nothing to disclose T Chitnis: Nothing to disclose T Lotze: Nothing to disclose J Graves: Nothing to disclose L Benson: Nothing to disclose JM Tillema: Nothing to disclose M Rodriguez: Nothing to disclose J Rose: Nothing to disclose B Weinstock-Guttman: Nothing to disclose L Krupp: Nothing to disclose A Belman: Nothing to disclose P255 Interferon beta-1b in treatment-naïve paediatric patients with relapsing-remitting MS: 1-year results from the BETAPAEDIC study J. Gärtner1, W. Brück1, A. Weddige1, H. Hummel1, J.-P. Bugge2, the BETAPAEDIC Study Group

1University

Medical Center Göttingen, Göttingen, 2Bayer Pharma AG, Berlin, Germany Background: BETAPAEDIC is the first prospective, international, multicentre, observational study to assess the safety and tolerability of interferon beta-1b (IFNB-1b) in paediatric patients with relapsing-remitting multiple sclerosis (RRMS). Objective: To present 1-year results from BETAPAEDIC Methods: Treatment-naïve patients (12-16 years old) diagnosed with RRMS according to McDonald (2005) or Poser criteria and scheduled by the investigator to be treated with IFNB-1b were enrolled. Follow-up was planned for every 6 months for 2 years. Clinical effectiveness was evaluated by annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) progression (>=1.0-step increase), and magnetic resonance imaging (MRI). Neuropsychological function was measured by WISC-IV, SPM+, Beery VMI, and d2 at Baseline and will be measured again after 2 years. Fatigue was assessed by the Fatigue Severity Scale (FSS). Enrolment is complete and outcomes after 1 year are reported. Results: 67 patients were enrolled (mean age: 14.2 years, 3.5:1 female:male). Mean time since disease onset was 1 year with a mean time since diagnosis of 0.53 years. 68.7% of patients were diagnosed by both McDonald and Poser criteria and 31.3% by McDonald criteria only. 98.5% reported >=1 clinical event and EDSS progression in the 2 years prior to study entry. Based on current data, 64.2% (n=43) had no relapses and 83.6% (n=56) had no change in disease status after 1 year on treatment. Mean ARR was 0.45 (n=57). 59.7% of patients (n=40) had stable EDSS (ie, no progression) while 50.7% (n=34) were relapse free and progression free. Nearly all patients (98.2%) had no change in their physicians’ impression of their cognitive function. FSS responses indicated that patients did not show fatigue (mean score on FSS items 1-9: 2.5, item 10: 3.0, n=37). MRI scans indicated the presence of new T2 and gadolinium-enhancing lesions (relative to baseline) in 49.3% (n=33) and 29.9% of patients (n=20), respectively. Preliminary analyses revealed no unexpected safety signals in this population. The most frequent adverse events were flu-like symptoms, injection site reactions, and elevations of liver transaminases. Conclusions: 1-year results from BETAPAEDIC suggest that IFNB-1b is an effective treatment option for paediatric patients with MS. No new or unexpected adverse events were reported. Further follow up will provide more comprehensive information on the treatment of this population. Disclosure ● J Gärtner has received honoraria and consultancy fees from Bayer Vital, Biogen, Merck Serono, Teva, and Novartis and has received research grant support from Novartis and Biogen. ● W Brück has received honoraria for lectures from Bayer Vital, Teva Pharma, Sanofi-Aventis, Genzyme, Novartis, Biogen and Merck-Serono and is member of Advisory Boards for Teva, Genzyme, Novartis and Biogen. W Brück has received research grants from Teva Pharma, Novartis and Biogen. ● A Weddige has received consultancy fees from Bayer Phama AG ● H Hummel has nothing to disclose. ● JP Bugge is a salaried employee of Bayer Pharma AG.


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Poster Session I, 21(S11) P256 Assessing motivations and perspectives of children and youth in pediatric multiple sclerosis studies C. Phan1, J. O’Mahony1, C. Darrell-Chang1, E.A. Yeh1, B.L. Banwell1,2 1Hospital for Sick Children, Toronto, ON, Canada, 2Children’s Hospital of Philadelphia, Philadelphia, PA, United States Human research volunteers are an essential component of research to develop new knowledge. The characteristics, motivations and perspectives of research participation among youth with paediatric multiple sclerosis (MS) and age-matched healthy controls are unknown. The validated Reaction to Research Participation Questionnaire was completed by adolescents and young adults with MS and healthy controls as part of five MS studies hosted by two Canadian children’s hospitals between 2010 to 2012. Participants completed two or more testing components, including MRI, cognitive evaluation, genetic interviews, blood or saliva sample procurement, neck ultrasound, and optical coherence tomography. Univariate analyses were performed using Fisher’s exact, χ2, or Wilcoxon tests as appropriate. Continuous variables are presented as median (IQR). The questionnaire was completed by 86 participants [75% female; 16.0 (15.0-17.4) years], of whom 12 (14%) had MS and 74 (86%) were healthy controls. Participants with MS were older (19.1 [16.8-20.0] years) than healthy controls (15.7 [14.9-17.1] years; p=0.003). Participants contributed to a median (IQR) of 1 (1-2) procedures; 76% provided blood and 42% saliva samples, 33% underwent research MRI, and 26% performed cognitive testing. When asked to rank the top three motivations for participation in research, ‘helping others’ and ‘curiosity’ were the two most common responses among healthy controls and people with MS. People with MS were more likely to choose ‘helping self’ as a motivation when compared to healthy controls whereas healthy controls were more likely to choose ‘financial reward’ (p=0.064). Participants < 18 years were more likely to be motivated by ‘financial reward’ compared to participants ⩾ 18 years (p=0.083). When asked to reflect on their reactions to participating in the study, 95% of participants indicated they would participate in the study again if given the opportunity, 89% indicated that they gained something positive from participating, 94% reported that their participation was a choice they made freely, and 97% of participants agreed or strongly agreed that they were glad to be asked to participate in research. As a greater number of studies are designed to study paediatric MS, it is essential to understand the characteristics, motivations and perspectives of volunteers. Further research regarding cultural and regional influences on participation, and studies of younger participants are needed. Disclosure Dr Banwell serves as an advisor to Biogen Idec, Novartis, Eli Lilly, and Sanofi-Aventis; she does not receive any financial remuneration for her advisory role but is remunerated for work pertaining to centralized imaging analyses by Novartis. Dr Banwell also serves as a chief editor for Multiple Sclerosis and Related Disorders and is on the editorial board for Neurology. The authors have indicated they have no potential conflicts of interest to disclose.

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P257 Investigation of DNA methylation and pediatric multiple sclerosis risk H.E. Hanwell1, E.A. Yeh1,2,3, B.-L. Chang4, H. Hakonarson4, S. Ramagopalan5, G. Disanto6, D.L. Arnold7, A. Bar-Or8,9, R.A. Marrie10, A.D. Sadovnick11, B. Banwell1,12, the Canadian Paediatric Demyelinating Disease Network, and the CIHR New Emerging Team in Clinical Autoimmunity 1Neurosciences and Mental Health, Hospital for Sick Children, 2Paediatrics, University of Toronto, 3Division of Neurology, Hospital for Sick Children, Toronto, ON, Canada, 4Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States, 5Evidera, London, United Kingdom, 6Department of Neurology, Regional Hospital, Lugano, Switzerland, 7Brain Imaging Centre, 8Experimental Therapeutics Program, 9Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, QC, 10Internal Medicine and Community Health Sciences, University of Manitoba, Winnipeg, MB, 11Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada, 12Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States

Background: Risk of MS varies with month of birth, suggesting that etiologically-relevant exposures may occur around birth. Similarly, MS concordance is higher in dizygotic twins than nontwin siblings in spite of similar shared genetics, possibly due to the similarity of twins’ exposures, including those occurring prenatally. Since early life exposures could affect risk of MS through changes in DNA methylation, we evaluated whether such differences were present between healthy children and those diagnosed with MS in childhood in DNA from whole blood samples collected at birth and also at first attack of MS. Methods: DNA was collected within 6 mos of first clinical presentation in children (< 16y) with MS and healthy children (HC) matched for age at time of phlebotomy, and from a subset with neonatal blood spots (DBS; MS and HC). We profiled whole blood DNA methylation via the Illumina HumanMethylation450K BeadChip Infinium Assay. After normalization, we tested the association between MS and CpG site methylation beta values, adjusting for potential confounders such as sex, ancestry, and age. Results were compared against published MS case-control methylation data. Results: Data from neonatal DBS (8 MS; 14 HC) and childhood DNA samples (48 MS; 48 HC) were analyzed. We did not observe epigenome-wide significant differences between MS and HC in individual CpG-site DNA methylation at birth or clinical onset of MS. 209 nominally significant (uncorrected p< 0.05 in each comparison) CpG-sites were congruently associated with MS both at birth and clinical onset of MS. Of the genes near to these CpGsites, 19% have also shown nominal association in previously published MS DNA methylation studies. Conclusions: The presence of persistent, nominally significant MS-associated differences in DNA methylation at birth suggests the prenatal environment may influence MS etiology through persistent DNA methylation modification. The overlap of our findings with previously published studies adds significant credence to our results. Next, we will evaluate differential MS-associated changes in DNA methylation between birth and clinical disease


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onset to elucidate effects of childhood exposures on MS risk. The absence of epigenome-wide significant DNA methylation differences at individual CpG-sites suggests that effects of differential DNA methylation on MS pathogenesis are likely small or celltype specific. Larger studies using cell-type-specific analyses are warranted. Disclosure HEH is supported by a Hospital for Sick Children Restracomp Fellowship. The research was enabled by the MS Scientific Research Foundation, Dairy Farmers of Ontario, the Canadian Institutes of Health Research, and a Multiple Sclerosis International Federation Du Pré Grant. EAY: No disclosures. B-LC: No disclosures. HH: No disclosures. SVR is an employee of Evidera Inc. GD: No disclosures. DLA reports having served on advisory boards, received speaker honoraria, served as a consultant or received research support from Acorda, Bayer, Biogen Idec, Eli Lilly, Serono, Genentech, Genzyme, GSK, Medimmune, Novartis, Opexa Therapeutics, Receptos, Roche, Sanofi-Aventis, Teva, CIHR, and the MSSC. ADS: No disclosures RAM has conducted clinical trials for sanofi-aventis. She receives research funding from CIHR, the MS Society of Canada, the NMSS, Rx & D Health Research Foundation and Research Manitoba. AB-O participated as a speaker at meetings sponsored by, received consulting fees and/or received grant support from: Amplimmune, Bayhill Therapeutics, Berlex/Bayer, Biogen Idec, Diogenix, EliLilly, Genentech, GlaxoSmithKline, Guthy-Jackson/GGF, Merck/ EMD Serono, Medimmune, Mitsubishi Pharma, Novartis, Ono Pharma, Receptos, Roche, Sanofi-Genzyme, Teva Neuroscience, Wyeth. BB serves as an advisor to BiogenIDEC, sanofi, and Novartis, but is not remunerated for this work. BB received financial compensation for her role as a central MRI reviewer for Novartis. Dr. Banwell received compensation for her role as Senior Editor for Multiple Sclerosis and Related Disorders. P258 The cognitive reserve theory in the setting of pediatric-onset multiple sclerosis L. Pasto’1, E. Portaccio1, B. Goretti1, A. Ghezzi2, S. Lori1, B. Hakiki1, M. Giannini1, I. Righini1, L. Razzolini1, L. Moiola3, M. Falautano3, M. Simone4, R.G. Viterbo4, F. Patti5, S. Cilia6, C. Pozzilli7, V. Bianchi7, M. Roscio2, V. Martinelli3, G. Comi3, M. Trojano4, M.P. Amato1, MS Study Group of the Italian Neurological Society 1University of Florence, Forence, 2Hospital of Gallarate, Gallarate (VA), 3San Raffaele Scientific Institute, Milan, 4University of Bari, Bari, 5University of Catania, Catania, 6ASP 209, Trapani, 7La Sapienza University, Rome, Italy Background: Cognitive impairment (CI) is increasingly appreciated in pediatric-onset multiple sclerosis (POMS). In the setting of

adult-onset multiple sclerosis (MS), the theory of cognitive reserve is receiving growing attention. The study of cognitive reserve in relationship with cognitive efficiency may provide cues to identifying subjects at higher risk of impairment and scope for therapeutic strategies. Objectives: To assess the potential impact of cognitive reserve on cognition in a cohort of POMS patients. Methods: Forty-eight POMS patients (25 females; age 15.2 ± 2.6 years) were followed-up for 4.7 + 0.4 years. CI was defined as the failure of ⩾3 tests on an extensive neuropsychological battery. An individual cognitive change index (CCI) was also calculated. At baseline, cognitive reserve was estimated by measuring the intelligence quotient (IQ) through the Wechsler Intelligence Scale for Children-Revised. The relationships between estimated cognitive reserve and cognitive performance were assessed through multivariate logistic regression analyses. Results: At baseline, CI was detected in 14/48 (29.2%) patients. Multivariate analysis indicated that it was predicted only by a lower reserve in terms of IQ score (OR=0.94; 95%CI 0.89-0.99; p=0.011). At follow-up assessment, CI was found in 18/48 subjects (37.5%). As for the CCI, a deteriorating performance was observed in 27/48 patients (56.3%). In the whole group, no demographic or clinical characteristics predicted the cognitive outcome at follow-up. However, among the 34 cases who were cognitively preserved at baseline, a higher reserve predicted stable/improving performance (OR = 1.12; 95% CI 1.03-1.21; p= 0.005). Conclusions: Our results suggest that higher cognitive reserve in POMS patients may protect from CI. Over the follow-up, this effect remained significant in subjects with initial cognitive preservation, whereas it disappeared in subjects with CI at baseline. These findings can have relevant implications for counseling and rehabilitation strategies in POMS patients. Disclosure Dr. Pastò has received research support from Biogen Idec. Dr. Portaccio serves on a scientific advisory board for Biogen Idec, Bayer and Merck Serono received speaker honoraria from Biogen Idec, Genzyme, Novartis, Bayer, Merck Serono, and receives research support from Merck Serono. Dr. Goretti serves on a scientific advisory board for Biogen, received honoraria for speaking from Biogen-Idec and Teva Dr. Ghezzi serves on scientific advisory boards for Merck Serono and Teva Pharmaceutical Industries Ltd; has received speaker honoraria from Merck Serono, Biogen Idec, Bayer Schering Pharma, and Novartis; serves as a consultant for Novartis; and receives research support from Sanofi-aventis, Biogen Idec, and Merck Serono. Dr. Lori has nothing to disclose. Dr. Hakiki has received research support from Teva Dr. Giannini has received research support from Biogen Idec and Teva Dr. Righini has received research support from Novartis Dr. Razzolini has nothing to disclose. Dr. Moiola received speaking honoraria and travel grant from Merck Serono and Biogen Idec. Dr. Falautano has nothing to disclose. Dr. Simone has nothing to disclose. Dr. Viterbo has nothing to disclose


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Poster Session I, 21(S11) Dr. Patti has served on scientific advisory boards for Merck Serono, Bayer Schering Pharma, Novartis, and Biogen Idec; has received speaker honoraria from Biogen Idec, Bayer Schering Pharma, sanofi-aventis, and Novartis; and has received research support from the University of Catania and FISM. Dr. Cilia has nothing to disclose. Dr. Pozzilli serves on scientific advisory boards for and has received speaker honoraria from Novartis, Merck Serono, Biogen Idec, Bayer Schering Pharma, and Sanofi-Aventis. Dr. Bianchi has nothing to disclose. Dr. Roscio has nothing to disclose. Dr. Martinelli has received funding for travel and speaker honoraria from Biogen Idec, Merck Serono, Bayer Schering Pharma, Novartis, and sanofi-aventis; and has served as a consultant to Bayer Schering Pharma, sanofi-aventis, and Teva Pharmaceutical Industries Ltd. Dr. Comi serves on scientific advisory boards for Bayer Schering Pharma, Merck Serono, Teva Pharmaceutical Industries Ltd., sanofi-aventis, Novartis, and Biogen Idec; and has received speaker honoraria from Teva Pharmaceutical Industries Ltd., sanofi-aventis, Serono Symposia International Foundation, Biogen Idec, Merck Serono, Novartis, and Bayer Schering Pharma. Dr. Trojano serves on scientific advisory boards for Novartis, Biogen Idec, Merck Serono and Genzyme; has received speaker honoraria from Merck Serono, Bayer Schering Pharma, SanofiAventis, and Biogen Idec; and has received research support from Biogen Idec, Novartis and Merck Serono. Dr. Amato serves on scientific advisory boards for and has received speaker honoraria and research support from Biogen Idec, Merck Serono, Bayer Schering Pharma, and sanofi-aventis; and serves on the editorial board of BMC Neurology. P259 Clinical phenotypes of pediatric and adult patients with anti-MOG antibodies D.K. Sato1,2, K. Kaneko2, I. Nakashima2, S. Tanaka3, N. Fukuyo2, L.M. Oliveira1, L. Pandit4, S. Siritho5, P.J. Waters6, T. Takahashi7, H. Kuroda2, S. Nishiyama2, T. Akaishi2, K. Kurosawa2, T. Misu2, N. Prayoonwiwat5, K. Nomura3, D. Callegaro1, K. Fujihara2, M. Aoki2 1University of Sao Paulo, Sao Paulo, Brazil, 2Tohoku University School of Medicine, Sendai, 3Saitama Medical Center, Saitama, Japan, 4Nitte University, Mangalore, India, 5Siriraj Hospital, Mahidol University, Bangkok, Thailand, 6Oxford University, Oxford, United Kingdom, 7Yonezawa National Hospital, Yonezawa, Japan Objective: To evaluate clinical features among pediatric (onset age < 12 years) and teenager/adult patients with antibodies against myelin oligodendrocyte glycoprotein (anti-MOG). Methods: Consecutive sera from 821 patients from Japan, Brazil, India and Thailand diagnosed with idiopathic inflammatory central nervous system disorders (all negative for aquaporin-4 antibodies) tested for anti-MOG using a cell-based assay. Results: A hundred and twenty-nine patients (15.7%) were positive for anti-MOG. The median onset age was 24 (range 1 - 79) years, and 40 (31%) had less than 12 years at the first attack. There was no gender predominance in both age groups. During a

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median follow-up of 3 years, 57.5% (23/40) of pediatric patients and 51.7% (46/89) of patients > 12 years had further attacks. Fifty patients (56.2%) with onset > 12 years had optic neuritis (ON) as the first manifestation, but more than half of the patients < 12 years also developed ON during the disease course. Brain syndromes were the initial manifestation in 47.5% (19/40) of patients < 12 years; encephalopathy and/or seizures were more common in this group than > 12 years (45% vs 9%, p < 0.0001). Only one adult patient had persistent vomiting for more than 48 hours. Brain demyelinating lesions on the magnetic resonance imaging (MRI) were more commonly seen in patients < 12 years than in older patients (70% vs 40%, p = 0.0023). Overall, they responded well to corticosteroid treatment, but some patients remained with sustained visual (visual acuity < 20/200) or motor disability (Expanded Disability Status Scale > 6). Conclusions: Patients with anti-MOG might belong to a unique entity, but ON was the most common initial manifestation above 12 years, while younger patients commonly had demyelinating brain lesions associated with encephalopathy and seizures. More than half of the patients relapsed in both age groups. Disclosure This study was partially supported by grant-in-aid for scientific research from the Japan Society for the Promotion of Science (KAKENHI 15K19472), research grant from CAPES/Brasil (88881.068012/2014) and by the Health and Labour Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labour and Welfare of Japan. Dr Sato has received scholarship from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, grant-in-aid for scientific research from the Japan Society for the Promotion of Science (KAKENHI 15K19472), research support from CAPES/Brasil (88881.068012/2014-01) and speaker honoraria from Novartis. Dr. Nakashima reports grants from Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and from Ministry of Health, Labour and Welfare of Japan, personal fees from Mitsubishi Tanabe Pharma Corporation, Biogen Idec Japan, Novartis Pharmaceuticals Japan, Bayer Yakuhin, Ltd, and grants from LSI Medience Corporation. Dr. Tanaka: nothing to disclose Dr Fukuyo: nothing to disclose Dr Oliveira: nothing to disclose Dr Pandit: nothing to disclose Dr Siritho: nothing to disclose Dr Waters: nothing to disclose Dr Takahashi: nothing to disclose Dr Kuroda: nothing to disclose Dr. Nishiyama reports grant from JSPS KAKENHI Grant (Grantin-Aid for Research Activity Start-up) Number 24890017. Dr Akaishi: nothing to disclose Dr Kurosawa: nothing to disclose Dr. Misu has received speaker honoraria from Bayer Schering Pharma, Biogen Idec Japan, Mitsubishi Tanabe Pharma Corporation, Asahi Kasei Medical Co., and Astellas Pharma Inc. and has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical Co., The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Teijin Pharma, and Grants-in-Aid for Scientific Research from the Ministry of


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Education, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan. Dr Prayoonwiwat nothing to disclose Dr Nomura nothing to disclose Dr Callegaro nothing to disclose Dr. Fujihara serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, Medimmune and Medical Review; has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical; serve as an editorial board member of Clinical and Experimental Neuroimmunology (2009-present) and a advisory board member of Sri Lanka journal of Neurology; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The ChemoSero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical,Ono Pharmaceutical, Nihon Pharmaceutical, and Genzyme Japan; is funded as the secondary investigator (#22229008, 2010-2015) by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan and as the secondary investigator by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan (2010-present). Dr Aoki nothing to disclose P260 Relapsing central nervous system demyelination in children with myelin oligodendrocyte glycoprotein (MOG) antibodies Y. Hacohen1, M. Absoud2, C. Hemingway3, J. Palace4, E. Wassmer5, K. Mankad6, P. Waters4, A. Vincent4, M. Lim2, on behalf of United Kingdom Childhood Inflammatory Demyelination (UK-CID) 1Oxford University, 2Children’s Neurosciences, Evelina Children’s Hospital at Guy’s and St Thomas’ NHS Foundation Trust, King’s Health Partners Academic Health Science Centre, 3Department of Paediatric Neurology, Great Ormond Street Hospital for Children, London, 4University of Oxford, Oxford, 5Department of Paediatric Neurology, Birmingham Children’s Hospital, Birmingham, 6Neuroradiology, Great Ormond Street Hospital for Children, London, United Kingdom Background: Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) have been identified in up to 50% of children with acquired demyelinating syndrome (ADS). Although these antibodies have been reported in both in adult and children with relapsing demyelination syndromes such as AQP4-Ab negative neuromyelitis optica spectrum disorder (NMOSD); little is known about the clinical course of the patients who relapse. Objective: To evaluate the clinical features of patients with MOG-Ab and relapsing disease. Methods: Fifty-three consecutive children with ADS and MOG-Ab positivity from five paediatric neurology referral centers were identified between 2011-2104. Clinical and neuroimaging

features were reviewed and the treatment and outcomes evaluated. Results: The initial presenting demyelination syndrome, clinical, radiological and investigative features could not distinguish the 13 patients that had a relapsing course from the other monophasic patients. Of the 13 relapsing patients (7 Female, mean 7.8yrs, median 6.5yrs; range 3-15yrs); four presented with monophasic/ recurring episodes of acute disseminated encephalomyelitis (ADEM) followed by monophasic/relapsing optic neuritis (ON); three fulfilled criteria for AQP4-Ab negative NMOSD; two had relapsing ADEM; and four with multiple sclerosis (MS). Intrathecal oligoclonal bands were only detected in 8%(1/12) tested. All 12 patients with abnormal brain MRI had brainstem and/or cerebellar lesion. Eight patients (non-MS) managed on long-term immunosuppression (n=2) and/or prompt acute treatment (n=8) made a complete clinical and radiological recovery at one year from last relapse. All patients with ON (n=8) had a complete visual recovery. Three out of four patients with MS are currently undergoing interferon therapy but continue to have more than one relapse/year. Conclusion: 25% of MOG-Ab positive patients have a relapsing demyelination, often with a good clinical and radiological recovery. However, 30% (4/13) of this relapsing group may fulfill the diagnosis of MS, although may not have intrathecal bands and appear to have a poor response to MS treatment. Disclosure Yael Hacohen has nothing to disclose Michael Absoud has received funding from the MS Society and Action Medical Research charities. Cheryl Hemingway has received travel grants from Merck Serono and Bayer. Jacqueline Palace is partly funded by highly specialised services to run a National congenital myasthenia service and a neuromyelitis service. She has received support for scientific meetings and honorariums for advisory work from Merck Serono, Biogen Idec, Novartis, Teva, Chugai Pharma and Bayer Schering, and unrestricted grants from Merck Serono, Novartis, Biogen Idec and Bayer Schering. Her hospital trust receives funds for her role as clinical lead for the MS risk sharing scheme, and she has received grants from the MS society and Guthy-Jackson Foundation for unrelated research studies. She is a board member for the charitable European MS foundation ´The Charcot Foundation´ and on the steering committee for a European collaborative MS imaging group ´MAGNIMS´. Evangeline Wassmer receives research grants from Action Medical Research and MS Society; has received travel grants from UCB, Shire and Biogen Idec, educational grants to organize meetings from Merck Sereno, Novartis, Bayer and Biogen Idec, speaker’s fees from Merck Sereno and consultancy fees from Genzyme. Kshitij Mankad has nothing to disclose Patrick Waters is supported by the NHS national specialized commissioning group for neuromyelitis optica and by the NIHR Oxford biomedical research centre. He has received speaker honoraria from Biogen Idec and Euroimmun AG. Patrick Waters, Angela Vincent and the University of Oxford, hold patents and/or receive royalties and payments for antibody assays in neurologic diseases.


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Poster Session I, 21(S11) Angela Vincent serves/has served on scientific advisory boards for the Patrick Berthoud Trust, the Brain Research Trust and the Myasthenia Gravis Foundation of America; has received funding for travel and a speaker honorarium from Baxter International Inc and Biogen Inc; serves as an Associate Editor for Brain; receives royalties from the publication of Clinical Neuroimmunology (Blackwell Publishing, 2005) and Inflammatory and Autoimmune Disorders of the Nervous System in Children (Mac Keith Press, 2010); receives/has received research support from the European Union, NIHR Biomedical Research Centre Oxford, Euroimmun AG and the Sir Halley Stewart Trust; and has received Musk antibody royalties and consulting fees from Athena Diagnostics Inc. Ming Lim receives research grants from Action Medical Research, DES society, GOSH charity, NIHR, MS Society, SPARKS charity and; receives research support grants from the London Clinical Research Network and Evelina Appeal; has received consultation fees from CSL Behring; received travel grants from Merck Serono; and awarded educational grants to organize meetings by Novartis, Biogen Idec, Merck Serono and Bayer. P261 Effect of obesity and puberty on risk and age at onset of pediatric MS T. Chitnis1,2, J. Graves3, B. Weinstock-Guttman4, A. Belman5, M. Misra6, C.S. Olsen7, G. Aaen8, L. Benson1, M. Candee7, M. Gorman1, B. Greenberg9, T. Lotze10, J. Ness11, M. Rodriguez12, J. Rose13, J. Rubin14, T. Schreiner15, J. Mendelt-Tillema12, T.C. Casper7, E. Waubant3, U.S. Network of Pediatric MS Centers 1Partners Pediatric MS Center, Massachusetts General Hospital, 2Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 3UCSF Regional Pediatric MS Center, University of California San Francisco, San Francisco, CA, 4Pediatric MS Center at the Jacobs Neurological Institute, SUNY Buffalo, Buffalo, 5Department of Neurology, SUNY Stony Brook, Stony Brook, NY, 6Department of Pediatrics, Massachusetts General Hospital, Boston, MA, 7Department of Pediatrics, University of Utah, Salt Lake City, UT, 8Pediatric MS Center, Loma Linda University Children’s Hospital, Loma Linda, CA, 9Department of Neurology, UT Southwestern, Dallas, 10Blue Bird Circle MS Center, Baylor College of Medicine, Houston, TX, 11Alabama Pediatric MS Center, University of Alabama, Birmingham, AL, 12Department of Neurology, Mayo Clinic, Rochester, NY, 13Department of Neurology, University of Utah, Salt Lake City, UT, 14Department of Pediatric Neurology, Northwestern Feinberg School of Medicine, Chicago, IL, 15Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States Background: There is increasing evidence that obesity during adolescence is a risk factor for adult and pediatric MS. The elevated female:male sex ratio at puberty, additionally suggests a role for gonadal hormones. Goals: To examine the relative contributions of body mass index (BMI) measures and pubertal measures for risk of MS and age of onset of MS in a pediatric MS cohort compared to contemporaneously collected controls.

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Methods: Case-control study conducted at 14 U.S. Network Pediatric MS Centers (NPMSC) with a centralized data coordinating center. 254 (63.4% female) cases of MS (onset< 18 years of age) and 420 (49.3% female) controls collected at the same institutions were included in this analysis. Sex stratified BMI percentiles and z-scores were calculated using CDC growth charts from height and weight measured at control enrollment, and within 1 year of onset for cases. BMI for age, and age at menarche in girls were compared using Wilcoxon tests. Univariable and multivariable logistic regression methods modeled the relation between MS risk and age at MS onset, with BMI, menarcheal age (girls), Tanner stage for age (boys), and race/ethnicity for post-pubertal girls and boys separately. Results: In girls, BMI for age-percentile and BMI for age z-scores were higher in MS cases versus controls (median BMI-for-age percentiles 87 vs 68, p< 0.001)). In boys, BMI for age percentiles and z-scores were also higher in MS cases versus controls (median BMI-for-age percentiles 83 vs 69, p=0.017). Mean age at menarche was younger in MS girls vs. controls (11.6 versus 11.9 years; p=0.024). 80% of girls have post-menarcheal onset of MS. Higher BMI scores are associated with lower age at menarche in MS cases (p=0.014) and controls (p=0.002). Only BMI predicted MS risk in multivariable models in girls (OR 1.5, 95% CI 1.1,2.2) and boys (OR 1.3, 95% CI 1.0, 1.7). Neither age at menarche (girls), pubertal development (boys), BMI nor race/ethnicity, were significantly associated with earlier age at onset of MS. In contrast, among post-menarcheal girls, in a step-wise model selection procedure, menstrual age was linked to age of onset (p=0.011). A one-year decrease in menstrual age was associated with younger age at MS onset by 0.34 year (95% CI 0.08, 0.60). Conclusion: Increased BMI is associated with MS risk in girls and boys. In post-menarcheal girls, younger menstrual age was associated with younger age at MS onset. Disclosure T. Chitnis: nothing to disclose J. Graves: nothing to disclose B. Weinstock-Guttman: nothing to disclose A. Belman: nothing to disclose M. Misra: nothing to disclose C.S. Olsen: nothing to disclose G. Aaen: nothing to disclose L. Benson: nothing to disclose M. Candee: nothing to disclose M. Gorman: nothing to disclose B. Greenberg: nothing to disclose T. Lotze: nothing to disclose J. Ness: nothing to disclose M. Rodriguez: nothing to disclose J. Rose: nothing to disclose J. Rubin: nothing to disclose T. Schreiner: nothing to disclose J. Mendelt-Tillema: nothing to disclose T.C. Casper: nothing to disclose E. Waubant: nothing to disclose (for the U.S. Network of Pediatric MS Centers) Funding: Supported by NIH: R01NS071463-03 (PI E. Waubant). Supported by the National MS Society: Grant, HC 0165 (PI T. C. Casper).


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P262 Prospective observational data on 30 patients starting fingolimod before the age of 21 years Y.D. Fragoso1, S.V. Alves-Leon2, S.L. Apostolos-Pereira3, A.A. Barreira4, J.B. Brooks1, D. Callegaro3, M.L. Ferreira5, A. Finkelsztejn6, S. Gomes7, M.V. Goncalves8, A.K. Grzesiuk9, M.I. Machado5, V.D. Marques4, A.P. Matta10, R.M. PapaisAlvarenga11, H.H. Ruocco12, H. Sato13, C.B. Tauil14 1Universidade Metropolitana de Santos, Santos, 2Universidade Federal do Rio de Janeiro, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, 3Hospital das Clínicas da Universidade de Sao Paulo, Sao Paulo, 4Universidade de Sao Paulo Campus Ribeirao Preto, Ribeirao Preto, 5Hospital da Restauracao de Recife, Recife, 6Hospital de Clinicas de Porto Alegre, Porto Alegre, 7Hospital Beneficencia Portuguesa, Hospital Paulistano, Sao Paulo, 8Hospital Regional Hans Dieter Schimidt, Joinville, 9Centro de Reabilitação Integral Dom Aquino Correa, Cuiaba, 10Universidade Federal Fluminense, Niteroi, 11Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, 12Faculdade de Medicina de Junidiaí, Jundiai, 13Instituto de Neurologia de Curitiba, Curitiba, 14Hospital de Base do Distrito Federal, Brasilia, Brazil Background: Young patients with multiple sclerosis (MS) face decades of treatment for their disease. They may develop neurological disabilities earlier in life, thus requiring early and effective therapeutic interventions to avoid sequelae. Fingolimod is an oral drug for treating multiple sclerosis that has proven to be efficient and safe for adults. Patients in clinical trials for fingolimod have typically been in their mid-thirties. The aim of the present study was to report on the short-term safety and efficacy of fingolimod among patients with MS who started treatment before the age of 21 years. Analyses on a subgroup that started before the age of 18 years were also carried out. Participants and methods: Data were collected prospectively and no patient was lost to follow-up. Thirty patients were treated with fingolimod in 15 MS units in Brazil. The average age of the patients at the time of the first dose of fingolimod was 16.5 years (range: 14 to 20). Twenty-two patients received the first dose before the age of 18 years. There were 12 males and 18 females. Results: Fingolimod showed a good safety and efficacy profile among these patients, who all had very active multiple sclerosis. No major adverse events were reported in relation to the first dose of the drug, or in relation to short and medium-term treatment. The patients’ degree of disability did not progress. Three patients (10%) presented a new relapse and an increased number of lesions on magnetic resonance imaging, and fingolimod was withdrawn in two of these cases. No patient has been followed for longer than 18 months, and therefore no long-term conclusions can be drawn. Conclusions: Fingolimod in patients before the age of 21 years was shown to be a good therapeutic option for controlling multiple sclerosis. One limitation to this clinical observation is the short follow-up of patients. To discuss the efficacy and long-term safety of fingolimod in a young population would require a much longer follow-up period, especially in open observations like this one. Our patients continue under strict observation and long-term data will be reported in the future.

Disclosure Yara D Fragoso: nothing to disclose, Soniza V Alves-Leon: nothing to disclose, Samira L Apostolos-Pereira: nothing to disclose, Amilton A Barreira: nothing to disclose, Joseph BB Brooks: nothing to disclose, Dagoberto Callegaro nothing to disclose, Maria Lucia B Ferreira: nothing to disclose, Alessandro Finkelsztejn: nothing to disclose, Sidney Gomes: nothing to disclose, Marcus VM Goncalves: nothing to disclose, Anderson K Grzesiuk: nothing to disclose, Maria Iris M Machado: nothing to disclose, Vanessa D Marques: nothing to disclose, Andre PC Matta: nothing to disclose, Regina M Papais-Alvarenga: nothing to disclose, Heloisa H Ruocco: nothing to disclose, Henry Sato: nothing to disclose, Carlos B Tauil: nothing to disclose. P263 Dimethyl fumarate in children with multiple sclerosis: a dual-center experience N. Makhani1, T. Schreiner2 1Pediatrics and Neurology, Yale University, New Haven, CT, 2Pediatrics and Neurology, University of Colorado, Denver, CO, United States Background: Dimethyl fumarate is an oral medication approved for use in adult-onset multiple sclerosis (MS). It is sometimes used for the treatment of children with MS who are either intolerant to treatment with conventional first-line injectable therapies or who have ongoing radiological or clinical disease activity despite treatment with traditional first-line agents. The safety and tolerability of dimethyl fumarate in children with MS is not known. Objectives: To characterize our dual-center experience with dimethyl fumarate in the treatment of children with relapsing-remitting MS. Methods: Retrospective chart review of children with MS ⩽ 18 years treated with dimethyl fumarate. Clinical, demographic, and MRI parameters were collected. Results: We identified 13 children with MS treated with dimethyl fumarate for a mean duration of 12.9 months (range 1-22 months). Eleven children (85%) had at least one relapse in the year prior to treatment initiation. Dimethyl fumarate was utilized first-line in five children (39%). Eleven children (85%) tolerated dose escalation from 120 mg BID to 240 mg BID. Common side effects included flushing (8/13, 62%), nausea (5/13, 38%), abdominal pain (3/13, 23%), rash (3/13, 23%), and malaise (2/13, 15%). Diarrhea, vomiting, pruritis, and nasal discomfort were observed in one patient each. Three children (23%) discontinued treatment due to side effects. No patients displayed laboratory abnormalities including lymphopenia (12/13 assessed) or transaminitis (9/13 assessed). There were no reported infections. Nine children had ⩾ 12 months of follow-up on treatment. All nine (100%) displayed either stabilized or reduced EDSS scores while on treatment. Six children (46%) had brain MR imaging performed after at least six months of therapy. New T2 lesions were observed in two children (33%), one of whom had been non-adherent to therapy.


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Poster Session I, 21(S11) Conclusions: Oral dimethyl fumarate appears to be safe and generally well-tolerated in children with MS. Formal clinical trials to evaluate efficacy are ongoing.

Conclusion: Higher salt intake was not associated with decreased time to relapse in patients with pediatric-onset MS. This finding might be limited by sub-optimal sensitivity and specificity of measuring daily sodium intake by the food frequency questionnaire.

Disclosure Dr. Makhani has nothing to disclose. Dr. Schreiner has nothing to disclose. P264 Association of dietary salt intake and relapse rate in pediatric multiple sclerosis B. Nourbakhsh1, J. Graves1, S. Lulu1, A. Waldman2, A. Belman3, B. Greenberg4, B. Weinstock-Guttman5, G. Aaen6, J.-M. Tillema7, J. Hart1, M. Lee1, J. Ness8, J. Rubin9, L. Krupp3, M. Gorman10, L. Benson10, M. Rodriguez7, T. Chitnis10, T. Simmons11, C. Casper11, J. Rose12, L. Barcellos13, E. Waubant1 1Neurology, University of California San Francisco, San Francisco, CA, 2Neurology, University of Pennsylvania, Philadelphia, PA, 3Neurology, SUNY Stony Brook, Stony Brook, NY, 4UT Southwestern, Dallas, TX, 5SUNY Buffalo, Buffalo, NY, 6Loma Linda University, Loma Linda, CA, 7Neurology, Mayo Clinic, Rochester, MN, 8Alabama Pediatric MS Center, Birmingham, AL, 9Northwestern Feinberg School of Medicine, Chicago, IL, 10Partners Pediatric MS Center, Massachusetts General Hospital, Boston, MA, 11Pediatrics, 12Neurology, University of Utah, Salt Lake City, UT, 13Epidemiology, UC Berkeley, Berkeley, CA, United States Background: Salt intake was reported to be associated with increased clinical and MRI activity in adult patients with relapsing-remitting multiple sclerosis (MS) and disease severity in experimental autoimmune encephalomyelitis. Objective: To determine if salt intake is associated with time to relapse in a patients with pediatric-onset MS. Methods: Pediatric-onset MS and clinically isolated syndrome (CIS) patients within 4 years of disease onset were recruited from 15 pediatric MS centers in the US as part of a case-control study. Patients who had available prospective relapse data subsequent to enrollment in the case-control study were included in this project. Dietary sodium intake was assessed by self-report questionnaire using the validated Block Kids Food Screener. Multivariable Cox proportional-hazards regression models were employed to determine the association of sodium density (sodium intake in mg/day, divided by total energy intake in kcal/day), excess sodium intake and sodium density tertiles with time to relapse following study enrollment; adjusting for age, gender, race/ethnicity, disease duration, body mass index and use of disease-modifying treatment. Results: 129 relapsing-remitting MS/CIS patients were included in this analysis (mean age of 14.9 and 60% females). Median duration of follow-up after completion of food frequency questionnaire was 1.76 years. In an unadjusted analysis, amount of daily sodium intake was not associated with time to relapse (hazard ratio [HR] per 1 mg/10 kcal 1.05; 0.96-1.15, p=0.29) and patients with excess sodium intake had no decrease in time to relapse (HR 0.83; 0.48-1.45, p=0.51) as compared to patients with non-excess sodium intake. The multivariable analysis demonstrated that patients in the medium and high tertile of sodium density had a HR of 1.22 (0.54-2.74, p=0.64) and 1.52 (0.67-3.44, p=0.32) compared to patients in the lowest tertile, respectively.

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Disclosure Bardia Nourbakhsh is a grantee of National MS Society. This research was conducted while B.N. was a Biogen Idec Postdoctoral Fellow. Dr. Graves was supported by the Foundation for Consortium of Multiple Sclerosis Centers and the NIH Bridging Interdisciplinary Research Careers in Women’s Health programs during this work. She has been a one-time consultant for EMD-Serono. Dr. Waubant is funded by the National MS Society, the NIH and the Race to Erase MS. She has received honorarium from Teva Neuroscience and Genzyme for two educational lectures, and is an ad-hoc consultant for Actelion, Sanofi-Aventis and Roche. She is on an advisory board for a clinical trial of Novartis. Dr. Krupp is supported by the National MS Society, NIH, Robert and Lisa Lourie Foundation, Department of Defense. She has received honoraria, consulting payments, grant support or royalties from Biogen, Medimmune, Novartis, Teva Neuroscience, Sanofi-Aventis, and EMD Serono. Dr. Weinstock-Guttman received honoraria for serving in advisory boards and educational programs from Teva Pharmaceuticals, Biogen Idec, Novartis, Accorda EMD Serono, Novartis, Genzyme and Sanofi. She also received support for research activities from the National Institutes of Health, National Multiple Sclerosis Society, National Science Foundation, Department of Defense, EMD Serono, Biogen Idec, Teva Neuroscience, Novartis, Acorda, Genzyme and the Jog for the Jake Foundation. Dr. Tanuja Chitnis has served as a consultant for Biogen-Idec, Teva Neurosciences, Novartis, Sanofi-Aventis, and has received grant support from NIH, National MS Society, Guthy-Jackson Charitable Foundation, CMSC and Merck-Serono and Novartis. Dr. Rose has research funding from Teva Neuroscience and Biogen. He is a member of the Medical Advisory Board for the DECIDE trial which is funded by Biogen and AbbiV Dr. Casper has been supported by the National MS Society and the NIH (R01NS071463). He is an ad-hoc consultant for Biovest International, Inc. Drs. Lulu, Belman, Ness, Gorman, Patterson, Lotze, Rodriguez, Aaen and James have no disclosures. Janace Hart and Timothy Simmons have no disclosures.

Natural course P265 Defining the overlapping period of relapsing-remitting and progressive phases of multiple sclerosis for continuing disease modifying treatments M. Novotna1, M.M. Paz Soldán2, N. Abou Zeid3, N. Kale4, M. Tutuncu5, O.H. Kantarci1 1Department of Neurology, Mayo Clinic, Rochester, MN, 2Department of Neurology, Imaging and Neurosciences Center, University of Utah, Salt Lake City, UT, 3Department of Neurology, Wake Forrest Medical Center, Winston-Salem, NC, United States, 4Department of Neurology, Bakirkoy State Hospital, 5Department of Neurology, Cerrahpasa School of Medicine, Istanbul University, Istanbul, Turkey


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Background: In 75% of patients with relapsing-remitting multiple sclerosis (RRMS) the disease evolves to a progressive phase in an age-dependent manner. In 14% of patients relapses may continue after the onset of progressive phase. In this study we define and present the age limits of the overlapping period between the relapsing-remitting and progressive phases of multiple sclerosis (MS) to help disease modifying treatment decisions. Methods: We studied age at first relapse, age at progressive MS onset and age at last relapse (before or after progressive MS onset) in patients with bout-onset progressive MS (BOPMS) including singleattack progressive MS (SAPMS, n=128) and secondary progressive MS (SPMS, n=347). Overlapping age range for clinically relapsingremitting and progressive phases of MS as well as absolute lifetime risk of relapses after progressive MS onset was studied. Results: Median age at first relapse was 32.6 (range 10-67), median age at progressive MS onset was 45.9 (range 17-76) and median age at last relapse was 42.0 years (range 16-76). Overlap age range (95%) was 27- 47 years. There is an expected shift since individuals with older age at MS onset are expected to be older at progressive MS onset (correlation coefficient 0.701; decreases with time). After grouping patients according to the age at progressive MS onset based on mean ± SD of 45.4 ± 9.5 into < 35, 35-44, 45-54, and > 55 years, the absolute lifetime risk of ongoing relapses after progressive MS onset were; 18%, 17%, 13% and 5% respectively. The last expected relapse age for these groups was 50, 65, 70 and 70 years, respectively. Conclusions: Overall, there is a notable chance of ongoing relapses in patients before age 47 regardless of being in the progressive phase of MS and in 95% of patients the relapses stop by age 55. However, this age limit shifts with the age at onset of progressive MS. All patients with progressive MS onset before age 35 will have completed relapses by age 50, while patients with progressive MS onset after age 45 can still have a relapse until age 70. Therefore decision to continue disease modifying treatments to prevent relapses after progressive MS onset can be based on these age limits. Disclosure M. Novotna receives support from the European Regional Development Fund Project FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123), European Social Fund and the State Budget of the Czech Republic. M.M. Paz Soldán, N. Abou Zeid, N. Kale and M. Tutuncu have nothing to disclose. O.H. Kantarci receives research support from the European Regional Development Fund (FNUSA-ICRC CZ.1.05/1.1.00/ 02.0123), the National Multiple Sclerosis Society, and has given a scientific presentations at meetings supported by Teva and Novartis Pharmaceuticals but has received no personal fees or personal compensation for this activity (all compensation for consulting activities paid directly to Mayo Clinic) nor has spoken about the specific medications involving these companies. P266 Multiple sclerosis in the treatment era: longterm evolution of neurological impairments and low rates of secondary progression B.A.C. Cree1, J.R. Oksenberg1, C. Bevan1, E. CrabtreeHartman1, J. Gelfand1, D.S. Goodin1, J. Graves1, A. Green1, E. Mowry2, D. Okuda3, D. Pelletier4, H.-C. von Büdingen1, S.S.

Zamvil1, A. Agrawal1, S. Caillier1, C. Ciocca1, R. Kanner1, R. Lincoln1, A. Lizee1, R. O’shea1, P. Qualley1, A. Santaniello1, L. Suleiman1, M. Bucci1, V. Panara1, N. Papinutto1, W. Stern1, A. Zhu1, S. Baranzini1, R. Henry1, S.L. Hauser1 1Neurology, UCSF, San Francisco, CA, United States, 2Neurology, Johns Hopkins, Baltimore, Cambodia, 3Neurology, UT Southwestern, Dallas, TX, 4Neurology, USF, Los Angeles, CA, United States Despite the success of disease modifying therapies for multiple sclerosis (MS), there is limited data regarding their impact on longterm disability or on how clinical and MRI data can be used to monitor therapeutic response. Here we present the results of a prospective, long-term cohort study of 517 patients enrolled at a single center over a 15-month period beginning in July 2004. More than 90% of patients were retained, with data ascertained 8-10 years after the baseline visit. At this last assessment, 44% of patients had either unchanged or improved neurologic disability as measured by the Expanded Disability Status Score (EDSS). At a median time of 16 years after disease onset, 11.9% (95% CI 8.5 to 15.3) of patients had reached an EDSS ⩾ 6 and 14.7% (95% CI: 10.4 to18.7%) of patients evolved from relapsing MS (RMS) to the more disabling secondary progressive MS (SPMS). These rates of disability worsening and evolution to SPMS are significantly lower than expected based upon natural history studies from the pretreatment era. Subjects with no evidence of disease activity (NEDA) by clinical and MRI criteria during the first 2 years of the study, a composite endpoint of interest in clinical trials, had long-term outcomes that were no different from those of the cohort as a whole (p=0.0850.99). As expected, serum levels of 25-OH vitamin D were inversely associated with short-term MS disease activity, but no association between vitamin D levels and long-term disability was present. Patients who advanced from standard platform treatments to higher potency therapies were more likely to have experienced relapses (OR=2.31, p=0.015) or developed brain volume loss (OR=2.55, p= 0.006) prior to treatment escalation. We conclude that although many patients on long-term therapy develop new impairments over time, the long-term course of MS has become less disabling in the treatment era. These data also call into question the utility of annual MRI assessments as a treat-to-target approach for MS care. Disclosure Bruce Cree has received personal compensation for consulting from Abbvie, Biogen Idec, EMD Serono, MedImmune, Novartis, Genzyme/sanofi aventis, Teva and has received contracted research support (including clinical trials) from Acorda, Biogen Idec, EMD Serono, Hoffman La Roche, MedImmune, Novartis and Teva. Pierre-Antoine Gourraud has received personal compensation for presenting at journal clubs and advisor boards from EMD Serono and Biogen Idec. Jorge Oksenberg: Nothing to disclose. Carolyn Bevan: Nothing to disclose. Elizabeth Crabtree-Hartman has received personal compensation for serving on advisory boards for Biogen Idec, Genzyme, Novartis and Teva. Dr. Gelfand has received compensation from Medimmune for consulting on a scientific advisory board; compensation from Quest Diagnostics for work related to a dementia care pathway; compensation for medical-legal consulting.


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Poster Session I, 21(S11) Douglas Goodin has received personal compensation for lectures from EMD Serono, Genzyme, Teva and has received contracted research support (including clinical trials) from Biogen Idec and Novartis. Jennifer Graves: Nothing to disclose. Ari Green has received personal compensation from Inception Sciences and Mylan Pharmaceuticals, serves on endpoint adjudication committees for Biogen Idec and Medimmune, serves on a steering committee for Novartis and serves on a scientific advisory board for Bionure. Ellen Mowry has received research support from Biogen Idec and medication for a clinical trial from Teva Neurosciences. Darin Okuda has received personal compensation for for consulting from Genzyme and Teva, has received lecture honoraria from Acorda, Genzyme and Teva and has received research support from Biogen. Daniel Pelletier has received research support from Biogen Idec and Genzyme and has received personal compensation for consulting from Acorda, Biogen Idec, Genentech, Genzyme and Novartis. Hans-Christian von Budingen has received research support from Genentech, Pfizer and Roche and has received personal compensation for consulting from Novartis and Roche. Scott Zamvil has received grant support from Biogen Idec and Teva, serves as deputy editor at Neurology, Neuroimmunology and Neuroinflammation and has received personal compensation for consulting from Biogen Idec, EMD Serono, Genzyme, Novartis, Questcor, Roche and Teva and serves on data safety monitoring committees for BioMS, Lily, Opexa and Teva. Alicia Agrawal: Nothing to disclose. Stacy Caillier: Nothing to disclose. Caroline Ciocca: Nothing to disclose. Rachel Kanner: Nothing to disclose. Robin Lincoln: Nothing to disclose. Antoine Lizee: Nothing to disclose. Refujia O´Shea: Nothing to disclose. Pamela Qualley: Nothing to disclose. Adam Santaniello: Nothing to disclose. Leena Suleiman: Nothing to disclose. Monica Bucci: Nothing to disclose. Valentina Panara: Nothing to disclose. Nico Papinutto: Nothing to disclose. William Stern: Nothing to disclose. Alyssa Zhu: Nothing to disclose. Sergio Baranzini has received personal compensation for consulting from EMD Serono, Genzyme. Novartis Pharma and TEVA Neuroscience. Roland Henry has received contracted research support from Hoffman La Roche. Stephen Hauser serves on the scientific advisory boards for Symbiotix, Annexon, and Bionure.

P267 The effect of age on the disease phenotype before the onset of progressive MS A. Scalfari1, L. Christian2, M. Daumer2, R. Nicholas1, G. Ebers3, P. Muraro1 1Neuroscience, Imperial College London, London, United Kingdom, 2Sylvia Lawry Centre, Munich, Germany, 3Oxford University, Oxford, United Kingdom

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Background: The new consensus framework for MS phenotypes has proposed to qualify more precisely the disease course based on the occurrence of focal inflammatory activity. We investigated the influence of age on the pre-progressive clinical phenotype. Methods: Among 751 untreated progressive MS patients (PP = 217; SP = 534) from the London Ontario database, we assessed: 1) the relationship of age with relapse frequency; 2) the impact of relapses on the age at onset of progression; 3) the influence of age on the evolution of the progressive phase. Results: Among SP patients, age at relapsing-remitting (RR) phase onset did not influence the number of attacks during the first two years (early relapses) (r=-0.05; p=0.13). Subgroups with different early relapse frequency had similar mean age at disease onset. In contrast, being older at onset associated not only with a shorter latency to SP, but also with a smaller number of relapses after year 2 (r=-0.26; p< 0.001) and of total attacks before progression (r=-0.24; p< 0.001), revealing an inverse relationship between age and the relapse frequency. Accordingly, SP patients with ⩾ 4 total attacks were younger at disease onset (27.4 mean years) compared to those with 2-3 (31.0 mean years) or 1 (32.8 mean years) attack. The clinical phenotype and the relapse frequency did not influence the age at onset of progression. Different progressive MS subtypes with no attacks (PPMS), or with low (1), intermediate (2-3) and high (⩾4) number of relapses during the RR phase started progressing at similar age (38.6, 41.3, 41.4 and 39.2 mean years, respectively). However, the age at onset of progressive disease did not affect its evolution (time from onset of progression to DSS 6/8). Conclusions: Progressive MS patients exhibit widely different age-related clinical phenotypes before the onset of progression. Those younger at onset of RRMS are more likely to display a predominantly inflammatory course. However, the age at onset of progression is not affected by the relapses frequency. Our results support the notion of a window of opportunity for suppressing inflammation at younger age and highlight the importance of identifying age-related pathological processes, which could be targeted therapeutically. Disclosure Dr Scalfari receives research supports from the UK MS society and received personal compensation for speaking activities from Teva and Genzyme. Dr Lederer has no conflicts of interests to disclose. Dr Daumer receives research support from the European Union FP7 and from the Federal Ministry of Education and Research. Dr Nicholas received personal compensations for speaking activities from Bayer, Biogen, Genzyme, Merck Serono, Novartis, grant support from Teva and served on the scientific advisory board of Biogen, Genzyme, Merck Serono. Prof Ebers has no conflicts of interests to disclose. Dr Muraro declares honoraria for speaking and travel support from Merck Serono, Biogen, Bayer, and Novartis. P268 No evidence of disease activity in treated patients after first clinical event suggestive of multiple sclerosis - follow-up study T. Uher1, M. Vaneckova2, L. Sobisek3, M. Tyblova1, J. Volna1, Z. Seidl2, J. Krasensky2, D.P. Ramasamy4, R. Zivadinov4,5, E. Havrdova1, D. Horakova1


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1Department

of Neurology and Center of Clinical Neuroscience, of Radiology, Charles University in Prague, First Faculty of Medicine and General University Hospital, 3Department of Statistics and Probability, University of Economics in Prague, Prague, Czech Republic, 4Buffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, 5MR Imaging Clinical Translational Research Center, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States 2Department

Background: No evidence of disease activity (NEDA) is a composite measure reflecting measurable suppresion of disease activity and is proposed as a new treatment goal in multiple sclerosis (MS) patients. However, persistence of NEDA in treated patients after first clinical event suggestive of MS is not well described. Objectives: To investigate, in a prospective study, NEDA during 4 years assessed by absence of MRI (new and new enlarging lesions, gadolinium-enhancing lesions, brain atrophy) and clinical (confirmed disability progression, relapses, 25-foot walk test) disease activity. Methods: This study examined 210 CIS patients treated with weekly intramuscular interferon beta-1a. All study patients showed ⩾2 hyperintense T2 lesions at disease onset and were enrolled in the study within 4 months after first clinical symptoms suggestive of MS. MRI and clinical assessments were performed at baseline, 6, 12, 24, 36 and 48 months. Cut-off value for pathological brain volume loss over 1 year was established as a >0.4%. Results: Total of 180 (85%) patients did not show confirmed disability progression and 92 (44%) did not experience new relapse activity during 4 years. No evidence of MRI disease activity (not considering brain atrophy) was present in 95 (45%) patients after 1 year and only in 38 (18%) patients after 4 years of the study. NEDA-3 status was observed in 71 (37%) patients after 1 year, but only in 19 (10%) after 4 years. When considered also brain volume loss, only 12 (6%) patients maintained NEDA-4 status after 4 years. Although patients continued to lose NEDA status during 4 years, highest proportion of patients (63%) lost NEDA status during the first year of the study. There was only a trend of association between NEDA-3 status at first year of the study and sustained disability progression during 4 years (HR=0.52, p=0.1) in Cox proportional hazard model adjusted for age, sex and time between first clinical symptoms and baseline. Conclusions: Although confirmed disability progression was observed in small proportion of patients, loss of NEDA status occurred in the vast majority of individuals, despite of treatment with interferon beta-1a. Loss of NEDA status was observed especially during the first year of disease progression and was driven mostly by occurence of new and new enlarging lesions on MRI. Addition of brain volume change did not lead to substantial decrease of proportion patients with NEDA status. Disclosure Dr. Uher received support from Biogen Idec, Novartis, Merck Serono and Genzyme. Drs. Ramasamy and Sobisek have nothing to disclose. Drs. Tyblova and Volna received support from Biogen Idec, Sanofi Aventis, Teva and Merck Serono.

Drs. Seidl, Vaneckova, and Krasensky received support from Biogen Idec. Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. Received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health. Dr. Havrdova received speaker honoraria and consultant fees from Biogen Idec, Merck Serono, Novartis, Genzyme and Teva, support for research from Biogen Idec and Merck Serono. Dr. Horakova received compensation for travel, speaker honoraria, consultant fees from Biogen Idec, Novartis, Merck Serono, Bayer Shering, and Teva, support for research from Biogen Idec. P269 Clinical course of childhood-onset multiple sclerosis: results from the Swedish multiple sclerosis register A. Manouchehrinia, O. Beiki, A. Kavaliunas, R. Ramanujam, A. Glaser, J. Hillert Karolinska Institutet, Stockholm, Sweden Background: Childhood-onset multiple sclerosis (COMS) occurs in about one to 10% of MS patients. A few population-based cohorts have investigated the clinical and demographic characteristics, and long-term progression of disability in COMS. Goals: We aimed to investigate the clinical course of COMS patients in Sweden. Methods: All patients with a diagnosis of MS and disease onset before or at 16 years of age registered in Swedish MS register (SMSreg) were identified. Incidence of COMS was calculated and demographic and clinical characteristics of COMS and adultonset MS (AOMS) were compared. Median age at the onset of secondary progressive MS (SPMS) was calculated using KaplanMeier method. In a Cox multivariate survival model we investigated the role of sex, number of relapses within the first two years from MS onset and onset age on the risk of SPMS while adjusting for duration of exposure to disease-modifying treatments (DMTs). Results: Of 13,226 patients with clinically definite MS and available data, 344 (2.6%) had COMS with the overall crude incidence rate per 1000 person-year of 0.77 (95% confidence interval [CI]: 0.69 to 0.85). The initial clinical course was relapsing in COMS patients (97%) with the sex ratio of 2:1. The mean age at onset of disease was 14 years in COMS and 34.2 years in AOMS. From the 265 COMS patients with full data, 75 had developed SPMS at a median age of 48 (95% CI: 40 to 51). This was significantly different from 53.4 years (95% CI: 52.6 to 54.0) in AOMS. None of the investigated factors showed any influence on time to SPMS in COMS patients. Conclusions: In comparison with AOMS, COMS patients are more likely to present with a relapsing onset and reach SPMS in a significantly younger age. We did not find any significant risk factor for conversion to SPMS. Disclosure Dr. Ali Manouchehrinia: Nothing to disclose. Dr. Omid Beiki: Nothing to disclose. Dr. Ryan Ramanujam: Nothing to disclose.


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Poster Session I, 21(S11) Dr. Andrius Kavaliunas: Nothing to disclose. Dr Glaser is receiving research support from Biogen. Prof. Jan Hillert: Received honoraria for serving on advisory boards for Biogen and Novartis and speaker’s fees from Biogen, Merck-Serono, Bayer-Schering, Teva and Sanofi-Genzyme. He has served as P.I. for projects sponsored by, or received unrestricted research support from, Biogen, Sanofi-Genzyme, MerckSerono, TEVA, Novartis and Bayer-Schering. His MS research is funded by the Swedish Research Council and the Swedish Brain Foundation. Authors report no conflict of interest Funding: This study was supported by Biogen P270 The topographical model of MS: translation into quantified clinical metrics S.C. Krieger1, K. Cook2, S. De Nino2, M. Fletcher2, F.D. Lublin1 1Corinne Goldsmith Dickinson Center for MS, Mount Sinai Medical Center, 2MS Working Group, Harrison and Star, New York, NY, United States Background: The topographical model of MS has been proposed as a unified visualization of clinical course. It encapsulates 5 factors: topographical distribution of lesions and relapses they cause; relapse frequency, severity, and recovery; and progression rate. The CNS is depicted as a pool, with a shallow end and a deep end representing increasing functional reserve, and the water´s surface denoting the clinical threshold. This clinical manifestation framework posits that progression clinically takes the form of prior relapses/lesions, incrementally revealing above the clinical threshold the underlying lesion topography. We have shown this model can encompass relapsing and progressive forms and a range of severity from very mild through highly active and rapidly progressive disease. Goals: Here we detail the methodology for 1) translating the topographical model into quantifiable disability metrics, and 2) creation of an interactive disease course editor. These represent crucial steps in operationalizing this model for empirical testing/ validation. Methods: Dynamic 3D rendering of the topographical model was implemented using a real-time simulation engine. Topographical peaks are mapped to their referable EDSS Functional Systems (FS) by lesion location (spinal cord, optic nerve, brainstem, hemispheres), with laterality and severity coordinates. Above-threshold clinical manifestations are expressed quantitatively through automated FS score counters. Results: Topographical peaks are calibrated by above-threshold clinical severity, iteratively generating multiple FS counters. These counters are dynamically populated via both relapsing and progressive changes in above-threshold disease. The set of FS scores conditionally generates summative EDSS steps that evolve over the depicted timeframe. We thus utilize the topographical model to output disability tracings that are notably congruent with Lublin/ Reingold clinical phenotypes. This framework will be benchmarked against FS and EDSS trajectories from well-characterized cohorts. Conclusions: The interactive disease course editor allows clinicians to use the topographical model to generate clinical course visualizations of individual patients. We outline the methodology

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for empirical testing of the mathematical relationship among factors framed by this model. Using this model, the slope of clinical progression can be correlated to composite atrophy metrics with prognostic/predictive implications. Disclosure S. Krieger has received compensation for consulting and advisory board work with Acorda Therapeutics Inc.; Bayer; Biogen Idec; EMD Serono (Merck & Co., Inc.); Genentech; Genzyme; Novartis; Questcor Pharmaceuticals, Inc; and Teva Pharmaceutical Industries Ltd. and has given non-promotional lectures with Biogen Idec and Genzyme. K. Cook, S. De Nino, and M. Fletcher are employees of Harrison and Star, LLC, a healthcare communications company, which provided services for this project on a pro bono basis. F.D. Lublin has served on Scientific Advisory Boards for Acorda Therapeutics Inc.; Actelion Pharmaceuticals Ltd.; Bayer; Biogen Idec; EMD Serono, Inc. (Merck & Co., Inc.); F. Hoffman-La Roche Ltd.; Facilitate, LTD; Forward Pharma; MedImmune, LLC; Novartis; Osmotica Pharmaceutical Corp.; Questcor Pharmaceuticals, Inc.; Receptos Inc.; Revalesio Corporation; Teva Pharmaceutical Industries Ltd.; XenoPort, Inc.; and sanofi-aventis.

Epidemiology P271 Exploring causes associated with MS-related deaths on death certificates: a populationbased study in British Columbia, Canada M.D. Alotaibi1,2, F. Zhu1, T. Duggan1, H. Tremlett1, E. Kingwell1 1Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada, 2Faculty of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia Introduction: Life expectancy is reduced in people with MS by approximately 6-10 years but there is limited information on what contributes to a MS-related death. Objectives: To identify causes of death that are associated with MS on the death certificate. Materials and methods: This was a population-based study using the Vital Statistics Agency Multiple Cause of Death data from British Columbia, Canada. All adult deaths (⩾18 years old) from 1986-2009 were accessed. Mentioned causes of death (underlying or contributing) were grouped using the International Classification of Disease codes. Associations between mention of MS and other specific causes were assessed for men and women separately by conditional logistic regression (stratified by groups of age and calendar year), and expressed as odds ratios (OR) with 95% confidence intervals (CI). Results: A total of 643,125 deaths were reported of which MS was mentioned as a cause in 1,795; this represented 0.38% of female and 0.19% of male deaths. Among the deaths in which MS was mentioned, 1,039 (58%) listed MS as the underlying cause. Pulmonary-related inflammation or infections were significantly more likely to be mentioned together with MS than without MS: pneumonitis [ORwomen:7.2 (95% CI:5.9-8.9); ORmen:7.8 (95% CI:6.1-10.0)] and pneumonia/flu [ORwomen:3.0 (95% CI:2.6-3.5); OR men:3.4 (2.8-4.1)]. Septicemia [ORwomen:2.3 (95% CI:1.8-2.8);


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ORmen:2.5 (95% CI:1.8-3.3)] and urinary tract infections (UTIs) [ORwomen:9.8 (95% CI:7.6-12.4); ORmen:16.5 (95% CI:11.9-22.6)] were also highly associated with MS deaths. When MS was mentioned on the death certificate, other major causes including cancer, cardiovascular disease and suicide were significantly less likely to be mentioned. Conclusions: Deaths that included MS as a cause were twice as common for women than men, which is consistent with the sex distribution of MS incidence. Known complications of late-stage MS (pulmonary-related causes of deaths and infections such as pneumonia, UTI and septicemia), were highly associated with deaths attributed to MS. However, other major causes were less likely to be recorded with MS, such as cancer. Whole population Multiple Cause of Death data are complex but they provide a different perspective and opportunity for assessing the role of contributing causes to MS-related deaths. Disclosure This study was funded by a grant from the Canadian Institutes of Health Research (MOP-82738; PI:HT). MA was funded by a MITACS Globalink Research Internship Award. EK, FZ and TD were funded through research grants from the US National MS Society. HT is funded by the Multiple Sclerosis Society of Canada (Don Paty Career Development Award), and she is a Michael Smith Foundation for Health Research Scholar and the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. She has received: research support from the National Multiple Sclerosis Society, the Canadian Institutes of Health Research, and the UK MS Trust; speaker honoraria and/or travel expenses to attend conferences from the Consortium of MS Centres (2013), the National MS Society (2012, 2014), Bayer Pharmaceuticals (2010), Teva Pharmaceuticals (2011), ECTRIMS (2011, 2012, 2013, 2014), UK MS Trust (2011), the Chesapeake Health Education Program, US Veterans Affairs (2012), Novartis Canada (2012), Biogen Idec (2014), American Academy of Neurology (2013, 2014, 2015). Unless otherwise stated, all speaker honoraria are either donated to an MS charity or to an unrestricted grant for use by her research group. P272 Incidence of multiple sclerosis in Puerto Rico: a multicenter initiative A. Chinea1,2, GECPREM 1Research, San Juan MS Center, Guaynabo, 2Research, San Juan Bautista School of Medicine, Caguas, Puerto Rico Background: Multiple sclerosis (MS) patients often experience high disability and poor quality of life for extended periods of time. It is critical to have accurate and up to date MS incidence estimates to better understand MS etiology and ensure availability of resources. Puerto Rico (PR) is located in the Caribbean, geographically pertaining to North America and its population consists of genetically mix European, African, and Amerindian groups. In a previous study, we estimated the incidence of MS in 2013 in 3.1/100,000. Objective: To assess the incidence, clinical, and demographic characteristics of MS in PR for the year 2014. Method: Multi-site, population-based study including more than 50% of practicing neurologist in PR. Multiple sources were

contacted to capture all newly diagnosed MS cases.The sources were the PRMS Foundation, specialty pharmacies, MRI centers, health insurance companies and Department of Health of PR. All patients were 18 years and older, of Puerto Rican origin and established residence in PR for at least 2 years prior to diagnosis. All patients were newly diagnosed during 2014 by a neurologist using the 2010 revised McDonald Criteria. A standardized MS questionnaire was developed and used in face to face interviews with MS patients. Questionnaires consisted of two parts. Part 1 asked about demographic, medical, and MS history of patients. Part 2 was completed by the neurologist to ensure patients met criteria for diagnosis of MS. Informed consent was obtained prior to the interview. Data collected was evaluated and analyzed using Stata version 12. Chi-square analyses were used to examine bivariate associations between categorical variables. Student’s t-tests and analyses of variance (ANOVA) were used for continuous variables. The usual 0.05 threshold for Type I error was used for statistical significance. Results: A total of 146 new MS patients were diagnosed in 2014. The mean age of onset was 40.6 (±11.9 SD) with women comprising 75.3% of all new cases.The 2014 MS incidence rate was 5.1/100,000. For women, the incidence rate was 7.4/100,000 and 2.8/100,000 for men. No statistically significant differences were found for mean MS age of onset between males and females. Conclusion: The rate of 7.4/100,000 is high compared to other Latin American MS incidence studies. This study alerts to the importance of establishing an island-wide continuous patient registry that will help understand MS etiology and risk factors. Disclosure Dr. Angel Chinea and the PR Collaborative group in MS (GECPREM) did not receive any grants or monetary support for this study. P273 Prevalence of depression and anxiety among patients with multiple sclerosis attending the MS clinic at Sheikh Khalifa Medical City, UAE: cross sectional study A. Mudhafar1, K. ElHammasi2, M. Raoof2, T. Shahrour2, M. Shakra3, L. Turkawi3, T. Alsaadi3 1Internal Medicine, 2Psychiatry, 3Neurology, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates Purpose: To report the rates of depression, anxiety and QOL among PWMS attending MS clinic in UAE, and to correlate with various variables. Method: Patients seen in the MS clinics at SKMC were asked to complete the PHQ-9, GAD-7 and WHOQOL-BREF questionnaires. All patients who have completed the questionnaires underwent a formal psychiatric assessment for the presence and absence of depression and anxiety. Age, gender, level of education, marital status, duration of MS, number of attacks in the 6 months prior to the clinic visit, EDSS score, current immunomodulators, and, PHQ-9, GAD-7 and WHOQOL-BREF scores were recorded. We compared the rates of depression and anxiety to age, and gender matched controls. In a multivariate model, we examined whether any of the variables were related to the degree of depression, anxiety, and QOL.


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Poster Session I, 21(S11) Results: A total of 80 patients have participated. The mean age was 35 years. A total of 14 of the 80 patients (17.6%) reported PHQ-9 scores >10 consistent with major depression. As for anxiety scores, 16 patients (20%) had scores >10 consistent with anxiety disorder. However, the rates were not statistically different when compared to the controls. Almost two-third (64%) of patients with scores consistent with major depression and anxiety were not on antidepressant and anti-anxiety medication. Among all the studied variables, none had any statistical significance to either depression or anxiety rates. On the other hand, QOL scores correlated significantly with only anxiety and depression (p< 0.005). Conclusion: Although depression and anxiety were not more prevalent than matched controls in our region, both were the only predictors of patients’ QOL. Disclosure Abdulla Mudhafar: Nothing to disclose P274 Demographic and clinical profile of PEDIATRIC patients with multiple sclerosis: descriptive analysis of a prospective monitored, population-based cohort study in the Basque Country (Spain) M. Mendibe1, S. Boyero1, C. Llarena2, A. RodriguezAntigüedad2 1Hospital Universitario Cruces, Baracaldo, 2Hospital Universitario Basurto, Bilbao, Spain Background: Pediatric multiple sclerosis (MS) is uncommon and, although the patient’s age has been linked with the clinical evolution and progression of this disease, very few longitudinal studies concerning patients with pediatric MS have been published. Objective: To describe the characteristics of pediatric MS patients and to compare them with adult-onset MS patients. Description of clinical characteristics and progression was the primary endpoint. Methods: All patients from the province of Biscay (Basque Country - Spain) with a clinically confirmed diagnosis of MS who attended the regional MS clinic at any time during the past 24 years were included. All clinical information was stored systematically, according to specified protocols, in a computerized database. Pediatric MS (aged < 18 years) was compared with adult-onset (aged ⩾18 years) MS. Results: The study included 1304 MS patients: pediatric cohort n=64 (4.9%); mean age, 14.5±20.2 years; female (64.1%). Adult cohort n=1240 (95.1%); mean age, 32.6±9.7 years; female (70.2%). Pediatric patients were diagnosed with relapsing-remitting MS in 95.3% of cases, the average number of relapses from MS onset was 7.2±7.7 and the mean Expanded Disability Status Scale score was 3.8±2.9. Secondary progressive MS (SPMS) developed in 27.9% of patients, at a mean age of 37.8±11.5 years. Adult patients showed fewer relapses (p< 0.001). Fewer patients developed SPMS (p=0.027), in a shorter time. Conclusions: 4.9% of MS patients in our cohort presented before 18 years of age. The male/female ratio is lower in pediatric MS, although the difference is not statistically significant. Although

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the prevalence of pediatric MS is low and its progression to SPMS is slower, more patients may develop SPMS and at a younger age than adult patients. Disclosure Mar Mendibe: Nothing to disclose. Sabas Boyero: Nothing to disclose. Cristina Llarena: Nothing to disclose. Alfredo Rodriguez-Antigüedad: Nothing to disclose P275 Generalized increase in the burden of psychiatric comorbidity in multiple sclerosis as compared to the general population: a population-based Canadian study R.A. Marrie1, J.D. Fisk2, H. Tremlett3, C. Wolfson4, S. Warren5, S.B. Patten6, CIHR Team in the Epidemiology and Impact of Comorbidity in Multiple Sclerosis 1Internal Medicine, University of Manitoba, Winnipeg, MB, 2Dalhousie University, Halifax, NS, 3University of British Columbia, Vancouver, BC, 4McGill University, Montreal, QC, 5University of Alberta, Edmonton, 6University of Calgary, Calgary, AB, Canada Objective: Estimates of the prevalence of depression, anxiety and bipolar disorder in multiple sclerosis (MS) vary widely and prevalence estimates of schizophrenia are limited. Incidence estimates for psychiatric comorbidities are even more limited than are prevalence estimates, existing only for depression. We compared the incidence and prevalence of psychiatric comorbidity in the MS population with that in age, sex and geographically-matched controls from the general population. Methods: Using population-based administrative health data from 4 Canadian provinces we identified 46938 persons with MS and 233207 age, sex and geographically-matched controls. We applied validated case definitions to estimate the incidence and prevalence of depression, anxiety, bipolar disorder and schizophrenia. Within provinces we modeled age-standardized incidence or prevalence estimates using Poisson regression, adjusting for year and sex. We pooled province-specific estimates using random-effects meta-analysis. Results: Of the MS cases, 33466 (71.3%) were female with a mean (SD) age at the index date of 43.9 (13.9) years. In 2005 the annual incidence of depression per 100000 persons with MS was 986 while the incidence of anxiety was 656, of bipolar disorder was 335, and of schizophrenia was 58. The crude prevalence of depression in the MS population was 20.1%, while the prevalence of anxiety was 7.4%, of bipolar disorder was 4.6% and of schizophrenia was 1.3%. The incidence and prevalence estimates of all conditions were higher in the MS population than in the matched population. Although the incidence of depression was higher among women than men in both populations, the disparity in incidence rates between the sexes was less in the MS population (Females vs. Males IRR 1.26; 95%CI: 1.07-1.48) than in the matched population ( IRR 1.59; 95%CI: 1.21-1.84). Incidence rates were stable over ten years of observation (1995-2005) while prevalence increased slightly. Conclusion: Psychiatric comorbidity, in general, is common in MS and psychiatric conditions more frequently affect the MS


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population than matched persons from the general population. This suggests a non-specific effect of MS on psychiatric comorbidity; MS increases the risk of all psychiatric disorders. This implies the need for general psychiatric support rather than illness-specific strategies. Relative to the general population, the risk of developing depression appears greater for men with MS than for women. Disclosure Supported by Canadian Institutes of Health Research (CIBG 101829), the Rx & D Health Research Foundation, a Don Paty Career Development award from the MS Society of Canada (to RAM) and Manitoba Research Chair from Research Manitoba (to RAM). All inferences, opinions, and conclusions drawn in this publication are those of the authors and do not reflect the opinions or policies of the Data Stewards. No official endorsement by Manitoba Health, Population Data BC, Pharmanet, the Regie D’Assurance Maladie du Quebec, or The Commission dáccès à línformation (CAI) of Quebec is intended or should be inferred. Some data used in this report were made available by Health Data Nova Scotia of Dalhousie University. Although this research is based on data obtained from the Nova Scotia Department of Health and Wellness, the observations and opinions expressed of those of the authors and do not represent those of either Health Data Nova Scotia or the Department of Health and Wellness. RA Marrie has conducted clinical trials for Sanofi-Aventis. C Wolfson received a speaking honorarium from Novartis. S Patten received honoraria for reviewing investigator-initiated grant applications submitted to Lundbeck, Pfizer and received speaking honoraria from Teva and Lundbeck. H Tremlett received speaker honoraria and/or travel expenses to attend conferences from Biogen Indec. J Fisk received speaker honoraria and travel expenses to attend meetings from EMD Serono. P276 A retrospective review to identify real-world hospitalization rates and steroid use due to relapse D. Davidson Bayshore Healthcare, Mississauga, ON, Canada Background & objective: Relapse remains the hallmark event in relapsing remitting MS (RRMS), but in the MS population using disease modifying therapies, there is a paucity of published data on hospitalizations specifically due to relapse. The purpose of this retrospective database review was to improve our understanding of the real-world incidence of relapse related hospitalization and steroid use. Design: This was a retrospective, private database review of over 21,000 MS patient records maintained by a Canadian patient assistance program provider and dating back to June 2002. Records were included in the analysis only if relapse data was captured, and the patients were/are using disease-modifying therapies. Results: We identified 7,615 records that met our criteria and of these, 80% are from 2013 onward. The average age was 42 years, 60% had experienced 1 relapse, 21% 2 relapses, 8% 3 relapses, and the rest 4 or more. A total of 319 patients were hospitalized

due to a relapse and all of these events occurred from 2013 onward. Hospitalization due to relapse was observed in 4.2% of all cases that met our criteria or in 5.2% of cases from 2013 onward; this represents an annualized incidence of around 2.3%. A higher overall incidence of relapse leading to a hospitalization was observed in the cohort aged 20-39 (4.9%) versus those aged 40-59 (3.8%). Steroids were used by 62% of patients experiencing a relapse leading to hospitalization with IV therapy used at least 71% of the time (oral therapy at least 5.5%, others unknown). 15% percent of patients who were not hospitalized used steroids for relapse treatment. In this population, IV steroids were used at least 42% of the time, orals at least 17% and the balance unknown. Overall steroid use irrespective of a hospitalization was observed in 17% of all cases. Conclusions: Although MS-related hospitalizations have decreased over time, a small proportion of our contemporary patients are at risk of suffering a relapse leading to a hospitalization. Our review suggests a preference for IV steroid administration in those suffering a relapse leading to hospitalization. The full sequalae of relapse and its impact on healthcare resource utilization requires continued research. Disclosure Deidre Davidson is an employee of Bayshore Healthcare, a provider of third-party patient assistance programs. The source of funding for this abstract was provided by Bayshore Healthcare Ltd. Michelle Capon BA, MA, Sr. Manager Data & Analytics: nothing to disclose. Bayshore Data and Analytics Team: nothing to disclose. P277 Relationship of headache and vitamin D supplementation in MS patients C.E. Uy1, G. Vorobeychik2, Q. Xu3, E. Dilli1 1Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, 2Fraser Health MS Clinic, Burnaby Hospital, Burnaby, 3Division of Neurology, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada There is a growing body of evidence implicating vitamin D deficiency in multiple sclerosis (MS) and migraine headache (MH). Both of these conditions increase in prevalence at higher latitudes and some observational studies have directly linked low serum vitamin D (Vit D) levels to risk of developing MS. Headache is an important comorbidity in multiple sclerosis with higher prevalence of MH and tension type headache (TTH) found in MS populations compared to control groups. We compared prevalence of MH, TTH and use of Vit D supplementation using a survey tool in 203 sequential patients in a multiple sclerosis clinic from December 2009 to May 2010. We hypothesized that supplementation of vitamin D was associated with lower headache prevalence in MS patients. Our data showed that the prevalence of headache in the Vit D group was lower than the No Vit D group (87.4% vs 93.2%), but this difference was not statistically significant. However, there was a much higher prevalence of headache overall in our patient population than in general population and compared to what has


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Poster Session I, 21(S11) been previously reported in MS patients in the literature. We concluded that supplementation with vitamin D did not correlate with reduction in headache. Future studies would benefit from a larger collection of patient surveys and using serum vitamin D level as a more objective measure of vitamin D deficiency to further investigate the relationship between headache and MS. Disclosure Christopher E. Uy: Nothing to disclose. Galina Vorobeychik: Nothing to disclose. Qi Xu: Nothing to disclose. Esma Dilli: Nothing to disclose. P278 Prevalence of multiple sclerosis in Iranian emigrants: review of the evidence Z. Nasr1, M. Etemadifar2, A. Rostami3, M.A. Sahraian4, A. Minagar5, A. Amini6 1Medical Student Research Center, Isfahan University of Medical Science, 2Department of Neurology, Isfahan University of Medical Science, Isfahan, Islamic Republic of Iran, 3Department of Neurology, Thomas Jefferson University, Philadelphia, PA, United States, 4Department of Neurology, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran, 5Louisiana State University Health Sciences Center, Louisiana, LA, United States, 6Department of Neuroscience, Faculty of Life Sciences, London, United Kingdom Background: Iran is now well known for its high prevalence of MS, particularly in Asia and the Middle East. Increasing emigration from Iran to other countries in the past four decades has resulted in the publication of a number of epidemiologic studies on the prevalence of MS in Iranian populations in various countries around the world. Hereby, we present a comprehensive review of the recently published literature on the epidemiology of MS in Iranian emigrants. Methods: A comprehensive literature search was performed using Pubmed, Embase, and, Web of Science on April 30, 2015. We also did manual search of reference lists from primary articles and relevant reviews. Results: Nine papers from Sweden, Canada, Norway, UK and India were reviewed. Of which only three reported the ageadjusted prevalence and six of them reported age of disease onset. MS prevalence among Iranians in these studies varies geographically, ranged from 21 per 100,000 in Bombay, India in 1985 to 433 in British Columbia, Canada in 2012. Five studies reported the prevalence rate in the region of destination, which varied from 1.33 in Bombay, India to 240 in British Columbia, Canada. Five studies also reported the prevalence of MS in the population of the destination country, in all of which the prevalence of MS in Iranian immigrants was higher. Conclusion: Based on epidemiological studies of MS prevalence in Iran and Iranian emigrants, we believe that genetic susceptibility and ethnicity might have more of an impact than environmental factors in the susceptibility of Iranians to MS. Furthermore, it maybe concluded that, apart from genetic susceptibility, living in a high-risk area increases the prevalence rate of MS in Iranian emigrants.

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Disclosure Zahra Nasr: Nothing to disclose Masoud Etemadifar: Nothing to disclose Abdolmohamad Rostami: Nothing to disclose Mohamad Ali Sahraian: Nothing to disclose Alireza Minagar: Nothing to disclose Arman Amini: Nothing to disclose P279 Children of chronically ill parents: relationship between parental multiple sclerosis and childhood developmental health N. Razaz1, K.S. Joseph1, T. Boyce2, M. Guhn1, B. Forer1, R.A. Marrie3, H. Tremlett1 1University of British Columbia, Vancouver, BC, Canada, 2University of California, San Francisco, CA, United States, 3University of Manitoba, Winnipeg, MB, Canada Objectives: Exposure to parental chronic illness is associated with adverse developmental outcomes, but little is known in multiple sclerosis (MS). We examined the association between parental MS and parental MS-related clinical factors on developmental health. Methods: We conducted a population-based cohort study in British Columbia, Canada, using linked health databases. MS was identified through hospital, physician and prescription drug claims. The outcome of interest was childhood development, expressed as vulnerability (absent vs present) on 5 areas of childhood development at 5 years of age: physical health, social competence, emotional maturity, language development and communication skills, measured by the Early Child Development Instrument (EDI). Comparisons were made between children who had a parent with vs. without MS, matched on school district and year of the EDI assessment. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. Results: MS affected parents (n=783) were older, more likely to be English speakers and had higher rates of mental health morbidity (39.6% vs. 22.2%, P< 0.001) than unaffected parents (n=2,988). Children of mothers with MS (aOR 0.62, 95% CI 0.44-0.87), but not children of fathers with MS (OR 1.15, 95% CI 0.75-1.78), had a lower risk of vulnerability on the social development domain of the EDI (P value for interaction=0.01). However, mental health morbidity (aOR 1.62, 95% CI 1.05-2.50) and physical morbidity (aOR:1.67;95%CI:1.05-2.64) among MS mothers was associated with increased vulnerability on the EDI. Furthermore, there was a 2-fold greater odds of vulnerability on the physical health domain (aOR 2.58, 95% CI 1.10-6.05) and 4-fold greater odds of vulnerability on the language and cognitive development (aOR 4.43, 95% CI 1.55-12.6) domain of the EDI, among children of parents with greater disability (Expanded Disability Status Scale score ⩾4 vs. < 4.0). Conclusion: Maternal MS, but not paternal MS, was associated with lower rates of developmental vulnerability on the social development domain. However, presence of mental and physical comorbidity in the MS-affected mothers and disability in the MS parents were associated with higher risk of vulnerability in children.


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Disclosure Helen Tremlett is funded as a Canada Research Chair and has received research support from the National Multiple Sclerosis Society, the Canadian Institutes of Health Research, and the UK MS Trust and travel expenses to attend meetings or conferences from the Consortium of MS Centres (2013), the National MS Society (2012, 2014), Bayer Pharmaceuticals (2010), Teva Pharmaceuticals (2011), ECTRIMS (2011, 2012, 2013, 2014), UK MS Trust (2011), the Chesapeake Health Education Program, US Veterans Affairs (2012), Novartis Canada (2012), Biogen Idec (2014), American Academy of Neurology (2013, 2014, 2015). Dr. Marrie has received research support from CIHR, the MS Society of Canada, the National MS Society, Research Manitoba, and the MS Scientific Research Foundation. She has conducted clinical trials for sanofi-aventis. Drs Joseph, Martin and Boyce have nothing to disclose. Ms. Neda Razaz has nothing to disclose. Funding support: The study was supported by an operating grant from the Canadian Institute of Health Research (MOP-119393; PI: Tremlett). P280 Vitamin D, race/ethnicity and the risk of multiple sclerosis A.M. Langer-Gould1,2, R. Lucas3, L.H. Chen1, A. Xiang1, L. Barcellos4 1Research & Evaluation, Kaiser Permanente Southern California, Pasadena, 2Neurology, Southern California Permanente Medical Group, Los Angeles Medical Center, Los Angeles, CA, United States, 3National Center for Epidemiology and Population Health, Australian National University, Canberra, ACT, Australia, 4QB3 Genetic Eopidemiology and Genomics Lab, University of California, Berkeley School of Public Health, Berkeley, CA, United States Importance: Hypovitaminosis D has been associated with an increased risk of multiple sclerosis (MS) in whites. Whether this is true in darker skinned individuals (who have lower levels of vitamin D) is unknown. Objective: To determine whether hypovitaminosis D is a risk factor for MS in blacks and Hispanics. Design: Incident case-control Setting: Membership of Kaiser Permanente Southern California (KPSC). Data were collected from a structured in-person interview, blood draw and the complete electronic health record. Participants: Cases with newly diagnosed MS or its precursor, clinically isolated syndrome (CIS), were identified through the multiethnic KPSC Demyelinating Disease Cohort between 2011 and 2014. Controls were matched on age, sex, race/ethnicity and zip code. Exposure: Deseasonalized serum 25-hydroxyvitamin D levels were modeled as a continuous variable, by quintiles and pre-specified thresholds. Main outcome measure: MS/CIS analyzed using conditional logistic regression within each racial/ethnic group. Results: We recruited 457 incident cases of MS/CIS and 472 controls of which 108 cases and 116 controls were black; 146 and 151 Hispanic and 203 and 205 white, non-Hispanic, respectively. 25-hydroxyvitamin D levels were highest in whites followed by Hispanics and blacks (median 70, 55 and 47nmol/L respectively).

Higher serum 25-hydroxyvitamin D levels were associated with a lower risk of MS/CIS in whites particularly in those with levels greater than 75nmol/L (OR 0.30, 95% CI 0.17-0.56; p< 0.001 adjusted for obesity, smoking, mononucleosis and family history of MS; reference category < 50nmol/L). No association was found in blacks or Hispanics regardless of how 25-hydroxyvitamin D was modeled. Conclusions and relevance: 25-hydroxyvitamin D levels appear to be associated with the risk of MS only in whites. A non-causal association cannot be excluded as vitamin D is a better surrogate measure of sunlight exposure in light than dark-skinned individuals. Another possible explanation is complex interactions between vitamin D and genotype as several genes that increase vitamin D bioavailability are more common in blacks. Our findings indicate that vitamin D supplementation to prevent MS is premature. They also underscore the importance of including multiple racial/ethnic groups in studies of vitamin D. Disclosure Source of funding National Institute of Neurological Disorders and Stroke (NINDS, 1R01NS075308 PI:Langer-Gould); site principal investigator for 2 phase 3 clinical trials. Other authors have nothing to disclose. P281 10-year progression predictors after first treatment initiation in a relapsing-remitting MS cohort V.G. Jokubaitis1,2, T. Spelman1, T. Kalincik1,2, D. Travaglini3, D. Paolicelli4, P. Duquette5, M. Girard5, A. Prat5, E. Havrdova6,7, D. Horakova6,7, G. Izquierdo8, P. Grammond9, E. Pucci10, F. Grand’Maison11, R. Bergamaschi12, F. Granella13, V. Van Pesch14, R. Hupperts15, G. Iuliano16, D. Spitaleri17, P. Sola18, C. Boz19, R. Fernandez-Bolanos20, T. Petersen21, F. Verheul22, J. Olascoaga23, P. McCombe24, C. Rozsa25, J. Lechner-Scott26,27, M. Terzi28, S. Hodgkinson29, C. Ramo30, M.L. Saladino31, H. Butzkueven1,2,32, A. Lugaresi3, M. Trojano4, for the MSBase Study Group 1Department of Medicine, University of Melbourne, 2Department of Neurology, Royal Melbourne Hospital, Parkville, VIC, Australia, 3MS Center, Department of Neuroscience and Imaging, University ‘G. d’Annunzio’, Chieti, 4Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy, 5Hopital Notre Dame, Montreal, QC, Canada, 6Department of Neurology, General University Hospital, 7First Faculty of Medicine, Charles University, Prague, Czech Republic, 8Hospital Universitario Virgen Macarena, Sevilla, Spain, 9Centre de Réadaptation Déficience Physique Chaudière-Appalache, Levis, QC, Canada, 10Ospedale di Macerata, Macerata, Italy, 11Neuro Rive-Sud, Hopital Charles LeMoyne, Greenfield Park, QC, Canada, 12Neurological Institute IRCCS Mondino, Pavia, 13University of Parma, Parma, Italy, 14Cliniques Universitaires Saint-Luc, Brussels, Belgium, 15Orbis Medical Centre, Sittard, The Netherlands, 16Ospedali Riuniti di Salerno, Salerno, 17AORN San Giuseppe Moscati, Avellino, 18Nuovo Ospedale Civile S.Agostino/Estense, Modena, Italy, 19Karadeniz Technical University, Trabzon, Turkey, 20Hospital Universitario Virgen de Valme, Sevilla, Spain, 21Kommunehospitalet, Arhus C, Denmark, 22Groene Hart Ziekenhuis, Gouda, The Netherlands, 23Hospital Donostia, San Sebastián, Spain, 24Royal Brisbane Hospital, Brisbane, QLD,


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Poster Session I, 21(S11) Australia, 25Jahn Ferenc Teaching Hospital, Budapest, Hungary, 26John Hunter Hospital, 27University of Newcastle, Newcastle, NSW, Australia, 28Medical Faculty, 19 Mayis University, Samsun, Turkey, 29Liverpool Hospital, Liverpool, NSW, Australia, 30Hospital Germans Trias i Pujol, Badalona, Spain, 31INEBA, Buenos Aires, Argentina, 32Department of Neurology, Box Hill Hospital, Box Hill, VIC, Australia Introduction: A principal objective when managing the clinical care of people with multiple sclerosis (MS) is to prevent the irreversible accumulation of neurological disability. Clinical trials provide evidence for clinical efficacy of disease modifying therapies (DMT) in reducing disease burden, however, the clinical trial environment does not necessarily reflect real-world patient characteristics or behaviours. Predictors of long-term expanded disability status scale (EDSS) score change in a cohort of patients treated with first-line disease modifying therapies in real-world clinical settings are not known. Objective: To identify long-term predictors of EDSS change in patients with relapsing-remitting multiple sclerosis that initiated with any interferon-beta (IFNβ) preparation or glatiramer acetate (GA) as a first therapy. Methods: Data were extracted from the MSBase Registry. Median EDSS changes over 8 year (n=2271) and 10-year (n=1563) periods were determined. Predictors of EDSS change were analysed using adjusted quantile median regression. Continuation on firstline therapy was not a condition for remaining in the analysis. Results: Annualised relapse rate (ARR) was highly predictive of increases in median EDSS score over both 8-year (β=0.88, p< 0.0001) and 10-year (β=1.37, p< 0.0001) periods. Additionally, ontreatment relapses in the first 8 (β=0.5, p< 0.0001) and 10 years (β=0.72, p< 0.0001), but not off-treatment relapses were predictive of an EDSS increase. Increasing proportion of the observation period on DMT therapy was associated with a significant decrease in EDSS score change at 8 (β=-0.78, p< 0.0001) and 10 years (β=1.00, p< 0.0001). Additionally, pregnancy was shown to correlate with a decrease in EDSS score within the first 8 years of observation post-baseline (β=-0.45 per pregnancy; p=0.002). Conclusions: In this real-world cohort of patients observed for 8 and 10 years after first DMT initiation, high ARR, particularly on-treatment relapse activity, is a poor prognostic indicator. Pregnancy and cumulative time one therapy, however, are associated with decreased disability accumulation over the long-term. These results provide a rationale for switching therapy in patients with highly active disease whilst on therapy in order to limit longterm disability accrual. Disclosure Vilija Jokubaitis’ salary is supported by NHMRC project grant #1032484 and has received conference travel support from Novartis. Timothy Spelman received compensation for travel from Biogen Idec. Tomas Kalincik received compensation for travel from Novartis, Biogen Idec, Sanofi Aventis, Teva and Merck Serono. Daniela Travaglini received travel grants and honoraria from Bayer Schering, Biogen, Merck Serono, Sanofi and Teva; her institution received research grants from Biogen, Bayer, Merck, Novartis and Teva.

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Damiano Paolicelli received honoraria for consultancy and/or speaking from Biogen Idec, Merck-Serono, Bayer-Schering, Novartis and TEVA. Pierre Duquette did not declare any competing interests Marc Girard received consulting fees from Teva Canada Innovation, Biogen Idec, Novartis and Genzyme Sanofi; lecture payments from Teva Canada Innovation, Novartis and EMD Serono. Dr Girard has also received a research grant from Canadian Institutes of Health Research. Alexandre Prat did not declare any competing interests. Eva Havrdova received speaker honoraria and consultant fees from Biogen Idec, Merck Serono, Novartis, Genzyme and Teva, as well as support for research activities from Biogen Idec and Merck Serono. Dana Horakova received speaker honoraria and consulting fees from Biogen Idec, Merck Serono, Teva and Novartis, as well as support for research activities from Biogen Idec. Guillermo Izquierdo received speaking honoraria from BiogenIdec, Novartis, Sanofi, Merck Serono and Teva. Pierre Grammond is a Novartis, Teva-neuroscience, Biogen Idec and Genzyme advisory board member, consultant for Merck Serono, received payments for lectures by Merck Serono, TevaNeuroscience and Canadian Multiple sclerosis society, and received grants for travel from Teva-Neuroscience and Novartis. Eugenio Pucci served on scientific advisory boards for Genzyme and Biogen-Idec; he has received honoraria and travel grants from Sanofi Aventis, UCB, Lundbeck, Novartis, Bayer Schering, Biogen Idec, Merck Serono, Genzyme and Teva; he has received travel grants from Associazione Marchigiana Sclerosi Multipla e altre malattie neurologiche. Francois Grand’Maison received honoraria or research funding from Biogen Idec, Genzyme, Novartis, Teva Neurosciences, Mitsubishi and ONO Pharmaceuticals. Roberto Bergamaschi received speaker honoraria from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, Teva; research grants from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis, Teva; congress and travel/accommodation expense compensations by Almirall, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, Teva. Franco Granella did not declare any competing interests. Vincent Van Pesch has served on advisory boards for Biogen Idec, Novartis Pharma and Sanofi-Genzyme; has received travel grants and consultancy fees from Biogen Idec, Bayer Schering, Sanofi Aventis, Merck Serono, Sanofi-Genzyme and Novartis Pharma; has received research grants from Bayer Schering. Raymond Hupperts received honoraria as consultant on scientific advisory boards from Merck-Serono, Biogen-Idec, GenzymeSanofi and Teva, research funding from Merck-Serono and Biogen-Idec, and speaker honoraria from Sanofi-Genzyme and Novartis. Gerardo Iuliano had travel/accommodations/meeting expenses funded by Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis, and Teva Daniele La Spitaleri received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and SanofiAventis and compensation for travel from Novartis, Biogen Idec, Sanofi Aventis, Teva and Merck-Serono Patrizia Sola did not declare any competing interests


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Cavit Boz received conference travel support from Biogen Idec, Novartis, Bayer-Schering, Merck-Serono and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. Ricardo Fernandez-Bolanos received speaking honoraria from Biogen-Idec, Novartis, Merck Serono and Teva. Thor Petersen received funding or speaker honoraria from Biogen Idec, Merck Serono, Novartis, Bayer Schering, SanofiAventis, Roche, and Genzyme. Freek Verheul is an advisory board member for Teva Biogen Merck Serono and Novartis. Javier Olascoaga did not declare any competing interests. Pamela McCombe has received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi and travel grants from Novartis, Biogen Idec and Bayer Schering. Csilla Rozsa has received speaker honoraria from Bayer Schering, Novartis and Biogen Idec, congress and travel expense compensations from Biogen Idec, Teva, Merck Serono and Bayer Schering. Jeannette Lechner-Scott has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment and also clinic support from Bayer Health Care, Biogen Idec, CSL, Genzyme Sanofi, Merck Serono and Novartis. Murat Terzi received travel grants from Merck Serono, Novartis, Bayer-Schering, Merck-Serono and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. Suzanne Hodgkinson did not declare any competing interests. Cristina Ramo received research funding and compensation for travel from Biogen-Idec and Novartis. Maria Laura Saladino did not declare any competing interests. Helmut Butzkueven has served on scientific advisory boards for Biogen Idec, Novartis and Sanofi-Aventis and has received conference travel support from Novartis, Biogen Idec and Sanofi Aventis. He serves on steering committees for trials conducted by Biogen Idec and Novartis, and has received research support from Merck Serono, Novartis and Biogen Idec. Alessandra Lugaresi is a Bayer Schering, Biogen Idec, Genzyme, Merck Serono Advisory Board Member. She received travel grants and honoraria from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis and Teva, research grants from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis and Teva, travel and research grants from the Associazione Italiana Sclerosi Multipla and was a Consultant of “Fondazione Cesare Serono”. Maria Trojano has served on scientific advisory boards for Biogen Idec, Novartis and Merck Serono, received speaking honoraria from Biogen-Idec, Bayer-Schering, Sanofi Aventis, MerckSerono, Teva and Novartis; has received research grants from Biogen-Idec, Merck-Serono, and Novartis. P282 Risk of self-harm and suicide in people admitted to hospital with multiple sclerosis: record-linkage study S. Ramagopalan Evidera, London, United Kingdom Background: Risk factors for self-harm in patients with multiple sclerosis (MS) are common, such as mood disorder and anxiety. However, it is unclear if MS patients do, in fact, have an increased risk of self-harm and suicide.

Methods: We analysed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999-2011). Rate ratios for self-harm and suicide were determined, comparing an MS cohort with a comparison cohort. Results: There were significantly elevated risks of self-harm (rate ratio (RR)=1.59, 95% confidence interval (CI) 1.49 to 1.69) and suicide (RR=1.86, 95% CI=1.37-2.47) in people who have been hospitalised with MS. The excess risk of self-harm was greater in males (RR=1.94, 95% CI=1.73 to 2.17) than females RR=1.48, 95% CI=1.37 to 1.59), and lower in patients aged younger than 45. Conclusions: Patients with MS have an increased risk of both self-harm and suicide. Patients at risk should be identified and, where deemed appropriate, support should be given. Disclosure SVR is an employee of Evidera Inc. P283 Month-of-birth-effect in multiple sclerosis in Austria N.K. Walleczek1, H. Rauschka2, G. Bsteh3, C.B. Birkl4, M. Khalil4, S. Fuchs4, C. Enzinger4, F. Fazekas4, C. Eggers5, F. Leutmezer6, S. Salhofer-Polanyi6, A. Baumgartner6, S. Blechinger6, S. Koppi7, J. Sellner8, J. Kraus8, H. Assar9, M. Gugger10, R. Ehling11, H. Moser12, B. Raber13, H. Liendl13, S. Parigger14, M. Mayr15, M.-S. Hiller16, B. Meister17, G. Morgenstern18, H.K. Spiess19, I. Kempf20, A. Cisar21, H. Bachler22, R. Lehninger23, T. Berger3, W. Kristoferitsch1, F. Aboulenein-Djamshidian1,2 1Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, SMZ-Ost Donauspital, 2Department of Neurology, SMZ-Ost Donauspital, Vienna, 3Medical University of Innsbruck, Innsbruck, 4Medical University of Graz, Graz, 5Krankenhaus der Barmherzigen Brüder Linz, Linz, 6Medical University of Vienna, Vienna, 7LKH Rankweil, Rankweil, 8Medical University of Salzburg, Salzburg, 9Landes-Nervenklinik Wagner-Jauregg, 10AKH Linz, Linz, 11Reha-Zentrum Münster, Münster, 12Neurologisches Therapiezentrum Gmundnerberg, Altmünster am Traunsee, 13LKH Judenburg-Knittelfeld, JudenburgKnittelfeld, 14Wilhelminenspital der Stadt Wien, Vienna, 15Bezirkskrankenhaus Kufstein, Kufstein, 16SMZ BaumgartnerHöhe - Otto-Wagner-Spital, Vienna, 17LKH FeldbachFürstenfeld, Feldbach, 18Private Practice, Lienz, 19Private Practice, Imst, 20Haus der Barmherzigkeit, Vienna, 21Private Practice, Amaliendorf-Aalfang, 22Private Practice, Innsbruck, 23Private Practice, Retz, Austria Background: The month-of-birth-effect (MoBE) is an observation first published about ten years ago, noticing that people later developing multiple sclerosis (MS) seem to have been born more frequently in certain months (precisely in May) and noticeable more rarely in other ones (precisely in November). These observations have been made in countries north of the 45th latitude, such as Scandinavia, Canada, Great Britain and Denmark. The purpose of our study was to verify a possible MoBE in MS in Austria, with its population of 8.4 million people and approximately 8000 to 10000 MS patients. Methods: A nation-wide survey with several calls for participation (via email newsletters, articles in the official journal of the


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Poster Session I, 21(S11) Austrian Society of Neurology) was initiated in spring 2014. Data were anonymised. Database closure was December 31st, 2014. All co-operators were offered co-authorship. Comprehensive statistical analysis included the comparison with the data of the Austrian nation-wide birth registry and a special ‘cluster-analysis’ to determine if the MoBE follows a different pattern in Austria or if the MoBE can only be seen in certain vintages, or sex. The Austrian birth registry was established in 1940. Data from the Austrian birth registry were obtained commercially from the Statistik AustriaTM. Results: We were able to include in total 8176 MS patients. 286 MS patients were born before 1940 and 7890 MS patients were born thereafter (male MS patients: n=2466; mean,46.7 ± 12.8; range from 5.2 to 75.0; female MS patients: n=5424, age 46.8 ± 12.8; range from 5.2 to 75.0). Data of the Austrian nation-wide birth registry (from 1940 to 2010) included the entries of 3.726.633 males (mean, 52.488 births per year ± 10.378; range from 38.597 to 79.707 births per year) and 3.491.501 females (mean, 49.879 births per year ± 9.695; range from 36.861 to 74.654 births per year). The mean age of males was 39.6 ± 20.7 (range from 4.5 to 74.6 years). The mean age of females was 40.1 ± 20.4 (range from 5.5 to 74.6). However, we were not able to identify a pattern suggesting a MoBE in Austrian MS patients or in the normal population, with proposed highest birthdays of MS patients in May and proposed lowest birthdays in November. Conclusions: Our preliminary data do not suggest the existance of a MoBE in Austria. The reason remains to be elucidated. Disclosure Nina-Katharina Walleczek: Nothing to disclose; Helmut Rauschka: Nothing to disclose; Gabriel Bsteh: Nothing to disclose; Christoph Birkl: Nothing to disclose; Michael Khalil: Nothing to disclose; Siegrid Fuchs: Nothing to disclose; Christian Enzinger: Nothing to disclose; Franz Fazekas: Nothing to disclose; Christian Eggers: Nothing to disclose; Fritz Leutmezer: Nothing to disclose; Sabine Salhofer-Polanyi : Nothing to disclose; Anna Baumgartner: Nothing to disclose; Stephan Blechinger: Nothing to disclose; Stefan Koppi: Nothing to disclose; Johann Sellner: Nothing to disclose; Jörg Kraus: Nothing to disclose; Hamid Assar: Nothing to disclose; Michael Guger: Nothing to disclose; Rainer Ehling: Nothing to disclose; Hermann Moser: Nothing to disclose; Bettina Raber: Nothing to disclose; Herburg Liendl: Nothing to disclose; Silvia Parigger: Nothing to disclose; Markus Mayr: Nothing to disclose; Maria-SophieHiller: Nothing to disclose; Birgit Meister: Nothing to disclose; Gabriele Morgenstern: Nothing to disclose; Heinrich K. Spiss: Nothing to disclose;

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Ines Kempf: Nothing to disclose; Astrid Cisar: Nothing to disclose; Herbert Bachler: Nothing to disclose; Reinhard Lehninger: Nothing to disclose; Thomas Berger: Nothing to disclose; Wolfgang Kristoferitsch: Nothing to disclose; Fahmy Aboulenein-djamshidian: Nothing to disclose P284 Medication adherence and the impact of oral medications: a study from the pacific northwest multiple sclerosis registry T. Stuchiner1, C. Chen1, E. Baraban1, S. Cohan2 1Providence Brain and Spine Institute, Providence Health and Services, 2Providence Multiple Sclerosis Center, Providence Brain and Spine Institute, Portland, OR, United States Objective/background: Medication adherence for people with multiple sclerosis has long been an issue, as the majority of disease modifying therapies (DMTs) in the past were by injection. However, with three oral DMTs now available, patients are increasingly being treated with non-injectable drug. This study describes the impact of oral medications upon adherence rates, compared to those for injection and infusion DMT. Methods: Participants in the Pacific Northwest MS Registry (PNMSR) are sent an annual survey which includes questions on specific DMT use and adherence. Patients reported the number of missed doses over the past three months. Non-adherence rate was calculated as number of missed doses divided by the prescribed number of doses for that medication. Analysis of variance tests were used to determine differences in non-adherence rate between type of DMT (oral, injection, or infusion). Results: Of the 1,100 participants who had returned a follow up survey at time of analysis (86.8% of total), 57.2% (n=372) were on an injection DMT, 10.6% (n=69) were on an infusion DMT, and 32.2% (n=209) were on an oral DMT. Participants who were on non-FDA approved medications for MS were excluded from the analysis (n=33). Participants taking oral medications reported higher number of missed doses (1.91±3.09) than those on injectable (1.23±3.23) or infusion (.11± .44) (p< .01), but their nonadherence rate appeared to be lower .012 (±.02) than those receiving injectable (.43 ± .10) or infusion DMTs (.039± 0.15) (p< .01), after accounting for the number of doses prescribed. Nonadherence to either injectable or oral DMTs was unaffected by frequency of prescribed use. Conclusions: Our data demonstrate the use of oral DMTs for multiple sclerosis results in improved adherence when compared to self-administered injection therapies. Comparing adherence across DMTs is problematic because of variation in administration methods and frequency. Patient reported outcomes are subject to recall bias and the causes for poor adherence are multi-factorial. This study does not address causes of non-adherence unique to specific DMT groups. Our future studies will focus on developing strategies to address these challenges. Disclosure Stanley Cohan serves on advisory boards for Biogen Idec, Novartis, Sanofi Genzyme, and Mallinckrodt, and has received research support from Biogen Idec, Novartis, Sanofi Genzyme,


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Opexa, Teva, Mallinckrodt, and Roche, has received speaker honoraria from Biogen Idec, Novartis, Sanofi Genzyme and Acorda. Tamela Stuchiner has nothing to disclose. Chiayi Chen has nothing to disclose. Elizabeth Baraban has nothing to disclose. P285 Best practices for assessing environmental tobacco smoke exposure in children using questionnaires: a systematic review of measurement properties S. Magalhaes1, C. Tansey2, B. Banwell3, A. Bar-Or4, I. Fortier5, H.E. Hanwell6, M. Pugliatti7, C. Wolfson1,5 1Epidemiology, Biostatistics and Occupational Health, 2McGill University, Montreal, QC, Canada, 3Children’s Hospital of Philadelphia, Philadelphia, PA, United States, 4Neurology and Neurosurgery, McGill University, 5Research Institute of the McGill University Health Centre, Montreal, QC, 6Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada, 7University of Ferrara, Ferrara, Italy Background: Tobacco smoke exposure has been shown to be both a risk and prognostic factor for adult onset MS and a risk factor for pediatric onset MS. The question remains whether environmental tobacco smoke (ETS) exposure may also be related to MS prognosis in children. In the absence of expensive biomarker assays, self-reported questionnaires can be used to estimate exposure over time. It is critical for questionnaires to have good measurement properties (validity/reliability) in order to obtain unbiased results in observational studies. The objective of this work was to identify, describe and compare questionnaires that ascertain ETS exposure in children. Methods: Using systematic review methodology we identified publications that (i) report on a questionnaire that assesses ETS, (ii) assess measurement properties, (iii) include children, and (iv) are written in English. PubMed, EMBASE and CINAHL were searched in December 2014 using a validated search strategy. Two reviewers independently extracted data and performed quality assessment using the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist. Random effects models are being used to meta-analyze quantitative results. Results: Of the 4742 abstracts screened, 140 met the inclusion criteria. These studies were conducted in Europe, North America, Asia and the Middle East, providing evidence of cross cultural validity of assessing ETS exposure. Over 90% of studies assessed concurrent validity using serum, saliva or urine biomarkers for ETS exposure (usually cotinine) and/or household air monitoring. In the majority of these studies, measurement properties were not the focus, but were assessed to ensure accuracy of results. Having a smoking mother was most predictive of ETS exposure; however underreporting by smoking parents was common. Reliability assessment included agreement between parent/child reports and test-retest. Agreement between parent/child reports varied greatly across studies (kappa range: 0.23-0.95). Conclusions: Overall we show that simple questions can be used to validly and reliably measure ETS exposure. The results of this

review provide researchers designing questionnaires with key information about the measurement properties of assessing ETS in children. We are developing the PedMS Tool-Kit which will include an evidence-based questionnaire module to estimate ETS exposure in pediatric MS case-control studies. Disclosure Funding This investigation was supported by a grant from the National Multiple Sclerosis Society (US). Sandra Magalhaes received doctoral studentship funding from the Canadian Institutes of Health Research (2011-2014) and the MS Society of Canada (2014-2016). Heather Hanwell: Is supported by a Hospital for Sick Children Restracomp Fellowship and has received a speakers honorarium from Teva Neuroscience. The other authors have nothing to disclose related to the work presented in this abstract. P286 Cigarette smoking does not influence disability accumulation in primary progressive multiple sclerosis O. Javizian1, W. Wall1, L. Metz1, M. Koch1,2 1Clinical Neuroscience, 2Community Health Science, University of Calgary, Calgary, AB, Canada Background: Modifiable risk factors are well researched in relapsing-remitting multiple sclerosis (RRMS), but much less is known about the effect of modifiable risk factors on the natural history of primary progressive MS (PPMS). The modifiable risk factor cigarette smoking is associated with the risk of developing RRMS as well as disability accumulation in RRMS. However, it is not known whether smoking is associated with disability progression in PPMS. Here we present our investigation on the association of the modifiable risk factor smoking on disability progression in PPMS. Objectives: To determine how the modifiable risk factor cigarette smoking influences the time from disease onset to the disability milestones of EDSS 4 and 6 and whether the influence of this risk factor differs between early and late disease phase. Methods: This was a retrospective analysis of prospectively collected data from PPMS patients followed at the Calgary MS clinic. We identified 371 patients with PPMS and available smoking history. Kaplan-Meier survival analysis and Cox regression modeling were used to investigate the influence of cigarette smoking on the time to Expanded Disability Status Scale (EDSS) 4 and 6, as well as the time from EDSS 4 to 6. Results: The analyses on time to EDSS 4 included 321 patients, and those on time to EDSS 6 included 353 patients. The median times to EDSS 4 were 4 and 5 years (p=0.27) in ever- and never-smokers, respectively, and 9 years to EDSS 6 in both ever- and never-smokers (p=0.48). Lastly, the analysis of time from EDSS 4 to 6 included 280 patients, with median times of 2 and 3 years (p=0.93) in ever- and never-smokers, respectively. Cox regression hazard ratio (HR) estimates showed no significant effect of smoking on time to EDSS 4 (HR: 1.17, 95%CI: 0.90-1.50), EDSS 6 (HR: 1.14, 95%CI: 0.871.49), and from EDSS 4 to 6 (HR: 0.97, 95%CI: 0.73-1.28). Conclusions: Our investigation in a large, well-characterized PPMS cohort showed no association between cigarette smoking and time to disability milestones in PPMS.


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Poster Session I, 21(S11) Disclosure

Disclosure

Research conducted by Omid Javizian is funded by the Canadian Institute of Health Research. No conflicts to disclose from all participating authors.

Carmen Lienert received travel support for scientific meetings from TEVA, Biogen and Merck-Serono Andy Schötzau has nothing to disclose Serafin Beer has nothing to disclose Peter Hänni has nothing to disclose Marcus D’Souza received travel support from Bayer AG, Teva and Genzyme and research support from the University of Basel Jens Kuhle has received research support by an ECTRIMS Research Fellowship Programme, University of Basel, Swiss MS Society, Swiss National Science Foundation, Protagen AG, Roche, Genzyme and Novartis. Ludwig Kappos has received in the last 3 years and used exclusively for research support: steering committee, advisory board and consultancy fees from Actelion, Addex, Bayer Health Care, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, Xenoport; speaker fees from Bayer Health Care, Biogen, Merck, Novartis, Sanofi-Aventis, Teva; support of educational activities from Bayer Health Care, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva; royalties from Neurostatus Systems GmbH; grants from Bayer Health Care, Biogen, Merck, Novartis, Roche, Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations. Özgür Yaldizli has nothing to disclose in the last two years

P287 Time to relapse and disability progression in a long-term cohort of people with clinically isolated syndrome and relapse-onset multiple sclerosis treated with disease-modifying drugs: a prospective nationwide survey in Switzerland C. Lienert1, A. Schötzau2, S. Beer3, P. Hänni4, M. D’Souza5, J. Kuhle5, L. Kappos5, Ö. Yaldizli5 1Neurology, Department of Medicine, Cantonal Hospital Baselland, Bruderholz, 2Statistical Consultant, Basel, 3Center of Rehabilitation Valens, Department of Neurology, Valens, 4Swiss Federation for Common Tasks of Health Insurances, Solothurn, 5Neurology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland Background: The efficacy of disease modifying drugs (DMDs) to prevent relapses in relapsing-remitting multiple sclerosis (RRMS) has been shown in numerous Phase-III trials. However, the longterm effect on disability progression is still a matter of debate. Aim: To determine time to relapse and disability progression in a large long-term MS cohort treated with DMDs. Methods: Analysis of data from the Swiss Federation for Common Tasks of Health Insurances (SVK) that includes standardised annual information on diagnosis, disease onset, relapses and neurological status assessed using the Expanded Disability Status Scale (EDSS) of about 80% of all MS patients treated with DMDs in Switzerland. The case record forms provided by the treating neurologists were reviewed for completeness and internal plausibility and queries about missing or inconsistent data were issued by the SVK under the supervision of an independent physician. EDSS progression was defined as>= 1 step if EDSS was < = 5.0 and >= 0.5 if EDSS was >=5.5 confirmed at two consecutive annual evaluations. Patients who switched or discontinued treatment before confirmation of the EDSS change were censored. Hazard ratios were propensity-score adjusted for clinically relevant baseline characteristics including age, gender, disease duration, disease subtype, EDSS at treatment start and time of DMD introduction. Results: From 1995 to 2010, 8044 patients were included in this study: 472 clinically isolated syndrome, 6832 RRMS, 740 secondary-progressive MS (SPMS); mean age 39.6±11.3, disease duration 7.15±8.01 years, annualised relapse rate 0.91±0.66 [based on the two antecedent years], median EDSS at treatment start 2.5 (range 0-8), mean time of follow-up 4.4±3.94 years. In the year prior to treatment start, 16.6% of the patients were relapse-free. This proportion increased after one year of treatment to 60.6% similar across the treatment groups. After 10 years on DMD treatment, 15.1% of the patients had still relapses. Median time to confirmed EDSS progression was 7.92 years (interquartile range [IQR] 7.68-8.74) in RRMS and 4.96 years (IQR 4.33-5.97) in SPMS calculated from treatment start. In a propensity-score adjusted analysis, both the median time to relapse and confirmed EDSS progression was similar across the treatment groups. Conclusions: In this comprehensive and large long-term MS cohort, time to relapse and confirmed EDSS progression was similar across interferon-beta products and glatiramer acetate.

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P288 Hazards of cerebrovascular, cardiovascular and lung comorbidities in multiple sclerosis - a nationwide study in Denmark using multiple data sources A. Thormann1,2, M. Magyari1,2, N. Koch-Henriksen2,3, B. Laursen4, P. Soelberg Sorensen1 1Department of Neurology, Danish Multiple Sclerosis Center, 2The Danish Multiple Sclerosis Registry, Copenhagen University Hospital Rigshospitalet, Copenhagen, 3Department of Clinical Epidemiology, Clinical Institute, University of Aarhus, Aarhus, 4National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark Background: Previous reports on the risk of comorbidities in multiple sclerosis (MS) are conflicting. Objectives: To investigate whether persons with MS are at higher risk of getting cerebrovascular, cardiovascular, and lung comorbidities than the background population. Methods: We conducted a cohort study. All Danes with onset of MS between 1980 and 2005 were identified from the Danish Multiple Sclerosis Registry. Via Statistics Denmark, each MS case was randomly matched with five controls without MS regarding year of birth, sex, and municipality on January 1st in the year of MS onset. Individual-level information on diagnoses was obtained from nationwide registries and linked to the study population by unique personal identification numbers. After linkage, the identity of persons was scrambled. MS-cases and controls were followed from MS onset through 31st December 2012 (or death, or emigration, whichever came first) to collect information on comorbidities diagnosed after MS onset. We used Cox regression to compute hazard ratios (HRs).


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Results: A total of 9514 MS cases and 44735 controls were eligible for inclusion. Unadjusted HRs for comorbidity after onset of MS were: cerebrovascular disease excluding subarachnoid haemorrhage 1.418 (p< 0.001); subarachnoid haemorrhage 0.701 (p=0.318); cardiovascular disease 0.959 (p=0.288); lung diseases 0.792 (p< 0.001), including asthma 0.673 (p< 0.001), and chronic obstructive pulmonary disease 0.773 (p=0.007). When adjusted for age at MS onset and sex, HRs were: cerebrovascular disease excluding subarachnoid haemorrhage 1.384 (95% CI: 1.237-1.549, p< 0.001); subarachnoid haemorrhage 0.682 (0.339-1,372, p=0.283); cardiovascular disease 0.917 (0.8490.990, p=0.026); lung diseases 0.787 (0.731-0.846, p< 0.001), including asthma 0.670 (0.555-0.809, p< 0.001), and chronic obstructive pulmonary disease 0.738 (0.613-0.890, p=0.001). Conclusions: This study, using data from multiple nationwide sources, confirms previous findings of different comorbidity patterns in persons with MS compared with controls. For some comorbidities, we found an increased hazard among persons with MS. Whether this reflects common underlying traits, differences in health behaviour, or surveillance bias is unclear. Conversely, decreased hazard of a disease among persons with MS could indicate a protective effect of MS or a tendency towards underdiagnosing yet another chronic condition in chronically ill persons. Disclosure This study is funded by The Danish Mulitple Sclerosis Society. A. Thormann has served on a scientific advisory board for Biogen Idec. She has received support for congress participation from BiogenIdec, Novartis, Teva, and UCB. M. Magyari has served on scientific advisory board for BiogenIdec and TEVA and has received honoraria for lecturing from BiogenIdec, MerckSerono, Novartis, and Teva. She has received support for congress participation from BiogenIdec, MerckSerono, Novartis, TEVA and Genzyme. N. Koch-Henriksen has received honoraria for lecturing and participation in advisory councils, travel expenses for attending congresses and meetings, and financial support for monitoring the Danish MS Treatment Register from Bayer-Schering, MerckSerono, BiogenIdec, TEVA, Sanofi-Avensis, and Novartis. B. Laursen has nothing to disclose. P.S. Sørensen has received personal compensation from Biogen Idec, Merck Serono, Novartis, Genmab, TEVA, GSK, and Sanofiaventis, Genzyme as member of scientific advisory boards, steering committees or independent data monitoring boards in clinical trials, or as speaker at meetings. His research unit has received research support from Biogen Idec, Bayer Schering, Merck Serono, TEVA, Sanofi-aventis, Novartis, RoFAR, Roche, and Genzyme, the Danish Multiple Sclerosis Society, the Danish Medical Research Council, and the European Union Sixth Framework Programme: Life sciences, Genomics and Biotechnology for health. P289 Evidence of an association between multiple sclerosis and renal disease M. Wenten1, I. Bhan2, N. Payas1, V. Meka1, M. Novas1 1Biogen, Cambridge, 2Divison of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States

Background: The relationship between multiple sclerosis (MS) and renal disease is unknown. In a preliminary analysis of a health claims database in the United States (US), an increased association of MS and renal disease was observed, but no validated algorithms were available to assess outcome. Goal: We evaluated electronic medical records databases at 2 major US hospitals (Massachusetts General [MGH] and Brigham and Women’s [BWH]) to assess the association between MS and renal disease. Methods: Patients were included if they had ⩾1 visit to the participating hospitals from 1 July 2004 to 30 June 2014 and ⩾1 creatinine measurement. Patients with a coded MS diagnosis were matched to controls by age, race, and gender. Laboratory studies, diagnoses, medications, and appointments were evaluated. Renal disease was defined as a diagnostic code including “renal” or “kidney” but not “congenital” and lacked “without” preceding “renal” or “kidney;” subsets were defined for “acute” and “chronic” disease. Results: Records were obtained for 7425 MS patients and 5731 controls. Populations were predominantly female (MS, 71.7%; control, 73.3%) and non-black (MS, 94.2%; control, 93.9%), with a median age of 53 years. Diagnosis of renal disease was significantly more frequent among MS patients (19.1%) than controls (16.8%; P=0.00053). The difference in incidence of renal disease was greater for patients older than 60 years (MS, 30.8% vs controls, 24.0%; P< 0.0001), but not for those ⩽60 years (13.2% vs 12.9%; P=0.73). Hematuria occurred in significantly more MS patients than controls (8.5% vs 6.3%; P< 0.0001), while hypertension was diagnosed in fewer MS patients than controls (32% vs 34%; P=0.019). Acute and chronic renal disease occurred similarly in both groups (5% and 4%, respectively). Use of medications associated with renal disease was not significantly different among MS patients and controls for nonsteroidal anti-inflammatory drugs (38.8% vs 38.6%; P=0.77) or angiotensin II receptor blockers (4.1% vs 4.3%; P=0.53) but was significant for angiotensin converting enzyme inhibitors (14.3% vs 12.9%; P=0.029); differences in drug use for patients >60 years were 1.7%, 0.9%, and 8.4%, respectively (P=NS). Conclusion: Using the MGH/BWH databases allowed identification of MS and control patients from a large common population and determined an increased risk of renal disease among MS patients that was most prominent among older MS patients. Disclosure MW, MN, NP, VGM: employees of Biogen. IB: None P290 ReMuS - Czech national registry of multiple sclerosis patients - 2 years experience D. Horakova1, M. Valis2, M. Vachova3, P. Hradilek4, J. Sucha5, A. Novotna6, R. Ampapa7, M. Grunermelova8, I. Stetkarova9, P. Stourac10, J. Mares11, E. Meluzinova12 1Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, First Faculty of Medicine and General University Hospital, Prague, 2Department of Neurology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, and University Hospital Hradec Kralove, Hradec Kralove, 3KZ a.s. Hospital, Teplice,


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of Neurology, University Hospital Ostrava, Ostrava, of Neurology, Charles University in Prague, Faculty of Medicine in Pilsen, and University Hospital Pilsen, Pilsen, 6Neurology Clinic, Pardubice Regional Hospital and Faculty of Health Studies, University of Pardubice, Pardubice, 7Department of Neurology, Hospital of Jihlava, Jihlava, Czech Republic, Jihlava, 8Department of Neurology, Thomayer Hospital, 9Charles University in Prague, 3rd Faculty of Medicine, Hospital Kralovske Vinohrady, Prague, 10Department of Neurology, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Brno, 11Department of Neurology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic, Olomouc, 12Department of Neurology, Charles University in Prague, 2nd Faculty of Medicine, Motol, Prague, Czech Republic 5Department

Background: Multiple sclerosis is a lifelong disease with a very heterogenous clinical course. Randomised controlled clinical trials bring reliable but only short term data. Long term data from real life conditions are needed. Objectives: To report a structure, evolution, and first results from the Czech national registry ReMuS. Methods: The ReMuS is operated and completely funded by the endowment foundation Impuls (www.multiplesclerosiscz) in collaboration with the Czech neuroimmunological society. The preparation phase started in 2012 (included all administrative work related to data protection, signing contracts, implementation of software iMed (www.imed.org) in local MS centers). An Operational manual that defines logistics and all items to be collected was created. Demographic and history data are collected retrospectively at the first visit and then prospectively at each visit in local center. Data is exported to a centralised database every 6 months. Final report is created and put on the web twice per year. The first stratum to be added to this database was patients treated by disease modifying drugs. In first two years, only data from this demographic were collected and added to the database. Since the third year, data of all patients followed in the MS centers has been collected and sent. Results: 12 out of 15 Czech MS centers have already joined the registry. The number of patient records has increased gradually from 1501 to 5639 in the last export in December 2014. Sex ratio female / male is 72/28%, average age 40.2 (SD 10.2), EDSS 2.7 (1.5), annual relapse rate 0.298. Data about treatment show the rate of particular drugs with interferons and glatiramer acetate as a leading preparations. The registry provides further data about distribution of patients in particular regions, health insurance assignment, and important data about employment and disability pension (68.8% of patients are employed and working full or part time). Conclusions: ReMuS, the Czech national registry, has already collected comprehensive data of almost 6000 patients. The aim is to enroll a majority of MS patients (approx. 13000) in the Czech Republic within the next 2 years. The registry will soon provide not only crossectinal, but also important longitudinal data. This data will help to better organize care for MS patients in the Czech Republic and also serve as an important scientific platform for future endeavors. Disclosure Dana Horakova received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck Serono, Teva, Genzyme and

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Bayer Schering and financial support for research activities from Biogen Idec. Martin Valis, nothing to disclose; Marta Vachova, nothing to disclose; Pavel Hradilek, nothing to disclose, Jaroslava Sucha, nothing to disclose; Alena Novotna, nothing to disclose; Radek Ampapa, nothing to disclose; Marketa Grunermelova, nothing to disclose; Ivana Stetkarova, nothing to disclose; Pavel Stourac, nothing to disclose; Jan Mares, nothing to disclose; Eva Meluzinova, nothing to disclose P291 On-going increase in incidence and prevalence of multiple sclerosis in Newcastle, Australia: a 50-year study K. Ribbons1,2, R. Lea2, C. Tiedeman3, L. MacKenzie4, J. Lechner-Scott1,2 1Neurology, John Hunter Hospital, 2Hunter Medical Research Institution, 3Medicine, Hunter New England Local Health District, 4School of Health Sciences, Faculty of Health and Medicine, University of Newcastle, Newcastle, NSW, Australia Introduction: Previous surveys conducted in the east coast Australian city of Newcastle (latitude 32o52’S, longitude 151o49’E) in 1959, 1981 and 1996, have supported global trends of a progressive increase in the prevalence and incidence of MS. In the current study we evaluated if these trends have continued and provide 50 years of MS epidemiological follow-up for this southern hemisphere city. Methods: Prevalence per 100 000 population living in the study area was calculated for patients with a confirmed diagnosis of MS on 9th August 2011, a national census day. Incidence was based on the number of cases with a confirmed diagnosis of MS made during the decade August 2001 to August 2011 and was expressed per 100 000 person years. To enable comparisons with prior surveys, data was age standardised to the total Australian population on the prevalence day. Statistical comparisons were undertaken using chi-squared analysis of proportions with Yates corrections. Results: The prevalence rate of MS in 2011 was 124.4/100 000, which is a 2 fold increase in case rate from the last survey conducted in 1996 (P< 0.0001), and a 6 fold increase from the initial 1961 rate. In 2011, the female to male prevalence ratio was 3.1:1, which represents a 53% increase in female predominance since the last survey in 1996 (P=0.017). The age-specific prevalence peaked at the 5th decade in 2011 which is a decade earlier than that reported in 1996. In 2001 - 2011 MS incidence was 6.7/100 000, a 3 fold increase compared to the incidence in 1986-1996 (P< 0.0001). There was also larger number of new female cases compared to males in 2011 (3.1:1, P< 0.0001). This F:M ratio is 3 times higher than that seen in 1950-1959 (P< 0.0001). Conclusions: During the period between 1959 and 2011 there has been a steady escalation in the prevalence and incidence of MS in Newcastle. Prevalence and incidence rates have risen substantially from the previous 1996 survey in this region, which are associated with higher rates of diagnosis in women and increased cases of younger patients. The utilisation of updated diagnostic criteria and increased patient awareness of MS may be contributing to the increased numbers of cases being seen.


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Disclosure K Ribbons, R Lea, C Tiedeman, L Mackenzie have nothing to disclose. J Lechner-Scott has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment and also clinic support as well as research grants from Bayer Health Care, Biogen Idec, CSL, Genzyme Sanofi, Merck Serono and Novartis. This study was supported by a non-directive grant from CSL. P292 Prognostic indicators of secondary progression in a pediatric-onset multiple sclerosis cohort S. Akhtar1, R. Alroughani2,3, S.F. Ahmed4,5, J. Al-Hashel4,6 1Department of Community Medicine and Behavioural Sciences, University of Kuwait, Jabriya, 2Division of Neurology, Amiri Hospital, Sharq, 3Neurology Clinic, Dasman Diabetes Institute, Dasman, 4Department of Neurology, Ibn Sina Hospital, Safat, Kuwait, 5Department of Neurology and Psychiatry, Minia University, Minia, Egypt, 6Medicine, University of Kuwait, Faculty of Medicine, Jabriya, Kuwait Background: Pediatric-onset multiple sclerosis (POMS) is regarded as less frequent compared to multiple sclerosis (MS) in adults. Furthermore, risk of secondary progression of the disease among POMS patients is largely unknown. This study aimed to assess the risk and examine the relationship of demographic and clinical covariates with time to secondary progressive MS (SPMS) in a cohort of POMS patients. Methods: Kuwait National MS Registry (KNMSR) database was used to identify a cohort of POMS cases (diagnosed before the age < 18 years) registered from 1994 through 2013. Once entered in the KNMSR database, POMS patients were followed prospectively on regular basis i.e. at least one visit every six months and their clinical data were updated. Data on demographic and clinical variables were abstracted from patients` records. Non-parametric Kaplan-Meier method and Cox proportional-hazard model were used model to evaluate the prognostic significance of both demographic and clinical variables. Results: During the study period, of 808 MS patients in KNMSR database, 127 (15.7%) were POMS cases. The median age (years) at the disease onset was 16.0 (range: 6.5 - 17.9); mean ± SD: 15.4 (± 2.04). In the study cohort of 127 POMS cases, 20 (15.8%) developed SPMS. Female gender represented 71.7% of the study cohort and among 20 POMS cases who had SPMS, 12 (60%) were female. Cox proportional-hazards model revealed that at any point during the follow-up years, POMS patients with brainstem /cerebellar presentations at the disease onset had 5.71 times higher risk of secondary progression, when compared to POMS patients presented with other clinical manifestations at disease onset (adjusted hazard ratio = 5.71; 95% CI: 1.53 - 21.30; p = 0.010). Also, among the POMS patients, there was statistically significant 38% increased risk of secondary progressive course with each year increase in the patient’s age at the disease onset, after adjusting for the effect of brainstem/ cerebellar presentations at MS onset (adjusted hazard ratio = 1.38; 95% CI: 1.01 - 1.88; p = 0.042). Conclusions: This study showed that POMS patients with brainstem/ cerebellar presentations and relatively increasing age at MS

onset had enhanced risk of secondary progression of disease and warrants aggressive therapeutic approach in patients with these characteristics. Disclosure Dr. Alroughani received honoraria as a speaker and for serving in scientific advisory boards from Bayer, Biogen, Biologix, Genpharm, Genzyme, GSK, Merck Sorono and Novartis. Dr. Akhtar, Dr. Ahmed & Dr. Al-Hashel have nothing to disclose. P293 Clinical features and updated epidemiology data of multiple sclerosis and neuromyelitis optica from the Hong Kong Multiple Sclerosis Registry A. Lau1, C.C.K. Au1, A. Wong1, L. Shi1, J. Abrigo1, J. Fok2, K.K. Wong2, S.H. Li3, K.K. Yip4, J. Yeung5, K.K. Lau6, R. Ip7, E. Chan7, K.S. Wong1, V. Mok1 1The Chinese University of Hong Kong, 2Yan Chai Hospital, 3North District Hospital, 4Ruttonnjee Hospital, 5Alice Ho Miu Ling Nethersole Hospital, 6Princess Margaret Hospital, 7Queen Mary Hospital, Hong Kong, Hong Kong Background and goals: Lack of clinical data on distinction between multiple sclerosis (MS) and neuromyelitis optica (NMO) among Chinese patients cause constant challenges for neurologists. We aimed to set up a prospective territory-wide registry for central nervous system (CNS) demyelinating diseases to identify the clinical features, updated epidemiology, natural disease course, and treatment responses of MS and NMO in Hong Kong. Methods: Chinese patients (aged >= 18 years) with confirmed diagnosis of CNS demyelinating diseases (MS, NMO, optic neuritis, transverse myelitis) are recruited to a prospective registry. We prospectively collected data at entry-, post-relapse, and annual visits, including demographics, socioeconomic status, details of diagnosis and relapses, medication use and hospitalization records, neurological and functional assessment (Expanded Disability Status Scale [EDSS] and Multiple Sclerosis Functional Composite [MSFC]). Results: From March 2013 to January 2015, 114 subjects were recruited from 6 hospitals in Hong Kong; 65 (57%) had MS, 32 (28%) had NMO, and 17 (15%) had clinically isolated syndrome (CIS). The median onset age is 28 (13-51) for MS, and 35 (16-70) for NMO (p=0.002); the majority are female (78% vs. 75%). CSF oligoclonal band is positive in 60% MS and 10% NMO subjects, respectively (p< 0.001); 60% NMO subjects are seropositive for AQP4-Ab. The median EDSS is 3 (0-8) for MS, and 4 (0-9) for NMO. A favorable response to interferon-beta (46% reduction of annualized relapse rate) was observed in MS subjects. EDSS score >4 is associated strongly associated with unemployment (45% vs. 15%, p< 0.05), and dependence on social assistance (36% vs. 19%, p< 0.05). The estimated prevalence (per 100,000 persons) is 7.2 per for MS and 3.8 for NMO. The annual incidence (per 100,000 persons) is 2.2 for MS, and 0.7 for NMO. Conclusions: We identified a rising prevalence and incidence of MS and NMO among Chinese subjects with CNS demyelinating diseases in a prospective registry. Further clinical studies are warranted.


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Poster Session I, 21(S11) Disclosure

Disclosure

The study is funded by the Hong Kong College of Physicians Young Investigator Grant (2012), and educational grants from Novartis and Merck Pharmaceuticals (PI: Dr. Alexander Lau)

S. Schmidt has received speaking honoraria, travel compensations and has served on advisory boards for BayerVital, Biogen, MerckSerono, Novartis and Teva. J. Koehler has received honoraria for lecturing, travel expenses for attending meetings from Almirall, Bayer, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Sanofi-Aventis, and TEVA and is consultant for Allmiral, Genzyme, Novartis and Roche. B. Kallmann has received honoraria for serving on advisory boards and as speaker from Merck Serono, Biogen, Sanofi/ Genzyme, Teva and Novartis. C. Winterstein, P. Schicklmaier, C. Wernsdörfer are employees of Biogen GmbH.

P294 Course of disease and treatment decisions in patients with relapsing-remitting multiple sclerosis after two years of first-line disease modifying treatment: a retrospective observational study S. Schmidt1, J. Koehler2, C. Winterstein3, P. Schicklmaier3, C. Wernsdörfer3, B. Kallmann4, for the EPIDEM Investigators 1Neurologische Gemeinschaftspraxis Schmidt, Neudecker & Viebahn GbR, Bonn, 2Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Kempfenhausen, 3Medical Department, Biogen GmbH, Ismaning, 4Multiple Sklerose Zentrum Bamberg - MSBZ, Bamberg, Germany Background: According to a previous study performed in Germany in 2007/08, roughly 25% of relapsing-remitting multiple sclerosis (RRMS) patients receiving ongoing first-line disease-modifying therapies (DMT) met the clinical and magnetic resonance imaging (MRI) criteria for treatment with second-line therapies (Mäurer M, et al. Eur J Neurol 2011). However, the recent availability of novel therapeutic options and MS risk stratification approaches may have changed treatment strategies in clinical practice. Goals and methods: This retrospective, non-interventional, multicenter study performed between 2010-2014 investigated the disease evolution and treatment approaches in RRMS patients receiving first-line DMTs for ⩾24 months. Our present analysis focused on clinical/radiological parameters, rating of the course of MS and treatment considerations by the treating neurologists as well as quality of life (QOL) reported by the patients by means of the MSQoL-54 questionnaire. Results: Characteristics of patients (n = 4215) at the time of data acquisition were: mean age 44.8 years, female 73.1%, mean MS duration 9.6 years, median Expanded Disability Status Scale (EDSS) score 2.0. For 1594 patients, EDSS, MRI findings, relapse rate, rating of MS course by neurologist, and treatment considerations were available. 810 patients of this subgroup showed evidence of clinical and/or MRI disease activity, defined as >1 relapse or EDSS progression ⩾ 0.5 or increased MRI-activity within the last 24 months. The course of MS was rated as “improved” in 2.3%, “stable“ in 64.8%, and “worsened” in 31.9% of these patients by the neurologists. Patients with an EDSS increase of at least 0.5 points during the observation period reported lower categories in QoL assessments (“less good“ or “poor“) more frequently than those with stable/improved EDSS (34.3% vs. 16.3%). A switch to a second-line therapy was considered in only 24.7% of patients with documented disease activity. Conclusions: Treating physicians considered the majority of patients with evidence of clinical and/or subclinical disease activity as “stable” (64.8%). Therefore only a minority was considered suitable for treatment optimization (24.7%). These results underline the importance of a systematic documentation of MS activity and its inclusion in treatment algorithms to optimize therapeutic decisions in clinical practice. Study supported by: Biogen.

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P295 Clinical manifestations of multiple sclerosis are determined by both latitude and HLA class II allele in Japanese Y. Nakamura1, S. Sato1, M. Niino2, T. Matsushita3, Y. Miyazaki2, S. Kikuchi4, J.-I. Kira1, the Japan Multiple Sclerosis Genetics Consortium 1Department of Neurology, Neurological Institute, Graduate School of Medical Science, Kyushu University, Fukuoka, 2Department of Clinical Research, Hokkaido Medical Center, Sapporo, 3Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Science, Kyushu University, Fukuoka, 4Department of Neurology, Hokkaido Medical Center, Sapporo, Japan Background: Susceptibility and clinical features of multiple sclerosis (MS) are influenced by genes such as human leukocyte antigen (HLA) genes. We previously reported that MS patients with HLA-DRB1*04:05 showed a milder clinical course than those without it. The fourth nationwide survey of MS in Japan also revealed differences in clinical and MRI features according to the latitude. Objective: We aimed to clarify the differences in disease susceptibility and clinical manifestations according to HLA genes and latitude in Japanese MS patients. Methods: The study enrolled 247 MS patients and 159 healthy controls (HCs) from the northern Japan (more than 37 degree north) and 187 MS patients and 235 HCs from the southern Japan. Patients with primary progressive MS or longitudinally extensive spinal cord lesions were excluded. We compared phenotypic frequencies of HLA-DRB1 and -DPB1 alleles and clinical features between MS patients from southern and northern Japan. Results: DRB1*04:05 allele was a susceptibility allele in both regions. DRB1*09:01 was a protective allele only for southern Japanese. DRB1*01:01 and DRB1*13:02 were protective alleles only for northern Japanese. No DPB1 alleles studied were associated with MS in Japanese. Southern patients had higher Multiple Sclerosis Severity Scores than northern patients, while northern patients had a higher frequency of brain lesions that met the Barkhof criteria (Barkhof brain lesions) and higher frequencies of cerebrospinal fluid (CSF) IgG abnormalities than southern patients. The patients with DRB1*04:05 had a younger age at onset, and lower frequencies of Barkhof brain lesions and CSF IgG abnormalities than non-DRB1*04:05 carriers. Multivariate


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analyses revealed that age at onset was associated with DRB1*04:05 while both Barkhof brain lesions and CSF IgG abnormalities were associated with the latitude and DRB1*04:05. Conclusions: Clinical manifestations are in part determined by HLA alleles and latitude in Japanese MS patients. Disclosure Yuri Nakamura: Nothing to disclose Shinya Sato: Nothing to disclose Masaaki Niino: Nothing to disclose Takuya Matsushita has received research support from Bayer Schering Pharma, Biogen Idec, Novartis Pharma, and Mitsubishi Tanabe Pharmahas; and he has received speaker honoraria from Mitsubishi Tanabe Pharma. Yusei Miyazaki: Nothing to disclose Seiji Kikuchi has received support from Otsuka Pharmaceutical Co., Ltd. Jun-ichi Kira has received speaker honoraria from Novartis Pharma K.K., Biogen Idec Japan Ltd., and Mitsubishi Tanabe Pharma Corporation; and he has received grants for commissioned/joint research from Biogen Idec Japan Ltd., UCB Japan Co.Ltd., and Mitsubishi Tanabe Pharma Corporation; and he has received scholarship grants from Pfizer Japan Inc., Otsuka Pharmacetutical Co. Ltd., Astellas Pharma Inc., Esai Co. Ltd., Biogen Idec Japan Ltd., Novartis Pharma K.K., Bayer Yakuhin Ltd., and Mitsubishi Tanabe Pharma Corporation. This work was supported in part by a Health and Labor Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labor and Welfare of Japan, and a grant-in-aid (B; no. 22390178) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

MS and gender P296 Childlessness and pregnancy issues in multiple sclerosis patients: a multicenter retrospective prevalence study D. Ferraro1, G. Adani1, F. Vitetta1, A.M. Simone1, C. Mauri2, S. Strumia3, C. Senesi4, E. Curti4, E. Baldi5, M. Santangelo6, S. Montepietra7, P. Immovilli8, A. Guareschi9, W. Neri3, F. Granella10, L.M. Caniatti5, M.R. Tola5, L. Motti7, I. Pesci9, E. Montanari9, P. Sola1 1Department of Biomedical Metabolic and Neurosciences, University of Modena and Reggio Emilia, 2Radiology Unit, Department of Diagnostic Services and Image, AUSL Modena, Modena, 3Neurology Unit, Ospedale G.B. Morgagni - L. Pierantoni, Forlì, 4Neurology Unit, University of Parma, Parma, 5Neurology Unit, Department of Neuroscience/Rehabilitation, Azienda Ospedaliera-Universitaria S. Anna, Ferrara, 6Neurology Unit, Ospedale Ramazzini, Carpi, Modena, 7Neurology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, 8Department of Specialistic Medicine, G. da Saliceto Hospital, Piacenza, 9Neurology Unit, Vaio-Fidenza Hospital, 10Department of Neurosciences, University of Parma, Parma, Italy Background: The frequency of childlessness in Multiple Sclerosis (MS) women may be higher than in the general population. This is not necessarily explained by infertility; rather, it

could be caused by a reduced propensity to maternity due to concerns about disability and postponement of maternity while on immonomodulatory drugs. MS may also affect the delivery procedure, with a higher number of planned caesarean deliveries (CD) in MS women, and breast-feeding, since women may choose not to breastfeed so they can resume their preventive therapies. Objective: To assess whether: 1) there is a higher frequency of childlessness in MS women and to examine its possible causes, 2) there is a higher proportion of CD and 3) the frequency of breast-feeding is reduced in MS women. Methods: Female MS patients aged >43 years attending eight MS Centers in Emilia-Romagna, Italy, and control subjects (CS) aged >45 years enrolled at the Breast Cancer Screening Center of Modena, were asked to fill-out a self-administered anonymous questionnaire exploring pregnancy issues. Results: We enrolled 303 patients and 500 CS; 67 MS women (22%) were childless, compared to 66 controls (13%) (p=0.001). The lack of a stable relationship was more frequent in the MS cohort (55; 17% vs 59; 11%) (p=0.01), though after correction for relationship status, nationality and thyroid dysfunction, MS diagnosis still determined two-fold higher odds of childlessness (OR:1.7 [1.2-2.6], p=0.008). We found similar rates of miscarriage in MS (57; 24%) compared to CS (99; 24%) but a higher rate of elective abortions (EA) (47; 20% vs 49; 12%) (p=0.004). There were no differences in the proportion of pregnancies achieved by assisted reproductive technology (4; 2% vs 4: 1%). The main reported reasons for childlessness were similar in MS patients and CS: “no stable relationship” (35% vs 23%), followed by “no desire to have children (29% vs 36%) and reported infertility (17% vs 22%). CDs were not significantly more frequent in MS (56; 26% vs 89; 21%). There were no differences in the percentage of women who did not breast-feed (55; 27% vs 82; 19%). Conclusion: MS is associated with higher frequencies of childlessness and elective abortions while it does not affect the frequency of CDs and breast-feeding. Our results indicate that childlessness in MS may in part be due to the lack of a stable relationship and to higher rates of elective abortion rather than to infertility issues. Disclosure Ferraro D reports no conflicts of interest. Adani G reports no conflicts of interest. Vitetta F reports no conflicts of interest. Simone AM reports no conflicts of interest. Mauri C reports no conflicts of interest. Strumia S reports no conflicts of interest. Senesi C reports no conflicts of interest. Curti E reports no conflicts of interest. Baldi E reports no conflicts of interest. Santangelo M reports no conflicts of interest. Montepietra S reports no conflicts of interest. Immovilli P reports no conflicts of interest. Guareschi A reports no conflicts of interest. Neri W reports no conflicts of interest. Granella F reports no conflicts of interest. Caniatti ML reports no conflicts of interest. Tola MR reports no conflicts of interest. Motti L reports no conflicts of interest.


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Poster Session I, 21(S11) Pesci I reports no conflicts of interest. Montanari E reports no conflicts of interest. Sola P reports no conflicts of interest. P297 Post-partum MRI activity in patients with multiple sclerosis M. Houtchens, T.B. Kaplan, B. Healy, R. Bakshi, R.M. Bove, T. Chitnis Neurology, Harvard Medical School, Brigham and Women’s Hospital, Brookline, MA, United States Background: Studies have indicated that while relapses in multiple sclerosis (MS) patients are reduced in pregnancy, clinical disease activity increases in the first 3-6 months after delivery. Recent work showed clinical worsening and increased MRI activity in MS patients following failed assisted reproductive treatments. However, there is no consistent large sample data on the status of MRI-defined disease activity in the postpartum period. Goals: Our objective was to examine effects of pregnancy on brain and spinal cord MRI findings and to correlate clinical and neuroimaging features of post-partum breakthrough disease in patients with MS. Methods: We reviewed 257 pregnancies at our center in patients with established MS diagnosis. We identified 125 patients with two MRI scans: the baseline within 6 months pre-conception and the follow-up in the 6 months post-delivery. Eleven (9.6%) patients had a clinically isolated syndrome, 111 (88%) had relapsing remitting and 3 (2.4%) had secondary progressive MS. Brain and spinal MRI was obtained with gadolinium (Gd). Disease duration was [mean (SD)]: 7.75 (5.33) years. Expanded Disability Status Scale at baseline was [median (range)]: 1 (0, 6.5). Follow-up MRI was compared to baseline for any new T2 or Gd+ lesions as a marker of disease activity. Results: Forty-five percent of patients had a clinical relapse within 6 months postpartum (95% CI: 0.36, 0.54). The proportion with MRI-defined disease activity in the post-partum period was 54% (95% CI: 0.44, 0.63). This was comprised by 64% of patients (95% CI: 0.51, 0.76) with Gd+ lesions and 82% (95% CI: 0.71, 0.90) with new T2 lesions. When the association between a relapse and any MRI change was assessed, 74.5% of subjects with a relapse had MRI activity compared to only 35.3% of subjects without a relapse (p< 0.001). Collectively, 52% of patients had either a relapse or a Gd+ lesion postpartum and 24% had both a relapse and a Gd+ lesion. Conclusions: These results show a high level of disease activity, on both clinical and neuroimaging measures, in postpartum patients with MS. We also found a significant correlation between clinical and MRI evidence of disease activity. Such findings are in line with previous reports of the immune and inflammatory effects of pregnancy. Further analysis will be performed to ascertain any association between post-partum MRI changes and longer term disease outcomes in this cohort. Disclosure Funding for this project via an unrestricted research grant was provided by Genzyme, a Sanofi company. Dr. Maria Houtchens has served as a consultant and received research grant support from Teva Neuroscience, Biogen Idec, Genzyme, and Novartis.

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Dr. Brian Healy has received research grant support from Merck Serono, Novartis and Genzyme. Dr. Tamara Bochow Kaplan has nothing to disclose. Dr. Rohit Bakshi has served as a consultant and received research grant support from Biogen Idec, Genzyme, and Novartis. Dr. Riley Bove has nothing to disclose. Dr. Tanuja Chitnis has received research grant support from Merck Serono, Biogen Idec, Genzyme, and Novartis. P298 Gender identity disorders and multiple sclerosis risk: a national record-linkage study J. Pakpoor1, C.J. Wotton1, R. Goldacre1, K. Schmierer2, G. Giovannoni3, M.J. Goldacre1 1University of Oxford, Oxford, 2Blizard Institute, Queen Mary University of London, Barts and the London School of Medicine and Dentistry, 3Blizard Institute, Blizard Institute, Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London, United Kingdom Background: The demographic profile of multiple sclerosis (MS) implicates gender as an important factor influencing disease risk and clinical course. Sex hormones may be important in mediating gender differences in MS, but their influence on MS risk remains largely uncharacterised. We hypothesize that an altered balance of sex hormones in males with gender identity disorders (GID) will inherently, and secondary to treatment in undergoing male-tofemale conversion (which typically involves taking feminizing hormones, anti-androgens and/or sex reassignment surgery), increase MS risk. Objective: To investigate a potential association between GID and subsequent MS risk. Methods: We analysed linked English Hospital Episode Statistics from 1999-2011. A cohort of males with GID and a cohort of females with GID were constructed by identifying the first episode of day-case care or hospital admission in which a GID or sexual transformation procedure was coded (using the International Classification of Diseases and the Office of Population Censuses and Surveys Classification of Interventions and Procedures). A reference cohort was similarly constructed from individuals admitted for various other minor conditions. We searched for subsequent day-case care or inpatient admission for, or death from, MS in these cohorts. We calculated rates for MS, stratified and then standardized by age, calendar year of first recorded admission, region of residence, and socio-economic status. Results: There were 1157 males and 2390 females in the GID cohorts, and 4.6 million males and 3.4 million females in the respective reference cohorts. The adjusted rate ratio (RR) of MS following GID in males was 6.63 (95% confidence interval (95%CI) 1.81-17.01, p=0.0002), based on 4 observed cases and 0.6 expected. The adjusted RR of MS following GID in females was 1.44 (95%CI (0.47-3.37), p=0.58), based on 5 observed cases and 3.5 expected. Conclusions: We report a strong positive association (a near seven-fold elevation of rates) between GID and subsequent MS in males. A strength of this study is the use of a huge dataset to study an otherwise extremely difficult logistical undertaking. Our findings support a previously reported association between testicular hypofunction and MS risk, and a potential role for low


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testosterone as a MS risk factor in males. We highlight a need for further exploration of the influence of feminizing sex hormones on MS risk. Disclosure This study received no specific funding. The building of the linked datasets was funded by the English National Institute for Health Research. Julia Pakpoor: nothing to disclose Clare J Wotton: nothing to disclose Raph Goldacre: nothing to disclose Michael Goldacre: nothing to disclose Klaus Schmierer has received speaking honoraria from, and/or served on advisory boards for Novartis, Biogen, Teva, MerckSerono and Merck Inc, and has received support for travelling to the AAN 2014 from Genzyme. KS has been supported by a HEFCE Clinical Senior Lectureship. Gavin Giovannoni serves on scientific advisory boards for Merck Serono and Biogen Idec and Vertex Pharmaceuticals; served on the editorial board of Multiple Sclerosis; has received speaker honoraria from Bayer Schering Pharma, Merck Serono, Biogen Idec, Pfizer Inc, Teva Pharmaceutical Industries Ltd,, Vertex Pharmaceuticals, Genzyme Corporation, Ironwood, and Novartis; has served as a consultant for Bayer Schering Pharma, Biogen Idec, GlaxoSmithKline, Merck Serono, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd., UCB, Vertex Pharmaceuticals, GW Pharma, Novartis, and FivePrime; serves on the speakers bureau for Merck Serono; and has received research support from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, UCB, Merz Pharmaceuticals, LLC, Teva Pharmaceutical Industries Ltd, GW Pharma, and Ironwood. P299 Differential effects of sex steroid hormones on the chronic and acute phases of experimental autoimmune encephalomyelitis M.G. Massa, C. David, J. Berg, Y. Mahmoudjanlou, R. Gold, A. Haghikia Neurology, Ruhr University Bochum, Bochum, Germany The relationship between sex and multiple sclerosis (MS) has long been of interest. Though MS is traditionally viewed as a primarily autoinflammatory, demyelinating affliction of the central nervous system, recent research has demonstrated that neurodegenerative processes occur throughout disease course and contribute to patients’ steady neurological decline. Indeed, like many autoimmune diseases, women incur an increased risk of development, particularly with regards to the relapsing-remitting disease course. However, this disparity reaches beyond mere incidence, with severity, disability, and even responsiveness to existing treatments being correlated with patient sex. This, coupled with recent studies demonstrating varying actions of hormonal treatments depending on timing to and type of stressor, gives reason to suggest that sex steroid hormones may differentially affect the inflammatory and neurodegenerative processes in MS. In an effort to dissociate the effects of sex steroid hormones on these processes, our study investigated the consequences of elevated androgens and estrogens during the various phases of EAE. Female mice

aged 8-10 weeks were induced with an active myelin oligodendrocyte glycoprotein (MOG)-induced EAE. Mice were treated daily with testosterone (T) alone (considered the estrogenic group due to in vivo conversion of T to estradiol by aromatase) or T with the aromatase inhibitor fadrozole (FAD; androgenic group) at day of immunization (acute, inflammatory phase) or at day of first symptom onset (chronic, neurodegenerative phase). While androgens demonstrated a protective effect during the inflammatory stage, elevated estrogen levels conferred greater disease amelioration within the chronic phase, thus providing evidence within an animal model of the sex disparities seen in increased female incidence and male disability, respectively. These results contribute to a model which may partially account for sex differences found in MS disease incidence and subsequent disease course in the human population. Disclosure Megan G. Massa: Nothing to disclose Christina David: Nothing to disclose Johannes Berg: Nothing to disclose Ralf Gold: Nothing to disclose Aiden Haghikia: Nothing to disclose P300 “Injectables” during pregnancy in women with multiple sclerosis S. Herbstritt, R. Gold, K. Hellwig Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany Background: Most studies investigated the effect of first trimester immunomodulatory drug exposure during pregnancy. Reports on interferon-beta (IFN) or glatirameracetate (GLAT) exposure during the entire pregnancy are rare, as women are generally advised to stop treatment latest with the discovery of pregnancy. Sometimes women might detect pregnancy later or be advised to continue disease modifying drugs (DMT) throughout pregnancy. For this abstract we compared the outcome and course of pregnancies exposed to IFN-beta and GLAT through the entire pregnancy with pregnancies of women with MS without DMT exposure during pregnancy. Objective: To determine if exposure to IFN-beta or GLAT during the entire pregnancy influences the outcome of pregnancies in women with MS. Methods: We included 26 pregnancies with IFN-beta exposure (n=21) and GLAT exposure (n=5) and compared the outcomes (number of: life births, malformations, spontaneous abortions, cesarean sections and birth weight) with 32 pregnancies of women with MS without DMT exposure during pregnancy. All pregnancies were collected prospectively in the nationwide German MS and Kinderwunsch Registry (DMSKW). Results: Baseline characteristics (age, disease duration, BMI, smoking, number of relapses in the 2 years prior to pregnancy) did not differ between the two groups. Pregnancy outcomes (life birth, spontaneous abortions, ectopic pregnancies or stillbirths, preterm birth or delivery with cesarean section) were not statistically different between exposed and non exposed pregnancies. Gestational week of birth and birth weight were similar and not statistically different between the two groups.


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Poster Session I, 21(S11) Women with DMT exposure throughout pregnancies had not significantly fewer relapses during pregnancy (2/3.5%) than non exposed women (5/8.6%) and postpartum. Conclusion: DMT with IFN or GLAT exposure during entire pregnancy did not impact the outcome of pregnancies in this small group of women with MS. Disclosure KH and RG got speaker honoraria and research support from Bayer Healthcare, Biogen Idec, Merck Serono, Novartis Pharma, Sanofi Aventis/Genzyme and Teva Pharma. SH has nothing to disclose.

MS symptoms P301 Managing complex MS symptoms: international challenges experienced by community-based neurologists P. Ng, S.M. Hayes, S. Murray AXDEV Group Inc, Brossard, QC, Canada Background: Community-based neurologists face different clinical practice realities than those practicing in academic settings. It is hypothesized that community-based neurologists may have unique educational needs due to differences in the availability of resources and access to the most recent developments in Multiple Sclerosis (MS). An international mixed-methods study was conducted to identify knowledge, skill and confidence issues experienced by neurologists throughout the continuum of MS care. Based on these findings, a targeted follow-up study was conducted to obtain an in-depth understanding of the challenges experienced by community-based neurologists with no affiliation with an academic institution and academic-affiliated neurologists regarding specific issues in MS treatment and management. Objectives: To compare knowledge and confidence issues experienced by community-based and academic-affiliated neurologists in the management of complex MS symptoms including relapses. Methods: This IRB-approved study utilized a quantitative survey to investigate MS treatment and management challenges experienced by actively practicing Neurologists. Quantitative data were analyzed using frequencies and cross-tabulations. Chi-square tests were used to identify differences by practice setting. Results: The study sample included 241 actively practicing neurologists from France (n=47), Germany (n=52), Italy (n=47), Spain (n=56) and the UK (n=39). The majority of the sample was composed of community-based neurologists (75%), with 11 or more years of practice (79%) and a patient caseload greater than 75 patients/year (68%). The three most challenging MS symptoms to treat/manage for community-based neurologists were fatigue (34%), cognitive deficits (27%) and bowel and bladder dysfunction (13%). Almost one third (31%) of community-based neurologists reported their knowledge to define an MS relapse was not acceptable/could be improved compared to 18% of academic-affiliated neurologists reporting knowledge as not acceptable/could be improved (p=0.025). Significant differences were also seen for confidence in defining a relapse with 47% of community-based neurologists reporting low-moderate confidence compared to 23% of academic-affiliated neurologists (p=0.007). Conclusions: Findings indicate that community-based neurologists have different educational needs regarding the management

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of MS and could inform the design of local educational initiatives for this group. Disclosure This study was financially supported with education research funds from Merck KGaA, Darmstadt, Germany Pamela Ng: nothing to disclose Sean M. Hayes: nothing to disclose Suzanne Murray: nothing to disclose P302 Association between sleep disturbance and perceived cognitive dysfunction over 12 months in individuals living with multiple sclerosis A.J. Hughes1,2, A.P. Turner1,2, K.N. Alschuler1, M. Beier1,3, D. Atkins4, D. Amtmann1, D.M. Ehde1 1Rehabilitation Medicine, University of Washington, 2MS Center of Excellence West, VA Puget Sound Health Care System: Seattle Division, Seattle, WA, 3Rehabilitation Medicine, Johns Hopkins, Baltimore, MD, 4Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States Background: Cognitive dysfunction is a significant problem among individuals living with multiple sclerosis (MS). Sleep disturbance is also prevalent in MS and may contribute to cognitive dysfunction in this population. At present, however, the relationship between sleep disturbance and cognitive dysfunction in MS remains poorly understood. Objective: The purpose of this study was to evaluate the relationship between self-reported sleep disturbance and perceived cognitive dysfunction in MS at four time points over the course of 12 months, controlling for age, sex, education, disability severity, disease duration, depression, and pain. Methods: Participants were 163 individuals (ages 25 to 76) with clinically-definite MS enrolled in a single-site randomized controlled clinical trial of two telephone-delivered interventions for MS symptom management. Sleep disturbance was assessed using the Sleep Index - 9 of the Medical Outcome Study Sleep Scale. Perceived cognitive dysfunction was assessed using the Applied Cognition - General Concerns Short Form of the Quality of Life in Neurological Disorders assessment tool. Linear mixed model regression analyses examined the association between selfreported sleep disturbance and perceived cognitive dysfunction with sleep treated as a time-covarying covariate at each of four time points over a 12-month period. Results: Sleep disturbance was consistently associated with perceived cognitive dysfunction (β = -0.05, t = -3.39, p = .001), with greater levels of sleep disturbance accompanying worse perceived cognitive dysfunction at the same time point. The relationship between sleep disturbance and perceived cognitive dysfunction was significant even after accounting for relevant demographic and disease-related characteristics. Depression was a significant covariate in the final model (β = -1.21, t = -7.30, p < .001). All other covariates assessed were non-significant (all ps > .05). Conclusions: Multiple factors contribute to perceived cognitive dysfunction in MS. Nonetheless, the present study was the first to support the hypothesis that sleep disturbance may significantly contribute to or exacerbate perceived cognitive dysfunction in


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MS. Clinical interventions to improve sleep have important implications for reducing the negative impact of sleep disturbance on cognitive function and potentially improving other aspects of health-related quality of life in MS. Disclosure Funding: Contents of this abstract were developed under grants from the Department of Education National Institute on Disability and Rehabilitation Research (grant number H133B080025; PI: Ehde); and the National Multiple Sclerosis Society (grant number MB0026; PI: Turner). Conflicts of interest: Hughes: Nothing to disclose. Turner: Nothing to disclose. Alschuler: Nothing to disclose Beier: Nothing to disclose. Amtmann: Nothing to disclose. Ehde: Nothing to disclose. P303 Potentially modifiable prognostic factors for disability progression in multiple sclerosis: the symptom triad of fatigue, depression and bladder dysfunction K.V.L. Turpin1, L.J. Carroll1, J.D. Cassidy2, W.J. Hader3 1School of Public Health, University of Alberta, Edmonton, AB, Canada, 2University of Southern Denmark, Odense, Denmark, 3MS Clinic, University of Saskatchewan, Saskatoon, SK, Canada Background: Disability progression is a common and distressing consequence of multiple sclerosis (MS). We know that being male, older, and having motor symptoms at onset increase the likelihood of disability progression; however these are non-modifiable and cannot be targets for disability prevention interventions. Fatigue, depression and bladder dysfunction are modifiable and their effective management is shown to improve outcomes such as cognitive reserve and quality of life, however there is little research on their prognostic role in disability prevention. Goals: The purpose of this study is to determine if fatigue, depression and bladder dysfunction independently predict disability progression in persons with MS. Methods: This study is part of a larger study evaluating the impact of disease modifying therapies on the disability level and quality of life of persons with MS over time. Baseline fatigue was measured on a scale of 0 to 10; depression using the Beck Depression Inventory (BDI); and bladder dysfunction using a comorbidity questionnaire, which asked respondents about presence and severity of kidney/urinary/bladder dysfunction. The outcome was change in disability level from baseline to year 3, assessed using the Expanded Disability Status Scale (EDSS). Data were analysed using general linear models. Results: The majority of the respondents (N=254) were female (70.9%), with an average age of 39.3, disease duration of 9.1 years and baseline EDSS of 2.4. By year 3, almost one-third (31.2%) had a worse EDSS score, 17.8% had no change, and 51.0% had a better EDSS score. Baseline fatigue, depression and bladder dysfunction were each independently prognostic of a worse EDSS score at year 3. When examined together as a triad, fatigue, depression and bladder dysfunction were also collectively

prognostic of a worse EDSS score, adjusting for gender, age, relapse rate and disease duration at first measurement (F=2.45, p=0.02). Conclusions: These findings are particularly relevant and meaningful given all 3 of these symptoms have the potential to be modified in a positive direction. While bench scientists continue to research ways to halt, or even reverse, the neurological damage MS creates, addressing fatigue, depression and bladder dysfunction in MS patients today may result in decreased disability progression. Disclosure Karen V.L. Turpin: Nothing to disclose. Linda J. Carroll: Nothing to disclose. J. David Cassidy: Nothing to disclose. Walter J. Hader: Nothing to disclose. P304 Characterizing the phenotype of depression in multiple sclerosis: relative contribution of somatic symptoms as a moderator of depression severity H. Hasselmann1,2, J. Bellmann-Strobl2,3, R. Ricken4, T. Oberwahrenbrock2, C. Otte1, M. Adli4,5, F. Paul2, S.M. Gold1, C. Finke6,7, A.U. Brandt2 1Clinic for Psychiatry and Psychotherapy, Charité Campus Benjamin Franklin, 2NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, 3Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin-Buch, 4Clinic for Psychiatry and Psychotherapy, Charité Campus Mitte, Charité Universitätsmedizin Berlin, 5Fliedner Klinik Berlin, 6Department of Neurology, Charité Universitätsmedizin Berlin, 7Berlin School of Mind and Brain, Humboldt Universität, Berlin, Germany Background: Fatigue and depression are among the most common symptoms of multiple sclerosis (MS) and both frequently cooccur. Presentation of fatigue overlaps with somatic symptoms in depression. Thus, it has been proposed that somatic symptoms may lead to overestimation of depression prevalence in MS patients. However, the contribution of somatic symptoms to depression “phenotype” and severity in MS is unknown. Moreover, it is unclear if the relationship between fatigue and depression is unique to MS-associated depression or can be observed in depression in general. Methods: Mean relative contribution of somatic-affective and cognitive subscales to total Beck Depression Inventory II (BDI-II) as well as Fatigue Severity Scale (FSS) were evaluated in 139 MS patients. Next, we compared relative contribution of somatic items in a subgroup of 36 MS patients with depression and fatigue (F+D+) to 36 non-MS patients with idiopathic major depressive disorder (MDD) matched for age, sex, and depression severity. Lastly, we investigated differences in F+D+ patients compared to patients with fatigue but without depression (F+D-). Results: About a quarter of MS patients (27%; n=38) had BDI-II scores >19 (indicating clinical depression) and significant fatigue (FSS>4) was present in 87% (n=121). Virtually all patients with BDI scores >19 also had fatigue (95%; n=36). Relative


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Poster Session I, 21(S11) contribution of somatic-affective symptoms decreased with increasing depression severity in MS (F3,135=7.39, p< 0.01). There were no differences between depressed MS and matched MDD patients on the somatic-affective subscale. F+D+ MS patients had significantly lower mean somatic-affective contribution to total BDI-II compared to F+D- MS patients (64.8% vs. 80.4%; t70 =-5.83, p< 0.01). For every one point BDI-II increase, mean somatic-affective contribution decreased by 0.6% in F+D+ and by 1.3% in F+D- MS patients. Conclusions: Our results suggest that inclusion of somatic items on self-report measures of depression (in this case, BDI-II) does not lead to misattribution of somatic complaints as symptoms of depression. In MS-associated depression as well as idiopathic MDD, somatic complaints characterize less severe depression, while with higher scores, cognitive symptoms carry more weight. BDI-II scores above the clinical cut-off are unlikely to be driven by fatigue and should trigger appropriate diagnostics and treatment for depression. Disclosure HH, CO, SMG, CF and AUB: nothing to disclose. JBS has received speaking fees and travel grants from Bayer Healthcare, sanofi-aventis/Genzyme, and Teva Pharmaceuticals. RR has received a research grant from Aristo Pharma GmbH. TO received speaker honorary from TEVA, Germany. MA has received grants or research support from Aristo, Servier, and Bristol-Myers Squibb; honoraria for speaking from Deutsche Bank, the Johanniter Order, East German Savings Banks Association, Pusch Wahl Legal Lawyers, HRM Forum, Helios Media, Lundbeck, Bristol-Myers Squibb, Boehringer Ingelheim, Servier, Aristo, Viiv, and Gilead; travel grants from the Alfred Herrhausen Society, Lundbeck, and Servier; and has been a consultant to Deutsche Bank, Bristol-Myers Squibb, Aristo, Merz, and Lundbeck. FP has received travel grants, research support and personal compensation for activities with Alexion, Bayer, MerckSerono, Teva, Sanofi Genzyme, MedImmune, Chugai, BiogenIdec and Novartis. AUB received consulting fees unrelated to this study from Biogen, Novartis, Teva, Nexus, and Motognosis HH is supported by a NeuroCure Fellowship (Deutsche Forschungsgemeinschaft, EXC257). TO is supported by EXIST-Forschungstransfer (German Federal Ministry for Economic Affairs and Energy, 03EFEBE079) FP is supported by the Deutsche Forschungsgemeinschaft (DFG EXC257), the Bundesministerium für Bildung und Forschung (BMBF Competence Network Multiple Sclerosis) and the Guthy Jackson Charitable Foundation. SMG is supported by a Heisenberg Fellowship (German Research Foundation GO1357/5-1). AUB received funding for research from Novartis, Biogen, BMWi and BMBF. P305 Long-term stability of pain type and severity among people with multiple sclerosis S. Shahrbanian1,2, P. Duquette3, S.C. Scott4, N.E. Mayo1 1School of Physical and Occupational Therapy, McGill University, Montreal, QC, Canada, 2Physical Education and Sport Science/ Rehabilitation of Sport Injuries, Bu Ali Sina

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University, Hamedan, Islamic Republic of Iran, 3Notre-Dame Hospital (CHUM), University of Montreal, 4Division of Clinical Epidemiology, McGill University Health Centre, Montreal, QC, Canada Background: Given the impact of pain on the lives of people with multiple sclerosis (MS), the diagnosis and treatment of pain have received increasing attention over the past decade, but little is known about pain stability over time. Objective: The main purpose of this manuscript was, among individuals with MS, to estimate the extent to which pain type and severity change over time. Methods: This was a longitudinal study assessing participants’ pain type and severity at baseline and follow-up. A centre-stratified random sample comprising of 139 women and 49 men were recruited from three major MS clinics in Montreal. The McGill pain questionnaire (MPQ) and ID-Pain questionnaire (ID-Pain) were used to assess type of pain at first assessment and follow-up, respectively. The 0-10 Numeric Rating Scales (NRS) was used to assess pain severity in the sample. McNemar test and the Cohen’s un-weighted Kappa Coefficient were calculated to assess the agreement between recorded changes in pain type over time. Paired t- test was used to examine if serial ratings of NRS have been stable over time. Generalized estimating equation (GEE) was performed to test change in pain severity between the different pain type groups at first assessment and follow up. Results: Results showed that, on average, all ratings of pain severity increased; however, the group-based analysis showed that pain type was stable in the majority of study participants. Results of GEE analysis suggested that pain type was a significant predictor of lowest pain severity scores over the follow-up period, while it did not emerge as significant predictor of subsequent pain ratings of worst pain severity. Conclusion: The findings of this study have practical applications for chronic pain management programs. We have argued that because so many factors influence responses on pain measures, a single choice of pain aspect measured on a single occasion is less reliable than serial measures of different aspects of pain. Disclosure The Authors declare that there is no conflict of interest. P306 Anxiety levels are a predictor of cognitive performance in an Australian MS patient cohort K. Ribbons1, R. Lea1, P. Schofield2, S. Agland3, J.S. LechnerScott1,3 1Hunter Medical Research Institution, 2Neuropsychiatry Services, Calvary Mater Hospital, 3Neurology, John Hunter Hospital, Newcastle, NSW, Australia Introduction: In Multiple Sclerosis both neurological and psychological symptoms have the potential to impact on cognitive function. While there have been extensive reports devoted to the impact of depression in MS, anxiety levels are rarely routinely monitored in patients. Our major objective was to evaluate the prognostic value of mood indices, including depression, anxiety and stress on cognitive function in our MS clinic cohort.


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Methods: We performed a retrospective, observational study in 322 MS patients enrolled through the John Hunter Hospital MS outpatient clinic between 2008 and 2014. Cognitive function was evaluated using the Audio Recorded Cognitive Screen (ARCS). Psychological symptoms, including depression, anxiety and stress were evaluated using the short form of the Depression Anxiety Stress Scale (DASS-21). Bivariate correlations were performed using Pearson’s (r) coefficient tests. Relative contribution of each psychological symptom on cognitive ability was undertaken using linear regression modeling. Results: In our MS cohort severe or extremely severe anxiety, DASS scores > 8,were seen in 34% of patients. Cognitive function was more than 1.5 STD below age and education norm in 34% of patients. Clinical parameters, including age at disease onset and age at the time of cognitive testing, were significantly correlated with memory and attention and overall cognitive performance (P< 0.05) despite age and education adjusted scores for ARCS. In a linear regression analysis, after accounting for the effect of depression and stress symptoms and the other clinical covariates, increased anxiety scores were a significant predictor of reduced cognitive performance (Β=-0.20, P=0.01). Analysis of cognitive subdomains showed that the predictive effect of anxiety appeared to be acting specifically on memory (B=-0.22, P=0.001) and fluency (B=-0.17, P=0.03). Conclusions: In our MS cohort we have shown that anxiety is a common symptom. Anxiety level has more impact on cognitive impairment than stress and depression. It should be monitored on a regular basis and addressed early. Disclosure K Ribbons, R Lea, P Schofield declare no conflicts. S Agland has received speaker fees and travel compensation from Biogen, Merch Serono and Novartis. J Lechner-Scott has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment and also clinic support as well as research grants from Bayer Health Care, Biogen Idec, CSL, Genzyme Sanofi, Merck Serono and Novartis. P307 Impact of a maximal endurance test on perceived symptoms and walking capacity in persons with multiple sclerosis P. Van Asch1, F. Van Halewyck2, L. Vanschoenwinkel2, L. Moumdjian2, N. Velkeneers2, B. Op ‘t Eijnde2, I. Wens2, P. Feys2 1Physiotherapy Center FIT UP, Kontich, 2REVAL-BIOMED, Hasselt University, Hasselt, Belgium Background: Previous studies focusing on exercise in persons with Multiple Sclerosis (pwMS) have indicated that temporary symptoms may occur particularly during endurance training. Goals: This study aimed to evaluate how a maximal endurance test and recovery period impact on perceived symptoms and walking capacity in pwMS. Methods: Forty-two pwMS with EDSS< 3 were recruted via MS centers and community based health care professionals. PwMS reported on the perceived severity of 10 symptoms or dysfunctions (fatigue, sensory function, balance, etc.) by means of the Visual Analogue Scale (VAS) and repeatedly performed 6-Minute

Walking Tests (6MWTs) before and after the maximal endurance test. The study was performed in partnership with Move to Sport Flanders, a non-for-profit organization focusing on education and sportive challenges for patients. Results: Perceived intensity of symptoms increased significantly immediately after the maximal endurance test (p< 0,0001), but normalized already after a 15 and 60 minute recovery period. PwMS ranked general fatigue as highest (4,5 ± 2,3), followed by muscle fatigue (3,6 ± 2,3). Muscle fatigue was the symptom with the strongest increase after the maximal endurance test, followed by general fatigue. However, there was no significant difference between the distance covered during the 6MWT before (575,1 ± 63,2 m) and 15 minutes after (577,5 ± 65,6 m) the maximal endurance test. Conclusion: Perceived intensity of symptoms in persons with MS increased considerably after a maximal endurance test, but returned to baseline values after a 15 minute-recovery period. Furthermore, the maximal endurance test had no impact on walking capacity in pwMS. Acknowledgements: The study received support from Move to Sport, with kind contribution of Biogen, Teva, Genzyme and Novartis. Disclosure Feys Peter. Advisory board member or consultant for Novartis, Biogen Idec, Teva. Lore Vanschoenwinckel, Inez Wens, Florian Vanhalewyck, Lousin Moumdjian, Bert Op ´t Eijnde: nothing to disclose. Paul Van Asch is president of Move to Sport and received support from Genzyme, Biogen, Novartis and Teva. P308 Multiple sclerosis, fatigue & sleep disorders: exploration of sleep latency, REM latency and total REM in a community cohort of people with multiple sclerosis reporting fatigue M. Gudesblatt1, S. Xian1, M. Zarif1, B. Bumstead1, S. Thotam1, K. Bardhi1, K. Wissemann1, K. Blitz1, M. Buhse1,2 1South Shore Neurologic Associates, Patchogue, 2Nursing, State University of New York at Stony Brook, Stony Brook, NY, United States Objective: Explore polysomnography (PSG) documented abnormalities related to sleep latency and REM latency in people with Multiple Sclerosis (PwMS) who report fatigue. Background: Fatigue is a common and disabling symptom reported in PwMS. Fatigue likely reflects a complex problem even if reported as a simple complaint. More effective understanding of aspects contributing to the symptom might improve treatment and satisfaction. PwMS also report insomnia. Patient reported time to sleep onset can be unreliable. There is limited information about time to sleep onset by PSG in PwMS with fatigue. Sleep Latency (SL) is defined as: time in bed to time of sleep onset. Normal SL is defined as < 30 minutes. REM Latency (REM-L) is defined as: Time from Sleep Onset to REM sleep. A normal REM-L is defined as occurring between 80-110 minutes. Normal REM sleep occupies: 17-28 % of Total Sleep/night. Reduction of both total night sleep and REM sleep might impact daytime fatigue, mood, and cognition.


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Poster Session I, 21(S11) Methods: Retrospective analysis in PwMS reporting fatigue (PsMS-F) and completed PSG. Results: 206 PwMS who reported fatigue completed PSG. SL in PwMS-F < 30Minutes 102/207 (49%), SL >30Minutes 105/207 (51%), and >60Minutes 52/207(25%). Absent REM sleep in 25/206 (12%) of PwMS-F. In PwMS-F who achieved REM sleep: 115/181 (63%) REM-L>110 minutes, 63/181 (35%) REM-L>180 minutes. PwMS-F achieving REM sleep, Normal % REM in 67/180 (37%); 105/180 (58%) < 17% total REM sleep; and 50/180 (28%) < 10% REM. Conclusion: Fatigue is a common in PwMS. Sleep disorders are common in PwMS-F. Prolonged sleep latency and REM latency are common in PwMS-F. Prolonged latency to both sleep onset and REM sleep onset can result in less time available to sleep and for REM sleep. Reduced or absent REM might directly contribute to daytime symptoms in PwMS and PwMS-F. Disclosure Mark Gudesblatt - nothing to disclose Steven Xian- nothing to disclose Barbara Bumstead - nothing to disclose Myassar Zarif - nothing to disclose Smitha Thotam - nothing to disclose Lori Fafard - nothing to disclose Konstantina Bardhi- nothing to disclose Karl Wissemnann- nothing to disclose Marijean Buhse - nothing to disclose P309 Sexual functioning in multiple sclerosis C.A. Young1,2, A. Tennant3, TONiC Group 1Walton Centre NHS Trust, 2University of Liverpool, Liverpool, United Kingdom, 3Swiss Paraplegic Research, Nottwil, Switzerland Introduction: As Sexual Functioning is in the International Classification of Functioning Core Set for Multiple Sclerosis (MS), ascertainment of Sexual Functioning is required for comprehensive understanding of the lived experience of MS. Methods: TONiC is a multicentre, UK study inviting people with MS to complete a questionnaire containing many measures, including the MS Intimacy and Sexuality Questionnaire-15 (MSISQ-15). This describes three aspects of functioning designated Primary (aspects such as orgasm), Secondary (symptoms which interfere with functioning) and Tertiary (worries). Each aspect has five items scored on a four category frequency response (Never to Always), giving a 0-20 score. Results: 431 people with MS chose to answer questions on their sexual functioning, mean age 47.0 years (SD11.2) and mean duration of MS 10.8 years (SD 8.7). 71.2% were female. 68.7% had relapsing-remitting MS, 20.7% secondary progressive MS and 8.0% primary progressive MS. 42% were EDSS< 4. There was no significant difference in the likelihood of responding to the sexual functioning questions by gender (Chi-Square 0.978; p= 0.346), but older people were less likely to respond (t= 5.850; p= < 0.001), as were those with progressive MS (Chi-Square 12.0; p=0.001). The median score (IQR) for Primary aspects was 8 (3-13); Secondary 5(1-9) and Tertiary 6 (1-10). Just 9% reported no

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Primary aspects, 13.2% Secondary, and 12.9% Tertiary. Both bladder (60%) and bowel problems (38.4%) demonstrated a strong association across all aspects of sexual functioning (MannWhitney p < 0.001). Although much less prevalent, reported speech problems (25.7%) also demonstrated an association across all aspects. In all aspects, those with the progressive form had significantly greater problems with sexual functioning (Mann Whitney p < 0.001). Again, for all aspects, there was a strong association with EDSS (Kruskal Wallis p < 0.001). However, only the Primary aspect showed a strong age gradient (Kruskal Wallis p=0.0010). While Primary and Secondary aspects were similar for males and females, males reported significantly higher levels of Tertiary aspects (worries) than females (Mann Whitney p 0.015). Conclusion: Impairment of sexual functioning was found to be common and shown to be closely linked to type of MS and EDSS, as well as to symptoms such as bladder problems. Males appeared to express more worries about aspects such as their ability to satisfy their partners. Disclosure Young CA has received financial support for research and educational purposes, hospitality, fees for speaking and advisory boards, from Biogen Idec, Genzyme, Novartis, Roche, and Teva. Tennant A: nothing to disclose. The TONiC study was supported by unrestricted grant support from NIHR, MNDA, Walton Neuroscience Charity, Biogen, Novartis, Roche, Teva. P310 Exploring the association between fatigue and autonomic dysfunction in multiple sclerosis O. Tolson1, J.V. Guadagno2, M. Duddy2, J. Newton1 1Newcastle Fatigue Research Centre, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, 2Neurology, Royal Victoria Infirmary, Newcastle Upon Tyne, United Kingdom Background: Fatigue is a common debilitating symptom of multiple sclerosis (MS) but its pathophysiology is poorly understood. Recent studies in a variety of diseases have shown dysfunction of the cardiovascular autonomic nervous system correlates with fatigue severity. Aims: (i) To identify the prevalence of fatigue in MS pateints attending the Newcastle MS clinic (ii) To investigate the prevalence of orthostatic intolerance and its relationship to fatigue (iii) To investigate objective markers of cardiovascular autonomic function in fatigued secondary-progressive patients Methods: 144 consecutive patients attending the Newcastle MS Clinic (85.2% response rate) were assessed for fatigue severity, using the Fatigue Impact Scale (FIS) and Fatigue Severity Scale (FSS), and for orthostatic intolerance using the Orthostatic Grading Scale. Subsequently, eleven fatigued secondary-progressive MS patients underwent objective autonomic assessment of resting heart rate variability, blood pressure variability and baroreflex sensitivity. Results: Fatigue was identified in 71.3% (FSS) to 74.8% (FIS) of MS patients, with fatigue severity significantly higher in the secondaryprogressive subtype. Moderate orthostatic intolerance was identified


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in 54.3% of patients and correlated significantly with fatigue scores (r=0.49, p< 0.0001). Objective assessment revealed significant reductions in the low-frequency domain of heart rate and blood pressure variability in the fatigued secondary-progressive group versus controls. The most substantial reduction was seen in low-frequency systolic blood pressure variability (33.6% versus 48.9%, p=0.03), an established marker of sympathetic vasomotor function. Furthermore reductions in this parameter were significantly correlated with orthostatic symptoms (r=−0.87, p=0.0007) and fatigue severity (r=−0.66, p=0.03). Conclusion: Fatigue severity correlates significantly with increasing levels of orthostatic intolerance. Additionally, fatigued secondary-progressive patients have objective evidence of sympathetic vasomotor dysfunction. Disclosure Olie Tolson: nothing to declare Joe Guadagno: travel grants and advisory boards from Biogen, Novartis, Merck, Teva and Genzyme. No conflicts of interest with this work. Martin Duddy: travel grants and advisory boards from Biogen, Novartis, Merck, Teva and Genzyme. No conflicts of interest with this work. Julia Newton: nothing to declare.

Clinical assessment tools P311 Empirical evidence supporting the validity of the NeuroQOL Scales in a large clinical sample of persons with MS D.M. Miller1, K.F. Cook2, D.E. Victorson2, D. Cella2 1Mellen Center, Cleveland Clinic, Cleveland, OH, 2Northwestern University, Chicago, IL, United States Background: The National Institutes of Health funded development of patient reported outcome measures targeting concerns of individuals with neurologic conditions and diseases. Initial testing of included individuals living with multiple sclerosis (MS), but until recently the measures’ psychometric properties had not been evaluated in a large clinical sample of persons with MS. Methods: NeuroQOL (NQ) measures were administered using computer adaptive testing (CAT) to N=3555 individuals with MS in the course of their routine care at Cleveland Clinic. With CAT, items presented are tailored based on individuals’ responses to previous items. N=1712 completed both the Sleep (S) and the Fatigue (F) measures. N=1846 completed both the Upper Extremity (UE) and Mobility (Mob) measures. Concurrent validity was evaluated by comparing associations between NQ scores and scores measuring similar constructs. Analysis of variance (ANOVA) estimated how NQ scores discriminated subclasses of individuals with expected different levels of the measured domains. Clinically relevant ceiling/floor effects were defined as endorsing, to all times, the response category indicateing “worst health” (lowest scores on UE and MOB; highest scores on S and F). Results: Spearman correlation coefficients supported concurrent validity of NQ measures. For example, r=-712 between UE and the MSPSP hand function item; r=-.769 between Mob and EQ-5D mobility item; r=.769 between F and MSPS fatigue item; and

r=.695 between S and PHQ sleep item. Based on omnibus ANOVA results (alpha< .05), UE and Mob discriminated by (years since diagnosis and work status (WS),(working without restrictions vs. not working for medical reasons). S and F scores also discriminated among individuals based on WS, but not on years since diagnosis—scores for these symptoms were high across subgroups. Only small clinically relevant ceiling/floor effects were observed. Only 0.1% of participants answered in the highest response category for all sleep or fatigue items indicating the highest levels of problems. For UE and LE, only 0.2% and 2.6%, respectively, responded in the lowest response category for all items indicating the lowest levels of functioning. Conclusions: There is strong evidence for the validity of NQ measures for use with persons with MS. Clinically relevant floor effects for NQ-UE and NQ-Mob could be addressed by adding items that extend the item bank. Disclosure Dr. Miller received funding from the NMSS to support this research. Dr. Cook received funding from the NMSS to support this research. Dr. Victorson received funding from the NMSS to support this research. Dr. Cella has no conflict of interest to report.

P312 Easy EDSS Score: simplified EDSS rating using a smartphone application M. Cohen, C. Lebrun Hopital Pasteur - Service de Neurologie, Nice, France Introduction: Expanded Disability Status Score (EDSS) is usually considered as the gold standard for disability evaluation in multiple sclerosis (MS) patients in daily practice as well as clinical trials. EDSS rating is highly variable between raters because of subjective ratings. Moreover, several functional system scores (FSS) ratings can be considered as complex (such as visual or sensitive FSS), which can lead to rating mistakes. Objective: To present a smartphone application which is meant to simplify EDSS rating in daily practice. Results: We develop an application for iOS devices running on iOS 8 (iPhone and iPad). First, the user is invited to determine the ambulatory function which allows the determination of the EDSS if the patient is not fully ambulatory. Then, the user will be able to rate each FSS. For each FSS, the user will only be invited to precise the neurological exam findings. For example, for the sensitive FSS determination, the user will have to precise if there is an alteration of vibration sense, graphesthesia, nociception and proprioceptive tests. Severity and number of affected limbs are asked if the function is declared to be altered. Then the FSS score will be automatically determined according to Kurtzke definitions. EDSS score is automatically determined depending on each FSS and ambulatory function. Discussion: Even if EDSS remains a simple and reliable tool for assessing disability in MS, inter and intra rater variability has often been considered as a weakness.


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Poster Session I, 21(S11) In the research setting, the Neurostatus is widely used in order to reduce rating variability. The application we developed aims to simplify EDSS rating in the daily practice setting, by reducing the risk of FSS rating mistakes and EDSS step determination. Inter rater variability due to subjective rating may remain however. Easy EDSS Score is available in the AppStore. Disclosure Mikael Cohen: Nothing to disclose regarding this study Christine Lebrun: Nothing to disclose regarding this study P313 Real-life outcomes in Rebif-treated MS patients I. Rouleau1, E. Roger2, R. Langlois1, N. Nadeau2, P. Duquette2 1Psychology, UQAM, 2Neurology, CHUM Notre-Dame, Montreal, QC, Canada Introduction: The impact of Rebif on standard clinical measures (relapses, progression, and MRI parameters) is well known, but its effect on real-life outcomes such as cognition, employment retainment, and quality of life (QoL) needs better documentation. We evaluated these using patient-reported outcomes, and the MACFIMS battery in 296 Multiple Sclerosis (MS) patients from the CHUM MS Clinic. Methods: Through an online survey, 111 patients treated with Rebif (and no other DMT) for at least two years and 185 patients who had never received any MS treatment, were asked to respond to questions on employment and QoL using the MSQoL-54 questionnaire. Cognition was evaluated in a subgroup of 100 patients with MACFIMS. Results: We studied 296 patients; 239 women; 57 men. Compared to the never-treated group, the Rebif-treated had a shorter disease duration (15.2 vs 21.4 years) but a similar mean age of onset, as well as a mean EDSS score of 2 (range: 1.7-2.6). There were no differences between the two groups in the degree of work retention and on the measures of quality of life. Women and men had similar outcomes. When change had occurred in work status, it was attributed mainly to physical reasons, rather than to cognitive ones. MACFIMS was administered to 50 Rebif-treated and 50 never-treated patients, matched on age, gender, education, and disease duration. No significant difference emerged between the groups on the scores obtained on any of the tests or on the frequency of impairment observed for each test. Overall, 29% of patients were found to be cognitively impaired (Rebif: 26%, never treated: 32%) based on the standard of impairment on two or more tests, suggesting that our population was only mildly affected (hence, the mean EDSS score of 1.5 ± 1.9). Discussion: The outstanding conclusion from this study is that Rebif-treated and never-treated MS patients remain employed despite a relatively long disease duration. This could be explained by a low level of cognitive impairment, which is determinant in maintaining working capacity. In this study, Rebif had no untoward effect on the diverse outcomes examined here. As treated patients presumably have a more aggressive course than the untreated, Rebif might have been instrumental in preserving their functional status. The positive scores obtained with the extensive MACFIMS battery could mean that, although frequent in MS,

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cognitive impairment is mild and without consequence on these real-life outcomes. Disclosure This investigator-initiated study has been supported by an unrestricted grant from EMDSerono. Pierrre Duquette has served on editorial boards and has been supported to attend meetings by EMDSerono, Biogen-Idec, Novartis, Genzyme, and TEVANeuroscience. Biogen-Idec, Novartis, and Genzyme are supporting similar investigator-initiated trials. P Duquette holds grants from the CIHR and the MS Society of Canada. Elaine Roger, Nancy Nadeau, Roxane Langlois and Isabelle Rouleau have no disclosures. P314 Efficacy and safety of a three-times weekly dosing regimen of glatiramer acetate in relapsing-remitting multiple sclerosis patients: 3-year results of the glatiramer acetate lowfrequency administration (GALA) open-label extension study O. Khan1, P. Rieckmann2, S. Kolodny3, M.D. Davis4, N. Ashtamker5, J.R. Steinerman4, R. Zivadinov6 1The Sastry Foundation Advanced Imaging Laboratory & Multiple Sclerosis Center, Detroit, MI, United States, 2Bamberg Academic Hospital, Bamberg, Germany, 3Teva Pharmaceuticals, Cleveland, OH, 4Teva Pharmaceuticals, Frazer, PA, United States, 5Teva Pharmaceutical Industries, Netanya, Israel, 6State University of New York at Buffalo, University at Buffalo School of Medicine and School of Medicine and Biomedical Sciences, State University of New York (SUNY), Buffalo, NY, United States Background: The placebo-controlled (PC) phase of the Glatiramer Acetate Low-frequency Administration (GALA) study showed that glatiramer acetate 40 mg/mL three-times weekly (GA40) significantly reduced the annualized relapse rate (ARR) versus placebo at Year 1 in patients with relapsing-remitting multiple sclerosis (RRMS). Of the 1404 randomized patients, 1289 completed the PC phase and were invited to participate in an open-label (OL) extension. Objective: To evaluate the effects of early and delayed initiation of GA40 treatment over 3 years in the GALA study. Methods: The vast majority (97.2%, 1253 of 1289) of patients consented to receive GA40 in the OL extension after completing the 1-year PC phase. Early-start (ES, n=943) patients received GA40 throughout, whereas delayed-start (DS, n=461) patients switched from placebo to GA if they entered the OL phase. Clinical evaluations occurred every 6 months; a follow-up MRI was offered at Year 3. ARR was the primary endpoint; additional endpoints included gadolinium-enhancing (GdE) T1 lesions and new/enlarging T2 lesions, time to first relapse, and time to EDSS 4. Results: A total of 716 (75.9%) ES patients and 325 (70.5%) DS patients completed 3 years of follow-up, and 562 (59.6%) ES patients and 260 (56.4%) DS patients completed the Year 3 MRI. During Year 1, ES patients had a significantly lower ARR than DS patients (risk ratio [RR] = 0.652; 95% confidence interval [CI]: 0.537-0.793; P< .001); during the OL phase, both groups receiving GA40 showed comparable yearly ARRs (range: 0.20-0.22). Significantly fewer GdE T1 and new/enlarging T2 lesions were


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observed in ES patients during the PC phase; at the Year 3 MRI, ES and DS patients demonstrated similar numbers of lesions with 2 years of OL GA40 treatment. Time to first relapse was significantly longer for ES patients than for DS patients (hazard ratio = 0.746; 95% CI: 0.628-0.887; P< .001). Likewise, ES patients had a longer time to sustained EDSS 4 for 6 months than DS patients (hazard ratio = 0.559; 95% CI: 0.319-0.979; P=.042). AEs were generally mild and consistent with the well-established GA safety profile. Conclusion: In the GALA study, OL treatment with GA40 in Years 2 and 3 was associated with low disease activity, comparable to the benefits observed in the PC phase. Compared with delayed initiation, early initiation of GA40 was associated with increased time to first relapse and postponed progression to the disability milestone of EDSS 4. Disclosure Omar Khan has received compensation for consulting from Biogen Idec, Genzyme, and Novartis, and for serving on speaker bureaus from Teva, Novartis, and Biogen Idec, and has received research support from NIH, NINDS, NMSS, Teva, Biogen Idec, Genzyme, Roche, and Novartis. Peter Rieckmann has received compensation for speaking from Bayer, Biogen Idec, Boehringer Ingelheim, Novartis, MerckSerono, Teva Pharmaceutical Industries, and Genzyme and has served on steering committees for clinical trials for Novartis, Merck-Serono, and Teva Pharmaceutical Industries. Robert Zivadinov has received compensation for speaking and consulting from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Inc., Novartis, Claret, and Sanofi-Genzyme, and has received research support from Biogen Idec, Teva Pharmaceutical Industries, Claret, Sanofi-Genzyme, Novartis, and EMD Serono, Inc. Natalia Ashtamker, Mat D. Davis, Joshua R. Steinerman, and Scott Kolodny are employees of Teva Pharmaceutical Industries. P315 Characterization of baseline cognitive profiles of RRMS and SPMS patients in international multiple sclerosis clinical trials utilizing MS-COG M. Mellion1, B. Brochet2, U. Nocentini3, J. Drulović4, G.L. Mancardi5, T. Kaushik6, L. Xu1, G. Phillips1, D. Mikol1, D. Steiner1, T. Soman1, Y. Zhang1, D. Cadavid1 1Biogen, Cambridge, MA, United States, 2Hôpital Pelligrin, Bordeaux, France, 3I.R.C.C.S. Fondazione “Santa Lucia”, Rome, Italy, 4University of Belgrade, Belgrade, Serbia, 5Universita di Genova, Genova, Italy, 6PanMedix, Inc., New York, NY, United States Background: Cognitive impairment associated with Multiple Sclerosis (CIAMS) is ubiquitous and progressive throughout the disease process. CIAMS primarily affects information processing speed, and learning and memory. The MS-COG is an optimized MS-specific assessment to characterize and evaluate change in CIAMS. Goals: Utilizing the MS-COG, compare the cognitive profiles of patients with secondary progressive MS (SPMS) and relapsingremitting MS (RRMS) at enrollment in the Phase 3b ASCEND and Phase 2b SYNERGY international trials to healthy adults.

Methods: SPMS patients from a 24-month MS-COG substudy in ASCEND (natalizumab or placebo) and RRMS/SPMS patients from the 22-month SYNERGY trial (anti LINGO-1 or placebo concurrently with weekly IM interferon beta-1a) were assessed at baseline using the 7 components comprising the MS-COG: both BVMT-R and SRT for Learning and Delayed Recall, 2- and 3-second PASAT, and SDMT oral version for information processing speed. The 2 trials’ assessment results were compared to results from healthy adults from a single US site. Differences were evaluated by calculating z scores. Healthy adults were matched to MS subjects for education, age, and gender. Results: MS-COG assessments included 490 MS patients from 11 countries: 312 RRMS from SYNERGY and 178 SPMS from ASCEND and SYNERGY. The SPMS population was ~10 years older and less likely to be employed. Compared with healthy US adults, 53% of the MS population demonstrated cognitive impairment (Z scores < -0.5) on the MS-COG composite score. There was a demonstrable impairment (Z scores < -0.5) of the learning/ memory and information processing domains in both RRMS (37% and 48%, respectively) and SPMS (63% and 74%, respectively) patients compared with healthy adults. SPMS patients consistently performed worse than RRMS patients on all 7 cognitive assessments and the overall MS-COG. Conclusions: This is the largest global dataset to use MS-COG to characterize CIAMS. Both RRMS and SPMS patients demonstrated evidence of cognitive impairment, with worse impairments at the domain level in information processing speed and at the population level in SPMS. Comparison to scores from 453 healthy subjects from 9 sites in 3 countries will be presented at the meeting. This study demonstrates that MS-COG is a feasible measure of CIAMS in global studies. Future work will assess the potential impact of natalizumab (in ASCEND) and anti LINGO-1 (in SYNERGY) on CIAMS. Disclosure Michelle Mellion is a full-time employee of Biogen and holds stock in Biogen. Bruno Brochet or his institution received research grants and/or consulting fees from Biogen, Bayer, Novartis, Genzyme, Roche, Medday, Merck-Serono, and Teva. Ugo Nocentini consultant for Biogen, Sanofi Aventis, Teva Pharmaceuticals, Novartis Pharma, and Boeringher-Ingelheim; travel and research grants from Merck-Serono, Novartis Pharma, and Biogen. Jelena Drulović scientific advisory boards for Merck, Bayer, and Novartis; speaker honoraria and travel grants from Novartis, Меrck, Bayer Schering Pharma, and Medis; research grant support from the Ministry of Education and Science, Republic of Serbia (project no. 175031). Giovanni L Mancardi has received honoraria for lecturing, travel expenses for attending meetings and financial support for research from: Bayer Schering, Biogen, Genzyme, Merck Serono,Novartis, Sanofi-Aventis and TeVa Pharmaceuticals. Tanya Kaushik a full-time employee of PanMedix, Inc., a vendor for Biogen. Lei Xu is a full-time employee of Biogen and holds stock in Biogen. Glenn Phillips is a full-time employee of Biogen and holds stock in Biogen.


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Poster Session I, 21(S11) Daniel Mikol is a full-time employee of Biogen and holds stock in Biogen. Deb Steiner is a full-time employee of Biogen and holds stock in Biogen. Teesta Soman is a full-time employee of Biogen and holds stock in Biogen. Yiwei Zhang is a full-time employee of Biogen and holds stock in Biogen. Diego Cadavid is a full-time employee of Biogen and holds stock in Biogen. This study was funded by Biogen (Cambridge, MA, USA). Biogen provided funding for medical writing support in the development of this abstract. Karen Spach, PhD (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Biogen reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P316 Development of a short version of the MSQOL-54 using factor analysis and item response theory R. Rosato1, S. Testa1, A. Bertolotto2, P. Confalonieri3, F. Patti4, A. Lugaresi5, M.G. Grasso6, A. Toscano1, A. Giordano7, A. Solari7 1Department of Psychology, University of Turin, Turin, 2Clinical Neurobiology Unit, Regional Referring Multiple Sclerosis Centre (CReSM), University Hospital San Luigi Gonzaga, Orbassano, 3Unit of Neuroimmunology, Foundation IRCCS Neurological Institute C. Besta, Milan, 4MS Center, Neurology Clinic, University Hospital Policlinico Vittorio Emanuele, Catania, 5Department of Neuroscience, Imaging and Clinical Sciences, G. d’Annunzio University of Chieti-Pescara, Chieti, 6Multiple Sclerosis Unit, Foundation IRCCS S. Lucia Rehabilitation Hospital, Rome, 7Unit of Neuroepidemiology, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy Objective: To develop a shortened version of the extensively used Multiple Sclerosis Quality of Life-54 (MSQOL-54, 52 items in 12 subscales plus two single items). Methods: MSQOL-54 dimensionality and metric properties were investigated by confirmatory factor analysis (CFA) and Rasch modelling on MSQOL-54s completed by 473 MS patients. Differential item functioning (DIF) was evaluated for gender, age and Expanded Disability Status Scale (EDSS) score. The subscales of the resulting short version were assessed by exploratory factor analysis (EFA) and CFA. Cognitive debriefing of the short instrument (vs. the original) was then performed on 12 patients. Results: Mean patient age was 41 years; 65% were women; median EDSS was 2.0 (range 0-9.5). CFA of MSQOL-54 subscales showed that the data fitted the overall model well. Two subscales (role limitation physical/emotional) did not fit the Rasch model, and were removed; two other subscales (health perception, social function) did not fit the model, but were retained as single items. Sexual satisfaction (single-item subscale) was removed. The resulting MSQOL-29 has 29 items (7 subscales plus 4 single items); Rasch fit statistics were within the acceptability range for all items except one which had significant DIF by age. EFA and CFA of MSQOL-29 indicated adequate fit to the original two-factor (physical/mental composite) hypothesis. Cognitive debriefing confirmed that MSQOL-29 was acceptable and lost no key items.

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Conclusions: The proposed MSQOL-29 is 50% shorter than MSQOL-54, yet preserves key quality of life dimensions. Prospective validation on a large independent MS patient sample is ongoing. Disclosure This work was supported by the Fondazione Italiana Sclerosi Multipla (FISM) grant number 2013/R/20. The authors have nothing to declare. P317 Baseline cognitive function predicts clinical disability progression in an integrated RRMS clinical trial database K. Raghupathi1, A. Pace1, G. Giovannoni2, B. WeinstockGuttman3, X. Montalban4, R. Rudick1, R. Hyde1, C. Castrillo1, J. Xiao1, F. Pellegrini1 1Biogen, Cambridge, MA, United States, 2Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, United Kingdom, 3Jacobs Neurological Institute, Buffalo, NY, United States, 4Vall d’Hebron University Hospital, Barcelona, Spain Background: The ability to identify predictive factors for clinical disability progression in relapsing-remitting multiple sclerosis (RRMS) patients would enable better risk stratification, allowing more tailored treatment decisions, that can potentially lead to better individual outcomes. This is particularly important, given the availability of more than ten disease-modifying treatment (DMT) choices for RRMS and their associated benefits and risks. Objectives: To utilize an integrated database of Phase 3 RRMS clinical trials as a platform to investigate baseline factors that predict clinically meaningful disability progression in placebotreated patients. Methods: Individual patient level clinical trial data from four Phase 3 trials of 3 different DMTs were integrated, employing common variable and outcome definitions. Missing baseline data were imputed employing Markov Chain Monte Carlo imputation. Complementary cross-validated Cox modelling approaches, including regression trees and the Least Absolute Shrinkage and Selection Operator (LASSO) method, were utilized to investigate baseline factors prognostic of time to various composite clinical disability progression outcomes, based on the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and/or Visual Function Test (VFT), in placebo-treated patients. Findings were assessed for consistency across the statistical approaches and the various composite disability outcome definitions. Results: Based on 1582 placebo-treated patients followed up to two years, 3-Second Paced Auditory Serial Addition Test (PASAT-3) was consistently identified as a baseline predictor across clinical disability progression outcomes, including outcomes not involving PASAT3, using both statistical approaches. The physical component summary (PCS) score of the 36-Item Short-Form Health Survey (SF-36) was also consistently identified as having predictive value. Conclusions: Baseline cognitive function - which has been associated with premorbid cognitive reserve, MS-related structural brain tissue damage, and functional connectivity - as well as patient self-reported assessment of physical health status are predictive of clinical disability progression in RRMS patients. Incorporating evaluation of cognitive function and


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patient-reported assessment of physical health into routine clinical care may be beneficial in guiding assessment of individual patient prognosis and management and care decisions. Disclosure Kartik Raghupathi is a full-time employee of Biogen and holds stock in Biogen. Amy Pace is a full-time employee of Biogen and holds stock in Biogen. Gavin Giovannoni receives consulting fees for serving on scientific advisory board: AbbVie, Biogen, Canbex, Genzyme Sanofi, Ironwood, Novartis, Merck, Merck Serono, Roche, Synthon, Teva, Vertex; speaker honoraria: Abbvie, Biogen, Bayer Schering Pharma, Genzyme, Merck Serono, Teva, Sanofi; co-editor-inchief Multiple Sclerosis and Related Disorders, Elsevier; research support unrelated to study from Biogen, Merck Serono, Novartis, Genzyme, Ironwood. Bianca Weinstock-Guttman has participated in speaker´s bureaus and served as a consultant for Biogen, Teva Neuroscience, EMD Serono, Novartis, Genzyme & Sanofi, Acorda Therapeutics, Inc. and Genentech. Dr. Weinstock-Guttman also has received grant/ research support from the agencies listed in the previous sentence as well as Questcor Pharmaceuticals, Inc., and Shire. She serves in the editorial board for BMJ Neurology, Journal of International MS and CNS Drugs. Xavier Montalban receives speaking honoraria and travel expense reimbursement for participation in scientific meetings, has been a steering committee member of clinical trials, or participated in advisory boards of clinical trials in the past years with: Actelion, Almirall, Bayer, Biogen, Genzyme, Merck, Neurotec, Novartis, Octapharma, Receptos, Roche, Sanofi, Teva and Trophos. Rick Rudick is a full-time employee of Biogen and holds stock in Biogen. Robert Hyde is a full-time employee of Biogen and holds stock in Biogen. Carmen Castrillo is a full-time employee of Biogen and holds stock in Biogen. James Xiao is a full-time employee of Biogen and holds stock in Biogen. Fabio Pellegrini is a full-time employee of Biogen and holds stock in Biogen. This study was funded by Biogen (Cambridge, MA, USA).

P318 Development and validation of employment-specific assessment instruments in German MS patients P. Flachenecker1, C. Sterz1, D. Ellenberger2, H. Meissner1, K. Gusowski1, T. Friede2 1Neurological Rehabilitation Center Quellenhof, Bad Wildbad, 2Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany Background: Multiple Sclerosis (MS) has a major impact on work ability and employment status of persons with MS (PwMS). Objective: We aimed to develop and validate a set of instruments that properly assess predictive factors for employment. Methods: In the first part of the project, we included 279 PwMS (189 employed and 90 early retired) and analysed the predictive

factors associated with workplace difficulties. We identified as main symptoms mobility/walking, balance problems, depression, vision disturbances, cognitive deficits, fatigue and pain. Based upon these results, we developed a set of instruments including standardized questionnaires and objective performance tests, and amended the Multiple Sclerosis Work Difficulties Questionnaire (MSWDQ) with the subjective dimensions of mood (ADS-L), pain (BPI), vision (NEI-VFQ), mobility/balance (MSWS-12), fear of falling (FES-I), fatigue (WEIMuS), cognitive complaints (MSNQ) and quality of life (MSIS-29); objective performance tests included standardized parameters of gait and balance (2min WT, 10mWT, TGUG, Tinetti score), comprehensive neuropsychological testing, and visual testing (visual acuity and contrast). These assessment instruments were validated in a second cohort of PwMS. Results: In this part of the study, we included 102 employed PwMS (mean age 44.7 years, 64% females, median EDSS 4.0), all admitted to inpatient rehabilitation. MS patients rated employment as very important (79%); according to the future anticipation of work (MSWDQ) only 22% considered to stop working or to change their job completely (27%), whereas 42% wanted to reduce their working time. Regression analysis outlined the importance of the subscales of the MSWDQ Non-SupportiveWorkplace (NSW), Financial-Security-Concerns (FSC) and Fatigue (F) for future working status. Multivariate regression between symptoms and MSWDQ showed mobility/walking, fatigue, pain and mood as most relevant factors associated with workplace difficulties. This is in line with the findings of the first part of our project. Further analyses are ongoing and will be presented during the meeting. Conclusion: The outcomes of our study may be used to (1) adequately assess the employment-related performance status in MS patients and (2) help to administer specific rehabilitation programs tailored towards the need for MS patients in order to keep them as long as possible in the work process and ultimately increase their quality of life. Disclosure This work is funded by a research grant of the German Pension Insurance (“Deutsche Rentenversicherung Baden-Württemberg”). Peter Flachenecker has received speaker’s fees and honoraria for attending advisory boards from Almirall, Bayer Schering, Biogen Idec, Genzyme, Novartis, Merck-Serono, Roche, Sanofi Aventis and Teva. He has participated in pharmaceutical company sponsored clinical trials by Almirall, Biogen Idec and Novartis. None resulted in a conflict of interest. Christiane Sterz: nothing to disclosure. David Ellenberger: nothing to disclosure. Heike Meissner: nothing to disclosure. Klaus Gusowski: nothing to disclosure. Tim Friede has received honoraria for attending scientific advisory boards or is a consultant to Novartis, Biogen, Bayer, Grünenthal, Janssen, AstraZeneca. None resulted in a conflict of interest. P319 Long-term follow-up of laquinimod in patients with relapsing-remitting multiple sclerosis G. Comi1, T.L. Vollmer2, F.D. Lublin3, Y. Dadon4, T. Gorfine4, M.D. Davis5, P.S. Sørensen6, V. Knappertz5,7


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Poster Session I, 21(S11) 1San

Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy, 2University of Colorado, Aurora, CO, 3Mount Sinai School of Medicine, New York, NY, United States, 4Teva Pharmaceutical Industries, Netanya, Israel, 5Teva Pharmaceuticals, Frazer, PA, United States, 6Danish Multiple Sclerosis Center, Copenhagen, Denmark, 7Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany Background: In the pooled ALLEGRO and BRAVO dataset, laquinimod 0.6 mg daily (LAQ) was associated with a 21% reduction in annualized relapse rate (ARR) and a 34% reduction in 3-month confirmed disability progression (CDP). Identified risks of LAQ were back and neck pain, appendicitis, and mild asymptomatic laboratory changes that occurred soon after treatment initiation and stabilized or returned to baseline. Laboratory changes included liver enzyme elevations; increases in CRP, fibrinogen, and WBC counts; and decreases in hemoglobin and platelet counts. Objectives: To evaluate the long-term safety and efficacy of LAQ in patients with RRMS. Methods: Safety assessments were conducted with patients from the extensions of LAQ5063, ALLEGRO, and BRAVO with >2 years LAQ treatment (LAQ2YR). Efficacy evaluation was performed with patients from ALLEGRO and BRAVO using an ITT approach for patients treated with LAQ during the core studies (early start) and patients who switched from placebo to LAQ after 2 years (delayed start). Results: Safety assessments included 1893 patients with a mean ± SD exposure of 4.8 ± 1.5 years, a maximum duration of 9.7 years, and a total exposure of 5264 patient-years (PY). No differences were noted in the baseline characteristics between patients in the core studies and patients in this cohort. There was no change from the core studies in rate or type of serious adverse events (AEs) associated with increased exposure (double-blind [DB] placebo, 7.29; DB LAQ, 8.7; LAQ2YR, 6.31). Event rates were lower during long-term follow-up, and no new common AEs were identified. No increase was seen in incidence of malignancies, myocardial infarction, pericarditis, pleuritis, peritonitis, pancreatitis, thrombotic events, or infections. Shifts to >3× ULN in ALT were notably less prevalent among LAQ2YR patients (1.2% vs 4.6% for DB LAQ and 1.9% for DB placebo). No further changes in the mean values of CRP, fibrinogen, hemoglobin, WBC counts, or platelets were observed with increased exposure. Efficacy evaluation included 1990 patients (total exposure, 7094.1 PY). At Year 6, ARR remained low (early start, 0.143; delayed start, 0.189). Early-start patients tended to have longer times to 6-month CDP (HR=0.842, P=.0929) and to 12-month CDP (HR=0.773, P=.0312) than delayed-start patients. Conclusions: The safety profile and benefits of LAQ described in the core studies are maintained during long-term follow-up. Disclosure Giancarlo Comi has received compensation for consulting and/or speaking from Teva, Novartis, Genzyme, Merck Serono, Biogen, Bayer, Almirall, Serono Symposia International Foundation, EXCEMED, Chugai, and Receptos. Timothy L. Vollmer has received compensation for consulting from Xenoport, Novartis, Novartis Canada, Teva, Teva Canada, Biogen Idec, and Genentech and has received research support

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from Teva Pharmaceutical Industries, Rocky Mountain MS Center, Acorda, Biogen Idec, Genzyme, Janssen-Sargeant, Ono Pharmaceuticals, and Vaccinex. Fred D. Lublin: Sources of Funding for Research: Biogen Idec; Novartis Pharmaceuticals Corp; Teva Neuroscience, Inc.; Genzyme; Sanofi; Celgene; Transparency Life Sciences; NIH; NMSS. Consulting Agreements/Advisory Boards/DSMB: Bayer HealthCare Pharmaceuticals; Biogen Idec; EMD Serono, Inc.; Novartis; Teva Neuroscience; Actelion; Sanofi; Acorda; Questcor/ Malinckrodt; Roche, Genentech; Celgene; Genzyme, MedImmune; Osmotica; Xenoport, Receptos; Forward Pharma; BBB technologies; Akros. Co-Chief Editor: Multiple Sclerosis and Related Diseases. Current Financial Interests/Stock Ownership: Cognition Pharmaceuticals, Inc. Tali Gorfine, Yuval Dadon, Mat D. Davis are employees of Teva Pharmaceutical Industries. Volker Knappertz is an employee of Teva Pharmaceutical Industries and holds stock in Knopp Neurosciences Per S. Sørensen: Served on scientific Advisory Boards for Biogen Idec, Merck Serono, Novartis, Genzyme, Teva Pharmaceutical Industries, and GlaxoSmithKline; on Steering Committees or independent data monitoring boards in clinical trials sponsored by Merck Serono, Teva Pharmaceutical Industries, and GlaxoSmithKline; and received speaker honoraria from Biogen Idec, Merck Serono, Teva Pharmaceutical Industries, Genzyme, and Novartis P320 Multiple sclerosis and EDSS: a walking scale with no legs M. Gudesblatt1, K. Wissemann1, P. Marcote1, M. Zarif1, B. Bumstead1, C. Burke1,2, S. Thotam1, M. Buhse1,3, J. Sosnoff4, L. Muratori2 1South Shore Neurologic Associates, Patchogue, 2Physical Therapy, State University of Stony Brook, 3Nursing, State University of New York at Stony Brook, Stony Brook, 4Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana-Champaign, NY, United States Background: EDSS classifies MS burden and progression most heavily by ambulation. Walking speed correlates with Quality of Life (QoL) and independence. Objective measures to quantify mean normalized velocity (MNV) are sensitive to change. Clinically significant disease progression is measured by a sustained EDSS change. A 20% change in walking velocity also a clinically meaningful change and can occur independently from EDSS. A discordant threshold for significant change suggest the EDSS has insufficient sensitivity to detect important disease change and inadequately quantifies subtle significant disease change at potentially critical time points. Purpose: Quantify PWS-MNV in PwMS, identify variability of gait velocity within EDSS, and investigate if >20% variability occurs in gait velocity between PwMS within EDSS groups. Methods: Cross sectional retrospective analysis of PwMS who underwent computerized gait analysis in the course of routine MS care, EDSS < 6.5. Results: 254 PwMS, 72% female, age range 46+/-10 years. EDSS scores were grouped: 0-2.5, 3-4.5, 5-6.5. Average MNV for each EDSS group was 1.35 (0.32SD), 0.99 (0.34SD), and 0.52 (0.28SD)


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leg lengths/second. The % variability within each EDSS group was 23.96%, 33.97%, and 53.14%, respectively. MNV scores for these EDSS groups overlapped by 29%, 25% respectively, and overlapped all groups (5%). Conclusion: PwMS demonstrated significant MNV variability even within an EDSS group. Variability was consistently >20% and suggests that community mobility and QoL varies within the EDSS. Computerized gait analysis provides independent objective measures of MNV in PwMS. Although EDSS is primarily a scale that is impacted by walking ability, within each EDSS group significant MNV variability reflects both the heterogeneous disease impact of MS and the ability of the EDSS and/or MNV to vary independently of the other. Better objective metrics than the EDSS are needed to accurately measure disease burden, to gauge disease impact, disease progression and ultimately therapy impact. Disclosure Mark Gudesblatt - nothing to disclose Karl Wissemann -nothing to disclose Peter Marcote -nothing to disclose Myassar Zarif -nothing to disclose Barbara Bumstead -nothing to disclose Christina Burke -nothing to disclose Lori Fafard - nothing to disclose Smitha M. Thotam -nothing to disclose Jacob Sosnoff -nothing to disclose Marijean Buhse -nothing to disclose Lisa Muratori -nothing to disclose P321 Multiple sclerosis: computerized objective gait analysis of the impact of a 6-Minute timed walk on selected gait characteristics in people with multiple sclerosis - putting long legs on the walking scale C. Burke1,2, M. Gudesblatt1, M. Zarif1, K. Wissemann1, B. Bumstead1, L. Fafard1, S. Thotam1, M. Buhse1,3, J. Magel4, L. Muratori2 1South Shore Neurologic Associates, Patchogue, 2Physical Therapy, State Univeristy of Stony Brook, 3Nursing, State University of New York at Stony Brook, Stony Brook, 4Physical Therapy, Touro College, Bay Shore, NY, United States Background: Multiple Sclerosis (MS) can cause impairment of ambulation. Analysis of disease impact typically includes evaluation by EDSS and 25 foot timed walk (T25W) which do not capture walking changes with exertion or prolonged ambulation. Patient reported outcomes (PRO) provide information about disease impact or change which may not correlate with EDSS or MRI. Identifying objective metrics that evaluate PRO are required to understand this discrepancy and accurately assess disease impact/progression. Objective analytics might effectively determine treatment needs. Objective: Investigate effects of a six minute walk (6MWT) on gait characteristics in PwMS and contrast a healthy control population. Methods: 24 PwMS (EDSS 0-6) and 24 age, gender, height and weight matched normal. Velocity, stride length and double support time were measured with an instrumented mat (GAITRite).

Two trials (test-retest) at a self-selected walking speed (preferred walking speed, PWS) were performed and averaged. Modified 6MWT was utilized to simulate motor fatigue with gait parameters measured prior to and following 6 minutes walking. Within and between group gait characteristic changes following the 6MWT were analyzed with dependent and independent t-tests, respectively. Results: The GAITRite system demonstrated test-retest reliability and reproducibility for Velocity (r=.955; r2=.912; t=2.131), Stride length (r=.966; r2=.933; t=1.457), Double support time (r=.961; r2=.924; t=1.186).　 Following 6MWT PwMS demonstrated decreased gait velocity and stride length (both P< .01) and increased double support time (P< .01).　 Comparison of pre-toposttest change scores demonstrated decreased velocity and stride length in PwMS (P< 0.01 for each) compared to controls, with PwMS slowing 14% more than their healthy peers.ost-test gait analysis. Conclusion: PwMS demonstrate greater impairment in gait velocity and stride length following 6MWT than controls. This impact is not captured in EDSS or T25W. Objective gait analysis of PWS in PwMS may capture disease impact beyond the EDSS or T25W when evaluating efficacy of therapeutic interventions. Disclosure Christina Burke - nothing to disclose Mark Gudesblatt - nothing to disclose Karl Wissemann - nothing to disclose Myassar Zarif - nothing to disclose Barbara Bumstead - nothing to disclose Lori Fafard - nothing to disclose Smitha M. Thotam - nothing to disclose John R. Magel - nothing to disclose Marijean Buhse - nothing to disclose Lisa Muratori - nothing to disclose P322 Tablet-based waiting room cognitive screening in a multiple sclerosis clinic H.N. Beadnall1,2, C. Wang1,3, R.H. Benedict4, C. Dawes5, M.H. Barnett1,2,3 1Brain and Mind Research Institute, University of Sydney, Camperdown, 2Neurology Department, Royal Prince Alfred Hospital, 3Sydney Neuroimaging Analysis Centre, Sydney, NSW, Australia, 4Buffalo General Hospital, State University of New York at Buffalo, Buffalo, NY, United States, 5Macquarie University, Sydney, NSW, Australia Background: Cognitive impairment (CI) is common in multiple sclerosis (MS), but often overlooked in routine practice. The selfadministered MS Neuropsychological Screening Questionnaire Patient Form (MSNQ-P) is designed to identify MS patients at risk of neuropsychological impairment. MSNQ-P scores >23 indicate high risk for CI or depression. The Health Status Questionnaire (SF-36) is a self-administered, widely used health status measure that covers a broad range of quality of life (QOL) domains. Objectives: To determine the utility of an electronic tablet-based version of the MSNQ-P in identifying patients with cognitive and depressive symptoms in routine clinical practice.


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Poster Session I, 21(S11) Methods: In a dedicated MS clinic, prior to their appointment, tablet-based versions of the MSNQ-P and SF-36 were completed on 94 occasions by patients in the waiting room. Total MSNQ-P scores, multiple SF-36 scale scores and time to complete the questionnaires, were automatically calculated and displayed in an Excel spreadsheet using the TaDiMuS® (Tablet-based Data collection in MS) system. Information regarding current and previous cognitive and depressive symptoms was manually extracted from the patients’ electronic medical record (eMR). This data was analysed using SPSS Statistics. Results: Mean (minimum-maximum) time to complete the MSNQ-P and SF-36, was 139.7 (41-406) and 344.3 (115-855) seconds respectively. MSNQ-P scores >23 occurred in 33 cases (35.1%); one third (11/33) had no eMR-documented history of cognitive or depressive symptoms. Statistically significant (p< 0.001) negative correlations were observed between MSNQ-P scores and all SF-36 scale scores using the Pearson correlation. Correlations were strongest with the Role-Physical (r=-0.592), Social Functioning (r=-0.543) and Mental Health (r=-0.537) subscales. Conclusions: Screening with a tablet-based version of the MSNQ-P using the TaDiMuS® system efficiently identified patients with MS at high risk for CI or depression, a proportion of whom had no relevant documented clinical history. Patients with higher MSNQ-P scores reported worse mental and physical QOL (SF-36). Incorporation of electronic questionnaires such as the MSNQ-P into the routine care of patients with MS accelerates the detection of cognitive and mood disturbance and facilitates early intervention. Research is ongoing to determine how well patientreported outcomes relate to formal neuro-performance scales. Disclosure Heidi N Beadnall - Nothing to disclose Chenyu Wang - Nothing to disclose Ralph H B Benedict - Nothing to disclose Caitlin Dawes - Nothing to disclose Michael H Barnett - Nothing to disclose P323 The WHOQOL-Bref in MS: impact and satisfaction? I. Pomeroy1,2, A. Tennant3, C.A. Young1,2, TONiC 1The Walton Centre, 2University of Liverpool, Liverpool, United Kingdom, 3Swiss Paraplegic Research, Nottwil, Switzerland Introduction: The WHOQOL-BREF provides a generic crosscultural measure of quality of life (QOL) across four separate health domains; physical health, psychological, social relationships and environment. However, it has two distinct response sets relating to impact and satisfaction. This study investigated the validity of a two-domain profile of impact and satisfaction by testing fit against the Rasch model. Methods: 722 people with MS were recruited into the longitudinal TONiC study by the end of 2014. Each had completed a questionnaire booklet with a range of patient reported outcome measures (PROMS), including the WHOQoL-Bref and Leeds MSQoL. Mean age was 48.9 years (SD11.6) and mean duration was 11.5 years (SD9.1). 71.9% were female. 60.6% had relapsingremitting MS; 23.3% secondary progressive MS; 5.8% rapidly

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evolving relapsing-remitting MS and 10.3% primary progressive MS. Just over a third (37.6%) had an EDSS < 4 at baseline of this study. Data were assessed for fit to the Rasch model using RUMM2030 software. Results: The original 24 item scale was found to be reliable (psi =0.93), but showed significant misfit to the Rasch model (p< 0.0001) and showed evidence of multidimensionality (t-test=16.2%). Splitting the scale into two domains, impact and satisfaction, showed some evidence of inter-item dependence within domains. Combining items into testlets within each domain resulted in satisfactory fit to the Rasch model in both cases (Impact Chi-Square 0.987; PSI=0.89; 7, t-test=3.5%: Satisfaction Chi-Square 0.761; PSI 0.68l t-test 1.95% ). One satisfaction testlet required to be split for Differential Item Functioning by EDSS. Latent estimates of impact and satisfaction were correlated at 0.712 and correlations with the MSQoL were .737and .725 respectively. Conclusions: The WHOQOL-Bref in MS may resolve to a 2-domain score for impact and satisfaction. Sufficiently distinct, they open up the possibility of examining the relationship between the two domains, and how they contribute together to influence QoL as defined by a disease-specific scale. Disclosure Pomeroy I, Tennant A and Young CA - nothing to disclose The Trajectories of Outcomes in Neurological Conditions (TONiC) study was supported by unrestricted grant support from NIHR, MNDA, Walton Neuroscience Charity, Biogen, Novartis, Roche, Teva. P324 Multiple sclerosis performance test: longitudinal validation in fingolimod-treated MS patients and healthy controls S. Rao1, B. Mamone1, L. Mourany1, C. Reece1, G. Losinski1, D. Kemeny1, F. Bethoux1, D. Miller1, D. Schindler1, N. Agashivala2, R. Hashmonay2, J. Alberts1 1Cleveland Clinic, Cleveland, OH, 2Novartis, East Hanover, NJ, United States Background: The Multiple Sclerosis Performance Test (MSPT) is an iPad®-based computerized system for conducting quantitative assessments of walking speed, upper extremity coordination, and information processing speed. Validation studies of the MSPT have demonstrated high test-retest reliability, convergent validity with comparable non-computerized tests, and sensitivity to MS in comparison to healthy controls (HC). We extend these validation studies by conducting a longitudinal study with the MSPT. Goals: Conduct MSPT longitudinal validation by prospectively studying MS patients during the initial 6 months of treatment with fingolimod and comparing performance with HCs examined at the same time intervals. This study focused on sensitivity to MS-related longitudinal changes and practice effects. Methods: Participants included 25 relapsing remitting MS patients starting fingolimod (18 females; mean age = 43.4; mean education = 14.4 years) and 25 healthy controls (HC; 20 females; mean age = 44.6; mean education = 14.4 years). Disease duration was 6.2 years and mean EDSS was 2.9. MS and HC participants were examined on three occasions: 0 (baseline), 3, and 6 months. A 2 (MS vs. HC) x 3 (time points) repeated measures ANOVA was


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performed on the MSPT subtests: Processing Speed Test (PST), Manual Dexterity Test (MDT; row and dish versions), and Walking Speed Test (WST). Results: Significant group main effects were observed for PST (p< 0.05) and WST (p=0.002), but not for row or dish versions of the MDT. Significant time effects were observed for PST (p=0.003) and row and dish MDT (p< 0.0001), but not for WST. Significant interaction effects were observed for row (dominant and non-dominant hands, p< 0.05), but not for the dish, version of MDT, with MS patients’ performance remaining stable over time, while HC’s improved. PST and WST did not demonstrate significant interaction effects. Conclusions: Patients had a relatively short disease duration and low physical disability. The MSPT was sensitive to processing speed and walking dysfunction. No differences observed between MS and HC on MDT (no group differences also on 9-Hole Peg Test). Practice effects observed on PST and MDT, but not WST. MS patients, tested during initial treatment with fingolimod, maintained stable levels of performance on MSPT subtests over the 6 month study duration. MSPT is a valid tool for tracking neurological function in MS patients. Study supported by: Novartis. Disclosure Dr. Rao has received honoraria, royalties or consulting fees from: Biogen, Genzyme, Novartis, American Psychological Association, International Neuropsychological Society and research funding from the National Institutes of Health, US Department of Defense, National Multiple Sclerosis Society, CHDI Foundation, Biogen, and Novartis. Dr. Alberts has received royalties or consulting fees from Biogen and Boston Scientific and research funding from the National Institutes of Health and Biogen. Dr. Miller has received royalties from Biogen and research funding from the National Multiple Sclerosis Society, Biogen and Novartis. Dr. Bethoux has received royalties, honoraria or consulting fees from: Biogen, Medtronic, Allergan, Merz, Acorda Therapeutics, and Innovative Neurotronics, and research funding from the National Multiple Sclerosis Society, Biogen, Acorda Therapeutics, Medtronic, Merz, and Innovative Neurotronics. Ms. Agashivala and Dr. Hashmonay are employees of Novartis Novartis Pharmaceuticals Corporation . D. Schindler has received royalties from Biogen. L. Mourany, B. Mamone, C. Reece, G. Losinski, D. Kemeny nothing to declare. P325 Clinically meaningful change of walking assessments in patients with multiple sclerosis treated with PR-fampridine N. Sola-Valls, Y. Blanco, M. Sepúlveda, S. Llufriu, E.H. Martinez-Lapiscina, I. Zubizarreta, D. La Puma, F. Graus, P. Villoslada, A. Saiz Neurology Department, Hospital Clinic and Institut d’Investigació August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain Background: The definition of clinically meaningful change to evaluate the response associated with prolonged-release (PR) fampridine is controversial.

Objective: To assess the effect of PR-fampridine in patients with multiple sclerosis (MS) using different walking tests measures. Methods: Clinical assessments, performed at baseline and 2 weeks after treatment with PR-fampridine, included: the International Physical Activity Questionnaire (IPAQ), 12-item MS walking scale (MSWS-12), quality of life (EQ-5D-5L), timed 25-foot walk (T25FW), 6-minute walk test (6MWT) and average daily walking activity (aDWA) by a triaxial accelerometer. An improvement in T25FW > 20% and/or MSWS-12 score > 6 points were used to define clinical response. Patients were grouped according to the clinical response: to two tests (T25FW and MSWS-12), one test (T25FW or MSWS-12) or no response. Results: We included 22 patients with a mean age of 51.7 years and disease duration of 15.8 years; median Expanded Disability Status Scale score was 5.8, and mean T25FW 14.6 seconds. Three patients had adverse events (imbalance, n=3, nausea, n=1) but only one discontinued PR-fampridine. After 2 weeks, 13 (61.9%) patients showed response to two tests, 6 (28.6%) to one test, and 2 (9.5%) no response. Patients with clinical response to two tests improved the 6MWT (% of change 31.8, p< 0.001), aDWA (% of change = 19.3, p=0.04) and quality of life (EQ-5D-5L, mean difference= 0.16, p< 0.001). In contrast, patients with clinical response to one test did not show significant differences in 6MWT (% of change=16.7%, p=0.08), and aDWA (% of change = -0.7%, p=0.7), and the significance was marginal in quality of life (EQ-5D-5L, mean difference=0.25, p=0.05). Conclusion: The combination of T25FW and MSWS-12 score improve the definition of clinically meaningful response to PR-fampridine. Disclosure All the authors have nothing to disclose. P326 Test-retest reliability and concurrent validity of a Dutch version of the 8-item actionable screening questionnaire for bladder overactivity in multiple sclerosis P.J. Jongen1,2, B. Blok3, J. Heesakkers4, M. Heerings5, W. Lemmens6, R. Donders6 1MS4 Research Institute, Nijmegen, 2Department of Community & Occupational Medicine, University Medical Centre Groningen, Groningen, 3Department of Urology, Erasmus Medical Centre, Rotterdam, 4Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, 5MH Advies & Organisatiebureau, Assen, 6Department for Health Evidence, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Background: In patients with multiple sclerosis (MS) the impact of urological symptoms on quality of life and daily activities is considerable. Yet, a substantial percentage of patients is not urologically evaluated and may thus fail to be treated adequately [1]. The 8-item Actionable questionnaire is a validated English screening tool for bladder overactivity in MS with a score ranging from 0 (no symptoms or impact) to 24 (extreme symptoms or impact) [2, 3]. Goals: The assessment of test-retest reliability and concurrent validity of a Dutch version of the Actionable questionnaire.


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Poster Session I, 21(S11) Methods: In an online observational study MS patients completed a Dutch translation of the Actionable at Days 1 and 8, and the Multiple Sclerosis Quality of Life 54-Items (MSQoL54) and Multiple Sclerosis Impact Profile (MSIP) at Day 1; the Expanded Disability Status Scale (EDSS) was assessed by phone at Day 1. Pearson’s correlation coefficients (r) were calculated between Day 1 Actionable score and EDSS score, Physical and Mental MSQoL-54 composites, and MSIP domain scores (concurrent validity); and between Day 1 and Day 8 Actionable scores (testretest reliability). Results: Study population: N=141 (106 female, 35 male) (80 relapsing remitting, 48 progressive, 13 unknown), mean age 47.8 (standard deviation [SD] 10.4) years, mean EDSS score 4.7 (SD 1.8); 137 patients completed the Day 8 assessment. At Day 1 and Day 8 the mean Actionable scores were 8.000 (SD 3.994) and 7.613 (SD 4.004), resp. Pearson’s r between Actionable scores Day 1 and Day 8: 0.8477 (P< .0001). Pearson’s r between Actionable score Day 1 and EDSS 0.413 (P< 0.0001), MSQoL-54 Physical -0.308 (P=0.0002), MSQoL-54 Mental -0.292 (P=0.0005), MSIP Muscle and Movement Function 0.393 (P< .0001), Excretion and Reproductive Functions 0.437 (P< 0.0001), Mental Functions 0.196 (P=0.0189), Basic Movement Activities 0.373 (P< 0.0001), Activities of Daily Living 0.322 (P< 0.0001) and Participation in Life Situations 0.2861 (P=0.0006). Conclusions: The Dutch version of the Actionable urological screening questionnaire for MS shows a good test-retest reliability (r = 0.85) and a good concurrent validity with EDSS (r = 0.41), physical and mental MSQoL-54 (r = -0.308, r = -0.292) and MSIP domain (0.20 < r < 0.44) scores.

References: 1. Mahajan ST et al. The Journal of urology 2010, 183(4):1432–1437. 2. Burks J et al. Int J MS Care 2013, 15(4):182–192. 3. Bates D et al. BMC neurology 2013, 13:78. Disclosure The study was investigator-sponsored with financial support from Allergan Inc. PJ Jongen has received honoraria from Biogen-Idec, MerckSerono, Novartis, sanofi-aventis and Teva for contributions to symposia as a speaker and for consultancy activities. BFM Blok has nothing to disclose. JP Heesakkers has received honoraria from Astellas, AMS, Allergan and Pfizer for consultancy activities. M. Heerings has nothing to disclose. WAJG Lemmens has nothing to disclose. R Donders has nothing to disclose. P327 Video-based paired-comparison ranking: a validation tool for fine-grained measurements of motor dysfunction in multiple sclerosis J. Burggraaff1, J. Dorn2, M. D’Souza3, C.P. Kamm4, P. Tewarie5, P. Kontschieder6, C. Morrison6, A. Sellem6, A. Criminisi6, F. Dahlke2, L. Kappos3, B.M.J. Uitdehaag5 1Neurology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands, 2Novartis Pharma AG, 3University Hospital Basel, Basel, 4University Hospital Bern, Bern,

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Switzerland, 5VU University Medical Center Amsterdam, Amsterdam, The Netherlands, 6Microsoft Research, Cambridge, United Kingdom Background: Clinical trials in Multiple Sclerosis (MS) will focus increasingly on therapies that slow or reverse disability progression, which requires sensitive and reliable rating scales. Established outcome measures, such as the Expanded Disability Status Scale (EDSS), do not adequately capture subtle changes in patients’ neurological performance necessary for a sensitive evaluation of treatment response. The problem is that humans have limited ability to make absolute assessments, which constrain us to coarse-grained ordinal scales that are not applicable for validating potentially finer-grained tools to measure motor dysfunction. As it is easier and generally feasible to perform comparative assessments, we propose to compare video-captured MS patients’ movements in pairs based on clinical judgement. Objectives: To investigate whether paired comparisons of patients’ neurological performance enable a consistent and finegrained classification of disability in MS. Methods: Nineteen experienced neurologists from Basel (BSL) and Amsterdam (AMS) were individually presented with randomly paired videos (N=70) of 44 MS patients performing the finger to nose test (FNT) or drinking from a cup (CUP), as a daily living task. For each pair, the clinicians were asked to evaluate the patient’s performance as worse, indistinguishable or better than the other. These assessments were evaluated and mapped onto a continuous scalar disability scale using an algorithm based on TrueSkill™, which was originally developed for rating players in online computer gaming. Results were analysed for intra- and interrater reliability and correlated with the matching EDSS subscores. Results: The FNT comparative disability ratings of all raters were significantly correlated with the EDSS subscores [Spearmen rho (r): 0.90 (BSL) and 0.76 (AMS)] and allowed to further discriminate between MS patients within the same subscore. Short-term test-retest reliability, which characterizes intra-rater consistency, was on average 90% (BSL) and 88% (AMS). Overall, consistency between raters was high for both FNT (BSL: r=0.9; AMS: r=0.83) and CUP tests (BSL: r=0.92). Conclusions: Video-based paired comparisons of patients’ movements allow a consistent clinical evaluation of disability and lead to finer-grained clinical judgment of motor dysfunction than the EDSS. This method may serve as an improved external validation in the development of more sensitive (automated) neurological outcome measures. Disclosure J. Burggraaff received travel support from Novartis Pharma AG, J. Dorn is an employee of Novartis Pharma AG, M. D`Souza received travel support from Bayer AG, Teva and Genzyme and research support from the University of Basel, Ch.P. Kamm received honoraria for lectures and consulting from Biogen idec, Novartis, Teva, Merck-Serono, Genzyme and Bayer Schweiz AG, P. Tewarie received travel support from Novartis Pharma AG, P. Kontschieder is an employee of Microsoft Research, C. Morrison is an employee of Microsoft Research, A. Sellen is an employee of Microsoft Research, A. Criminisi is an employee of Microsoft Research, F. Dahlke is an employee of Novartis Pharma AG, Ludwig Kappos´s


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institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof Kappos´ activities as principal investigator and member or chair of planning and steering committees or advisory boards in trials sponsored by Actelion, Addex, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Biogen Idec, CLC Behring, Genentech, GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Praxicon, Roche, SanofiAventis, Santhera, Siemens and Teva; royalties from Neurostatus GmbH; research grants from the Swiss MS Society, Swiss National Research Foundation, the European Union, Gianni Rubatto Foundation, and the Novartis and Roche Research foundations, Bernard M.J. Uitdehaag has received personal compensation for consulting from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche en TEVA. The Multiple Sclerosis Centre Amsterdam has received financial support for research activities from Biogen Idec, Merck Serono, Novartis, and Teva Pharmaceuticals.

Economic burden P328 Validation of the German version of the multiple sclerosis work difficulties questionnaire (MSWDQ) D. Ellenberger1, T. Friede1, C. Sterz2, P. Flachenecker2 1University Medical Center, Georg-August Universität Göttingen, Goettingen, 2Neurological Rehabilitation Centre Quellenhof, Bad Wildbad, Germany Background: Multiple sclerosis (MS) has a major impact on work ability. The Multiple Sclerosis Work Difficulties questionnaire (MSWDQ) is a validated, self-assessment instrument designed to understand the difficulties MS patients experience at their working place which measures the burden of work from therapeutic as well as from economic perspective[1]. Objective: We aimed to develop and validate a German version of the MSWDQ. Methods: After forward-back translation the German version of the MSWDQ was administered to 279 MS patients [189 employed (EM group); 90 early retired (ER group)] at the Neurological Rehabilitation Centre Quellenhof. The twelve subscales of MSWDQ were explored by confirmatory factor analysis and Cronbach’s alpha. Furthermore in the EM group, construct validity was assessed by Spearman’s rank correlation coefficients and nonparametric multivariate regressions of the MSWDQ with the Work Limitation Questionnaire (WLQ)[2] and the likelihood of early retirement, reducing work as well as changing work. Results: Mean MSWDQ was 30.2 (SD 15.2; median 27.8) and 29.4 (SD 18.3; median 27.4) in the EM and ER groups, respectively. Response scores ranged from 1.1 (little burden) to 80.6 (high burden). Confirmatory factor analyses proved the one-dimensionality of all twelve factors. Cronbach’s alpha of the twelve subscales ranged from 0.65 to 0.91 pointing to acceptable internal consistency. Nonparametric correlations between subscales of the WLQ and related subscales of the MSWDQ were found to be sufficiently high to indicate external validity (Spearmans rho ranging from 0.49 to 0.79). Furthermore, there was a high concordance with the likelihood of retirement, reducing work as well as changing work. Conclusion: High internal and external validity of the German version of the MSWDQ and its twelve subscales could be

demonstrated in employed and early retired MS patients. The MSWDQ offers an excellent tool to measure MS specific difficulties at the working place.

References: 1. Honan CA, Brown RF, Hine DW. The multiple sclerosis work difficulties questionnaire (MSWDQ): development of a shortened scale. Disabil Rehabil. 2014;36:635-41. 2. Lerner D, Amick BC, Rogers WH, Malspeis S, Bungay K, Cynn D. The Work Limitations Questionnaire. Med Care. 2001 Jan;39:72-85. Disclosure This work was partly supported by a research grant of the German Pension Insurance (“Deutsche Rentenversicherung Baden-Württemberg”). David Ellenberger: Nothing to disclose Tim Friede is a consultant to Novartis and Biogen Idec. This did not result in a conflict of interest. Christiane Sterz: Nothing to disclose Peter Flachenecker has received speaker’s fees and honoraria for attending advisory boards from Almirall, Bayer Schering, Biogen Idec, Genzyme, Novartis, Merck-Serono, Roche, Sanofi Aventis and Teva. He has participated in pharmaceutical company sponsored clinical trials by Almirall, Biogen Idec and Novartis. None resulted in a conflict of interest. P329 Multiple sclerosis relapse in US patients: a population-based analysis of healthcare resource use, productivity and costs in the 30 days post-event J. Lotya1, C. ONeill1, J.J. Ko2, T.A. Nazareth2, R. Sasane2 1Novartis Dublin Business Solution Centre, Global Business Services, Dublin, Ireland, 2US Health Economics & Outcomes Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States Background: Multiple Sclerosis (MS) is a chronic, disabling neurological disease characterized by intermittent exacerbations or relapses. Objectives: To evaluate the impact of relapse on healthcare resource use (HCRU) and costs in a commercially insured population in the 30-day period following an event. Methods: An analysis of Truven Health MarketScan claims database and Health and Productivity Management database (HPM) was conducted. The study identification period was 01 Jan 2006 to 31 Dec 2011. Patients aged 18-64 years were included if they had ⩾2 MS diagnoses (ICD9-CM: 340.xx) within 60 days and had continuous medical and pharmacy enrollment (gap ⩽40 days) in the year prior to, and following, the index date. Patients were divided into 2 cohorts based on their relapse status in the postindex period: (a) no relapse (NR), (b) relapse (R). The earliest date of the most severe relapse was chosen. For patients who did not relapse, a 30-day comparator period was randomly allocated. Descriptive statistics were calculated on baseline demographic and clinical characteristics. Mean all-cause HCRU (number of hospitalizations, ER visits, and physician office visits) and costs (direct and indirect) were also investigated.


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Poster Session I, 21(S11) Results: A total of 15,662 R patients and 1,921 NR patients were identified. Overall for the R patients, 74% were female, 55% were employed full-time, 75% were members of a Preferred Provider Organization, and 94% had a Charlson comorbidity score of zero. Mean [SD] physician office visits were notably higher in the R group compared to the NR group [2.04(1.33) vs. 1.62(1.05)] while ER visits and hospitalizations were similar [1.32(1.50) vs. 1.41(0.88); and 1.10(0.34) vs. 1.13(0.38), respectively]. For R and NR patients, mean [SD] costs for hospitalizations, ER visits, and physician office visits were $29,072(46,921) vs. $18,866(24,371); $393(713) vs. $339(598); and $267(445) vs. $188(289), respectively. Conclusion: Providing therapeutic interventions that can decrease the number of MS relapses may result in lower HCRU and costs. Disclosure Funding: Study sponsored by Novartis Pharmaceutical Corporation. USA. Juzer Lotya: A permanent employee of Novartis Dublin Business Solution Centre, Dublin, Ireland. Caitriona ONeill: A permanent employee of Novartis Dublin Business Solution Centre,Dublin, Ireland. John J Ko: A permanent employee of Novartis Pharmaceuticals Corporation (East Hanover NJ) with stocks Tara A Nazareth: A permanent employee of Novartis Pharmaceuticals Corporation (East Hanover NJ) with stocks Rahul Sasane: A permanent employee of Novartis Pharmaceuticals Corporation (East Hanover NJ) with stocks P330 Multiple sclerosis, cognitive function profile, & EDSS: a walking scale with cognitive problems and premature unemployment M. Gudesblatt1, D. Golan2,3, M. Zarif1, B. Bumstead1, L. Fafard1, K. Wissemann1, M. Buhse1,4, G. Doniger5 1South Shore Neurologic Associates, Patchogue, NY, United States, 2Department of Neurology, Carmel Medical Center, 3Technion Israel Institute of Technology, Haifa, Israel, 4Nursing, State University of New York at Stony Brook, Stony Brook, NY, 5NeuroTrax Corporation, Bellaire, TX, United States Background: Cognitive dysfunction, disease duration and physical disability are predictors of unemployment in people with Multiple Sclerosis (PwMS). Both EDSS and disease duration impact disability and correlate with cognitive impairment in PwMS. Further exploration is needed to determine whether cognitive dysfunction independently contributes to unemployment status. Objective: Evaluate cognitive impact on premature unemployment in PwMS. Methods: A cross-sectional, retrospective analysis of PwMS who were referred for cognitive testing in the course of routine care. Analysis included EDSS, disease duration from diagnosis (DD), employment status (patients´ self-report). Cognitive function was assessed by a standardized computerized battery (NeuroTrax) with analysis of age and education-adjusted index scores in each of 7 cognitive domains (CogD) and an average scores -Global Cognitive Score (GCS).

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Results: 295 PwMS, 75% Females, Mean age 48.8±11. Unemployed PwMS had lower scores in all CogD, had lower GCS (92.4 ± 14.5 vs. 100.1 ± 10.6, p< .001); percentage of working patients decreased with the number of CogD >1SD below average: 57% employed (0 CogD>1SD), 35% employed (2 or 3 CogD>1SD p< 0.008), and 19% employed (6 or 7 cogD >1SD p=.004). Unemployed PwMS had higher EDSS (3.2 ± 2.1 vs. 1.5 ± 1.1, p< .001). The proportion of working patients proportionally decreased with DD: 74% employed (DD< 5 years, 30% employed (DD>10 years p< .001). Unemployment odds were increased 1.8X by higher EDSS (95% CI: 1.3-2.6), 3.2X by longer disease duration (95% CI: 1.2-8.5) and 1.3 fold by cognitive impairment (95% CI: 1.01-1.6) in PwMS. Conclusion: Premature unemployment in PwMS is associated with EDSS, disease duration and cognitive impairment. EDSS is insensitive to any individual PwMS cognitive profile. Disease duration, EDSS and cognitive dysfunction independently influence premature unemployment in PwMS. Cognitive screening is an important adjunct in MS patient care to monitor cognitive factors impacting employment not identified by EDSS. Disclosure Mark Gudesblatt - nothing to disclose Daniel Golan - nothing to disclose Myassar Zarif - nothing to disclose Barbara Bumstead - nothing to disclose Lori Fafard - nothing to disclose Marijean Buhse - nothing to disclose Glen Doniger - is an employee of NeuroTrax P331 Association between time to treatment initiation of delayed-release dimethyl fumarate following MS diagnosis and medical costs in a real-world setting R. Iyer1, M. Sussman2, M. Fay3, B. Buckley3, A. Lee1, S. Sarda1, J. Rana1, J. Menzin2 1Biogen, Cambridge, 2Boston Health Economics, Waltham, 3Biogen, Weston, MA, United States Background and objective: Understanding the impact of treatment delays on patient outcomes may help to improve the quality of care among patients with multiple sclerosis (MS). The objective was to assess the relationship between MS diagnosis, timing of delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) use, MS related relapses, and medical costs. Methods: Using a large administrative US claims database, adult patients (18-64 years of age) treated with DMF on or after 4/1/2013 (index date), continuous eligibility 12 months pre- and post-index, and a baseline MS diagnosis were identified. Patients must not have received any disease-modifying therapies in the baseline period. The time from MS diagnosis to first DMF use was evaluated in tertiles, with the 1st tertile representing the fewest days from MS diagnosis to first DMF use and the 3rd tertile representing the most days. Study measures, stratified by tertiles, included MS-related relapses (defined as an MS-related hospitalization or an MS-related outpatient visit plus receipt of IV corticosteroid within 7 days of the visit) and MS-related direct medical event (non-pharmacy) costs (defined by an MS diagnosis on a claim) in the 1 year post-index.


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Results: 829 patients prescribed DMF met eligibility criteria. Mean (SD) time from baseline MS diagnosis to first DMF use was 224 (123) days. The 1st tertile had the lowest proportion of patients with an MS-related relapse, followed by patients in the 2nd and 3rd tertiles. Patients in the 1st tertile had the lowest mean (SD) annual direct medical event costs ($3,808 [$9,458]), followed by patients in the 2nd ($5,616 [$14,410]) and 3rd ($7,671 [$15,945]) tertiles, respectively. In each of the tertiles, MS-related outpatient (office, clinic, hospital outpatient) costs comprised the largest share of direct medical event costs. Conclusion: In real-world settings, the proportion of MS patients with an MS-related relapse and annual MS-related direct medical event (non-pharmacy) costs increased with greater time between MS diagnosis and DMF treatment. Further analysis of this relationship is warranted. Disclosure Ravi Iyer, Monica Fay, Brieana Buckley, Andrew Lee, Sujata Sarda, and Jitesh Rana are paid employees of Biogen, Cambridge, USA. Matthew Sussman and Joseph Menzin are employees of Boston Health Economics, Waltham, USA which was funded for the study by Biogen, Cambridge, USA. P332 Costs of illness of multiple sclerosis in Sweden - a population-based register study H. Gyllensten1, M. Wiberg1,2, P. Tinghög1, A. Norlund1, E. Friberg1, O. Ernstsson1, K. Alexanderson1 1Department of Clinical Neuroscience, Karolinska Institutet, 2Department of Analysis and Prognosis, Swedish Social Insurance Agency, Stockholm, Sweden Background: Multiple sclerosis (MS) causes both work disability and healthcare resource use, but most previous estimates of its economic impact are based on small and selective samples. Goals: We estimated the cost of illness (COI) of all MS-patients of working ages in Sweden, from a societal perspective. Moreover, we explored the distribution of costs for healthcare and sickness absence/disability pension specifically due to MS, by sex and socioeconomic factors, and years since diagnosis. Methods: We conducted a population-based cohort study of the 14,077 individuals with MS, age 20-64 years, identified in nationwide registers on healthcare use or social insurance benefits. During 2010, direct and indirect costs were estimated from resource use identified in registers, including drug use, outpatient and inpatient care, sick leave and disability pension. Costs for healthcare and sick leave/disability pension for which MS was the main diagnosis were compared by sex and socioeconomic groups, using two-tailed t-tests with unequal variances or ANOVA (statistical significance: p< 0.05). Results: The COI of all individuals with MS in Sweden were SEK 3950 million (≈EUR 414 million), of which 75% were indirect costs. In total, 38% of the healthcare costs and 67% of the indirect costs were attributed to resource use for which MS was the main diagnosis. The distribution of costs was skewed, with one fifth of MS patients contributing to half of the total COI. Healthcare costs for which MS was the main diagnosis were

higher among young adults, those born outside Sweden, living in larger cities, or living in the south of Sweden, compared to other population groups. In contrast, indirect costs for which MS was the main diagnosis were higher among those of older age, low education, born in Sweden, in small municipalities, and had had MS for more than eight years. Conclusions: Indirect costs contributed to approximately threefourths of the overall COI of MS patients in Sweden. Further studies are needed to gain knowledge on development of this over time and in relation to the development of costs in the general public and to other patient groups. Moreover, the younger individuals’ higher healthcare costs may suggest that resources are particularly allocated to MS patient early during their disease, a period when MS specific interventions also tend to be most effective. Study supported by Biogen and the Swedish Research Council for Health, Working Life and Welfare. Disclosure The research was funded by an unrestricted grant from Biogen and the Swedish Research Council for Health, Working Life and Welfare. The study sponsors had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The research was conducted independently from the sponsors. The authors declare that there are no conflicts of interest. Hanna Gyllensten: nothing to disclose. Michael Wiberg: nothing to disclose. Petter Tinghög: nothing to disclose. Anders Norlund: nothing to disclose. Emilie Friberg: nothing to disclose. Olivia Ernstsson: nothing to disclose. Kristina Alexanderson: nothing to disclose. P333 Budget impact model (BIM) in multiple sclerosis: experience of Italian centres E. Baldi1, I. Pesci2, S. Di Matteo3, G.M. Bruno3, G.L. Colombo3,4, L.M. Caniatti5, E. Montanari2, M.R. Tola5 1U.O. of Neurology - S. Anna Hospital, Cona Ferrara, 2U.O. Neurology - Civil Hospital of Fidenza, Parma, 3S.A.V.E. Studi Analisi Valutazioni Economiche, Milano, 4University of Pavia, Department of Pharmaceutical Sciences, Pavia, 5U.O of Neurology - S.Anna Hospital, Ferrara, Italy Objectives: Multiple sclerosis (MS) is an important, disabling neurological disease, affecting young adults. Some of the symptoms are: visual disturbances, balance and coordination problems, spasticity, abnormal speech, swallowing disorders, fatigue, bladder and bowel problems, cognitive and emotional disturbances and others. MS can substantially and adversely affect an individual’s quality of life (QOL) and is associated with high costs for patients, families, and society as a whole. We present the development of new software modelled on Emilia Romagna Region a Diagnostic-Therapeutic Care-Pathway (DTCP) in order to evaluate the impact of total costs related to treatment in MS. Materials and methods: A software in Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA), was developed on the


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Poster Session I, 21(S11) basis of DTCP of the Emilia Romagna Region, in order to calculate in detail direct costs (drugs, laboratory examinations, imaging and staff employed) related to the treatment of patients. A spreadsheet for each available MS therapy has been designed. The software is able to calculate the cost of treatment for each patient according to the duration of therapy and in line with the indications given in the DTCP. The Budget Impact Model (BIM) has been used by approximately 50 MS centres in Italy, to calculate the annual budget for treatment of MS patients. Results: The results of this work were presented in two National meeting. Total cost of each treatment comprehends costs of drugs, staff employment and monitoring procedures. The results demonstrate an underestimation of real direct costs in treatment management in MS with significant difference between “standard costs” per patient compared to “real costs” estimated using BIM. Discussion and conclusions: In Italy the annual social cost of MS has been estimated at about one billion and 600 million euro (Ponzio et al. 2014). BIM has several advantages: calculates the impact of the total costs in real time, takes in account possible variability of treatment course of the single patient (new or persistent patients, shift between drugs, discontinuations), assigns the correct value to the human and material necessary resources, is adaptable to different setting (every centre/region can modify included variables according with its care pathway), gives to neurologist stepby-step informations related to prescription rate per treatment. Disclosure All Authors: have nothing to disclose

Disclosure

Pathology P334 Antibodies to MOG and AQP4 in a patient with a fulminant demyelinating encephalomyelitis, clinical course and neuropathological examination: a case report F. Di Pauli1, R. Höftberger2, M. Reindl1, K. Schanda1, R. Beer1, D. Sato3, K. Fujihara3, H. Lassmann4, E. Schmutzhard1, T. Berger1 1Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, 2Department of Clinical Neurology, Medical University of Vienna, Vienna, Austria, 3Departments of Neurology and Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan, 4Center for Brain Research, Medical University of Vienna, Vienna, Austria Background: Antibodies to myelin oligodendrocyte glycoprotein (MOG) are detectable in patients with demyelinating inflammatory CNS diseases including acute disseminated encephalomyelitis (ADEM) and seronegative neuromyelitis optica and seemed to be associated with a better prognosis, although acute presentations can be severe. Objectives: To report a case of a patient with a fulminant demyelinating disease and MOG- and aquaporin(AQP)4 antibodies measured by a cell-based immunofluorescence assays. Methods: Case report with neuropathological examination. Results: We report a case of a patient with initial presentation of visual and gait disturbance who dramatically impaired with a bilateral amaurosis, complete tetraplegia and respiratory insufficiency

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with need of artificial ventilation within few days. During disease course cerebral and spinal MRI showed progressive findings with multiple cerebral and spinal lesions with diffusion restriction (including both optic nerves) and marginal contrast enhancement. Initial routine blood and cerebrospinal fluid (CSF) parameters including oligoclonal bands were normal. However, repeated CSF analyses showed inflammatory changes. At disease onset, high titer MOG-antibodies were detected (titer 1:1,280, corresponding CSF sample titer was 1:20), and remained positive during disease course. Although, AQP4-antibodies were absent at disease onset, antibody titer converted to positive. Additionally, CSF GFAP and MBP levels were very high at onset, but decreased during disease course. Four month after disease onset, patient died despite an immunotherapy with corticosteroids and intravenous immunoglobulins and an autopsy was arranged. Postmortem examination of neuropathological changes revealed the diagnosis of acute multiple sclerosis (MS) with multiple demyelinating lesions with pronounced destructive component and loss of astrocytes. Lesion pattern of optic chiasm met MS pattern II characterized by antibody and complement mediated demyelination. Loss of AQP4 was present in one subacute brainstem lesion. Conclusions: The case with clinical features of ADEM with predominantly optic and spinal involvement, absent oligoclonal bands, a histopathology of acute MS pattern II and development of AQP4-antibodies extended the spectrum of MOG-antibody associated encephalomyelitis. Although, MOG-antibodies are suspected to indicate a favourable prognosis, fulminate acute disease courses are possible and warrant an aggressive immunotherapy.

Di Pauli: nothing to disclose related to this Abstract, Höftberger: nothing to disclose related to this abstract, Reindl: nothing to disclose related to this abstract, Schanda: nothing to disclose related to this abstract, Beer: nothing to disclose related to this abstract, Sato: nothing to disclose related to this abstract, Fujihara: nothing to disclose related to this abstract, Lassmann: nothing to disclose related to this Abstract, Schmutzhard: nothing to disclose related to this Abstract, Berger: nothing to disclose related to this abstract P335 Peptide identification and mapping on MS tissue by MALDI IMAGING G. Maccarrone1, S. Nischwitz2, S.-O. Deininger3, C. Stadelmann4, F.B. König5, C.W. Turck6, F. Weber6,7 1Proteomics Core Unit, 2Neurology, Max Planck Institute of Psychiatry, München, 3Bruker Daltronic, Bremen, 4Institute for Neuropathology, Neurology, University Göttingen, Göttingen, 5Institut für Pathologie, Klinikum Kassel, Kassel, 6Max Planck Institute of Psychiatry, München, 7Medical Park, Bad Camberg, Germany Background: The detailed mechanisms of lesion formation and the processes leading to different extents of tissue damage and remyelination of multiple sclerosis (MS) brain lesions remain still elusive. Our aim was to identify peptides and proteins involved in these processes.


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Methods: Protein mapping on tissue section using MALDI Mass Spectrometry Imaging (MALDI-MSI) has become feasible. This technique performs a molecular imaging in situ of tissue sections providing the molecular mass (m/z), the spatial localization and ion signal intensity of the molecule. Hundreds of proteins/peptides can be simultaneously detected and identified at µm spatial resolution. The MALDI-MSI data enable to visualize the molecular distribution and to generate molecular maps within the tissue section. We employed MALDI-MSI to profile peptides and proteins expressed in normal-appearing white matter, grey matter and MS brain lesions with different extents of remyelination. The protein and peptide signatures mapping the brain lesions were identified by LC-ESI-MS/MS approach and validated by immunohistochemistry. Results: The resulting molecular images defined regions within the tissue slide in accordance with those obtained from histological analysis. Lesion areas with low remyelination extent (average over lesion area) were mapped by low molecular weight compounds, whereas those with higher remyelination extent were defined by high molecular weight compounds. In addition cortical lesions, not easily visible by routine histology, were discovered and confirmed by subsequent immunohistochemistry. Thymosin beta 4 (Tb4), a protein known to be involved in repair mechanisms in other tissues and cell mobility, was identified in a brain peptide extract and was validated in an independent MS patient cohort by immunohistochemistry. Tb4 was mainly expressed within the rim of MS lesions and in grey matter. Conclusion: We could demonstrate the ability of the MALDIMSI methodology to distinguish lesions with different extents of remyelination and to look beyond histology. This technology provides information on protein localization, which is the main focus in neuropathological analyses and relevant for the elucidation of mechanisms underlying lesion generation. Disclosure Giuseppina Maccarrone: G.M. received grant support from Novartis.Sandra Nischwitz: S.N. received travel grants for the attention of scientific meetings from Merck Serono and TEVA and grant support from Bayer-Schering and Novartis. Sören-Oliver Deininger: SO.D. works for Bruker Daltonik GmbH Christine Stadelmann: C.S. received honoraria for speaking and travel reimbursement from Novartis Pharma GmbH, Teva Pharmaceutical Industries Ltd., Biogen, and Bayer Health Care. She served on scientific advisory boards of Novartis and Teva. She receives research support from Teva. She is a member of the editoral boards of the Multiple Sclerosis Journal and Neurology: Neuroimmunology & Neuroinfammation. She receives research support from the Deutsche Forschungsgemeinschaft (DFG), the Gemeinnuetzige HertieFoundation and the Myelin Repair Foundation. Fatima Babara König: Nothing to disclose Christoph W. Turck: Nothing to disclose Frank Weber: F.W. received honoraria from Genzyme, Novartis and Biogen for serving on a scientific advisory board and a travel grant for the attention of a scientific meeting from Merck-Serono and Novartis. F.W. received grant support from Merck-Serono, Novartis and from the Federal Ministry of Education and Research (BMBF, Projects Biobanking and Omics in ControlMS as part of the Competence Network Multiple Sclerosis).

P336 Mitochondrial dynamics dysfunction in multiple sclerosis A.N. Carvalho1, P.G. Nijland1, T. Muntslag1, B. van het Hof1, S. van der Pol1, M.E. Witte2, J. van Horssen1 1VU University Medical Center Amsterdam, Amsterdam, The Netherlands, 2Institute for Clinical Neuroimmunology, LudwigMaximilian-University Munich, Munich, Germany Mitochondrial dysfunction is a key pathophysiological mechanism involved in the onset and progression of multiple sclerosis (MS) and contributes to axonal damage and neuronal degeneration. Here we investigated pathways involved in mitochondrial quality control mechanisms, which comprises the processes of fission, fusion and mitophagy. We hypothesized that, inflammatory events in the cortex of MS patients lead to impaired mitochondrial dynamics and subsequent mitochondrial dysfunction, which in turn underlies neurodegeneration and drives disease progression. The expression level of key genes and proteins involved in mitochondrial dynamics was assessed in cortical samples of MS patients and correlated with local pathology. In parallel, grey matter tissue samples from controls and MS patients were analyzed by confocal fluorescent microscopy to assess ultrastructural changes of neuronal mitochondria. The mechanisms through which inflammation can contribute to mitochondrial dynamics dysfunction were explored using rat primary neuronal cell cultures exposed to oxidative stress and inflammatory mediators. Gene and protein expression of factors involved in mitochondrial dynamics was analyzed as well as mitochondrial membrane potential, ATP production and reactive oxygen species formation. Confocal fluorescent microscopy was used to assess mitochondrial morphological changes and colocalization of mitochondrial markers with autophagy markers. Our results showed a significant decrease in mRNA expression levels of key factors involved in mitochondrial dynamics in MS grey matter. Additionally, fission and fusion-associated proteins display a predominantly neuronal distribution pattern and their expression is decreased in MS lesions, particularly in areas with activated microglia. Primary neurons stimulated with inflammatory mediators showed impaired mitochondrial function and altered mitochondrial dynamics. Our findings show that mitochondrial dynamics is impaired in MS. The imbalance of this important quality control mechanism might contribute to mitochondrial dysfunction and neurodegeneration in the progressive phase of MS. Disclosure Funding: European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) postdoctoral research fellowship to A.N.Carvalho A. N. Carvalho: nothing to disclose; P. G. Nijland: nothing to disclose; T. Muntslag: nothing to disclose; B. van het Hof: nothing to disclose; S. van der Pol: nothing to disclose; M. E. Witte: nothing to disclose; J. van Horssen: nothing to disclose P337 Axonal damage and loss in multiple sclerosis and neuromyelitis optica E. Bahn, V. Heide, W. Brück, C. Stadelmann Department of Neuropathology, University Medical Center, Georg-August University, Göttingen, Germany


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Poster Session I, 21(S11) Introduction: Neuromyelitis optica (NMO) is an autoimmune astrocytopathy with secondary demyelination that clinically and pathologically resembles multiple sclerosis (MS). However, recovery from NMO relapses is often limited, suggesting severe structural damage. In addition, MS and NMO differ in their propensity to develop progressive disease, which is rarely if at all seen in NMO patients. Pathologically, different degrees of axonal damage and loss may underlie these clinical features. Objective: To assess whether the extent of acute axonal damage differed between early demyelinating MS and NMO lesions, axonal density was evaluated in later stage MS and NMO lesions. Methods: Biopsy tissue from patients with early MS and NMO was assessed for acute axonal transport disturbance using amyloid precursor protein (APP) immunohistochemistry. Lesion activity was determined using macrophage activation markers and myelin degradation products in macrophages. Only anti-AQP4-seropositive NMO patients were included. Axonal density was studied in later stage lesions of autopsied MS and NMO patients using Bielschowsky silver impregnation. The density of APP-positive axonal swellings and Bielschowsky-impregnated axons was determined using an ocular morphometric grid. Results: The densities of APP-positive axons indicating acute axonal transport disturbance was similar in early MS and NMO lesions. However, axonal loss in later stage lesions was more pronounced in NMO. Conclusions: The extent of acute axonal damage is not different between early MS and NMO lesions. Astrocyte loss in NMO may contribute to the more extensive axonal loss observed in later stage NMO lesions. Disclosure Dr. Bahn has received honoraria for lectures by Biogen and Bayer Vital. V. Heide: nothing to disclose Dr. Brück has received honoraria for lectures by Bayer Vital, Biogen, Merck Serono,TevaPharma, Genzyme, Sanofi-Aventis and Novartis and is a member of scientific advisory boards for TevaPharma, Biogen, Novartis and Genzyme. Dr. Brück receives research support from TevaPharma, Biogen, Genzyme and Novartis Dr. Stadelmann received honoraria for speaking and travel reimbursement from Novartis Pharma GmbH, Teva Pharmaceutical Industries Ltd., Biogen, and Bayer Health Care. She served on scientific advisory boards of Novartis and Teva. She receives research support from Teva. She is a member of the editoral boards of the Multiple Sclerosis Journal and Neurology: Neuroimmunology & Neuroinfammation. She receives research support from the Deutsche Forschungsgemeinschaft (DFG), the Gemeinnützige Hertie-Foundation and the Myelin Repair Foundation. P338 Cytotoxic effects of antibodies on glial-neuronal networks in neuromyelitis optica and multiple sclerosis D.E. Harlow1, Y. Liu2, G.P. Owens2, W.B. Macklin1, J.L. Bennett2 1Cell & Developmental Biology, 2Neurology, University of Colorado School of Medicine, Aurora, CO, United States Background: Multiple sclerosis and neuromyelitis optica (NMO) are inflammatory immune-mediated diseases of the

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central nervous system (CNS) characterized by demyelination. Most NMO patients have a pathologic autoantibody response against aquaporin-4 (AQP4) that induces astrocyte-targeted complement-mediated cytotoxicity (CDC), oligodendrocyte loss and demyelination. The target of intrathecal oligoclonal IgG in the cerebrospinal fluid (CSF) of MS patients remains unknown but may also drive similar injury in the CNS. Methods: To understand the role of antibody-mediated immune responses in MS, we compared the effects of recombinant monoclonal antibodies (rAbs) constructed from CSF clonal plasma cells isolated from MS and NMO patients using organotypic cerebellar slices. Demyelination, gliosis, and cell death were assessed by immunohistochemistry, and cytokine levels were measured by multiplexed immunoassays. Results: NMO rAbs bound specifically to astrocytes and induced rapid, complement-dependent destruction of astrocytes. Astrocyte loss was followed by sequential demyelination and oligodendrocyte and neuronal death. Media from cerebellar slices exposed to NMO rAb and complement had >4-fold higher concentrations of IL-1b and IL-6 compared to control slices. In contrast, MS rAb bound to a subset of oligodendrocytes and around axons, and, importantly, did not require complement to induce demyelination and neuronal death. IL-1b and IL-6 were not elevated and destruction of astrocytes was not observed. Conclusions: Using an ex vivo cerebellar slice model, NMO and MS rAbs demonstrate distinct target-directed mechanisms of demyelination. NMO rAb-mediated demyelination is complement dependent and follows astrocyte destruction. Some mechanisms of MS rAb-mediated demyelination, however, are direct and complement independent. Oligodendrocytes, neurons, and myelin are destroyed while astrocytes are preserved. Disease-specific autoantibodies in CNS demyelinating disorders appear to drive CNS injury by disrupting glial-glial and glial-neuronal networks through direct and immune effector pathways. Understanding the mechanisms underlying antibody-induced pathology will identify potential targets for disease-specific therapy and restorative treatments. Disclosure Supported by a Collaborative Research Grant from National Multiple Sclerosis Society, NEI, NINDS, and the Guthy-Jackson Charitable Foundation.

Inflammation and tissue damage P339 CSF oxidative stress profiles in multiple sclerosis R.T. Ibitoye, K. Kemp, N.J. Scolding, A. Wilkins Institute of Clinical Neurosciences, University of Bristol, Bristol, United Kingdom Background: Inflammation in multiple sclerosis (MS) is linked to generation of reactive oxygen species (ROS) and subsequent activation of anti-oxidant defences. The balance of oxidative stress versus anti-oxidant activity may dictate the level of tissue injury and may be useful as a biomarker of disease-stage and response to therapies. The aims of this study were to determine profiles of oxidative markers and anti-oxidant responses in cerebrospinal fluid (CSF) of MS patients. Methods: CSF from suspected MS (taken during diagnostic work-up) and idiopathic intracranial hypertension (IIH) controls


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were collected. Suspected MS patients were classified into: relapsing-remitting MS (RRMS), progressive MS, possible MS and clinically isolated syndrome (CIS). 32 IIH patients and 28 patients with demyelinating disease were identified. IIH, RRMS and CIS groups were compared. None of the MS patients were exposed to disease modifying drugs prior sample collection. No samples were collected during relapse. Assays performed were: hydrogen peroxide (H2O2), total nitrate/nitrite (NOx) and superoxide dismutase (SOD) total activity. Western blots and integrated densities were evaluated for: malondialdehyde, SOD3 (extracellular SOD), gluthathione peroxidase-1 (GP1) and catalase. Results: There was no significant difference in H2O2 and NOx levels between groups. SOD3, GP1, catalase and malondialdehyde expression was higher in RRMS than IIH (p< 0.05), with higher levels seen in patients with RRMS compared to CIS (p< 0.05 except for GP1). Interestingly, however, SOD activity was greater in CIS compared to RRMS (p=0.0051). Conclusions: We find evidence of increased antioxidant enzyme expression (Catalase/SOD3/GP1) and lipid-peroxidation products (malondialdehyde) in RRMS compared to CIS. This anti-oxidant response may not however be effective as highlighted by reduced SOD activity in RRMS. Understanding oxidative profiles at different disease stages may be key to better targeting of therapies. Disclosure R. Ibitoye: Funding from National Institute of Health Research (UK) Academic Clinical Fellow Programme. K. Kemp: Nothing to disclose. A. Wilkins: Nothing to disclose. N. Scolding: Nothing to disclose. P340 Astrocyte and myelin injury in neuroinflammatory disorders with myelin oligodendrocyte glycoprotein or aquaporin-4 antibody positive cerebrospinal fluid K. Kaneko1, D.K. Sato2, I. Nakashima1, S. Nishiyama1, S. Tanaka3, R. Marignier4, J.W. Hyun5, H.J. Kim5, L.M. Oliveira6, D. Callegaro6, M. Reindl7, T. Berger8, T. Seifert-Held8, A. Saiz9, M. Sepulveda9, S. Siritho10, N. Prayoonwiwat10, P.J. Waters11, K. Kurosawa1, T. Akaishi1, H. Kuroda1, T. Misu2, K. Nomura3, K. Fujihara2, M. Aoki1 1Department of Neurology, Tohoku university, Sendai, Japan, 2Departments of Multiple Sclerosis Therapeutics, Tohoku university, Sendai, Japan, 3Department of Neurology, Saitama Medical center, Kawagoe, Japan, 4Hospital Pierre Wertheimer, Lyon, France, 5Research Institute and Hospital of National Cancer Center, Seoul, Republic of Korea, 6Department of Neurology, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil, 7Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria, 8Department of Neurology, Medical University of Graz, Graz, Austria, 9Service of Neurology, Hospital Clinics and Institute of Biomedical Research August Pi Sunyer, Barcelona, Spain, 10Division of Neurology, Siriraj Hospital, Mahidol University, Bangkok, Thailand, 11Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom Objective: To evaluate astrocyte and myelin injury in inflammatory central nervous system disorders with positivity to antibodies

against aquaporin-4 (AQP4) or myelin-oligodendrocyte glycoprotein (MOG) in the cerebrospinal fluid (CSF). Methods: We enrolled 59 anti-AQP4+ and 31 anti-MOG+ seropositive patients with stored CSF samples from Japan, Brazil, France, South Korea, Austria, Spain and Thailand. CSF was blindly tested for anti-AQP4 and anti-MOG using cell-based assays. Astrocyte and myelin damage was evaluated measuring glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) respectively using commercial ELISA. Results: Among 90 patients with serum positivity to anti-AQP4 or anti-MOG, 68 were positive in the CSF, representing 76% of anti-AQP4+ (45/59) and 74% of anti-MOG+ (23/31) cases．All antibody results in their CSF identified the same antibody present in sera. No CSF samples were positive for both antibodies. The median GFAP level in the CSF was remarkably elevated in the anti-AQP4+ CSF compared to anti-MOG+ CSF (p < 0.0001). On the other hand, elevation of MBP was similar between AQP4+ and MOG+ patients (p=0.6531). The concentration of GFAP correlated with anti-AQP4 titers in the CSF (Spearman rho = 0.5, p = 0.0005), especially in samples collected within a few days from attack and before any treatment. Conclusion: Our study confirmed a significant astrocyte damage in anti-AQP4+ CSF, and suggested a pathogenetic role of antiAQP4 in causing astrocytopathy. In contrast, anti-MOG+ disease seems to be predominantly demyelinating without evidence of astrocytopathy. Disclosure Kimihiko Kaneko: Nothing to disclose Douglas Kazutoshi Sato has received scholarship from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, grant-in-aid for scientific research from the Japan Society for the Promotion of Science (KAKENHI 15K19472), research support from CAPES/Brasil and speaker honoraria from Novartis. Ichiro Nakashima reports grants from Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and from Ministry of Health, Labour and Welfare of Japan, personal fees from Mitsubishi Tanabe Pharma Corporation, Biogen Idec Japan, Novartis Pharmaceuticals Japan, Bayer Yakuhin, Ltd, and grants from LSI Medience Corporation. Shuhei Nishiyama reports grant from JSPS KAKENHI Grant (Grant-in-Aid for Research Activity Start-up) Number 24890017. Satoru Tanaka: Nothing to disclose Romain Marignier: Nothing to disclose Jae-Won Hyun: Nothing to disclose Ho Jin Kim: Nothing to disclose Dagoberto Callegaro: Nothing to disclose Markus Reindl: Nothing to disclose Thomas Berger: Nothing to disclose Thomas Seifert-Held: Nothing to disclose Sasitorn Siritho: Nothing to disclose Naraporn Prayoonwiwat: Nothing to disclose Patrick Joseph Waters: Nothing to disclose Kazuhiro Kurosawa: Nothing to disclose Tetsuya Akaishi: Nothing to disclose Hiroshi Kuroda: Dr. Kuroda has received research support from a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.


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Poster Session I, 21(S11) Kyoichi Nomura Kazuo Fujihara serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, Medimmune and Medical Review; has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical; serve as an editorial board member of Clinical and Experimental Neuroimmunology (2009-present) and a advisory board member of Sri Lanka journal of Neurology; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The ChemoSero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical,Ono Pharmaceutical, Nihon Pharmaceutical, and Genzyme Japan; is funded as the secondary investigator (#22229008, 2010-2015) by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan and as the secondary investigator by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfre and Labor of Japan(2010-present) Masashi Aoki: Nothing to disclose

cytokine secreted by Th1 cells, also decreased Cx43 protein expression in astrocytes in a concentration dependent manner. Conclusions: Humoral factors secreted from Th1 cells, such as IFNγ, can decrease the Cx43 expression in astrocytes. These findings suggest that Th1-dominant inflammatory state can disrupt intercellular communication among astrocytes and may induce exacerbation of MS. Disclosure Mitsuru Watanabe: Nothing to disclose; Katsuhisa Masaki: Nothing to disclose; Ryo Yamasaki: Bayer Schering Pharma, Biogen Idec, Novartis Pharma and Mitsubishi Tanabe Pharma; Jun Kawanokuchi: Nothing to disclose; Hideyuki Takeuchi: Nothing to disclose; Akio Suzumura: Nothing to disclose; Jun-ichi Kira: Novartis Pharma K.K., Biogen Idec Japan Ltd., Mitsubishi Tanabe Pharma Corporation, UCB Japan Co. Ltd., Pfizer Japan Inc., Otsuka Pharmacetutical Co. Ltd., Astellas Pharma Inc., Esai Co. Ltd. and Bayer Yakuhin Ltd. Source of funding: This study was in part supported by Health and Labour Sciences Research Grants on Intractable Diseases (H25-Nanchitou-Ippan-100 and H26-Nanchitou-Ippan-069) from the Ministry of Health, Labour, and Welfare, Japan, “Glial assembly” Grant-in-Aid for Scientific Research on Innovative Areas (FY2013-2017) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and Center for Clinical and Translational Research of Kyushu University Hospital.

P341 Th1 cells inhibit the expression of connexins in astrocytes M. Watanabe1, K. Masaki1, R. Yamasaki2, J. Kawanokuchi3, H. Takeuchi3, A. Suzumura3, J.-I. Kira1 1Department of Neurology, Neurological Institute, 2Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 3Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

P342 Chronic lymphotoxin-alpha expression in the meninges produces sub-pial cortical pathology in the rat E. Browne1, R. James1, R. Schalks1, N. Mazarakis2, R. Reynolds1 1Medicine / Brain Sciences, 2Medicine / Gene Therapy, Imperial College, London, United Kingdom

Objective: Gap junction composed of connexins (Cxs) is a major intercellular channel that facilitates direct signaling between cytoplasmic compartments of adjacent cells. We previously reported extensive loss of astrocytic Cxs in Baló’s disease, neuromyelitis optica, and rapidly progressive multiple sclerosis (MS). In MS lesions, loss of Cx43 was accompanied by lymphocytic infiltration. Moreover it is widely accepted that autoimmune T cells mediate the formation of MS lesions. From these facts, we hypothesized that autoimmune T cells affect Cxs expression in astrocyte and contribute to exacerbation of CNS demyelinating disease. In this study, we aimed to clarify the effects of T cells on Cx43 expression in astrocytes in vitro. Methods: Naïve CD4+ T cells were isolated from splenocytes of C57BL/6 mice by magnetic bead separation. They were cultured under Th0, Th1, Th17 and Treg skewing conditions for 3 days, and the culture supernatants were collected. Primary cultured astrocytes were prepared from the forebrain of newborn C57BL/6 mice. Astrocytes were treated with the T cell culture supernatant. Cx43 expression in astrocytes was evaluated by real-time PCR and Western blotting. Results: The protein level of Cx43 in astrocytes showed approximately 40% decrease by Th1 supernatant stimulation, but not by the supernatants from other T cell subsets. IFNγ, which is a main

The accumulation of neurological disability that characterises secondary progressive multiple sclerosis (SPMS), and is currently untreatable, is suggested to be driven in part by cortical grey matter pathology. The presence of meningeal tertiary lymphoid organs (TLOs) in a large proportion of SPMS cases, is associated with faster clinical progression and more severe cortical pathology, suggesting that TLOs and chronic meningeal inflammation contribute to progression and pathology. Gene expression of the cytokine lymphotoxin-alpha (LTα), implicated in both TLO formation and cellular toxicity, is upregulated (2-fold) in post-mortem SPMS meninges (n=20) relative to controls by RT-PCR. We investigated the hypothesis that LTα drives TLO formation and exacerbates cortical pathology in SPMS using a novel animal model of cortical demyelination driven by chronic meningeal inflammation. Female dark agouti (DA) rats with subclinical experimental autoimmune encephalomyelitis (EAE; induced by immunisation with a low dose of recombinant mouse myelin oligodendrocyte glycoprotein (rmMOG) in incomplete Freund’s adjuvant), received an injection of a VSV-G pseudotyped lentiviral vector (LV) with a full CMV promoter expressing green fluorescent protein (GFP) or human LTa into the subarachnoid space (SAS). GFP expression by cells in the meninges was induced up to 12 weeks post-LVGFP injection. Expression of human LTα in

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rat brains at 90 days post-LVLTα was confirmed by RT-PCR, and detected in rat CSF. Infiltration of the meninges by macrophages, T-cells and B-cells, including the presence of large immune cell aggregates reminiscent of early TLOs, was observed at 7, 28 and 90 days post-LVLTα injection in both naive and rmMOG-immunised animals. Extensive subpial demyelination and microglial activation was observed in rmMOG-immunised animals at 28 and 90 days post-LVLTα, whereas only microglial activation was seen in naive LVLTα animals, suggesting that chronic meningeal LTα expression is sufficient to elicit meningeal inflammation and widespread activation of cortical microglia, but a pre-existing anti-MOG response is required for demyelination in this model. Together with our finding of increased LTα in SPMS meninges this suggests that LTα may contribute to subpial lesion formation and MS progression.

compared to those in Q4 and the difference between Q1 and Q4 was similar regardless of lesion activity (OR range: 1.51-2.45) or age (1.81-2.18) over both M24 and M48. During the same time period, correlation of BVL with time to EDSS⩾6 was more pronounced (Q1 vs Q4, OR 2.54-5.45). In patients with/without lesion activity (Q1 vs Q4), OR was 3.77-5.45/2.82-4.26, for age < />40 y, OR was 2.54-2.92/3.69-5.24. P< 0.05 for the majority of the comparisons. Over 48 months, patients >40 y had the highest progression rates across Q1 and Q4 for CDP6 (29% and 19%) and time to EDSS⩾6 (23% and 7%). Baseline parameters and other outcomes to be presented. Conclusion: Regardless of baseline or ongoing measures of disease activity, patients with the highest BVL had the worst disease outcome. Lesion activity and age did not have a major impact on the correlation between BVL and disability progression further supporting the clinical relevance of BVL.

Disclosure Nothing to disclose. Funding sources: MRC and MS Society P343 The effect of MRI inflammatory activity and age on the association of brain volume loss with disability progression: per-quartile subgroup analysis D. Jeffery1, T. Vollmer2, S. Ritter3, E. Verdun Di Cantogno4, D. Piani Meier4, E.-W. Radue5 1Piedmont Healthcare, Mooresville, NC, 2University of Colorado Denver, Denver, CO, 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States, 4Novartis Pharma AG, Basel, Switzerland, 5Medical Image Analysis Centre, University of Basel, Basel, Switzerland Background: Brain volume loss (BVL) reflects both diffuse and focal damage in relapsing MS and correlates with disability progression. Previously, we reported that the quartile of patients with the highest BVL at month (M) 24 experienced the most disability progression at M24 and M48. Objective: To investigate whether age and MRI inflammatory activity affects concomitant correlation of BVL with disability progression over 24 months and/or its prognostic value over 48 months in RRMS patients. Methods: Patients (N=1841) from the pooled phase 3 FREEDOMS/FREEDOMS II core (M24) and extension (M48) studies were categorised (post hoc) into quartiles by total percent BV change (PBVC) from baseline (BL) to M24 as assessed by the SIENA method. Mean annualised PBVC was determined for each quartile. Patients were further stratified into subgroups: age (< />40 y, n=1299) at BL, presence/absence of Gd+ lesions at BL (n=1477), or new/enlarging T2 lesions over 24 months (n=819). The proportion of patients at M24 and M48 with 6M-confirmed disability progression (CDP6) and time to EDSS⩾6.0 is reported. Odds ratios (OR) and p-values are derived by logistic regression with Q4 as a reference. Results: PBVC quartile ranges at M24 were: Q1 (n=455), −13.5% to −1.7%; Q2 (n=458), −1.7% to −0.77%; Q3 (n=467), −0.77% to −0.13%; and Q4 (n=461), −0.13% to +4.34%. Within Q1, patients with MRI activity had higher annual BVL than those without; no difference was seen within the other quartiles, and for age. Across all subgroups patients in Q1 were at higher risk for CDP6

Disclosure Funding source: This study is supported by Novartis Pharma AG, Basel, Switzerland. Douglas Jeffery received honoraria for speaking and consulting from Bayer, Biogen, Teva, Serono, Pfizer, Glaxo, Novartis, Acorda, Genzyme, Xenoport, and Questcor; research support from Bayer, Biogen, Teva, Serono, Pfizer, Genzyme, and Novartis. Timothy Vollmer received research grants from Teva Neuroscience, Biogen Idec, Novartis Pharma, Genzyme, Lilly Research Labs, Orasi, Sanofi-Aventis, Hoffmann-LaRoche, Jensen Research, Avanir, and MedImmune, and honoraria for consulting from Teva Neuroscience, Biogen Idec, Elan Pharma, Hoffmann-LaRoche, Genzyme, Novartis, Acorda, Xenoport, Medscape, Sanofi, and Rocky Mountain MS Center. Ernst-Wilhelm Radue has received research support from Biogen Idec, Merck-Serono, Novartis and Actelion. Daniela Piani Meier, Elisabetta Verdun Di Cantogno are employees of Novartis Pharma AG, Basel, Switzerland. Shannon Ritter is an employee of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. P344 RGC-32 regulates TGF-β extracellular matrix expression in astrocytes A. Tatomir1, C.A. Tegla1, C.D. Cudrici1, D. Boodhoo1, A. Martin1, A. Mekala1, V. Rus2, H. Rus1,3 1Neurology, 2Medicine, University of Maryland, 3Research Service, Veterans Administration Maryland Health Care System, Baltimore, MD, United States Extracellular matrix (ECM) deposition in active demyelinating multiple sclerosis (MS) lesions may impede axonal regeneration and can modify immune reactions. RGC-32 plays an important role in mediation of TGF- β downstream effects but its role in gliosis has not been investigated. To gain more insight into the role played by RGC-32 in gliosis we examined the role of RGC-32 in mediation of ECM and reactive astrocyte markers expression in cultured astrocytes. Collagen I, IV and V are expressed by astrocytes which were also expressing RGC-32. Since RGC-32 was found to be involved in mediation of TGF- β effects, we investigated its role in TGF- β -induced ECM expression and reactive astrocyte marker α-smooth


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Poster Session I, 21(S11) muscle actin (α-SMA). In cultured astrocytes, α-SMA, collagen I, IV and V were significantly induced at 18 h of stimulation with TGF-β. Next, we silenced RGC-32 expression by transfecting astrocytes with siRGC-32 and compared the effect of this treatment to that of control siRNA. The RGC-32 siRNA effectively decreased the mRNA RGC-32 expression by 92% and the protein expression by 87% when compared to astrocytes transfected with control siRNA. We found that RGC-32 silencing resulted in a significant reduction in TGF-β induced collagen I, collagen IV, and collagen V expression. Using astrocytes isolated from RGC-32 knockout (KO) mouse we found that TGF- β induced collagen IV and α-SMA expression were significantly reduced in RGC-32 KO when compared with wild type mouse. Our data also indicate that RGC-32 plays an important role in the TGF-β-mediated induction of ECM expression and possibly gliosis. The silencing on α-SMA expression suggests that RGC-32 is also required for the transition of astrocytes to a reactive state. Therefore RGC-32 may represent a new target for therapeutic intervention in MS. Disclosure None P345 Indicators of enterocyte damage and small intestinal permeability in multiple sclerosis: a pilot study I. Stetkarova1, I. Hoffmanová2, Š. Coufal3, A. Bartoš1, D. Zimová1, V. Bučilová1, Z. Szabová1, E. Medová1, H. TlaskalováHogenová3 1Department of Neurology, Third Faculty of Medicine, Charles University, Hospital Kralovske Vinohrady, 22nd Department of Internal Medicine, Third Faculty of Medicine, Charles University, Hospital Kralovske Vinohrady, 3Laboratory of Cellular and Molecular Immunology, Institute of Microbiology, v.v.i., Prague, Czech Republic Background: Intestinal mucosal barrier is of great importance for setting the individual immune reactivity. A growing body of evidence shows that impairment of intestinal barrier could play pathophysiological role in the development of multiple sclerosis (MS). In this study, we analyzed non-invasive serological markers of enterocyte damage and small intestinal permeability in clinically definite MS (CDMS). Material and methods: We investigated 40 patients with CDMS (28 females, mean age 40 yrs, aged 22-62, EDSS 0-3) and 40 healthy controls (29 females, mean age 43 yrs, aged 22-62, EDSS 0-5, mean 2,6). Marker of enterocyte damage (I-FABP, intestinal fatty acid binding protein) and a marker of intestinal permeability (zonulin) were tested by ELISA in serum of both groups. Results: No statistical significance was observed for serum concentration of zonulin in both groups. However, I-FABP values showed low level of statistical significance in group of CDMS in comparison to the control group. Moreover in the individual analysis, I-FABP level above cut-off had 11 out of 12 CDMS patients without any immunosuppressive treatment in comparison to 6 out of 19 CDMS patients on immunosuppressive therapy. Conclusions: Due to the small sample size there were no great value of statistical analysis. However, MS patients before starting imunosupresive therapy presented higher levels of marker of enterocyte

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damage. Long-term immunosuppressive treatment seemed to diminished this marker, i.e. impairment of intestinal barrier. Our preliminary data remains to be confirmed in large-scale studies. Supported by Research Project of Charles University PRVOUK P34, Czech Republic Disclosure Ivana Štětkářová, Iva Hoffmanová, Aleš Bartoš, Štěpán Coufal, Denisa Zimová Zuzana Szabová, Veronika Bučilová, Eva Medová, Helena Tlaskalová-Hogenová All presented authors have nothing to declare.

Experimental models P346 A novel and refined primate EAE model induced with recombinant human MOG in incomplete Freund’s adjuvant A. Jagessar1, N. Heijmans1, S. Hofman1, R. Weissert2, B. ‘t Hart1,3 1Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands, 2University of Regensburg, Regensburg, Germany, 3University Groningen, Groningen, The Netherlands Experimental autoimmune encephalomyelitis (EAE) in the common marmoset (Callithrix jacchus), a small-bodied Neotropical primate, is a valid preclinical model of multiple sclerosis (MS). The close genetic and immunological proximity of the marmoset to humans makes the model particularly useful for translational research into immunopathogenic mechanisms as a basis for development of new therapies. A particularly interesting aspect of the marmoset model for translational immunology research is that, similar to humans, albeit different from inbred/SPF rodents, the monkey’s immune system has been shaped by genetic diversity and the daily combat with opportunistic and new infections. Among the pathogen-induced T cells are autoreactive specificities, which after immunization of marmosets with recombinant human MOG (rhMOG) or a synthetic peptide representing residues 34 to 56 of human MOG, formulated with incomplete Freund’s adjuvant (IFA) display their capacity to elicit a destructive autoimmune attack on the CNS. These T cells constitute a new pathogenic pathway, which has not (yet) been defined in SPF mice EAE, but seems relevant for MS. The current study presents a pathological and immunological characterization of the novel EAE model induced with rhMOG protein formulated with IFA. We reported that all immunized monkeys developed clinically evident EAE, although the clinical course varied considerably between individual monkeys. The rhMOG/IFA model is pathologically characterized by inflammation and demyelination of the brain and spinal cord white matter, and in some animals also of the cortical grey matter. Longitudinal immune profiling showed development of dominant T cell responses against the overlapping peptides MOG14-36 and MOG24-46 (core epitope 24-36), but reactivity against the pathogenically highly relevant peptide MOG34-56 (core epitope 40-48) was conspicuously absent. This paradoxical finding prompted a test in three marmoset twins whether interaction between the two core epitopes could be detected. We observed that simultaneous immunization with the two dominant epitopes in physical linkage tends to suppress the activation of anti-MOG40-48 T cell by the MOG24-36 epitope in two of three twins.


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The overall conclusion of this study is that rhMOG may contain pathogenic and regulatory epitopes, but that the pathogenic hierarchy of rhMOG epitopes is strongly influenced by the adjuvant in which the protein is formulated. Disclosure A Jagessar, N Heijmans, S Hofman, R Weissert, B ´t Hart has nothing to disclose P347 Enhanced cortical activity in remission is due to compensatory neuronal TNFα production E. Ellwardt1, G. Kumar Pramanik2, T. Novkovic3, T. Mittmann3, A. Stroh2, F. Zipp1 1Focus Program Translational Neurosciences (FTN), Rhine Main Neuroscience Network (rmn2), Department of Neurology, University Medical Center of the Johannes-Gutenberg University Mainz, 2Institute of Microscopy, Anatomy and Neurobiology, University Medical Center of the JohannesGutenberg University Mainz, 3Department of Physiology and Pathophysiology, University Medical Center of the JohannesGutenberg University Mainz, Mainz, Germany The majority of patients with multiple sclerosis (MS) show a relapsing-remitting disease course, during which they initially recover despite the existence of lesions visible in magnetic resonance imaging (MRI) and potential subtle symptoms. Here, the experimental autoimmune encephalomyelitis (EAE) model was used in SJL animals to mimic parts of the human disease. In order to investigate and exploit intrinsic adaptive CNS mechanisms after an inflammatory bout, we applied two-photon calcium imaging in vivo, assessing neuronal microcircuit activity in layer II/III of visual, prefrontal and somatosensory cortex. Interestingly, we found an increased cortical microcircuit activity in vivo and an increased frequency of α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) mediated excitatory postsynaptic currents (EPSCs) in ex vivo cortical slices in clinically recovered mice. No further symptoms were observed in either EAE score or RotaRod. No immune cell infiltration, microglia activity or demyelination was present in the cortex at the same time. Remaining spinal cord sub-meningeal infiltrates counted for 10% of local white matter. In detailed behavioral experiments during remission, no motor or learning impairment was found, whereas subtle changes in motivational tasks could be observed. In fact, quantitative PCR analyses of the cortex displayed markedly increased TNFα synthesis in the remission phase compared to the relapse phase or control animals. By immunostaining, we found neurons themselves as a source of TNFα. Preliminary data show that blocking TNFα with TNFαantibody administered into the lateral ventricle 48 h before analyses reversed the observed upregulated excitatory frequency effect. Taken together, we conclude that the observed increase in neuronal network activity in clinical remission in EAE is caused by neuronal TNFα, an important mechanism reported earlier as an intrinsic CNS process inducing enhanced synaptic strength, and thus might act as a compensatory mechanism to restore homeostasis after neuroinflammation.

Disclosure Frauke Zipp has received research grants from Teva, Merck Serono, Novartis and Bayer as well as consultation funds from Teva, Merck Serono, Novartis, Bayer Healthcare, Biogen Idec Germany, ONO, Genzyme, Sanofi-Aventis and Octapharma. Her travel compensation has been provided for by the aforementioned companies. Erik Ellwardt: nothing to disclose Alrbrecht Stroh: Nothing to disclose Thomas Mittmann: Nothing to disclose Gautam Kumar Pramanik: Nothing to disclose Tanja Novkovic: Nothing to disclose P348 Treatment with relaxin reduces the severity, decreases chemokines, chemokine receptors and pro-inflammatory cytokines in experimental autoimmune encephalomyelitis in C57BL/6 mice R. Garvin Research and Development, BVBiomed Ltd., Glasgow, United Kingdom Relaxin (RLX), a member of the insulin super family is a pleiotropic hormone capable of influencing multiple pathways as an agonist for the glucocorticoid receptor (GCR) and relaxin family peptide receptors 1 and 2 (RXFP1 and RXFP2). The use of GCR agonists in treating acute multiple sclerosis (MS) is well established. RLX acts not only as an agonist of GCR, but also increases GCR expression. Agonists of RXFP1 and RXFP2 are of interest in MS since they have been shown to modulate the immune system. In addition, agonists of RXFP-1 and RXFP-2 suppress cell adhesion molecules, increases Cyclic adenosine monophosphate, regulate differential expression of metallopeptidase inhibitors and matrix metalloproteinases, inhibit cell-mediated pro-inflammatory activity by stimulation of the peroxisome proliferator-activated receptor gamma, increase vasodilation, stabilizes the blood brain barrier and are intrinsic timers of remyelination. In the present study we investigated the effectiveness of RLX treatment on experimental autoimmune encephalomyelitis (EAE) and some of the underlying mechanisms. Female C57BL/6 mice were induced with subcutaneous injections of myelin oligodendrocyte glycoprotein (MOG) on day 1. Followed by injections on days 1 and 2 of pertusis toxin (0.16ug/ dose). Mice were scored daily for clinical signs of EAE. Alzet continuous pumps to deliver 30µg/kg body weight per day of RLX or saline were inserted at onset of EAE for 10 full days. Mice were sacrificed at the end of treatment and spinal cords collected for reverse transcription polymerase chain reaction (RT-PCR) and histopathology. RT-PCR detected mRNA levels for the chemokine MIP-2, the C-C chemokine receptors; CCR2, CCR5, CCR7 and the pro-inflammatory cytokines; IL-6 and IL-17. For histology spinal cords were examined visually and scored for lesion size and load. We found that continuous injection with RLX suppressed the clinical signs of EAE within 3 days of commencing treatment. The results of RT-PCR showed that when compared to controls, the RLX treated group had a decrease in mRNA expression in relative units for MIR-2 (36 vs 76), chemokine receptors CCR2


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Poster Session I, 21(S11) (21 vs 44), CCR5 (23 vs 46) and CCR7 (94 vs 140) and the proinflammatory cytokines IL-6 (40 vs 70) and IL-17 (78 vs 246). Histology showed a decrease in lesion load and size indicating a decrease in infiltrating cells in the RLX treated group. These results suggest that RLX may present a novel candidate molecule in treating MS.

Disclosure

Disclosure

P350 Multi-dimensional analysis in two different types of murine experimental autoimmune encephalomyelitis K. Yamamura1, H. Okamura1, S. Kawazoe1, M. Yonetani1, F. Ayabe1, Y. Ohkubo1, T. Asakuni1, Y. Takeshita2, M. Fukunaga2, M. Ishikawa2, H. Ichikawa1 1Third Institute of New Drug Discovery, 2Laboratory of Bioenergetics Research, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan

Roy A. Garvin: Nothing to disclose P349 Oligodendrocyte damage triggers immunecell recruitment into the forebrain M. Scheld1, T. Clarner1, B. Rüther1, M. Kipp2 1Neuroanatomy, RWTH Aachen University, Aachen, 2Neuroanatomy, LMU München, München, Germany The general dogma suggests that the formation of new lesions in Multiple sclerosis begins with an immune dysregulation, with the consequence that the immune system targets the brain compartment, resulting in active demyelinating foci. Other studies, however, have proposed that brain-intrinsic degenerative cascades are the initial factors driving MS lesion formation, including oligodendrocyte death, focal microglia activation, or axonal damage. This series of events was recently termed “inside-outside model”, which suggests that oligodendrocyte degeneration is at the root of the disease, while adaptive immune involvement being a secondary phenomenon and not an immediate cause of MS lesion formation. Experimental evidence for this hypothesis, however, is missing. In this work we demonstrate that oligodendrocyte degeneration with concomitant reactive gliosis is, in the predisposed host, a potent trigger for peripheral immune cell recruitment into the forebrain. In our studies, animals were fed cuprizone for three weeks followed by a period of two weeks on normal chow to induce the formation of degenerated foci within the forebrain. Subsequent immunization with MOG35-55 peptide, which induces the formation of myelin auto-reactive T-cells in the periphery, results in massive immune cell recruitment into the affected forebrain, a region which is usually spared in MOGinduced EAE. Remarkably, such infiltrates were found widespread including the cortex, corpus callosum and subcortical regions, all of which are affected in MS. Results of additional adoptive transfer experiments together with FACS analyses underpin the importance of brain-derived signals for immune cell recruitment. Accumulation of adoptively-transferred encephalitogenic T-cells into the forebrain was more severe in cuprizone pre-treated animals; the primary anti-MOG immunoresponse was unchanged. Furthermore, we identified by genome-wide array analyses Ddit3 as an early regulator of oligodendrocyte apoptosis. Ddit3-deficient animals not just display less severe cuprizone-induced oligodendrocyte damage but in parallel show reduced forebrain peripheral immune cell recruitment after MOG-immunization. This study for the first time illustrates the importance of brainintrinsic degenerative cascades for immune-cell recruitment and thus the formation of new MS lesion. A better understanding of involved factors is now warranted.

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Markus Kipp: Nothing to disclose Tim Clarner: Nothing to disclose Miriam Scheld: Nothin to disclose Bern Rüther: Nothing to disclose

Background: As MS disease animal models, experimental autoimmune encephalomyelitis (EAE) is traditionally used for basic study or drug screening. Objective: To investigate underlying mechanisms, we evaluated various components in a sequential event of EAE symptoms. Methods: We optimized two types of EAE model mice (MOG3555 immunized in C57BL/6 as a chronic EAE model (C-EAE), and PLP139-151 into SJL as a relapsing-remitting EAE model (RR-EAE) to replicate a fine developing pattern of clinical score. To evaluate peripheral immunological state, we measured concentrations of proinflammatory cytokines in serum. To evaluate CNS state, we monitored gene expressions of proinflammatory cytokines, cell junction components, myelin sheath components and others in spinal cord and cerebellum. Additionally, we used immunohistochemistry method to characterize CNS inflammation. Moreover, gadolinium-enhanced magnetic resonance imaging (MRI) analysis was applied to evaluate the gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) leakage into the brain. Result: Changes of clinical score in EAE correlated more strongly with CNS inflammation state than peripheral state. Concentrations of proinflammatory cytokines were nearly the same as control in serum, on the other hand these gene expressions in CNS were dramatically increased at the peak of the clinical score in the C-EAE. Parenchymal infiltration of lymphocytes was also confirmed by immunohistochemistry in a developing phase of both models. Simultaneously or before the infiltration, we detected Gd-DTPA leakage in the brain. At that time, the gene expressions of cell junction components were decreased. Demyelination was also indicated by this gene expression analysis. However, in the remission phase of the RR-EAE, the number of lymphocytes decreased in the brain, and the gene expressions recovered to nearly normal levels. Conclusion: We confirmed 1) activated immunocytes invaded CNS during symptoms, 2) blood-CNS barrier disruption and demyelination occurred through the development of EAE, 3) these events were ameliorated in the remission phase. From these result, we suggest that effective approach for MS treatment is not only immunosuppression but also protection of leakage for CNS or regeneration of myelin sheath. Disclosure Otsuka reserve all rights regarding this disclosure.


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P351 DMF treatment in a B-cell dependent EAE model S. Traffehn, I. Metz, W. Brück, M.S. Weber University Medical Center Göttingen, Göttingen, Germany B cells are increasingly recognized as key players in the pathogenesis and progression of Multiple Sclerosis (MS). While earlier concepts focused on the pathogenic contribution of antibodies (ab), emerging evidence suggest that cellular B cell function, such as presentation of antigen and provision of pro-inflammatory cytokines may be equally important. Recently approved dimethylfumarate (DMF) substantially reduces MRI activity and relapse frequency in MS patients. While clinical benefit is associated with a decline of peripheral lymphocytes, the exact and possibly pleiotropic mechanism of action of DMF is currently evolving. We investigated whether DMF treatment modulates pathogenic B cell function in experimental autoimmune encephalomyelitis (EAE). Methods: EAE was induced in female C57B/l6 mice by immunization with recombinant mouse myelin oligodendrocyte glycoprotein (rMOG) 1-117, a model in which B cells contribute as APC and differentiating plasma-cells generate anti-MOG ab titers. 15 mg/kg body weight of DMF or methylcellulose (control) was fed twice a day by oral gavage. Treatment started either at day 0 post immunization (prevention) or when mice developed an EAE score ⩾ 2. EAE onset and severity was scored daily. In representative mice, anti-MOG serum ab titers were determined by ELISA and B cells were evaluated for expression of MHC-II, CD40, CD80, CD86, CD69, CD25, GL-7 and CD95 by FACS. Results: To our surprise, preventive DMF treatment did not significantly ameliorate the clinical disease course. This result could be associated with the observation that preventive treated mice developed an overall less severe EAE compared to mice that were treated only after EAE onset. Therapeutic DMF treatment significantly ameliorated disease severity in chronic EAE. This clinical effect was associated with substantial alterations in the expression of costimulatory molecules while expression of activation markers were largely unaffected. Conclusion: Our data indicate that preventive treatment with DMF could be less effective as it may influences onset and severity of EAE. In contrast, therapeutic DMF treatment of established B celldependent EAE could significantly improve the disease course. This clinical benefit of DMF in CNS autoimmune disease is associated with pleiotropic immunological effects. Our data indicate that selective interference with B cell antigen presentation to T cells may represent a novel mechanism of action of DMF. Disclosure Sarah Traffehn and Imke Metz receive research support from Biogen Idec. Wolfgang Brück: nothing to disclose M. S. Weber received travel funding and/or speaker honoraria from Biogen-Idec, Merck Serono, Novartis, Roche and Bayer. He receives research support from the National Multiple Sclerosis Society (NMSS; PP 1660), the Deutsche Forschungsgemeinschaft (DFG; WE 3547/4-1), from Novartis, TEVA, Biogen-Idec, Roche and the ProFutura Programm of the Universitätsmedizin Göttingen.

P352 Following anti-CD20 treatment, repletion kinetic and immune-competence of reappearing B-cells depends on peripheral stimulation L. Feldmann1, S. Zamvil2, W. Brück1, M.S. Weber1 1Neuropathology, University Medical Center Göttingen, Göttingen, Germany, 2Department of Neurology and Program in Immunology, University of California San Francisco, San Francisco, CA, United States Clinical studies suggest that anti-CD20-mediated B cell depletion is effective in multiple sclerosis (MS) and neuromyelitis optica (NMO). To date, it is unclear whether long-term treatment is required to maintain efficacy. Emerging data in NMO suggest that clinical activity may return before circulating B cells can be detected in blood. To investigate if this refers to an earlier reoccurrence of immune competent B cells in secondary lymphoid organs, we monitored compartment-specific repletion with B cells in formerly anti-CD20-treated mice. C57Bl/6 mice received 3 weekly subcutaneous injections with 0.2 mg murine anti-CD20 or isotype (control) antibody (ab). Mice remained naive or were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide (p) 35-55 or MOG protein 1-117, the latter of which is recognizable by B cells. Mice were monitored for reappearance of B cells which were then evaluated phenotypically as well as functionally for their capacity to act as antigenpresenting cells (APC) for MOG-specific T cells. Following anti-CD20 treatment, B cell depletion was virtually complete in blood and lymph node, while approximately 5% and 20% of B cells remained detectable in spleen and bone marrow, respectively. In naïve and MOG p35-55 immunized mice, a model which does not involve B cells, B cell repletion started in spleen and bone marrow at week 7, while repletion of lymph node and blood was substantially delayed. In these two settings, reappearing B cells remained phenotypically naïve and acted as weak APC. In contrast, in MOG protein induced EAE, a model in which B cells are activated, contribute as APC and differentiate into absecreting plasma cells, B cell repletion occurred earlier, more simultaneously within all compartments analyzed; furthermore, reappearing B cells rapidly differentiated and gained pathogenic APC function. Upon cessation of anti-CD20 treatment, B cells repopulate immune-relevant organs before they can be detected in blood. Phenotype and function of reappearing B cells depend on peripheral B cell stimulation; reappearing B cells remain naive in the absence of B cell antigen-recognition, while B cells gain pathogenic function when B cell-stimulating antigen is present when B cells reappear. In perspective, these preclinical findings suggest that NMO, in which pathogenic B cell function likely arises in the periphery, may require a higher frequency of anti-CD20 treatment than MS. Disclosure L. Feldmann receives research support from Roche. S.S. Zamvil has nothing to disclose. W. Brück has nothing to disclose. M. S. Weber received travel funding and/or speaker honoraria from Biogen-Idec, Merck Serono, Novartis, Roche and Bayer. He receives research support from the National Multiple Sclerosis


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Poster Session I, 21(S11) Society (NMSS; PP 1660), the Deutsche Forschungsgemeinschaft (DFG; WE 3547/4-1), from Novartis, TEVA, Biogen-Idec, Roche and the ProFutura Programm of the Universitätsmedizin Göttingen. P353 Novel mechanism of autoimmune demyelination regulation via miR-155-3p and heat shock protein 40 M. Cichalewska, M.P. Mycko, H. Cwiklinska, K.W. Selmaj Department of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, Lodz, Poland microRNA-155 (miR-155) plays an important role in posttranscriptional gene regulation of the immune system. We and others have described miR-155 upregulation in T helper cells (Th) during development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We have shown that mice in which miR-155 host gene (MIR155HG) has been deactivated are resistant to EAE. MIR155HG produces two different miRNA strands - miR-155-5p and miR-155-3p, and miR-155-5p has been considered as the only functional miR-155 form. Surprisingly, we found that miR-155-3p is also strongly upregulated in Th cells infiltrating the brain in EAE. Functional manipulation of miR-155-3p expression revealed its particular role in regulation of Th17 development. The search for miRNA-155-3p target genes highlighted transcripts of two heat shock protein 40 genes, Dnaja2 and Dnajb1. In vitro manipulation of the hsp40 genes expression led to negative regulation of Th17 differentiation. In vivo overexpression of hsp40 resulted in decreased EAE. Thus, our findings provide new insights into a previously unknown mechanism by which miR-155-3p controls Th17 cell differentiation and autoimmune demyelination. Supported by NCN OPUS grant to HC, NCN MAESTRO 2012/04/A/NZ6/004234 grant to KWS and PSPB-007-2010 grant to MPM. Disclosure Maria Cichalewska: nothing to disclose Marcin P. Mycko: nothing to disclose Hanna Cwiklinska: nothing to disclose Krzysztof W. Selmaj: nothing to disclose P354 Biodistribution of teriflunomide in naïve rats vs rats with experimental autoimmune encephalomyelitis J. Kaplan1, S. Cavalier2, S. Turpault3 1Genzyme, a Sanofi company, Framingham, 2Genzyme, a Sanofi company, Cambridge, MA, 3Sanofi, Bridgewater, NJ, United States Background: Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting MS. Patients treated with teriflunomide in clinical trials have demonstrated a clinical and radiological benefit potentially mediated by central, as well as peripheral, mechanisms. The tissue distribution of teriflunomide following oral administration was therefore studied to assess the level of teriflunomide exposure in various organs, and throughout

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the central nervous system (CNS). Since CNS permeability can be affected by inflammation, studies were conducted in non-immunized (naïve) rats and rats immunized to induce experimental autoimmune encephalomyelitis (EAE). Objectives: To assess the organ and tissue distribution, including CNS penetrance, of teriflunomide in naïve rats vs rats with EAE. Methods: Naïve rats and rats with EAE received a single dose of [14C]-teriflunomide (10 mg/kg) by oral gavage. Whole body autoradiography, using phosphorimaging, was performed at several time points up to 24 hours after dosing to determine the distribution and concentration of radioactivity in various organs and tissues. Results: Whole-body distribution patterns of radioactivity were similar in naïve and EAE rats, with extensive distribution throughout all organs and tissues examined. The highest concentrations of total radioactivity were observed in well-perfused organs, such as liver, kidney, and lung, whereas tissues such as the eye and testes had concentrations several-fold lower. Maximal concentrations were achieved in most tissues within 1 hour post dosing, declining thereafter. Detectable but low concentrations of total radioactivity (~2–4% of blood concentrations) were measured in the brain and spinal cord, and concentrations of total radioactivity were higher in the spinal cord of EAE rats compared with naïve rats. Conclusions: Oral administration of [14C]-teriflunomide resulted in a wide distribution of radioactivity throughout the body shortly after dosing. CNS radioactivity levels indicated that teriflunomide exhibited low CNS penetrance but was present at biologically relevant concentrations. These findings suggest that teriflunomide may exert local activity in the CNS. Disclosure Study supported by Genzyme, a Sanofi company. JK: Employee of Genzyme. SC: Employee of Genzyme, with ownership interest. ST: Employee of Sanofi. P355 MOG-induced EAE in rats triggers anti-neurofascin antibodies facilitated by non-MHC genes S. Flytzani1, A.G.-C. Ortlieb1, M. Ndiaye1, M. Lindner2, C. Linington2, E. Meinl3, P. Stridh4, M. Jagodic4, T. Olsson4 1Karolinska Institutet, Stockholm, Sweden, 2University of Glasgow, Glasgow, United Kingdom, 3University of Munich, Munich, Germany, 4Karolinska Insitutet, Stockholm, Sweden Background: Ιn multiple sclerosis (MS) axonal damage leads to permanent neurological disabilities and spreading of the autoimmune response to axonal antigens is implicated in disease progression. Experimental autoimmune encephalomyelitis (EAE) provides an animal model that mimics MS. Using different EAE models we investigated the pathophysiological basis of epitope spreading to neurofascin, a protein localised at the node of Ranvier and its regulation by non-MHC genes. Methods: We used two different EAE models in the DA rat; one induced with myelin oligodendrocyte glycoprotein (MOG) which leads to disease characterized by profound demyelination, the second, induced with myelin basic protein (MBP) peptide 63-88 which results in severe CNS inflammation but little or no demyelination. We determined anti-neurofascin antibody levels during the


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course of disease. Furthermore, the anti-neurofascin IgG response was correlated with clinical parameters in 333 (DAxPVG. 1AV1) x DA on which we performed linkage analysis to determine if epitope spreading to neurofascin was affected by non-MHC genes. Results: Spreading of the antibody response to neurofascin occurred in demyelinating MOG-induced EAE but not in EAE induced with MBP peptide 63-88. Anti-neurofascin IgG levels correlated with disease severity in (DAxPVG.1AV1) x DA rats and a genomic region on chromosome 3 was found to influence this response. Conclusions: Inter-molecular epitope spreading to neurofascin correlates with disease severity in MOG-EAE, is dependent on extensive demyelination, and is influenced by non-MHC genes. The findings presented here may shed light on factors involved in the severity of MS and its genetics. Disclosure Sevasti Flytzani: nothing to disclose Andre Ortlieb Guerreiro-Cacais: nothing to disclose Marie N’diaye: nothing to disclose Maren Lindner: nothing to disclose Chris Linington: nothing to disclose Edgar Meinl: nothing to disclose Pernilla Stridh: nothing to disclose Maja Jagodic: nothing to disclose Tomas Olsson: nothing to disclose This work was supported by the Swedish research council, the Swedish Brain foundation, the European Community’s Seventh Framework Programme (FP7/2007-2013) under Grant agreement HEALTH-F4-2010-241504 (EURATRANS), Knut and Alice Wallenberg Foundation and the Swedish foundation for neurologically disabled (NHR), the DFG (SFBTR128), the BMBF (Clinical competence network for multiple sclerosis) and the Gemeinnützige Hertie Foundation. P356 Angiotensin 1-7 ameliorates disease in a mouse model of multiple sclerosis R. Stone, B.T. Lund, A. Levy, S. Lee, R. Daily, D. James, K.E. Rodgers, E.E. Kelland University of Southern California, Los Angeles, CA, United States Background: Angiotensin 1-7 (A1-7), a metabolite of the protective arm of the renin angiotensin system (RAS) has been shown to be neuroprotective against Shiga toxin-induced demyelination and neuronal injury. Treatment with A1-7 is also associated with reductions of infarct size in rat models of stroke and stimulation of hematopoietic stem cells after myelosuppression. Based on these findings we hypothesize that A1-7 may be a novel candidate for the treatment of multiple sclerosis (MS). The efficacy of A(1-7) was tested in an acute model of MS - myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalitis (MOG-EAE). Methods: MOG-EAE was induced in 10-week old C57BL/6 mice and treatment, with either saline or A1-7 (0.5, 1, 2, or 4 mg/kg/day by either twice daily subcutaneous injection or by continuous infusion pumps), was initiated at onset of clinical disease presentation (therapeutic treatment). Clinical disease scores (CDS) were

assessed daily, in a blinded fashion, based on the widely used disability scale assessing weakness, paresis and paralysis. At the end of the study, mice were euthanized, transcardially perfused with saline then paraformaldehyde and spinal cord tissue collected for histological examination. Hematoxylin and eosin (to assess infiltrating mononuclear cells) and solochrome cyanine (to assess myelin) stained spinal cord sections were assessed in a blinded manner for evidence of disease activity. A disease burden score was given based on a scale of 0 (no demyelination or cellular infiltration: normal appearing tissue) to 5 (extensive demyelination and cellular infiltration). Results: Therapeutic A1-7 treatment significantly (p< 0.0001) reduced disease progression compared to saline treated MOG-EAE mice. Histological examination of spinal cord disease burden corroborated the CDS assessments and demonstrated a significant and correlative reduction in disease pathology (r2=0.85, p-value=0.0011) in A1-7 treated MOG-EAE mice (score 0.30±0.08) compared to saline treated MOG-EAE mice (score 3.08±0.83). Conclusion: Our findings demonstrated that A1-7 is an effective treatment for alleviating disease progression in the MOG-EAE model. Further studies are underway to elucidate the mechanism of action of A1-7 in demyelinating disease, as well as the potential use of A1-7 in an MS population. Disclosure This work was funded by grants from the Department of Defense (BTL) and the Southern California Clinical and Translational Science Institute (EEK). Roslynn Stone: nothing to disclose. Brett T Lund: nothing to disclose. Alex Levy: nothing to disclose. Sandy Lee: nothing to disclose. Ryan Daily: nothing to disclose. Daphne James: nothing to disclose. Kathleen E Rodgers is an inventor of patents covering the activities of A(1-7). Eve E Kelland: nothing to disclose. P357 In vivo modeling of the nascent multiple sclerosis lesion: epsilon toxin treated mice develop focal demyelinating lesions J.R. Linden, C. Flores, S.V. Shetty, B. Zhao, K.R. Rumah, Y. Ma, T. Vartanian Weill Cornell Medical College, New York, NY, United States Background: Clostridium perfringens epsilon toxin has recently been proposed as a candidate environmental factor responsible for initiating nascent Multiple Sclerosis (MS) lesion formation. The newly forming MS lesion is characterized by blood brain barrier (BBB) permeability, oligodendrocyte cell death, and microglia activation in the absence of immune cell infiltration. The newly forming MS lesion contrasts active demyelinating and chronic active lesions, which exhibit varying degrees of infiltrating phagocytes and perivascular lymphocytes. Epsilon toxin is known to cause BBB permeability and to exclusively kill oligodendrocytes causing demyelination in vitro. The cellular specificity of epsilon toxin fits mechanistically with the pathophysiology of the newly forming MS lesion.


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Poster Session I, 21(S11) Goal: The goal of this study was to determine if epsilon toxin treatment could recapitulate MS lesion development in vivo by specifically targeting the BBB and oligodendrocytes leading to secondary demyelination. Methods: Mice were treated with epsilon toxin and observed for up to three weeks post treatment. Neurological effects of epsilon toxin were evaluated by behavioral assessment and histopathology. Saline treated mice were used as controls. Results: Chronic exposure of mice to non-lethal doses of epsilon toxin via intra-peritoneal injections resulted in BBB dysfunction and permeability to indicator molecules. Demyelinating lesions were observed in the cerebellum and pericallosal white matter two weeks after epsilon toxin treatment, indicating specific oligodendrocyte cell death. Interestingly, lesions observed in the pericallosal white matter where morphologically similar to Dawson´s fingers, pathognomonic for MS. Epsilon toxin treated mice also exhibited behavioral deficits consistent with demyelination compared to saline treated controls. Conclusions: Chronic treatment of mice with non-lethal doses of epsilon toxin results in demyelinating lesions morphologically similar to MS lesions. Chronic exposure of mice to epsilon toxin may be an acceptable model for studying the earliest stage of MS lesion development in vivo. Disclosure Funding for Jennifer Linded provided by Questor/Mallinckrodt Research Fellowship Award Program. P358 A new animal model of cortical neuroinflammation induces neurodegeneration and cognitive impairment as an approach to the progressive forms of multiple sclerosis B. Silva1, M. Leal2, M. Farias2, V. Candedo2, F. Pitossi2, C. Ferrari1 1Institute of Basic Sciences and Experimental Medicine, Italian Hospital University Institute, 2Laboratorio de Terapias Regenerativas y Protectoras del Sistema Nervioso, Leloir Institute Foundation, Institute for Biochemical Investigations, CONICET, Buenos Aires, Argentina Background: Progressive forms of Multiple Sclerosis (PFMS) are unresponsive to conventional immunomodulatory treatments. Additionally, the pathology of the PFMS is still unknown. Neuroinflammation and cortical lesions, key features of these forms, could contribute to physical disabilities and cognitive impairment (CI). Therefore, the cortical microenvironment, influence the degree of inflammation, tissue damage, the repair of the lesions and the clinical outcome. We developed a model of chronic and focal inflammatory demyelination/remyelination triggered by the long term expression of the pro-inflammatory cytokine, interleukin-1beta (IL-1b), which exhibited regional differences to IL-1b response, in particular between striatum and Substantia Nigra. Objectives: To study the effect of the chronic expression of IL-1 in the cortex of adult rats and the influence of peripheral proinflammatory stimulus on these lesions. Methods: The chronic expression of IL-1 is achieved by an adenovector expressing human IL-1b (AdIL-1b) or betagalactosidase (Adbgal) as a control. We performed behavioral, histological, immunohistochemical and molecular analysis.

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Results: The long term expression of IL-1 in the cortex induces inflammation characterized by neutrophil and macrophages recruitment, edema, demyelination, astro and microglia activation, increased expression of pro-inflammatory cytokines and ferritin levels. The inflammation peaked at 15-21 days post injection (dpi) and the lesion is restored by 30dpi. These results are correlated with a worse performance in both cognitive and anxiety-like behavioural test at 15-21dpi, which are improved as far as the lesion is recovered (30 days). The peripheral stimulation exacerbates the cortical damage, with an increased glial and inflammatory response and neurodegeneration along with CI and anxiety-like behavior. Conclusions: Considering that no effective treatment is available for PFMS, the pathophysiology of the PFMS and its relationship with clinical features need to be better understood. We developed a new experimental model of cortical inflammation and neurodegeneration associated with CI and anxiety-like behavior. This simple model could allow the identification of pathological mechanisms of the PFMS, which could be use as targets for designing specific PFMS treatments. Disclosure The authors declare that they have no conflict of interest

Genetics/Epigenetics and Pharmacogenetics P359 Peptidylarginine deiminases as regulators of the epigenetic state of oligodendrocyte precursor cells A. Falcao1, M. Meijer1, S. Marques1, M. Varas1, M.L. Nielsen2, G. Castelo-Branco1 1Karolinska Institutet, Stockholm, Sweden, 2NNF Center for Protein Research, University of Copenhagen, Copenhagen, Denmark Epigenetics changes at neural cells have been suggested to play an important role in the development of multiple sclerosis (MS). For example, increased histone H3 citrullination, was reported in the brain of MS patients, possibly mediated by peptdidylarginine deiminase 4 (PADI4). Citrullination is the conversion of the positively charged peptidyl-arginine to the neutral peptidyl-citrulline. Citrullination of histones leads to local chromatin decondensation and has recently shown that it regulates pluripotency (1). Hipercitrullination also occurs on cytoplasmatic proteins such as myelin basic protein (MBP), one of the components of the myelin sheath. While most studies have been focused on PADI role in the citrullination of cytoplasmatic proteins in disease, little is known on the epigenetic role of PADIs on oligodendrocyte precursor cells (OPCs) lineage progression both in health and in multiple sclerosis. We have found that PADI2 and PADI3, but not PADI4 are expressed in OPCs. Furthermore, PADI2 is located both in the nucleus and cytoplasm of OPCs and is upregulated during differentiation from OPCs to mature OLs. In contrast, PADI3 expression levels are downregulated upon OPC differentiation. Interestingly, our data indicates that inhibition of PADIs leads to an arrest of OPCs in an undifferentiated, immature state. As such, we hypothesize that PADI2/3 might be involved in the pathological process of MS, not only by mediating citrullination of MBP, but also by regulating the epigenetic state of OPCs and the remyelination process.


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1. Christophorou MA, Castelo-Branco G, Halley-Stott RP, et al. Citrullination regulates pluripotency and histone H1 binding to chromatin. Nature 2014. Disclosure Ana Falcao: Nothing to disclose Source of funding: ECTRIMS postdoctoral research fellowship, Swedish Research Council, European Union (Marie Curie, FP7), Swedish Brain Foundation, Swedish Society of Medicine, Clas Groschinsky foundation, Åke Wiberg Foundation, Karolinska Institutet Research Foundations P360 Genome-wide association analysis in a German multiple sclerosis cohort T.F.M. Andlauer1,2, D. Buck3, B. Hemmer2,3, B. MüllerMyhsok1,2,4, KKNMS, BASE-II, BiDirect, DOGS, FOCUS, GSK, HNR, KORA, MARS, popgen, SHIP 1Statistical Genetics, Max Planck Institute of Psychiatry, 2Munich Cluster for Systems Neurology (SyNergy), 3Department of Neurology, Technische Universität München, Munich, Germany, 4Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom *These

authors contributed equally. whom correspondence should be addressed. Background: Genome-wide association studies (GWAS) have already identified various chromosomal loci that are associated with multiple sclerosis (MS). However, so far no large study has been carried out for a German population. Objective: To identify novel MS susceptibility loci in a population showing only limited genetic heterogeneity. Methods: A GWAS discovery study on over six million partially imputed SNPs was conducted with 3534 German cases and 14906 German controls. We aimed at replicating associated polymorphisms with 1631 German cases and 3930 German controls. Results: In a meta-analysis of the discovery and the replication study several novel loci showed genome-wide significance (p< 5×10-8) in addition to previously published MS susceptibility loci. Conclusions: We identified novel MS susceptibility loci by conducting a large GWAS in a population of German cases and controls. **To

Disclosure Till FM Andlauer: nothing to disclose. D. Buck has received compensation for activities with Bayer HealthCare, BiogenIdec, MerckSerono, and Novartis. She is supported by the Abirisk Consortium. Bernhard Hemmer has served on scientific advisory boards for Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GSK, Chugai Pharmaceuticals, Micromet, Genentech and Genzyme Corporation; serves on the international advisory board of Archives of Neurology and Experimental Neurology; has received speaker honoraria from Bayer Schering, Novartis, Biogen Idec, Merck Serono, Roche, and Teva Pharmaceutical Industries Ltd; and has received research support from Biogen Idec, Bayer Schering, Merck Serono, Five prime, Metanomics, Chugai Pharmaceuticals and Novartis. He has been filed a patent for the detection of antibodies and T cells against KIR4.1 in a

subpopulation of MS patients and genetic determinants of neutralizing antibodies to interferon-beta. Bertram Müller-Myhsok: nothing to disclose. The study was funded by the Competence Network Multiple Sclerosis (KKNMS) (BMBF 01GI0917) and the Munich Cluster for Systems Neurology (SyNergy). P361 Genes and environment in multiple sclerosis: an integrated study of multiple sclerosis risk factors in first-degree relatives Z. Xia1, C. White1, D. Reich2, L. Chibnik1, P. De Jager1 1Brigham and Women’s Hospital Harvard Medical School, Boston, MA, 2National Institute of Neurological Disorders and Stroke, Besthesda, MD, United States Objective: Insights into multiple sclerosis (MS) risk factors have not yet been translated into strategies for primary prevention. The Genes and Environment in Multiple Sclerosis (GEMS) project evaluates risk factors and tools that enable a prospective study of high-risk individuals. Methods: For early detection of MS in first-degree relatives, we initiated the GEMS project in 2011. For each subject, we calculated a weighted genetic and environmental risk score (GERS) that includes 64 genetic risk factors as well as sex, infectious mononucleosis, and smoking status. We ascertained the MS incidence by assessing the number of incident MS cases over personyears of follow-up. Results: By leveraging patient advocacy groups and social media, the GEMS study recruited over 2,600 first-degree relatives from across the US. Analyzing the first 1,696 subjects (1,583 asymptomatic and 113 MS), we confirmed the role of smoking but not infectious mononucleosis as a risk factor for MS in these high-risk individuals. Similar to MS subjects, aymptomatic first-degree relatives have twice the rate of mononucleosis as the general population. Using the GERS, we identified a subset of family members that have more than twice the risk of developing MS than the average first-degree family member. Finally, we confirmed four incident cases of MS in these family members, providing an incidence estimate (123 cases per 100,000 annually) that is 30 times greater than that of sporadic MS. Interpretation: The Genes and Environment in Multiple Sclerosis (GEMS) project establishes a platform to investigate the events leading to MS and to test primary prevention strategies in individuals at risk of MS. Disclosure Dr. Xia has nothing to disclose relevant to this research. Dr. White has nothing to disclose relevant to this research. Dr. Reich has nothing to disclose relevant to this research. Dr. Chibnik has nothing to disclose relevant to this research. Dr. De Jager has nothing to disclose relevant to this research. P362 MicroRNA sequencing identifies down-regulated microRNA in CD4+ T-cells of secondary progressive multiple sclerosis patients K.A. Sanders1,2, M.C. Benton3, R.A. Lea2,3, V.E. Maltby4, S. Agland5, R.J. Scott4, J. Lechner-Scott4,5, L. Tajouri1


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Poster Session I, 21(S11) 1Faculty

of Health Sciences and Medicine, Bond University, Gold Coast, QLD, 2Hunter Medical Research Institution, Newcastle, NSW, 3Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, 4Centre for Information Based Medicine, Hunter Medical Research Institution, 5Neurology, John Hunter Hospital, Newcastle, NSW, Australia The role of microRNA (miRNA) in multiple sclerosis (MS) extends beyond their use as biomarkers. Commonly, miRNAs are thought to regulate gene expression. Determining their impact on immune related cell functions during disease progression should greatly advance our understanding of MS pathophysiology. The total coverage approach of next generation sequencing (NGS) identifies all known, and potentially novel, miRNAs associated with disease. Aim: The aim of this study is to compare miRNA profiles of CD4+ T-cells from secondary progressive MS (SPMS) patients and healthy controls (HC). Methods: PBMCs were isolated from 25 untreated SPMS patients (17 female) and 22 age and gender-matched HC (14 female). RNA was extracted from CD4+ T cells and subjected to NGS for miRNA. Results: Our preliminary data is based on NGS of 12 SPMS patients and 12 HC samples. Sequence reads were aligned to the human genome (hg19) and miRBase v20. Using stringent statistical criteria (FDR< 0.5), the top ten differentially expressed miRNAs were identified; all ten candidates were down-regulated in SPMS compared to HC. Using mature miRNA TaqMan assays (Applied Biosystems) we confirmed down-regulation of three miRNAs in CD4+ T-cells of SPMS patients in all samples (25 SPMS and 22 HC): miR-21-5p (p< 0.005), miR-29b-3p and miR155-5p (p< 0.001). Conclusion: This is the first MS study to find miR-155 differentially expressed in CD4+ T-cells of SPMS patients. Interestingly, miR-155 was described to be up-regulated in active brain lesions promoting myelin phagocytosis. The functional consequence of miR-155 down-regulation in SPMS is unclear; however, it may be specific for progressive MS as expression is unchanged in patients with relapsing-remitting disease. Down-regulation of miR-29b may be caused by decreased IFNgamma in SPMS compared to RRMS though the impact of this down-regulation on CD4+ T-cell activity is yet to be elucidated. Furthermore, an up-regulation of miR-29b in lupus CD4+ T-cells is associated with DNA hypomethylation. There are currently no studies on DNA methylation in SPMS, though it would be interesting to see if the down-regulation of miR-29b that we have identified in SPMS CD4+ T-cells is associated with genome-wide hypermethylation. miR 21-5p has been described to target Il-12, pivotal for Th1 polarization. Further work is required to determine the effect of these miRNAs on CD4+ T-cell role in MS progression. Disclosure Katherine A Sanders, Miles C Benton, Rod A Lea, Vicki E Maltby, Rodney J Scott, Lotti Tajouri have nothing to disclose. Susan Agland has recieved speaker fees and travel compensation from Biogen, Genzyme and Novartis. Jeannette Lechner-Scott has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the

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honoraria for talks and advisory board commitment and also clinic support as well as research grants from Bayer Health Care, Biogen Idec, CSL, Genzyme Sanofi, Merck Serono and Novartis. This study was supported by HMRI and Jhh Charitable Trust. P363 Relapse-related miRNA signature regulates general metabolism processes in leucocytes and a different underexpressed miRNA subset in remission is involved in the regulation of innate immunity M. Muñoz-Culla1,2, H. Irizar1,2, M. Sáenz-Cuesta1,2, T. CastilloTriviño1,2,3, I. Osorio-Querejeta1,2, L. Sepúlveda1,2, A. López de Munain1,3,4, J. Olascoaga1,2,3, D. Otaegui1,2 1Biodonostia Institute, San Sebastian, 2Spanish Network on Multiple Sclerosis, Madrid, 3Hospital Universitario Donostia, 4University of the Basque Country, San Sebastian, Spain Background: In last years several studies have reported that miRNA expression levels are altered in multiple sclerosis (MS) patients comparing to healthy donors in leukocytes, MS brain lesions and circulating in serum and cerebrospinal fluid. Furthermore, few studies have identified some miRNAs to be altered during relapse phase of relapsing-remitting multiple sclerosis (RRMS). Yet, the meaning of the alteration in miRNA expression level is still unclear. Objectives: Our aim was to assess the implication of altered miRNA expression pattern during relapse and during remission phase of relapsing-remitting multiple sclerosis. Methods: Blood from 24 RRMS was collected during relapse and during remission (paired samples) and sex- and age-matched 24 healthy donors. Relapse blood sample was collected before giving any corticosteroid treatment. Total RNA was isolated from blood leucocytes and 500 ng were labeled and hybridized to the GeneChip miRNA array v1 (Affymetrix), which includes miRNA and snoRNA probes. For the relapse vs remission comparison, we only considered those patients who were receiving the same treatment at both phases of the disease and the comparisons were made segregating the groups by sex. To identify targets of differentially expressed miRNAs, first, in silico analysis was performed and afterwards protein-coding gene expression information was included, which was available for the same patients. These interactions were visualized as networks and gene ontology analysis was carried out to identify enriched biological processes regulated by miRNA in relapse and remission. Results: We found 25 altered miRNA in females during relapse while in males none of the miRNAs were differentially expressed in relapse. Yet, during remission phase 38 miRNA were altered in females and 5 in males, comparing to healthy controls. Female relapse-related differentially expressed miRNA subset seem to target genes which are involved in general metabolism of leucocytes, whereas remission-related miRNAs regulate genes taking part in innate immune response and homeostasis of number of cells in females. Male remission miRNA signature did not result in any enriched biological process. Conclusions: miRNA expression pattern related to relapse in female patients regulate general metabolism pathways in peripheral leucocytes whereas during remission a different miRNA signature regulate genes involved in innate immunity.


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Disclosure Muñoz-Culla M: nothing to disclose. Irizar H: nothing to disclose. Sáenz-Cuesta M: nothing to disclose. Castillo-Triviño T: nothing to disclose. Osorio-Querejeta I: nothing to disclose. Sepúlveda L: nothing to disclose. López de Munain A: nothing to disclose. Olascoaga J: nothing to disclose. Otaegui D: nothing to disclose. Funding: This work was supported by the Instituto de Salud Carlos III (grant PS09/02105). MMC, HI and IOQ were supported by pre-doctoral fellowships from the Basque Government. TCT and MSC were fellows from Rio Hortega programme from the Instituto de Salud Carlos III. IOQ has been partially supported by a grant from Fundación Gangoiti. P364 TARDBP Ala382Thr mutation and C9orf72 expansion in a Sardinian MS population L. Lorefice1, M.R. Murru2, G. Fenu1, D. Corongiu2, J. Frau1, S. Cuccu2, G. Coghe1, S. Tranquilli3, M.G. Marrou4, E. Cocco1 1Multiple Sclerosis Center, Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, Italy, University of Cagliari, 2Multiple Sclerosis Center, ASL8Department of Medical Sciences, University of Cagliari, Italy, 3Institute of Neurology, ASL8-Department of Medical Sciences, University of Cagliari, Italy, 4Multiple Sclerosis Center, Department of Medical Sciences, University of Cagliari, Italy, University of Cagliari, Cagliari, Italy Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by inflammation and accompanied and followed by neurodegeneration. 1 Missense mutations of the TARDBP gene located in the chromosome 1p36.22 region, and more recently, the exanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72), are pathogenic in other neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration.2 Assuming that TARDBP Ala382Thr mutation and C9orf72 expansion may underlie MS, we evaluated their frequency in a large cohort of MS patients and controls from Sardinia, an island characterized by a very high frequency of MS and an unusual genetic background. 3 Genomic DNA was extracted from peripheral blood and analyzed for the presence of a TARDBP Ala382Thr mutation and C9orf72 expansion. Difference in the frequency of these mutations between MS patients and controls was calculated using the c2 test with a standard 2×2 table. The Ala382Thr mutation in its heterozygous state was found in 27/1833 patients (1.4%) and 20/1475 controls (1.3%), whereas C9orf72 pathogenic repeat expansion was found in 4/1014 MS patients (0.3%) and 2/333 controls (0.6%). Individuals carrying the mutations did not present with other neurodegenerative conditions and any differences were reported between groups. TARDBP Ala382Thr variant and C9orf72 expansion do not play a major role in MS pathogenesis in the Sardinian population. Further analyses on larger samples of MS patients from other populations are needed to better define the possible role of these

genetic variants in the complex interplay between neuroinflammation and neurodegeneration in MS. Keywords: MS pathogenesis; neurodegeneration; TARDBP Ala382Thr mutation; C9orf72 expansion; genetic background; Sardinian population 1.Charil A, et Al. J Neurol Sci. 2007 Aug 15;259(1-2):7-15. 2.Chiò A, et Al. Arch Neurol. 2011 May;68(5):594-8 3. Lampis R, et Al.Hum Mol Genet. 2000 Dec 12;9(20):2959-65 Disclosure Conflict of Interest No conflict of interest exists regarding the present paper. Dr. Lorefice received speaker fee from Teva and serves on scientific advisory boards for Biogen. Dr. Fenu received honoraria for consultancy from Novartis and for speaking from Merck Serono and Teva. Dr. Frau serves on scientific advisory boards for Biogen, received honoraria for speaking from Merck Serono and Teva. Dr. Coghe received speaker fee from Teva. Professor Marrosu and Professor Cocco have received honoraria for consultancy or speaking from Bayer, Biogen-Idec, Novartis, Sanofi-Genzyme, Serono and Teva. P365 CD86 genetic risk in multiple sclerosis B. Fiddes, M. Ban, S. Sawcer University of Cambridge, Cambridge, United Kingdom Objective: Genome wide association studies (GWAS) have identified over 100 associated variants but little is known about the functional effects of these variants. Attempts to refine these genetic signals using the Immunochip showed that in several regions more than one independently associated variant exists. On chromosome 3q13 three closely mapped SNPs were identified rs9282641, rs2255214 and rs1920296 which positionally implicate the gene CD86. The CD86 gene plays an important immune role as a costimulatory molecule required for T cell survival and activation. There are at least seven alternatively spliced transcripts of CD86. In our study we sought to investigate how these variants may affect CD86 mRNA transcript and protein expression. Methods: Healthy controls from the Cambridge BioResource were selected according to genotype and donated blood from which PBMCs were isolated. Monocytes and B cells were then separated using magnetic bead technology. Separated cells were lysed and stored for subsequent RNA extraction, clean up, and conversion to cDNA. Quantitative real time PCR was then carried out with primers and probes designed to amplify the transmembrane, soluble, exon 1-, and exon 2-starting transcripts. Results: Interim analysis of the first 63/120 samples indicates that all 3 variants affect CD86 mRNA and cell surface protein expression, but with the strongest overall effect from rs9282641, the variant within the CD86 gene 5’ UTR. In monocytes, there is a consistent trend for lower expression of the soluble CD86 transcript in the risk homozygotes compared to the protective allele homozygotes and heterozygotes, but a higher expression of the CD86 transcripts overall (those starting with an exon 1 or an exon 2). Conclusions: Our data indicate that all three variants exerts effect on MS risk by altering CD86 expression.


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Poster Session I, 21(S11) Disclosure B. Fiddes is supported by the Sackler studentship and the research is funded by The Multiple Sclerosis Society M. Ban: nothing to disclose S. Sawcer: nothing to disclose P366 Influence of the multiple sclerosis-associated IL2RA SNP rs2104286 on gene expression in healthy individuals and multiple sclerosis patients S. Buhelt1, H.B. Søndergaard1, R. Ratzer2, J.R. Christensen2, L. Börnsen1, F. Sellebjerg2 1Danish Multiple Sclerosis Center, Copenhagen University Hospital Rigshospitalet, 2Department of Neurology, Section 2082, Danish Multiple Sclerosis Center, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark Introduction: Genome Wide Association Studies (GWAS) have shown an association between an intronic single nucleotide polymorphism (SNP) rs2104286 in the IL2RA gene and multiple sclerosis (MS) susceptibility. With an OR of 1.22 (p-value = 2.3 × 10-47) the rs2104286 is one of the most strongly associated nonMHC loci. Compared to the protective allele (CT or CC), the risk allele (TT) increases: Levels of soluble IL-2rα (sIL-2R-α)in sera; CD4+ naive T cells; CD25 surface expression on stimulated CD14+CD16+ monocytes and the frequency of GM-CSF producing helper T cells. Objective: To study whether gene expression in peripheral blood mononuclear cells (PBMCs) from healthy controls (HCs) and MS patients is associated with IL2RA SNP rs2104286 genotype, and whether gene expression levels correlate with sIL-2rα concentration. Method: The study was conducted on 18 HCs and 51 MS patients. The genotype distribution among HCs were 9/8 (TT/CT+CC) and 32/19 (TT/CT+CC) among the MS patients. Gene expression levels were analysed on PBMCs using Affymetrix Human Gene ST 1.0 microarray. Gene expression levels were compared between genotypes in MS patients and HCs. The level of significance was set at p-value < 0.01 and a 1.2 fold difference. The concentration of sIL-2rα in plasma was measured on all individuals and measurements were correlated with gene expression levels. The correlation cut-off was R > 0.707 and p-value < 0.01. Results: In MS patients, no genes were found to correlate with sIL-2rα concentrations. When comparing rs2104286 genotypes with gene expression in MS patients, 74 genes were differentially expressed. Among those were IL2RA, CTSW, GNLY, CD226, TLR6, CD64, KIR2D2S. In HCs sIL-2rα plasma concentrations correlated with expression of 111 genes. Among those were GABPA, TRADD and LITAF. The comparison of genotype and gene expression in HCs showed that 68 genes were differentially expressed. Conclusion: The study shows that the IL2RA SNP rs2104286 may influence gene expression levels in both HCs and MS patients, and that gene expression in HCs correlates with plasma sIL-2rα concentrations. This was not observed in MS, suggesting that immunological alterations in established MS may compromise the ability to demonstrate the biological effect of MS-associated SNPs. Future studies should be conducted on specific cell subsets and performed on HCs selected on genotype to

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increase the number of homozygote individuals for the protective allele (CC). Disclosure Sophie Buhelt has received travel grants from Merck Serono for seminar participation. Helle Bach Søndergaard reports no disclosures relevant to the manuscript Rikke Ratzer has had travel expenses reimbursed by Genzyme, Merck Serono, TEVA, Biogen Idec and Sanofi Aventis. Jeppe R. Christensen has received speaker honoraria from Genzyme and TEVA, consultant honoraria from Biogen Idec and TEVA, and has had travel expenses reimbursed by Biogen Idec and Merck Serono. Lars Börnsen has had travel expenses reimbursed by Novartis and by Genzyme for congress participation. Finn Sellebjerg has served on scientific advisory boards for Biogen Idec, Genzyme, Merck Serono, Novartis and Teva, served as consultant for Biogen Idec and Lundbeck; has received support for congress participation from Biogen Idec, Novartis and Teva; has received speaker honoraria from Biogen Idec, Genzyme, Merck Serono and Novartis. His laboratory has received research support from Biogen Idec and Novartis. P367 Whole exome and transcriptome sequencing identifies NR1H3 (LXRA) p.Arg415Gln in familial progressive multiple sclerosis C. Vilarino-Guell, A.L. Traboulsee, Z. Wang, W. Song, A.D. Sadovnick University of British Columbia, Vancouver, BC, Canada Background: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although genetic variants with relatively small effect on disease risk have been identified, pathogenic mutations responsible for Mendelian forms of MS have remained elusive despite the aggregation observed in some families. Methods: Whole-exome sequencing analysis was performed in a family with high incidence of MS. Variants of interest were assessed for segregation and genotyped in a case-control series consisting of 2,053 MS patients and 799 healthy controls from Canada. Whole transcriptome sequencing, protein binding assays and luciferase reporter analysis were used to determine the biological impact of the mutation. Results: We identified NR1H3 p.Arg415Gln in seven MS patients from two multi-incident families and not in controls. The clinical phenotype for mutation carriers was consistent for severe and progressive disease with an average age at onset of 35 years. NR1H3 encodes liver X receptor alpha (LXRA) which forms obligate heterodimer complexes with retinoid X receptors (RXR) and binds to LXR response elements activating transcription. The p.Arg415 position in LXRA is located on the surface of its ligand binding domain, and is highly conserved in orthologs and nuclear receptor paralogs. Co-immunoprecipitation and luciferase assays indicate that the NR1H3 p.Arg415Gln mutation identified in MS families disrupts LXRA heterodimerization resulting in deficient transcriptional activation of its target genes. In addition to this


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pathogenic mutation, association analysis of common variants in NR1H3 resulted in a 1.35-fold increased risk of developing primary progressive MS. No association was observed with relapsing remitting disease. Conclusions: We have identified a pathogenic mutation in NR1H3 causing familial progressive MS. In addition, common NR1H3 variants were shown to increase the risk of primary progressive MS. Biological characterization of LXRA indicates that these mutations disrupt the transcriptional regulation of inflammatory mediators and peripheral myelin genes triggering the onset of disease. This discovery will prove instrumental for the generation of physiologically relevant cellular and animal models of MS, and suggests that pharmacological activation of LXRA or its targets may lead to effective treatments for the highly debilitating and currently untreatable progressive phase of MS.

point. Next, DNA was isolated, bisulfite treated, amplified by PCR, cloned in One Shot® TOPTEN E. coli cells and eventually sequenced for each gene promoter. Then, percentage of DNA methylation for individual CpGs was assessed by QUMA software. Results: At the initial filtering stage, comprising the assessment of 4 patients versus 4 controls, we pinpointed a hypermethylated locus in RRMS patients within an alternative promoter of the vitamin D receptor gene (VDR). Namely, two CpGs located at the end of the examined amplicon showed a gain in methylation in RRMS patients compared to controls (CpG-263: 55.9% vs 34%; p=0.029 and CpG-298: 45.3% vs 20.1%; p=0.029). Conclusions: VDR is a highly conserved transcription factor that mediates the pleiotropic effects of vitamin D. Further studies are guaranteed to elucidate the functional meaning of this finding in RRMS patients.

Disclosure

Disclosure

ADS has received unrestricted research funding from Genzyme, Novartis, BiogeIdec and Teva Neuroscience as well as travel sponsorship from BiogenIdec. ALT received grant support from Hoffman la Roche and Sanofi Genzyme; steering committee membership for Hoffman la Roche; consultancy for Biogen, Chugai, EMD Serono, Hoffman la Roche, Medimmune, Sanofi Genzyme, Teva Neuroscience. CV-G reports grants from the Canada Research Chair, Canadian Institute of Health Research, Vancouver Coastal Heath Research Institute, Milan & Maureen Ilich Foundation and Vancouver Foundation. In addition, CV-G has a patent No. 62/042,956 “biomaker for multiple sclerosis” pending. All other authors have nothing to disclose.

Source of funding: This work was supported by funding from Novartis Pharma AG, Basel, Switzerland and a grant awarded by “Fundación Genzyme” (grant number FG EM02_2014). Aznar P.: nothing to disclose Ayuso T.: nothing to disclose Soriano L.: nothing to disclose Roldán M.: nothing to disclose Otano M.: nothing to disclose Ajuria I.: nothing to disclose Soriano G.: nothing to disclose Lacruz F.: nothing to disclose Mendióroz M.: nothing to disclose

P368 DNA methylation profiling of vitamin D pathway genes in T-cells from RRMS patients compared to healthy controls P. Aznar1,2,3, T. Ayuso1,2,3, L. Soriano3,4, M. Roldán3,4, M. Otano1,2,3, I. Ajuria1,2,3, G. Soriano1,2,3, F. Lacruz1,2,3, M. Mendióroz2,3,4 1Multiple Sclerosis Unit. Department of Neurology., 2Department of Neurology, Complejo Hospitalario de Navarra, 3Instituto de Investigación Biomédica de Navarra-IdisNA, 4Neuroepigenetics Laboratory, Navarrabiomed-Fundación Miguel Servet, Pamplona, Spain Background: Vitamin D deficiency has been linked to increased risk of multiple sclerosis (MS) and so, immunomodulating properties of vitamin D are being widely studied. Nevertheless, the specific role that vitamin D plays in MS remains still unknown. On the other hand, epigenetic mechanisms are thought to be involved in MS pathogenesis, since MS susceptibility is influenced by both genetic and environmental factors. One of the most relevant epigenetic mechanisms that regulate gene expression is DNA methylation at CpG sites (CpGs) in the genome. Goals: Our aim was to identify differentially methylated regions at the promoter of genes involved in the vitamin D pathway (i.e. CYP2R1, CYP27B1, CYP24A1, VDR and RXRB) in MS patients. Methods: We isolated human T cells derived from whole blood by negative selection in a set of 12 relapsing-remitting MS (RRMS) patients and 12 controls matched by age and gender. None of them was under vitamin D supplementation at the blood collection time

Immunology P369 Interleukine 17 is detected in CSF in radiologically and clinically isolated syndromes C. Lebrun1, M. Cohen1, B. Pignolet2, B. Seitz-Polzi3, A. Cornille3, F. Bucciarelli2, S. Benzaken3, D. Brassay2, CFSEP, BIONAT, BEST MS, RISC 1Neurologie, Nice, 2Neurologie, Toulouse, 3Immunology, Nice, France Background: Increased serum IL-17 levels are associated with numerous autoimmune diseases as rheumatoid arthritis, psoriasis, Crohns disease or systemic lupus erythematosus. In MS, exploratory studies reported increased levels in CSF but results in detecting IL-17 in serum are controversied, sometimes detected during relapses or in case of IFNbeta non response. Objectives: To investigate levels of IL-17 in serum and CSF in patients diagnosed as Radiologically Isolated syndrome, Clinically Isolated Syndrome or active multiple sclerosis patients (RIS, CIS, A MS) as a marker of inflammatory condition. To correlate IL-17 levels to known clinical and MRI markers of disease activity. Methods: 1177 patients with active MS, defined by 2 recent relapses and gadolinium enhancing lesions, 50 patients diagnosed with RIS, 50 with CIS were tested.The cytokine IL-17 A was measured in Serum and CSF using a FIDIS Human cytokine IL17 kit. Standards were reconstituted in assay diluents and serial dilutions were made to provide a standard curve. The mean coefficient


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Poster Session I, 21(S11) of variation for the samples assayed using these methods was 10% for the two groups and 5% for control group. Statistical analysis was conducted using Kruskall-Wallis test. Results: Patients characteristics were: women: 74%AMS, 65%CIS, 75%RIS; Mean age (Yrs): AMS:28.5, CIS:35.3, RIS:34.9. IL-17A was not detected in blood samples neither in AMS nor in RIS or CIS patients excepted for 25 AMS patients (0.32%, mean age:22yrs, 64%women) with a mean of 0.52 pg/ml (0.09-1.33). The detection rate of IL-17 A was strictly identical in the CSF of RIS or CIS patients, respectively 0.70 pg/ml (0.311.46) and 0.72 pg/ml (0.31-1.46). No correlation was found between CSF IL level and number of Barkhof Criteria on the initial brain MRI, detection of brain or spinal gadolinium enhancing lesions, presence of spinal cord lesions,CSF increased IgG Index or detection of oligoclonal band. No difference has been found between RIS who early clinically converted and with CIS patients who rapidly evolve in McDonald or clinically definite MS. Conclusion: These findings strongly suggest that in RIS and in CIS patients, intrathecal activation of the IL-17 is similar, confirming that RIS is the initial step of the demyelinating disease. IL-17A was not detected in sera patients even at the very active stage of the disease, excepted in few younger patients. No correlation has been found with known Clinical, CSF or MRI markers of disease activity. Disclosure Lebrun C: Nothing to disclose, Cohen M: Nothing to disclose, Pignolet B has a grant NCT00942214 and NCT01981161, Seitz-Polzi B: Nothing to disclose, Cornille A: Nothing to disclose, Bucciarelli F has a grant NCT00942214 and NCT01981161, Benzaken S: Nothing to disclose, Brassat D: Nothing to disclose. P370 Interleukin 18, chemokines CXCL10 and CXCL13 in the serum and cerebrospinal fluid of patients with relapsingremitting and primary progressive multiple sclerosis P. Iwanowski1, L. Kramer2, M. Wójcicka1, E. Kaufmann1, K. Kapica-Topczewska3, W. Drozdowski3, J. Losy4,5 1Department of Clinical Neuroimmunology, Chair of Neurology, 2Department of Computer Sciences and Statistics, Poznan University School of Medicine, Poznan, 3Department of Neurology, University of Medical Sciences, Białystok, 4Department of Clinical Neuroimmunology, Poznan University School of Medicine, 5Neuroimmunological Unit, Medical Research Center of the Polish Academy of Sciences, Poznan, Poland TITLE Interleukin 18, chemokines CXCL10 and CXCL13 in the serum and cerebrospinal fluid of patients with relapsing-remitting and primary progressive multiple sclerosis Background and goals: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with distinct clinical patterns. The differences between relapsing-remitting (RRMS) and primary progressive (PPMS) include differences in neuropathological and immunological

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profiles, which are not yet fully explored.CXCL13 chemokine play a role in recruitment of B cells and T cells subsets expressing receptor CXCR5 to the CNS.CXCL-10 chemokine is CXCR3 receptor ligand whose role consists in attracting T helper 1-type (Th1) cells to the CNS. Interleukin 18 (IL-18) is a proinflammatory cytokine which enhances the production of IFN-gamma by Th1 cells.The aim of the study is to investigate the concentrations of IL-18, chemokines CXCL10 and CXCL13 in serum and cerebrospinal fluid (CSF) of patients with RRMS and PPMS, and to compare both forms of the disease with a control group consisting of patients with other neurological disorders (OND). Methods: 15 patients with PPMS (46,8±11 years old), 15 patients with RRMS (39,9±13,6 years old) and 10 patients with OND (38,4±12,1 years old) have been included in the study.Quantitative test kit based on sandwich ELISA has been used for cytokine and chemokines measurement.Kruskal-Wallis test with Dunn´s Multiple Comparisons for statistical analysis. Results: The concentration of CXCL13 in CSF was higher in PPMS (30,6 ±17,9 pg/ml) than in RRMS (11,9 ±12,6 pg/ml) (p=0,18) or OND (5,5 ±7,9 pg/ml) (p=0,07) In PPMS serum IL-18 level (269,2 ±87,0 pg/ml) was significantly higher (p=0,048) in comparison with RRMS (196,5 ±51,4 pg/ml). In PPMS serum CXCL10 level (121 ±75 pg/ml) was also higher (p=0,07) in comparison with RRMS (73,5±31,2pg/ml) In RRMS CSF CXCL10 level (201,2 ±100,7 pg/ml) was higher (p=0,06) in comparison with control group (122,5 ±29,2 pg/ml). Conclusions: Results demonstrate some immunological differences between RRMS and PPMS. Immune and inflammatory mechanisms are present in both forms of MS.The higher concentration of CXCL13 in CSF among patients with PPMS in comparison with RRMS may be connected with more important role of humoral response in PPMS, because CXCL13 is chemoattractant for B cells trafficking to the CNS. Disclosure Piotr Iwanowski: Nothing to disclose Lucyna Kramer: Nothing to disclose Marlena Wójcicka: Nothing to disclose Elżbieta Kaufmann: Nothing to disclose Katarzyna Kapica-Topczewska: Nothing to disclose Wiesław Drozdowski: Nothing to disclose Jacek Losy: Nothing to disclose P371 Different pathophysiological relevance of branched fatty acid metabolism in mice and men: alpha-methylacyl-CoA racemase regulates the T cell response only in experimental autoimmune encephalomyelitis but not in multiple sclerosis C.A. Mayer1, N. Tafferner2, J. Barthelmes3, M. Eberle3, N. Ferreiros3, T. Ulshöfer2, M. Henke2, N. de Bruin2, G. Geisslinger2,3, C. Foerch1, M.J. Parnham2,3, S. Schiffmann2,3 1Neurology, Goethe University Frankfurt, 2Fraunhofer Institute for Molecular Biology and Applied Ecology IME, 3Pharmazentrum Frankfurt/ZAFES, Goethe University Frankfurt, Frankfurt am Main, Germany Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), therefore targeting the


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metabolism of immune cells is an attractive strategy to modify their function during autoimmunity in MS. We investigated the effects of modulating fatty acid metabolism in an animal model of multiple sclerosis, the experimental autoimmune encephalomyelitis (EAE). Alpha-methylacyl-CoA racemase (AMACR) prepares R-configurated branched fatty acids for metabolic ß-oxidation by coverting them into the S-configuration. We observed significant, disease-dependent elevation of AMACR expression in various immune cells from blood, draining lymph nodes and spleen in EAE mice during the preclinical phase. In vitro studies further revealed that genetic deletion of AMACR inhibits the proliferation of T cells. Activated T cells isolated from AMACR knockout (KO) mice are characterized by a higher production of IFN-γ, IL-17 and IL-10 and a lower production of IL-4 in comparison to T cells of wild type mice. AMACR-deficient mice showed a significant but, however, only slight worsening of early clinical symptoms of EAE in comparison to wild type mice. AMACR was not regulated in white blood cells of MS patients. Our data thus suggest that AMACR is regulated in immune cells during EAE but is neither essential for the development of EAE nor a relevant player in pathology of Multiple Sclerosis Disclosure Christoph Mayer: Received travel grants from genzyme, biogen and Merck serono and speakers honoraria from genzyme, Merck serono and biogen Nadja Tafferner: Nothing to disclose Julia Barthelmes: Nothing to disclose Max Eberle: Nothing to disclose Nerea Ferreiros: Nothing to disclose Thomas Ulshöfer: Nothing to disclose Marina Henke: Nothing to disclose Natasja deBruin: Nothing to disclose Marina Henke: Nothing to disclose Natasja deBruin: Nothing to disclose Christian Foerch received travel grants from TEVA pharma, biogen and genzyme and speakers honoraria from genzyme and biogen Gerd Geisslinger: Nothing to disclose Michael J. Parnham: Nothing to disclose Susanne Schiffmann: Nothing to disclose P372 Endogenous soluble TACI is elevated in multiple sclerosis patients and shares functional properties with atacicept F.S. Hoffmann1, P.-H. Kuhn2,3, S.A. Laurent1, S.M. Hauck4, M. Khademi5, T. Olsson5, R. Hohlfeld1,6, S.F. Lichtenthaler2,3,6, E. Meinl1 1Institute of Clinical Neuroimmunology, Ludwig Maximilian University, 2Neuroproteomics, Technical University, 3German Center for Neurodegenerative Diseases (DZNE), 4Research Unit Protein Science, Helmholtz Zentrum, Munich, Germany, 5Division of Clinical Neuroscience, Karolinska University Hospital, Stockholm, Sweden, 6Munich Cluster for Systems Neurology (SyNergy), Munich, Germany The BAFF-APRIL system is critically involved in controlling B-cell homeostasis. Deficiency of the BAFF-APRIL-receptor TACI results in hypogammaglobulinemia, lymphoproliferation,

tumor formation, and autoimmunity. TACI-Fc (atacicept), a soluble fusion protein containing the extracellular domain of TACI, was applied in clinical trials. However, disease activity in multiple sclerosis (MS) unexpectedly increased. Generation of soluble receptors is a common feature in the regulation of inflammatory processes. Here, we show that an endogenous soluble form of TACI exists in vivo and characterize the structure and function of this soluble receptor. TACI proteolysis involved shedding by ADAM10 releasing sTACI from activated B cells. The membrane-bound stub was subsequently cleaved by γ-secretase. The shed ectodomain assembled ligand-independently in a homotypic way. It functioned as a decoy receptor inhibiting BAFF- and APRILmediated B-cell survival and NFkB-activation. sTACI levels were increased in the cerebrospinal fluid (CSF) of MS patients correlating with intrathecal IgG production. Further, immunoregulatory treatment influenced sTACI levels as we found decreased sTACI levels in the CSF of MS patients 12 months after initiation of monthly intravenous natalizumab treatment and 3 days after corticosteroid treatment. Together, we show that TACI is sequentially processed by ADAM10 and γ-secretase. The released sTACI is an immunoregulator that shares decoy functions with atacicept. It reflects compartmentalized B-cell accumulation and activation. We identify a new regulatory player in the BAFF-APRIL system that one has to keep in mind when therapeutically targeting this system. Disclosure The autors report no conflicts of interest. This work was supported by the DFG (SFB TR128), the BMBF (‘Krankheitsbezogenes Kompetenznetz Multiple Sklerose’ and ‘Kompetenznetz Degenerative Demenzen’), the Munich Cluster for Systems Neurology (ExC 1010 SyNergy), the FriedrichBaur-Stiftung and the Verein zur Therapieforschung für Multiple-Sklerose-Kranke. P373 Modulation of tregs and invariant natural killer T cells by fingolimod in relapsing-remitting multiple sclerosis patients D. Ferraro1, A.M. Simone1, F. Vitetta1, S. De Biasi2, M. Nasi2, E. Bianchini2, L. Gibellini2, M. Pinti3, R. Orlandi1, C. Del Giovane4, A. Cossarizza2, P. Sola1 1Department of Biomedical Metabolic and Neurosciences, 2Department of Surgery, Medicine, Dentistry and Morphological Sciences, 3Department of Life Sciences, University of Modena and Reggio Emilia, Modena, 4Department of Diagnostic and Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy Introduction: Altered numbers and/or functions of T regulatory (Tregs) and invariant Natural Killer T (iNKT) cells have been reported in Multiple Sclerosis (MS). Tregs play a crucial role in controlling autoreactivity while iNKT cells are potent cytokine producers and have immunoregulatory potential. Objective: To evaluate the effect of fingolimod (FTY) on different lymphocyte subsets, including Tregs and iNKT cells, in Relapsing-Remitting (RR) MS patients before and after 3, 7, 14 days and 1, 6 and 12 months of treatment, and to correlate immunological data with efficacy and safety data.


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Poster Session I, 21(S11) Methods: CD3+, CD4+ and CD8+ T cells were volumetrically counted on whole blood using a CyFlow Counter (Partec, Muenster, Germany). Isolated PBMCs were stained with different mAbs and analyzed with a 16-parameter Partec CyFlow ML. Treg cells were identified using anti-CD3, -CD4, -CD25, -CD127, Foxp3; iNKT cells were recognized using anti-CD3, -CD4, -CD8, CD161 and -Va24Ja18. Baseline and follow-up clinical and MRI data was collected. Data was analyzed by FlowJo 9.7.4 and Stata 11.0 using Ranksum and Skillings-Mack test. Results: We enrolled 30 patients (21F, 9M, mean age: 40±9 years). To date, 13 have completed 12 months and 19 have completed 6 months of treatment. Eight patients discontinued FTY (2 due to relapses and 5 due to adverse events); 8 patients presented a relapse and 7 patients presented infections. As expected, the number of CD3+, CD4+ T and CD8+ T cells decreased significantly after 7 days of therapy and remained at low values throughout the year, while the percentage of CD8+ cells increased. The number of Tregs decreased while the percentage of Tregs increased (from 3.2% to 5.2% at six months). The number and percentage of iNKT cells did not change. However, within iNKT cells, the percentage of those expressing CD4+ decreased (from 50% to 17%), while those that were CD8+ and CD4- CD8- increased (from 19% to 41% and 21% to 33%, respectively, at six months). Patients who presented a relapse had higher values of CD4- CD8iNKT cells (which have a Th1 profile) and patients who presented with infections had lower amounts of CD8+ T cells (p=0.034 and p=0.041, respectively, though not significant after Bonferroni correction). Conclusion: The beneficial effects of FTY may, in part, be mediated by the increase in Tregs and in iNKT CD8+ cells, which could be important in regulating the proliferation of autoreactive cells. Disclosure Sponsored by FISM (Italian Foundation for Multiple Sclerosis) to Andrea Cossarizza Diana Ferraro has received travel grants from Novartis. Anna Maria Simone: Nothing to disclose. Francesca Vitetta: Nothing to disclose. Sara De Biasi: Nothing to disclose. Milena Nasi: Nothing to disclose. Elena Bianchini: Nothing to disclose. Lara Gibellini: Nothing to disclose. Marcello Pinti: Nothing to disclose. Riccardo Orlandi: Nothing to disclose. Cinzia Del Giovane: Nothing to disclose. Patrizia Sola has received travel grants from Novartis. P374 A multicenter study on the diagnostic significance of a single cerebrospinal fluid IgG band: preliminary results D. Ferraro1, E. Cocco2, M. Calabrese3, R. Orlandi1, R. Bedin1, F. Vitetta1, A.M. Simone1, C. Solaro4, C. Gasperini5, M.E. Rodegher6, P. Sola1, RIREMS Group (Rising Italian Researchers in Multiple Sclerosis) 1Department of Biomedical Metabolic and Neurosciences, University of Modena and Reggio Emilia, Modena, 2Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, 3Department of Neurological and Movement

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Sciences, University Hospital of Verona, Verona, 4Neurology Unit, Ospedale PA Micone, Genova, 5Neurology Unit, Ospedale San Camillo Forlanini, Rome, 6Scientific Institute, Ospedale San Raffaele, Milan, Italy Introduction: The finding of a single cerebrospinal fluid (CSF) Immunoglobulin G (IgG) band is rare and only few studies have explored its frequency and diagnostic significance. Objective: To establish 1) the diagnoses associated with the finding of a single CSF IgG band, 2) the proportion of patients with a single IgG band who will be diagnosed with Multiple Sclerosis (MS) within the following 2 years and 3) whether there are differences in the CSF characteristics of patients subsequently diagnosed with MS compared to those with alternative diagnoses, in a multicenter study. Methods: We collected clinical and CSF data of patients who showed a single CSF-restricted IgG band, with or without an associated “mirror pattern”, at CSF isoelectric focusing (IEF) analysis, carried out for any reason, from 2005 onwards. Results: Out of 4710 CSF IEF analyses, 112 showed a single CSF IgG band (2.4%). In another cohort of 500 CSF analyses carried out for suspected MS, only 2 showed a single CSF IgG band (0.4%). Clinical records were available for 52 patients and a definite diagnosis was established in 49 patients. MS was diagnosed in 19 (39%) patients, central nervous system (CNS) infections in 3 (6%), cerebral tumours in 3 (6%), inflammatory peripheral nervous system (PNS) diseases in 3 (6%), autoimmune diseases (Neuro-LES, Bickerstaff encephalitis, anti-phospholipid syndrome) in 3 (6%), paraneoplastic syndromes (anti-NMDA encephalitis) in 1 (2%), other demyelinating diseases (clinically isolated syndrome, neuromyelitis optica) in 5 (10%) and other diagnoses in 12 (25%): Tolosa-Hunt syndrome, reversible cerebral vasoconstriction syndrome, idiopathic intracranial hypertension, headache (2), spondylomyelopathy, hereditary spastic paraparesis, motor neuron disease (2), DYT1-positive dystonia, degenerative dementia and cerebral venous thrombosis. Patients who acquired a diagnosis of MS were significantly younger (37±13 versus 48±16 years; p=0.02) than those with other diagnoses. There were no differences in CSF data (cell number and type, proteins, Link’s Index, CSF/serum albumin ratio, presence of additional “mirror pattern”) between the two groups. Conclusion: The majority of patients with a single CSF IgG band have neurological diseases other than MS, the most frequent being CNS infections, tumours and autoimmune diseases, and inflammatory PNS disorders. Patients with a subsequent diagnosis of MS are significantly younger than those with other neurological diseases. Disclosure Cocco E reports no conflicts of interest. Calabrese M reports no conflicts of interest. Orlandi R reports no conflicts of interest. Bedin R reports no conflicts of interest. Vitetta F reports no conflicts of interest. Simone AM reports no conflicts of interest. Solaro C reports no conflicts of interest. Gasperini C reports no conflicts of interest. Rodegher ME reports no conflicts of interest. Sola P reports no conflicts of interest.


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P375 Casein kinase 2 controls encephalitogenicity of Th17 cells in experimental autoimmune encephalomyelitis E. Witsch1, A. Ulges2, K. Birkner1, G. Pramanik1, F. Zipp1, T. Bopp2 1Neurology, 2Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany T helper (Th) 17 cells are considered to be detrimentally involved in several autoimmune diseases, such as multiple sclerosis. In contrast, regulatory T (Treg) cells were shown to maintain peripheral tolerance. Thus, influencing the balance between Treg and Th17 cells is a promising approach to treat autoimmune diseases and a potentially interesting translational avenue. However, the molecular mechanisms controlling the plasticity of Th17 cells and Treg cells are still elusive. Here, we show that pharmacological inhibition of the protein Casein kinase (CK) 2 prevented Th17 cell development as evidenced by reduced secretion of IL-17. At the same time, inhibition of CK2 led to increased FoxP3 expression, a marker for Tregs, when cells were differentiated under Th17 promoting conditions. Detailed analyses revealed attenuated phosphorylation of STAT3 with a concomitantly reduced expression of IL-17A upon CK2 inhibition. Deep-sequencing analyses to detail the transcriptome of Th17 cells after CK2 inhibition showed reduced expression of Il23r, csf2 (GM-CSF), ccr6 and other genes related to the development of encephalitogenic Th17 cells. When T cell receptor transgenic Th17 cells specific against myelin oligodendrocyte glycoprotein (MOG) were used for the adoptive cell transfer into lymphocyte deficient mice, EAE symptoms were reduced when cells were pretreated in vitro with a CK2 inhibitor. Very recent results show that continuous treatment of mice upon EAE induction following subcutaneous injection with PLP peptide significantly ameliorated EAE severity in SJL mice, a relapsing- remitting mouse model for multiple sclerosis. Therapeutic treatment of EAE by inhibiting CK2 signaling shows promising first results in the same mouse model. Therefore, CK2 controls a nodal point in Th cell development and represents a valuable target as a translational approach in the treatment of multiple sclerosis. Disclosure Esther Witsch: nothing to disclose. Alex Ulges: nothing to disclose. Katharina Birkner: nothing to disclose. Gautam Pramanik:nothing to disclose. Tobias Bopp: nothing to disclose. Frauke Zipp has received research grants from Teva, Merck Serono, Novartis and Bayer as well as consultation funds from Teva, Merck Serono, Novartis, Bayer Healthcare, Biogen Idec Germany, ONO, Genzyme, Sanofi-Aventis and Octapharma. Her travel compensation has been provided for by the aforementioned companies.

P376 Polyfunctionality of peripheral blood iNKT cells as an immunological marker of different forms of multiple sclerosis and following different immunomodulatory treatments

A.M. Simone1, D. Ferraro1, F. Vitetta1, S. De Biasi2, M. Nasi2, E. Bianchini3, L. Gibellini2, M. Pinti3, C. Del Giovane4, A. Cossarizza2, P. Sola1 1Department of Biomedical, Metabolic and Neurosciences, 2Department of Surgery, Medicine, Dentistry and Morphological Sciences, 3Department of Life Sciences, 4Department of Diagnostic and Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy Introduction: Associations between Multiple Sclerosis (MS) and defects in invariant natural killer T cells (iNKT) have been reported, but data is constrasting. iNKT cells are potent cytokine producers, have immunoregulatory potential and can be divided into functionally distinct subsets. Aim of our study was to evaluate the number, phenotype and functional activities of iNKT cells in different MS forms and following different treatments. Methods: We studied 165 MS patients (pts): 17 untreated pts with Active Relapsing-Remitting MS (ARR), 19 untreated pts with not-active RRMS (NARR), 20 untreated Primary Progressive (PP) and 24 untreated Secondary Progressive (SP) MS pts. Furthermore, we enrolled 29 pts who had been treated for at least 6 months with glatiramer acetate (GA), 31 with Beta-Interferon-1a (IFN) and 25 with Natalizumab (NAT). We enrolled 55 healthy subjects as controls (CTR) (39 < 46 years of age -YCTR- and 16 >46 years -ACTR). Isolated PBMC were analyzed on a 6-color high speed acoustic focusing flow cytometer using antiVa24Ja18Vb11 TCR, -CD4, -CD8, -CD161, -CD3, -CD19 and -CD14 mAbs. We detected the polyfunctionality of iNKT cells by analyzing their capacity to produce IL-17A,-TNF-a, -IFN-g, and IL-4 simultaneously in 41 RR, 4 PP, 12 SP and 26 CTR. Results: No differences were found in the total amount of iNKT among different groups but SP pts had a higher percentage of CD4+ iNKT cells that produced the highest levels of TNF-a and a lower percentage of CD4+ iNKT expressing CD161 compared to ACTR. CD8+ iNKT of NARR pts cells expressed higher levels of total TNF-a compared to CTR. The percentage of CD4+ iNKT cells expressing CD161 was higher in pts treated with NAT compared to those treated with IFN-1b, but the latter showed a higher production of IL-17 and TNF-a in CD4+ iNKT cells and IL-17 in CD8+ iNKT, while pts treated with GA had a higher percentage of iNKT CD8+ producing IFN-g. Finally, age of NAT-treated RR pts correlated positively with the percentage of CD8+ iNKT cells. Conclusion: SP pts exhibited lower percentages of iNKT CD4+CD161+ cells and a sustained increase in the production of Th1 and Th17 cytokines by iNKT cells. This could suggest that the progressive phase of the disease is characterized by a permanent iNKT activation. RR patients treated with NAT showed a significantly lower production of IL-17 and TNF-a compared to pts treated with IFN or GA, which could reflect its higher level of efficacy on disease activity in RRMS. Disclosure Anna Maria Simone has received travel grants from Biogen Idec, Merk Serono, Teva; Diana Ferraro has received travel grants and speaker honoraria from Biogen Idec, Merk Serono, Teva; Francesca Vitetta has received travel grants and speaker honoraria from Biogen Idec, Merk Serono, Teva;


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Poster Session I, 21(S11) Sara De Biasi: nothing to disclose. Milena Nasi: nothing to disclose. Elena Bianchini: nothing to disclose. Lara Gibellini: nothing to disclose. Marcello Pinti: nothing to disclose. Cinzia Del Giovane: nothing to disclose. Andrea Cossarizza: sponsored by FISM (Italian Foundation for Multiple Sclerosis) to AC. Patrizia Sola has received has received travel grants and speaker honoraria from Biogen Idec, Merk Serono, Teva; P377 IL-35 is a critical regulator of immunity during helminth infections associated with multiple sclerosis J. Correale, M.F. Farez Neurology, Institute for Neurological Research Dr Raul Carrea, Buenos Aires, Argentina Background and goals: Helminth-infected MS patients have shown lower disease activity compared with uninfected ones. Parasite regulation of host immunity is mediated, at least in part by the induction of T (Treg) and B regulatory (Breg) cells producing high levels of IL-10. IL-35 is the newest member of the IL-12 family of heterodimeric cytokines, and is composed of an EBI3 b chain subunit, and the IL12 p35 α subunit. Our aim was to investigate the role of IL-35 on Breg and Treg cell induction during parasite infections in MS patients. Methods: Peripheral blood CD19+ B cells, CD4+CD25- and CD4+CD25high T cells from 16 helminth-infected MS patients, 16 patients without infection, and 16 healthy controls were purified by cell sorting. Production of IL-10, IL-17, IL-35, IFN-g, and TGF-b, as well as activation of STAT1, STAT3, and STAT4 was assessed by ELISA. Proliferation assays were assessed using 3H-thymidine incorporation. Results: Both IL-10 and IL-35 production by B cells were significantly higher in helminth-infected MS patients than in uninfected MS subjects and healthy controls. Stimulation of B cells with IL-35 promoted conversion to Breg cells producing both IL-35, and IL-10. IL-35 production blockade significantly decreased IL-10 production by Breg cells. Furthermore, co-culture of B cells from helminth-infected MS patients inhibited proliferation of polarized Th1 and Th17 MBP-specific T cell lines, as well as production of IFN-g, and IL-17. Inhibitory effects were significantly decreased by silencing IL-35, and completely abrogated when IL-10 was silenced. Moreover, IL-35 activated STAT1 and STAT3 in Breg cells. CD4-CD25- T cells activated with anti-αCD3/CD28 in the presence of IL-35 dramatically upregulated EBI3 and IL12A mRNA, the two constituents of IL-35, but not IL-10 or TGFβ, inducing a regulatory population, termed iTR35. Foxp3 was neither induced nor required for iTR35 generation. As occurred with Breg cells, co-culture of polarized Th1 and Th17 MBP- T cell lines together with IL-35-iTR cells, significantly suppressed T cell proliferation, as well as IFN-g and IL-17 production. Neutralizing mAbs to IL-35, but not to IL-10 or TGFβ, blocked suppression capacity. Interestingly, IL-35 activated STAT1, STAT3 and STAT4, in T cells. Conclusions: The data presented highlights the importance of IL-35 for both Breg and Treg cells, in helminth-infected MS

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patients, conditioning many of the immunoregulatory effects observed in these patients. Disclosure Jorge Correale is a board member of Merck-Serono Argentina, Biogen-IdecLATAM, and Merck-Serono LATAM, and Genzyme global. Dr. Correale has received reimbursement for developing educational presentations for Merck-Serono Argentina, Merck-Serono LATAM, Biogen-Idec Argentina, Genzyme Argentina, and TEVA-Tuteur Argentina, as well as professional travel/accommodations stipends. Mauricio F Farez has received professional travel/accommodations stipends from Merck-Serono Argentina and Novartis Argentina.

P378 Decreased concentration of Klotho in the cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis M.H. Harirchian1, M.S. Emami Aleagha2, B. Siroos1, M. Ahammadi2, M. Balood2, A. Palangi2 1Iranian Center of Neurological Research, Tehran University of Medical Sciences, 2Department of Clinical Biochemistry, School of Medical Sciences, Tarbiat Modares University, Tehran, Islamic Republic of Iran Background: Recent investigations support that an anti-aging protein, namely Klotho, protects neurons against the oxidative stress and demyelination. The aim of this study was to investigate the status of CNS-derived secretory form of Klotho in the CSF of patients with RRMS. Moreover, we aimed to elucidate the correlation between total anti-oxidant capacity (TAC) and the concentration of secretory Klotho. Methods: We evaluated the protein concentration of Klotho and total anti-oxidant capacity (TAC) in the cerebrospinal fluid (CSF) of patients with relapsing-remitting multiple sclerosis (RRMS ). A total number of 22 patients who were definitely diagnosed as having active RRMS by the revised McDonald´s criteria (Polman et al., 2011), were recruited in this study. In addition to patients with RRMS, 22 patients with other neurological diseases such as chronic headache, idiopathic intracranial hypertension (IIH) and cerebral venous sinus thrombosis (CVST) were enrolled as a control group. The MRI scan of control patients failed to show any sign of demyelination in their CNS. Results: Klotho concentration and TAC were significantly lower in patients as compared to controls. Klotho values showed a significant negative correlation with expanded disability status scale (EDSS). Moreover, a significantly positive correlation between TAC levels and Klotho concentrations was detected. The Klotho concentration in CSF of patients with RRMS was significantly lower than control groups (P b 0.0001). The means (95% CI) for Klotho concentration in controls and MS patients were 541.62 pg/ ml (95% CI; 428.47-654.77) and 233.62 pg/ml (95% CI; 151.48315.76), respectively. There is a nearly 2.3-fold decrease in CSF Klotho concentration of patients with RRMS in comparison to controls.In both control and case groups, we measured the FRAP (Ferric Reducing Anti-oxidant Power) levels in 19 samples out of 22 CSFs as a result of inadequacy of some CSF samples. The


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mean (95% CI) for controls was calculated as 314.93 µM (95% CI; 253.43-376.43), and for MS patients was 211.98 µM (95% CI; 184.23-239.73). The results obtained from the correlation studies showed that there was a significant negative correlation between EDSS and Klotho concentration (r = −0.568, P = 0.0058), whereas there was no significant correlation between EDSS and FRAP levels inMS patients (r = −0.258, P = 0.286). Klotho may play an important role in the pathogenesis of MS through the regulation of redox system. Disclosure Nothing to be disclosed P379 Serum chitinase 3-like 1 levels in patients with multiple sclerosis and neuromyelitis optica D. Kaya1, Z. Altun2, E. İdiman3, N. Karabay4, D. Arslan3, Z. Kuzu3 1Dokuz Eylul University, 2Biochemistry, 3Neurology, 4Radiology, Dokuz Eylul University, Izmir, Turkey Chitinases were found to be involved in inflammatory processes. Recent studies suggest an attractive role of prognostic biomarker for chitinase 3-like 1 in multiple sclerosis. We aimed to confirm the presence and role of chitinase-3 like 1 in patients with clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis (RRMS) and patients with neuromyelitis optica (NMO). Serum chitinase 3-like 1 levels of 35 pts with NMO, 31 pts with RRMS, 19 pts with CIS and 20 controls were measured using a commercially available ELISA kit (R&D System, Minneapolis, MN, USA), following manufacturer instructions. Serum chitinase 3-like 1 levels were significantly increased in pts with NMO (61.75±59,10 ng/ml), RRMS (49.86±28.36 ng/ml), CIS (51.77±25.16 ng/ml) compared with controls (27.26±10.14 ng/ ml). There was no significant differences in serum levels between NMO, RRMS AND CIS pts, but each group had higher CHI3L1 levels than control group (p=0.001 for all). Serum chitinase 3-like 1 levels showed no correlation with the mean age (r=0,193;p=0,110), the disease duration (r=0,037;p=0,801), expanded disability status scale (EDSS) (r=0,04;p=0,785), number of gadolinium enhancing lesions (r=-0,268;p=0,071), the cerebrospinal fluid immunoglobulin G index (r=-0,040;p=0,798) in patients with CIS and RRMS. On the other hand, NMO patients with a final poor visual score had higher chitinase 3-like1 levels than NMO patients with a final good visual score, but the difference was not statistically significant (70.73±80.33; 54.86±35.66, p=0.856). Chitinese 3-like 1 increased in the sera from patients with NMO, RRMS and CIS when compared to controls. However, current study failed to confirm a strong role for being prognostic biomarker. Disclosure

P380 Differential expression and putative pathogenic role of intracellular K2P channels in multiple sclerosis T. Ruck, M. Hofmann, H. Wiendl, S.G. Meuth, S. Bittner Neurology, University of Münster, Münster, Germany Two-pore-domain potassium (K2P) channels influence essential cellular parameters such as membrane potential and intracellular Ca2+ signaling pathways. Alterations in their function have been implicated in the pathogenesis of autoimmune and neurodegenerative processes of multiple sclerosis (MS). In human studies for instance TASK2 channels, another member of the K2P channel family, were highly expressed on pathogenic T cells. Of note, TASK2 channels were not only located in the cellular membrane, but also found in a large intracellular pool with so far unknown function. TWIK1 and TWIK2 are closely related to TASK2 and also predominantly located inside the cell. However, their cellular functions, especially in immune cells are still largely unknown. Their location might hint to an important role for the function of intracellular organelles such as lysosomes or mitochondria, which might have important implications for T cell function, differentiation and survival. Hence, we here aim to investigate the influence of the intracellular K2P channels TWIK1, TWIK2 and TASK2 on immune cell functions in the context of autoimmune neuroinflammation. Therefore, we isolated human CD4+ and CD8+ T cells from healthy controls and MS patients with stable or active relapsingremitting (RRMS) or secondary progressive MS (SPMS). The expression of TWIK1, TWIK2 and TASK2 were evaluated by RT-PCR and western blot under basal and stimulatory conditions. Human T lymphocytes expressed TWIK1, TWIK2 and TASK2. Under T cell receptor stimulation the channel expression was found significantly upregulated, both on gene and protein level. In agreement, CD4+ and CD8+ T cells from MS patients demonstrated significantly increased TASK2 and TWIK2 expression compared to healthy controls. The highest expression was found in patients with active RRMS. However, no significant differences were observed for TWIK1. In conclusion, intracellular K2P channels are expressed in T cells and upregulated under stimulatory conditions. In agreement with a putative role in MS pathogenesis their expression levels are increased, especially in active RRMS. Further studies are needed to clarify their functional relevance and potential as therapeutic targets in MS. Disclosure Tobias Ruck: Nothing to disclose Majella Hofmann: Nothing to disclose. Heinz Wiendl: Nothing to disclose. Sven G. Meuth: Nothing to disclose Stefan Bittner: Nothing to disclose

P381 Natalizumab-induced alterations in circulating B-cells of multiple sclerosis patients - special reference to chemokine receptors M. Saraste1, T.-L. Penttilä2, L. Airas1,3 1University of Turku, 2Tykslab, 3Division of Clinical NeuroSciences, Turku University Hospital, Turku, Finland

Derya Kaya: Nothing to disclose Zekiye Altun: Nothing to disclose Egemen İdiman: Nothing to disclose Nuri Karabay: Nothing to disclose Duygu Arslan: Nothing to disclose Zeynep Kuzu: Nothing to disclose


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Poster Session I, 21(S11) Background: B-cells are increasingly recognized as active players in multiple sclerosis (MS) pathogenesis. Natalizumab blocks the adhesion molecule VLA-4, prevents migration of T-cells into the central nervous system, and thereby provides excellent protection from relapses in patients with relapsing-remitting MS. Not much is known about how natalizumab-treatment affects B-cell immunology in MS. Goals: To evaluate longitudinally the effects of natalizumab-treatment on peripheral blood B-cell pool of MS-patients. Patients and methods: Fourteen MS-patients initiating natalizumab treatment were prospectively recruited into the study. Blood samples were obtained shortly before the initiation of natalizumab treatment and at one week, one month, three months and twelve months time points. Peripheral blood mononuclear cells were isolated, immunofluorescense stained and analyzed by flow cytometry to study the alterations taking place in B-cell subtypes with special reference to chemokine receptor expression on B-cells. Results: Natalizumab-treatment induced a rapid and persistent B-cell lymphocytosis with the percentage of CD19+CD20+ B-cells of all peripheral blood lymphocytes (PBL) increasing from 10.6% (standard deviation (SD) 5.5) at baseline to 19.7% (SD 7.4) already after one week of treatment (p=0.0098). There was a persistent increase in the percentage of premature B-cells in circulation already after one week of treatment. The % of CD19+CD10+ pre B-cells of all CD19+ cells increased from 2.6% (SD 3.2) at baseline to 5.5% (SD 3.8 ) at one week (p=0.039). Finally, the proportion of B cells expressing the chemokine receptor CXCR3 increased significantly and persistently from pre-treatment level. The proportion of CXCR3-expressing B-cells of all B-cells was 15.2% (SD 8.3) at baseline, 22.5% (SD 8.4, p=0.014) at one month, and 23.0% (SD 5.2), at 12 months (p=0.0058). No significant changes were observed in proportions of CD5-positive B-cells, or B-cells expressing chemokine receptors CCR5 or CCR6. Conclusions: Chemokines and chemokine receptors are involved in controlling the migration of pro-inflammatory lymphocytes into the central nervous system in MS. Not much is known about chemokine receptor expression or function on B-cells in relation to neuroinflammation. The enrichment of CXCR3-expressing B-cells in blood following natalizumab-treatment suggests that CXCR3 might play a role in controlling homing of B cells at sites of neuroinflammation. Disclosure MSc. Maija Saraste has nothing to disclose. Dr. Tarja-Leena Penttilä has nothing to disclose. Dr. Laura Airas has received speaker honoraria from Biogen Idec, Sanofi-Aventis, Merck Serono, Novartis and Genzyme, and has received research support from Biogen Idec, Novartis, GE and Merck Serono. Biogen Idec has supported this study by providing a grant to cover the costs for flow cytometry. P382 CNS migration of regulatory B cells in EAE is dependent on VLA-4 K. Lehmann-Horn, S.A. Sagan, S.S. Zamvil Department of Neurology and Program in Immunology, University of California, San Francisco, San Francisco, CA, United States

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Background: Through distinct functions, B cells can participate in both pathogenesis and regulation of multiple sclerosis (MS) and its model, experimental autoimmune encephalomyelitis (EAE). Recently, we demonstrated that very late antigen-4 (VLA4) dependent central nervous system (CNS) B cell migration contributes to pathogenesis of EAE, induced by recombinant human (rh) myelin oligodendrocyte glycoprotein (MOG), a model that is B cell-dependent. However, in other EAE models, including those induced by encephalitogenic myelin peptides, B cells remain mostly unactivated and may even exhibit a regulatory phenotype (Breg). Here, we studied the role of B cell VLA-4 expression in Breg CNS migration in EAE. Methods: EAE was induced in mice, which selectively lack VLA-4 on Bells (CD19cre α4flox/flox) and control mice by immunization with the encephalitogenic epitope MOG35-55. The clinical disease course was followed and CD19+B220+ B cells, Breg (CD1dhighCD5+ and/or IL-10 producing), CD4+ T cells, Treg, monocytes, and VLA-4 expression on those leucocyte subsets were quantified by flow cytometry/intracellular cytokine staining in the CNS and periphery. Results: In contrast to induction with rhMOG, where B cell VLA-4 deficiency reduced susceptibility to EAE, immunization with MOG35-55 exacerbated EAE in CD19cre α4flox/flox mice (p ⩽ 0.05 on days 16-31 post immunization). Similar to rhMOG-EAE, we observed a marked reduction of B cells in the CNS (p = 0.05), while the number of CD4+ T cells, Treg and monocytes and also CD4+ T cell polarization (Th1 or Th17) were not significantly altered. Interestingly, also the number of IL-10 producing B cells was significantly reduced in the CNS of CD19cre α4flox/flox mice, compared to controls (p = 0.05). Conclusions: Selective B cell VLA-4 deficiency was associated with a reduction of CNS B cells and Breg in MOG35-55-induced EAE. CD4+ T cells, Treg and monocytes were unchanged in the CNS. These data indicate that (1) CNS migration of Breg is dependent upon VLA-4 expression and (2) suggest that Breg may also provide regulatory function within the CNS. Disclosure K. Lehmann-Horn received fellowship grants from the Deutsche Forschungsgemeinschaft (Le 3079/1-1) and the US National Multiple Sclerosis Society (NMSS) (FG 2067-A-1). S.A. Sagan: nothing to disclose. S.S. Zamvil received research grant support from the NIH (RO1 AI073737 and RO1 NS063008), the NMSS (RG 4124), the Guthy Jackson Charitable Foundation, the Maisin Foundation, Biogen Idec, and Teva Pharmaceuticals. Consultancy, honoraria, Biogen Idec, EMD Serono, Genzyme, Novartis, Questcor, Roche, Teva Pharmaceuticals; data safety monitoring board, Lilly, BioMS, Teva, Opexa Therapeutics.

P383 Therapeutic potential of a novel NMDA receptor subunit 2B antagonist in a mouse model of autoimmune neuroinflammation S. Glumm1, T. Ruck1, D. Schepmann2, B. Wünsch2, H. Wiendl1, S.G. Meuth1, S. Bittner1 1Neurology, 2Pharmaceutical and Medical Chemistry, University of Muenster, Muenster, Germany


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Glutamate-mediated excitotoxicity and neurodegeneration have been shown as pathophysiological hallmarks of multiple sclerosis and other autoimmune inflammatory CNS disorders. NMDA (N-Methyl-D-Aspartate) receptors play a pivotal role in the mediation of neuronal glutamate excitotoxicity promoting an increased Ca2+ influx upon glutamate binding ultimately leading to cellular damage and apoptotic cell death. Current treatment approaches targeting glutamate excitotoxicity are unspecific and associated with severe adverse events due to the broad and important functions of NMDA receptors in the CNS. Hence, the present study investigates the neuroprotective potential of a novel specific NR2B (NMDA receptor 2B) subunit antagonist. The effects of the NR2B antagonist WMS14-10 (WMS) were investigated in MOG-EAE (myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis), a murine model of multiple sclerosis, and in vitro for several immune cell subsets including isolated murine microglia. Flow cytometry, immunohistochemistry, ELISA, proliferation assays and RT-PCR were used as readout parameters. Treatment with WMS significantly ameliorated the EAE disease course upon prophylactic and therapeutic administration. At disease maximum microglia from WMS treated mice showed decreased CD86 expression indicating reduced microglial activation. In agreement, activated microglia upregulated NR2B in vitro and in vivo. Under restimulation with MOG splenocytes from WMS treated mice demonstrated decreased secretion of TNFα, INFγ and IL-17. In vitro WMS showed no significant effects on the function of T cells and macrophages/monocytes. However, incubation with WMS reduced LPS (lipopolysaccharide)-mediated activation of microglia as assessed by CD86 and MHCII expression in flow cytometry. In conclusion, the current study provides first evidence for a therapeutic potential of WMS14-10, a novel highly specific NR2B inhibitor, in the EAE model. Our results indicate that inhibition of NR2B in microglia cells displays a newly identified pathway in neuroinflammatory degeneration. Ongoing studies aim at dissecting the underlying mechanisms and a putative additional effect on neuronal glutamate excitotoxicity. Disclosure Sarah Glumm: Nothing to disclose Tobias Ruck: Nothing to disclose Dirk Schepmann: Nothing to disclose Bernhard Wünsch: Nothing to disclose Heinz Wiendl: Nothing to disclose Sven G. Meuth: Nothing to disclose Stefan Bittner: Nothing to disclose P384 Molecular analyses of the multiple sclerosis susceptibility gene CLEC16A in T cells I.S. Leikfoss1,2, A.M. Eriksson1,2, P.K. Keshari1,2, V. SundvoldGjerstad3, G. Abrahamsen3, M.W. Gustavsen1,2, O.J.B. Landsverk4, E.G. Celius1,2, S.D. Bos1,2, H.F. Harbo1,2, A. Spurkland3, T. Berge1 1Department of Neurology, Oslo University Hospital, 2University of Oslo/Institute of Clinical Medicine, 3University of Oslo/ Institute of Basic Medical Sciences, 4Oslo University Hospital/ Department of Pathology, Oslo, Norway

Background: More than 100 non-HLA genetic risk variants are associated with Multiple sclerosis (MS). Single nucleotide polymorphisms (SNPs) in the CLEC16A gene are associated with susceptibility to develop MS and other autoimmune diseases. This gene encodes the C-type lectin like domain family 16A protein, CLEC16A, which recently was shown to be important for expression of HLA-II, endocytic transport and regulation of autophagy and mitophagy. Methods: To understand the role of CLEC16A in autoimmune diseases, we perform (1) expression analyses of CLEC16A in selected immune cells and (2) imaging and flow cytometry-based techniques to study its subcellular localization and its role in immune cell activation. Results: The risk allele at the MS-associated rs12927355 SNP in intron 19 of CLEC16A correlates with higher CLEC16A and SOCS1 expression in human CD4+ T cells. To understand the role of CLEC16A in T cells, we use Jurkat T cells as model system. We found that CLEC16A co-localizes with recycling Rab4a+ endosomes. Suppression or overexpression of CLEC16A in Jurkat cells do not have any impact on the size or distribution of early (Rab5+), recycling (Rab4a+) or late (Rab7+) endosomes or lysosomes (LAMP1+). CLEC16A did not affect the secretion of IL-2 or the cell surface expression of CD25 and CD69 in PMA and ionomycin stimulated Jurkat cells. Conclusion: An intronic MS-associated risk SNP in CLEC16A acts as an expression quantitative trait locus for CLEC16A and SOCS1 in CD4+ T cells. Further studies on CLEC16A in T cells are necessary to determine whether the association of CLEC16A SNPs in autoimmune diseases is mediated through an effect on T cell function. Disclosure Ingvild. S. Leikfoss is funded by The South-Eastern Norway Regional Health Authority, The Odd Fellow Society and Novartis. Pankaj K. Keshari is funded by The South-Eastern Norway Regional Health Authority. Tone Berge is funded by The South-Eastern Norway Regional Health Authority, The Odd Fellow Society and Henrik Homans Minde (UNIFOR). Anna M. Eriksson is funded by the Norwegian Research Council. Marte W. Gustavsen is funded by the Norwegian Research Council. Steffan D. Bos is funded by the Norwegian Research Council.

P385 The role of MS susceptibility gene PLEK in neuroinflammation C. Larochelle1, M. Paterka1, N. Hoppmann1, C.S. Abrams2, V. Siffrin1, F. Zipp1 1Neurology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany, 2University of Pennsylvania, Philadelphia, PA, United States Background: Several genetic susceptibility factors for multiple sclerosis (MS) have been identified; however, how they influence neuroinflammatory processes is still largely unknown. PLEK, coding for the protein pleckstrin, is expressed by leukocytes and is


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Poster Session I, 21(S11) a marker of cell differentiation and activation. PLEK single nucleotide polymorphisms associated with MS susceptibility have recently been shown to influence mRNA expression specifically in the CD4 T cell subset. Accordingly, in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we observed a striking upregulation of Plek mRNA in central nervous system (CNS)-infiltrating CD4 Th17 lymphocytes. The goal of this project is to identify the role of PLEK in neuroinflammatory processes such as MS and EAE. Methods: We characterized the expression of pleckstrin in human and murine samples using Western Blot and qPCR. We used a PLEK knock out (KO) transgenic animal to study the role of PLEK in immune cell populations ex vivo, in CD4 T cell activation in vitro, and in EAE disease course in vivo, as compared to littermates. Results: Pleckstrin is expressed by human memory CD4 T cells and is upregulated upon activation in murine CD4 T cells. Our preliminary results show an inverse correlation between pleckstrin protein levels and Plek mRNA levels, suggesting an autoinhibitory loop. PLEK ko animals show a slight increase in the absolute number of cells, and of CD4 T cells, in their LN and spleens, but normal proportion of immune cell populations. CD4 T cells isolated from KO animals show higher levels of Tbet mRNA ex vivo as compared to littermates. In vitro, PLEK KO CD4 T lymphocytes show normal activation and cytokine production. The course of active MOG35-55-induced EAE is not significantly altered in KO versus littermates. However, when isolating the role of PLEK in CD4 using active EAE in CD4-reconstituted RAG-/- mice, or transfer of MOG-reactivated CD4 T cells, EAE reproducibly started earlier and showed a more severe course in the recipients of PLEK KO CD4 T cells. In addition, expression of TNF was higher in CNS-infiltrating CD4 T cells of KO mice than of littermates. Conclusions: The expression of Plek in CD4 T lymphocytes is associated with MS susceptibility, and in EAE, its deletion is associated with higher numbers of CD4 T lymphocytes, which express higher levels of Tbet and induce a more severe EAE disease. Thus, this risk variant is indeed mirrored in the animal model of MS. Disclosure Catherine Larochelle: Nothing to disclose in relation to this project. Magdalena Paterka: Nothing to disclose in relation to this project. Nicola Hoppmann: Nothing to disclose in relation to this project. Charles S Abrams: Nothing to disclose in relation to this project. Volker Siffrin: Nothing to disclose in relation to this project. Frauke Zipp: Nothing to disclose in relation to this project. P386 The multiple sclerosis susceptibility genes TAGAP and IL2RA are regulated by vitamin D in CD4+ T cells T. Berge1, I.S. Leikfoss1,2, I.S. Brorson1,2, S.D. Bos1,2, C.M. Page1,2, M.W. Gustavsen1,2, A. Bjølgerud1,2, T. Holmøy2,3, E.G. Celius1,2, J. Damoiseaux4, J. Smolders5, H.F. Harbo1,2, A. Spurkland6 1Oslo University Hospital/Department of Neurology, 2University of Oslo/Institute of Clinical Medicine, Oslo, 3Akershus University Hospital/Department of Neurology, Lørenskog, Norway, 4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, 5Department of Neurology,

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Canisius Wilhelmina Hospital, Nijmegen, The Netherlands, 6University of Oslo/Institute of Basic Medical Sciences, Oslo, Norway Background: Vitamin D is a potent immunomodulator, and vitamin D deficiency has been suggested to be associated with increased MS disease susceptibility and activity. Vitamin D acts through its vitamin D receptor (VDR), which is a nuclear receptor and transcription factor. VDR heterodimerizes with the retinoic X receptor (RXR) and upon vitamin D ligation, the VDR-RXR heterodimer recognizes VDR recognition elements (VDRE) within regulatory regions of its target genes, thereby affecting gene transcription. Methods: CD4+ T cells were purified from peripheral blood mononuclear cells by magnetic separation and stimulated with anti-CD3/CD28 coated beads to induce VDR expression prior to treatment with calcitriol (the active form of vitamin D, 1.25(OH)2D3). Gene expression of selected genes was analyzed for vitamin D responsiveness by the use of quantitative real-time PCR. Gene expression of vitamin D responsive genes was also analyzed in freshly purified CD4+ T cells from MS patients with known serum level of vitamin D. Results: We chose to analyze vitamin D responsiveness of T cell expressed genes that contained an MS-associated single nucleotide polymorphism (SNP) and with one or more VDREs in their regulatory regions. Out of the 13 genes analyzed, IL2RA expression was induced, whereas TAGAP expression was reduced upon calcitriol treatment. The vitamin D response was observed in samples from both MS patients and controls and was not dependent on the genotype of MS associated SNPs in the respective genes. Furthermore, we show that there is a correlation between IL2RA expression in CD4+ T cells and serum levels of 25(OH)D in samples from MS patients. Conclusion: We identify two MS susceptibility genes, IL2RA and TAGAP, as novel vitamin D target genes in human CD4+ T cells. Disclosure T. Berge has received an unrestricted grant for running expenses in this project from Biogen Idec Norway AS, I.S. Leikfoss has received unrestricted grant for salary expenses from Novartis Norway AS and T.Holmøy has received research grants from Merck Serono. I.S. Brorson, S.D. Bos, C.M. Page, M.W. Gustavsen, A. Bjølgerud, E.G. Celius, J. Damoiseaux, J. Smolders. and A. Spurkland have nothing to disclosure. P387 Nonfunctional natural killer regulatory cells in multiple sclerosis A. Laroni1, E. Armentani1, N. Kerlero de Rosbo1, F. Ivaldi1, E. Marcenaro1, S. Sivori1, R. Gandhi2, H.L. Weiner2, A. Moretta1, G.L. Mancardi1, A. Uccelli1 1University of Genova, Genova, Italy, 2Harvard University, Boston, MA, United States Background: Recent evidence has shown that CD56bright NK cells (NKregs) may shape adaptive immune responses by interacting in particular with T cells. In MS, expansion of NKregs has been associated to response to different treatments (daclizumab,


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interferon-beta) and to remission in pregnancy; however it is not known what function they exert in physiologic conditions and whether it is impaired in MS. Aim of the study: To dissect the function of NKregs upon inflammatory conditions.in healthy subjects (HS) and in patients with MS. Methods: We isolated NKregs from peripheral blood or buffy coats of HS and untreated patients with CIS or MS (CIS/MS), prestimulated them with the proinflammatory cytokines interleukin (IL-) 12 and IL-15 and cultured them in presence of autologous CD4+ T cell to assess effect on T cell proliferation. We assessed cytotoxicity of NKregs towards autologous T cells in contact or transwell. Phenotype and number of NKregs were evaluated in HS and CIS/MS patients. We performed real-time PCR to evaluate the transcription of lytic enzymes in NKregs from HS and CIS/MS. NKregs/Tcell cocultures from HS and CIS/MS patients were performed in presence of selective blockers of NK activating receptors or HLA-class I. We evaluated by flow cyometry the expression of HLA E on T cells from HS and CIS/MS. Results: We found that NKregs from HS acquire, upon inflammatory cues, the capability of suppressing autologous CD4+T cell proliferation through direct cytotoxicity which requires engagement of natural cytotoxicity receptors (NCRs) and secretion of granzyme B. NKregs from CIS/MS patients had an impaired suppressor function towards autologous T cells. Expression of NCRs was upregulated in NKregs from MS patients and expression of granzyme B was similar in NKregs from HS and CIS/MS patients. Blocking HLA class I on T cells did not increase suppressor function of NKregs from HS, but restored normal suppressor function in NKregs from MS. Accordingly, expression of HLA-E molecule was upregulated in CD4 T cells from CIS/MS patients compared to HS. Conclusions: Our study suggests that NKregs physiologically control T cell functions by direct cytotoxicity and that this mechanism is impaired in MS due to increased inhibitory signals from CD4+T cells. This paves the road to treatments for MS that, modulating the inhibitory signals sent by T cells, restore the defective function of NKregs cells. Disclosure This study was funded by a grant to A. Laroni by Fondazione Italiana Sclerosi Multipla 297/09/F14. A. Laroni received honoraria to act as advisor or speaker from Biogen-Idec, Genozyme and Novartis and has received funds for travel from Biogen-Idec, Genzyme, Merck Serono, Novartis, and Teva E Armentani: nothing to disclose F Ivaldi: nothing to disclose N Kerlero de Rosbo: nothing to disclose E. Marcenaro: nothing to disclose S. Sivori: nothing to disclose R Gandhi received funding from Novartis, Biogen Idec and Serono A Moretta is founder and shareholder of Innate-Pharma G.L. Mancardi has received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Bayer Schering, Biogen Idec, Novartis, Teva, Sanofi-Aventis and Merck Serono Pharmaceuticals H Weiner received funds from Serono, Biogen, Therapix, Novartis, Genzyme, Teva A. Uccelli received honoraria to act as advisor or speaker from Biogen-Idec, Novartis, Merck Serono, Teva, Sanofi-Aventis,

Bayer-Schering, Roche, Genzyme and Allergan. Antonio Uccelli also received financial support for research from Merck Serono, Biogen-Idec and Novartis P388 T/B lymphocyte subset analysis of NMOSD with MOG autoantibody and AQP4 autoantibody S. Tanaka1, A. Kubota1, M. Kojima1, S. Izaki1, H. Fukaura1, K. Kaneko2, D. Sato2, K. Fujihara2, K. Nomura1 1Neurology, Saitama Medical University, Saitama Medical Center, Kawagoe, 2Tohoku University School of Medicine, Sendai, Japan Objectives: We determined the subsets of T and B cells that are present in the peripheral blood of patients with neuromyelitis optica spectrum disorder (NMOSD) who tested positive for myelin oligodendrocyte glycoprotein (MOG) or aquaporin 4 (AQP4) antibody (Ab) to reveal the immunological features of the disease. Design and methods: Subjects were 10 patients with MOG-Abpositive NMOSD, 24 patients with AQP4-Ab-positive NMOSD, and 55 healthy individuals as controls. Reactivity to anti-MOG and anti-AQP4 antibodies was tested at Tohoku University. Approximately 2 ml of peripheral venous blood was collected from each subject. Without removing red blood cells, the whole blood was stained for various T and B cell surface markers to identify T cell subsets comprising cytotoxic T (CD8+, CD11b−), suppressor T (CD8high, CD11blow), activated CD4 (CD4+ HLA+), activated CD8 (CD8+ HLA+), regulatory T (CD4+, CD25high), and natural killer cells (CD3−, CD16/56+), as well as B cell subsets of plasmablasts (CD19+, CD27+, CD38high, CD180−), memory B (CD19+, CD27+), naïve B (CD19+, CD27−), and transitional B cells (CD19+, CD24high, CD38high). Flow cytometry was performed using FACS Canto II (Becton, Dickinson and Company). Statistical analysis was performed to compare the MOG-NMOSD, AQP4-NMOSD, and control groups. Results: No significant differences in T cell subsets were observed between the three groups. With regard to B cell subsets, the level of transitional B cells in the MOG-NMOSD group was significantly higher than that in the AQP4-NMOSD or control group (p< 0.01 and p< 0.01, respectively). Similarly, the level of naïve B cells in the MOG-NMOSD group was significantly higher than that in the AQP4-NMOSD or control group (p< 0.05 and p< 0.01, respectively). The level of memory B cells was significantly higher in the MOG-NMOSD group than in the control group (p< 0.05), while the level of plasmablasts was significantly higher in the AQP4-NMOSD group than in the control group (p< 0.01). Disclosure Nothing P389 Complexity of the brain-infiltrating T-cell repertoire in Rasmussen encephalitis F. Al Nimer1, I. Jelcic1, C. Kempf1, T. Pieper2, H. Budka3, M. Sospedra1, R. Martin1 1Neuroimmunology and MS Research, University Hospital Zurich, Zurich, Switzerland, 2Epilepsy Center for Children and Adolescents, Schoen Klinik Vogtareuth, Vogtareuth, Germany,


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Poster Session I, 21(S11) 3Institute

of Neuropathology, University Hospital Zurich, Zurich, Switzerland

Background: Rasmussen encephalitis (RE) is a rare neurological disease mainly affecting children and causing epilepsy, intellectual decline and focal neurological deficits in parallel with progressive hemispheric atrophy. It commonly affects only one hemisphere, but very rare cases exist, in whom both hemispheres are influenced. Factors such as viruses, humoral and strictly CD8+ T-cell mediated autoimmunity have been suspected as the causes of RE, but its aetiology is still unknown. The best current treatment is functional hemispherectomy, which carries a high risk for neurological deficits. Aim: The objective of this study was to characterize the T cell repertoire infiltrating the brain in RE. Methods: A histopathological analysis of the T cell infiltrate of paraffin-embedded brain tissue from three cases of RE was performed. In addition, analyses were performed on freshly obtained brain tissue from a 5 year old boy, who developed neurological symptoms and in whom RE was diagnosed based on the radiological findings and bilateral brain biopsy. The brain tissue that was obtained during functional hemispherectomy was used for immunohistochemical studies, T cell receptor sequencing and phenotypic analysis of infiltrating T cells as well as generating T cell clones from the brain. Results: Immunohistology revealed prominent astrogliosis, both CD4+ and CD8+ T cell infiltrates, strong microglial activation and absence of B cells in all three cases. Flow cytometric analysis of leukocytes (CD45+) obtained from the fresh brain tissue revealed a predominant T cell infiltrate (CD3+, 93.1%) consistent of CD4+ (30.9%) and CD8+ (46.6%) T cells. Both subpopulations displayed effector memory phenotypes. TCR sequencing of the brain biopsy revealed oligoclonal expansions with frequencies ranging from15.6 to 1.4% of the ten most common TCR Vbeta chains. By further analysis, we observed that not only the brain-infiltrating CD8+ but also the CD4+ T cells are clonally expanded in RE. We also isolated several of the most common T cell clones and analyzed the cytokine expression profiles of the infiltrating T cells which exhibited a Th1/Tc1 phenotype and of the T cell clones. Conclusion: In summary, our data suggest a specific CD4+ and CD8+ T cell-mediated reaction, where CD4+ T cells orchestrate the function of the effector arm constituted by CD8+ T cells. The expanded top clones can now be used to search for possible antigens involved in the aetiology of the disease. Disclosure Faiez Al Nimer: nothing to disclose Ivan Jelcic: nothing to disclose Christian Kempf: nothing to disclose Tom Pieper: nothing to disclose Herbert Budka: nothing to disclose Mireia Sospedra: nothing to disclose Roland Martin: nothing to disclose

P390 Myelin-reactive antibodies initiate T-cell-mediated CNS autoimmunity by opsonisation of auto-antigen S. Kinzel1, K. Lehmann-Horn2, D. Häusler3, C.C. Bernard4,

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C. Stadelmann-Nessler3, P.H. Lalive5, W. Brück1, M.S. Weber1 1Universitätsmedizin Göttingen, Göttingen, 2Technische Universität München, München, 3University Medical Center Göttingen, Göttingen, Germany, 4Monash University, Melbourne, VIC, Australia, 5University Hospitals Geneva, Geneva, Switzerland Objective: To dissect the relative pathogenic relevance of myelin-specific antibodies (ab) from myelin-specific B cells in the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE). Background: B cells and B cell-derived ab may both play a pathogenic role in CNS autoimmune disease. Mice in which a majority of B cells recognizes myelin oligodendrocyte glycoprotein (MOG), plasma cells secrete high titres of MOG-specific ab and which further contain myelin-reactive T cells (Thx2D2 mice) spontaneously develop EAE. We utilized Thx2D2 mice in combination with B cell-depleting anti (a)-CD20 ab and adoptive transfer regimens to dissect the relative pathogenic contribution of myelin-reactive B cells from myelin-reactive ab and investigated the underlying mechanism of a-MOG ab in in vitro experiments. Methods: Thx2D2 mice were injected with a-CD20 weekly starting at the age of 4 weeks. Serum from Th mice immunized with rMOG1-117 (rMOG) or myelin-reactive 8.18C5 ab was transferred i.v. into naïve 2D2 mice. In vivo proliferation of T cells was determined by BrdU assay. In vitro, bone-marrow derived macrophages (BMDM) were co-cultured with CFSE-labelled T cells in the presence of 8.18C5, its F(ab’)2 fragment or an isotype control ab. Results: In Thx2D2 mice, a-CD20 treatment did not interfere with development of encephalitogenic T cells or incidence/severity of spontaneous EAE. While all peripheral compartments were depleted of B cells, a-CD20 did not affect constitutive secretion of a-MOG ab. Serum from Th mice containing high titres of a-MOG ab triggered spontaneous EAE when transferred into naïve 2D2 recipients. Further dissecting the role of pathogenic ab, transfer of purified 8.18C5 ab to 2D2 mice led to in vivo proliferation of T cells and triggered spontaneous EAE. In vitro, 8.18C5 ab, but not its F(ab’)2 fragment enhanced phagocytosis of rMOG by BMDM and led to enhanced proliferation of responding T cells. Conclusion: Our data indicate that besides promoting CNS demyelination, a-MOG ab enhance myelin-recognition of antigen-presenting cells by antigen-opsonization, subsequently resulting in accentuated activation of myelin-reactive T cells. This highlighted process could be of particular relevance for initiation of CNS autoimmune disease, when low concentration of self-antigen is initially recognized. These findings project an enormous therapeutic potential into targeting the early occurring humoral response against CNS auto-antigen in MS. Disclosure M. S. Weber is serving as an editor for PLoS One. He received travel funding and/or speaker honoraria from Biogen-Idec, Merck Serono, Novartis, Roche and Bayer. He receives research support from the National Multiple Sclerosis Society (NMSS; PP 1660), the Deutsche Forschungsgemeinschaft (DFG; WE 3547/4-1), from Novartis, TEVA, Biogen-Idec, Roche and the ProFutura Programm of the Universitätsmedizin Göttingen.


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P391 Impact and fate of distinct T-cell subsets in the course of autoimmune neuroinflammation R. Gollan, C. Larochelle, C. Wolf, U. Bühler, K. Rajalingam, V. Siffrin, F. Zipp Focus Program Translational Neurosciences (FTN), Rhine Main Neuroscience Network (rmn2), Department of Neurology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany Background: In multiple sclerosis (MS), a demyelinating inflammatory disease of the central nervous system (CNS), various T helper (Th) subsets are considered to play distinct pro- or antiinflammatory roles. In experimental autoimmune encephalomyelitis (EAE), an animal model mimicking aspects of MS, it is known that MOG-reactive Th1 and Th17 but rather not Th2 cells are capable of initiating severe debilitating neuroinflammatory processes. Much less is known about the collaboration of T cell subsets within the CNS and the role of these T cell subsets in the perpetuation of ongoing neuroinflammation in the presence of an already destabilized blood-brain barrier. Methods: EAE was induced by transfer of MOG-reactive 2d2 Th17 CD90.1+ cells into RAG1-/- mice. Seven days later, a second transfer of Th1, Th2, or Th17 CD90.2+ MOG-reactive 2D2 cells was performed to study their potential to influence the disease course, to enter the inflamed CNS, and to modify the profile of the disease-inducing population. Moreover, the surface proteome of these Th cell subsets as well as their cytokine profile upon co-culture with primary neurons were analyzed. Results: Our data show that Th1 and Th2 cells infiltrated the CNS less efficiently than Th17. Most importantly, co-transfer of Th1 or Th2 cells significantly improved the clinical course of EAE, as compared to co-transfer of Th17 cells. A strong influence of the second wave of MOG-reactive cells on the disease-inducing Th17 population infiltrating the CNS was observed, with the co-transfer of Th1 or Th2 but not Th17 cells resulting in a lower expression of inflammatory cytokines by the initial Th17 population. In vitro, the Th17 subset displayed a distinct surface proteome and higher IL-17 expression in response to contact with primary neuronal cultures, while the Th1 subset showed an enhanced IL-10 expression. Conclusions: Th1 and Th2 reduce clinical symptoms, presumably in competition with Th17 cells, by promoting plasticity of the disease-inducing population, and by expressing more anti-inflammatory cytokines in response to contact with the neuronal compartment. This suggests that even after disease initiation, the Th17, Th1 and Th2 subsets will affect the CNS microenvironment differently, and contribute to either the perpetuation or the control of the ongoing neuroinflammatory processes. Disclosure Frauke Zipp has received research grants from Teva, Merck Serono, Novartis and Bayer as well as consultation funds from Teva, Merck Serono, Novartis, Bayer Healthcare, Biogen Idec Germany, ONO, Genzyme, Sanofi-Aventis and Octapharma. Her travel compensation has been provided for by the aforementioned companies. René Gollan: nothing to disclose Catherine Larochelle: nothing to disclose

Christina Wolf: nothing to disclose Ulrike Bühler: nothing to disclose Krishna Rajalingam: nothing to disclose Volker Siffrin: nothing to disclose P392 CD20 expressing T-cells: phenotype, cytokine profile and response to immunomodulatory treatments in MS E. Schuh1,2, T. Kuempfel1, I. Meinl1, M. Bradl2, R. Hohlfeld1,3, M. Krumbholz1, E. Meinl1 1Institute for Clinical Neuroimmunology, Ludwig-MaximilianUniversity Munich, Munich, Germany, 2Department of Neuroimmunology, Medical University of Vienna, Vienna, Austria, 3SyNergy, Munich, Germany Monoclonal antibodies against CD20+ expressing cells (e.g. rituximab, ocrelizumab) reduce the occurrence of new relapses in multiple sclerosis (MS); a therapeutic effect commonly attributed to B-cells. Recently, however, a subset of CD3+CD20+ T cells has been described, that is also targeted by rituximab in MS patients. We herein analyzed the cytokine profile, the presence in the spinal fluid and the response to immunomodulatory treatments of CD3+CD20+ T cells. We found that about 5 % of all T cells in both blood and spinal fluid express CD20 on the surface, which is also reflected by mRNA levels for CD20. Upon activation, they produce IL-4, IL-17, TNF-α, and IFN-γ in a higher rate than conventional T cells. The number of these CD3+CD20+ T cells in blood is altered by fingolimod, natalizumab, dimethylfumarate, and alemtuzumab. Interestingly, while these cells are depleted by rituximab, they show an earlier and higher repopulation profile than CD20+ B cells. Taken together, the intrathecal presence of CD3+CD20+ T cells, their strong ability to produce pro-inflammatory cytokines and their response to MS disease modifying drugs suggest a potential role in the pathogenesis of MS. Disclosure Competing financial interests: The authors declare no competing financial interests. E. Schuh received travel expenses from Novartis. T. Kümpfel has received travel expenses and personal compensations from Bayer Healthcare, Teva Pharma, Merck-Serono, Novartis, Sanofi-Aventis, and Biogen-Idec as well as grant support from Bayer-Schering AG and Novartis. I. Meinl reports no disclosures. M. Bradl reports no disclosures. R. Hohlfeld is supported by the Deutsche Forschungsgemeinschaft (SyNergy, TRR128) and has received personal compensations from Bayer Healthcare, Teva, Merck-Serono, Biogen-Idec, Sanofi, Genzyme, and Novartis. M. Krumbholz received travel funding from Novartis, has consulted for Genzume, received research support from Novartis; E. Meinl received grant support by Novartis. P393 CXCL13, but not BAFF and APRIL, intrathecal synthesis associates with a decreased cortical thickness in multiple sclerosis at clinical onset


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Poster Session I, 21(S11) M. Puthenparampil1, L. Federle1, S. Miante1, L. Cacciaguerra1, D. Poggiali1, E. Toffanin2, S. Ruggero2, F. Rinaldi1, P. Perini1, P. Gallo1 1Multiple Sclerosis Centre of Padua, Neurological Clinic, Neuroscience Department, University of Padua, 2Neurological Clinic, Neuroscience Department, University of Padua, Padua, Italy Background: Meningeal B-cell follicule-like structures have been histologically associated with cortical inflammation and neurodegeneration in Multiple Sclerosis (MS), especially in patients with secondary progressive MS. However, to what extent the development of B-cell follicules is linked to cortical damage in the early disease phases has never been investigated. Objective: To analyse the presence in the cerebrospinal fluid (CSF) of cytokines that may play a role in B-cell development, differentiation and activation, and their association with magnetic resonance imaging (MRI) parameters of white and grey matter damage. Materials an methods: 20 patients with clinically isolated syndrome or very early RRMS (CIS/eRRMS) and 11 individuals with no evidence of neurological diseases (normal controls, NC) were enrolled in the study. All subjects underwent 3T MRI examination (including HD 3D-T1, to quantify Global Cortical Thickness, CTh, 3D-FLAIR, to quantify White Matter Lesion Volume, 3D-DIR, to quantify the Cortical Lesion Volume). Paired CSF and serum samples were obtained, analysed for diagnostic purposes (IgG Index and IgGOB) and stored at -80°C until cytokine testing. BAFF, APRIL and CXCL13 were analysed by means of commercially available Elisa Kits, and their concentration were expressed as Index ([cyt]CSF/[cyt]S/[Alb]CSF/ [Alb]S). Results: No difference in gender and age was observed between NC and CIS/eRRMS. BAFF and APRIL were detectable in both groups, but their Index values didn’t significantly differ. CXCL13 was detectable in 14 (70%) CIS/eRRMS (mean value: 27.74±38.77 pg/ml) and its Index correlated to IgG Index (r=0.54, p< 0.05) and CSF lymphocyte count (r=0.73, p< 0.05). Moreover, CXCL13+ CIS/eRRMS patients had a significantly higher frequency of IgGOB compared to the CXCL13- patients (92.8% vs 50%, p< 0.05). A decrease in CTh was observed in CXCL13+ compared to CXCL13- (2.38±0.09 mm vs 2.53±0.07 mm) and the difference was highly significant (p< 0.0005), while no difference in white and grey matter lesion volumes was observed between the two groups. Conclusions: The intrathecal synthesis of the CXCL13, but not that of BAFF and APRIL, is associated with a decreased cortical thickness in a subgroup of CIS/eRRMS. This chemokine, that also associated with CSF parameters of inflammation, may play a role in driving B-cell follicle formation in early disease phases. The use of CXCL13 as marker of cortical damage in MS merits further investigation. Disclosure Dr. Marco Puthenparampil has received funding for travel from Teva, Merck Serono, Biogen Idec, and Novartis. Dr. Lisa Federle has received funding for travel from Merck Serono, Biogen Idec, Sanofi-Aventis, and Bayer Schering Pharma and honoraria from Genzyme, Teva and Almirall.

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Dr. Silvia Miante has received funding for travel from Teva, Merck Serono, Biogen Idec, Almirall and Novartis. Dr. Laura Cacciaguerra has nothing to disclose. Dr. Davide Poggiali has nothing to disclose. Dr. Francesca Rinaldi has received honoraria from Biogen Idec, MerkSerono and Teva. Dr. Paola Perini has has received honoraria from Biogen Idec/ Elan, Merck Serono, Sanofi-Aventis and Teva; has been a consultant for Biogen Idec, Merck Serono and Teva. Prof. Paolo Gallo has received honoraria from Bayer Schering, Biogen Idec/Elan, Merck Serono, Novartis, Sanofi-Aventis and Teva; has been a consultant for Bayer Schering, Biogen Idec, Genzyme, Merck Serono and Novartis; has received research support from Bayer, Biogen Idec/Elan, Merk Serono, Genzyme and Teva; and has received research grant from the University of Padova, Veneto Region of Italy, the Italian Association for Multiple Sclerosis, the Italian Ministry of Public Health.

MS and infections P394 High CCR5 expression in natalizumab-associated progressive multifocal leukoencephalopathy immune reconstitution inflammatory syndrome supports anti CCR5 therapy L. Stork1, W. Brück1, A. Bar-Or2, I. Metz1 1Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany, 2Department of Neurology and Neurosurgery and Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, QC, Canada Progressive multifocal leukoencephalopathy (PML) is an opportunistic brain disease caused by the JC virus. It is a rare condition that can occur in multiple sclerosis (MS) patients treated with natalizumab (NTZ) but is also known in other immune deficient conditions. Clinical deterioration that may be life threatening can occur after withdrawal of NTZ in patients with PML due to the reconstitution of the immune system, termed immune reconstitution inflammatory syndrome (IRIS). IRIS is histologically characterized by a pronounced CD8+ T cell-dominated inflammation with numerous plasma cells within CNS lesions. A therapy for IRIS with proven efficacy is not yet available. Commonly used high-dose glucocorticosteroids may limit JC viral clearance. Recently the successful treatment of NTZ-associated PML-IRIS with the chemokine receptor 5 (CCR5) antagonist maraviroc was reported. CCR5 is predominantly expressed on T cells, macrophages and on B lineage cells and is involved in immune cell chemotaxis. CCR5+ cells are found in varying numbers in inflammatory CNS lesions. We analyzed CCR5+ cells in PML lesions in situ with immunohistochemistry. Biopsy or autopsy brain tissue from six MS patients with NTZ-associated PML IRIS were compared with six controls with inflammatory PML lesions not associated with NTZ treatment. Results showed that both NTZ-associated and non-NTZassociated PML lesions were populated by high numbers of CCR5+ immune cells. Up to 1500 CCR5+ cells/mm² were found. We analyzed the cell subsets expressing CCR5 and found that CD8+ and CD4+ T cells as well as plasma cells and B cells expressed CCR5. Macrophages showed little or no expression. In NTZ-associated PML IRIS lymphocyte subsets showed CCR5 expression in 43-59% of cells, with the highest percentage present


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in CD8+ T cells. In control patients an even higher percentage of CCR5-expressing lymphocytes (48% up to 77%) was found. In NTZ-associated PML-IRIS lesions, CCR5+ plasma cells were more numerous (21% of all CCR5+ cells) than in non-NTZ-PML lesions (13% of all CCR5+ cells). The high number of CCR5+ immune cells in inflammatory PML lesions provides histopathological evidence that CCR5+ lymphocytes may play an important role in the pathogenesis of PML IRIS. This could support treatment of IRIS with the CCR5 inhibitor maraviroc not only in NTZ-associated PML-IRIS, but also in PML-IRIS caused by other conditions. Thus we encourage further controlled studies of maraviroc treatment in PML IRIS. Disclosure L. Stork: nothing to disclose A. Bar-Or: nothing to disclose W. Brück und I. Metz were supported by grants from the German Ministry for Education and Research (BMBF, ‘’German Competence Network Multiple Sclerosis’’ (KKNMS), Pattern MS/NMO). P395 Toxoplasma gondii infection as a protective factor against multiple sclerosis risk A. Koskderelioglu1, I. Afsar2, B. Pektas2, M. Gedizlioglu1 1Neurology Department, Izmir Bozyaka Education and Research Hospital, 2Medical Microbiology Department, Katip Çelebi University Atatürk Training and Research Hospital, Izmir, Turkey Objective: To determine the association between the Toxoplasma gondii infection and Multiple Sclerosis (MS). Methods: 115 patients with MS were included in the study. Sixty age and gender matched healthy subjects were recruited as controls. Subjects were assessed for clinical and demographic parameters. The presence of spesific IgG antibodies against Toxoplasma gondii were searched by using an enzyme immunoassay test in the sera of all subjects. Results: T. gondii seropositivity was found to be lower in the patients with MS than in healthy controls (34,2% vs 55%, p=0.007). Mean age and disease duration were 41.15±11.20 (18-74) and 1,90±1.44 (0-6) years, respectively. MS patients with a high IgG titer had lower expanded disability status scale (EDSS) scores (p=0.001) and lower annualized relapse rates (ARR) (p=0.005). There was no significant association between T. gondii seropositivity and disease duration (p=0.59). Female MS patients tended to have higher T. gondii seropositivity than males although the difference did not reach statistical significance (p=0.192). We found a negative correlation between T.gondii seropositivity and both EDSS scores (r=-0.322, p=0.000) and ARR (r=-0.263, p=0,004). Conclusions: We demonstrated a negative association between Toxoplasma gondii infection and the presence of MS. Furthermore, parasite infected MS patients showed lower number of relapses and disability scores supporting the hypothesis of immunomodulatory effects of parasitic infections in autoimmune diseases. Future studies is required to establish whether parasitic infections are protective against MS.

Disclosure Asli Koskderelioglu: Nothing to disclose. Muhtesem Gedizlioglu: Nothing to disclose. Ilhan Afsar: Nothing to disclose. Bayram Pektas: Nothing to disclose. P396 Pilot baseline versus treatment clinical trial of the HIV drug raltegravir in patients with active relapsing remitting multiple sclerosis: the INSPIRE study J. Gold1, G. Giovannoni1, M. Calado Marta1, U. Meier1, D. Miller2, T. Christensen3, H. Maruszak4, D. Holden1, L. Bianchi1, B. Turner1 1Neuroscience and Trauma, Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, 2Institute of Neurology. University College London, London, United Kingdom, 3Depatment of Biomedicine, Aarhus University, Aarhus, Denmark, 4The Albion Centre, Prince of Wales Hospital, Sydney, NSW, Australia Although the aetiology of Multiple Sclerosis remains elusive, it is clear that Epstein Barr Virus (EBV) and possibly other viruses have a role in the pathogenesis of MS. Laboratory evidence suggests that a Human Endogenous Retrovirus (HERV) could have a role as a trigger or even be the cause of MS, but these data suffer from the lack of any interventional therapy that may assist in determining what will happen if HERVs are suppressed. Recent epidemiological evidence indicates that patients with HIV infection have a significantly lower risk of developing MS and that HIV antiretroviral therapies may be coincidentally inhibiting an endogenous retrovirus or retroelements that are implicated in MS. In order to further investigate this possibility, a 6 month Phase 2b pilot clinical trial was designed as a baseline versus treatment study to investigate the role of an HIV integrase inhibitor, raltegravir, in patients with active RRMS as determined by gadolinium-enhanced MRI. The twenty patients who were enrolled had monthly visits for comprehensive assessment that involved a Gd-enhanced MRI, saliva collection for EBV shedding, blood collection for safety monitoring, virology, including HERVs; measurement of immunological and inflammatory markers, and physical, neurological and quality-of-life determination. Patients were monitored monthly for three months as a baseline, followed by three months of treatment with raltegravir 400mg twice a day. All patients completed the six months trial period. This pilot study determined there were no serious adverse events and no withdrawals due to safety issues. The study drug was well tolerated. This is first clinical study conducted with an anti-retroviral therapy in patients with active RRMS. The effect of therapy on the number and rate of development of lesions on Gd-enhanced MRI, markers of HERV activity and other outcome parameters are currently the subjects of final analysis and review. Disclosure This investigator initiated clinical trial was funded by Merck Sharpe and Dohme (U.S.). The investigators have no conflict of interest.


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Poster Session I, 21(S11) P397 Vitamin D and Epstein-Barr virus antibody levels in a prospective cohort of MS patients S. Wergeland1, K.-M. Myhr2, K.I. Løken-Amsrud3, A.G. Beiske4, K.S. Bjerve5,6, H. Hovdal5, S. Bakke7, F. Lilleås8, R. Midgard9, T. Pedersen10, S.S. Kvistad11, G. Njølstad11, T. Holmøy12,13, T. Riise14, Ø. Torkildsen2,11 1Department of Neurology, Haukeland University Hospital, 2Department of Clinical Medicine, University of Bergen, Bergen, 3Department of Neurology, Innlandet Hosital Trust, Lillehammer, 4Multiple Sclerosis Center Hakadal, Hakadal, 5Trondheim University Hospital, 6Norwegian University of Science and Technology, Trondheim, 7Department of Neuroradiology, Oslo University Hospital, 8Curato Oslo, Oslo, 9Department of Neurology, Molde Hospital, Molde, 10Unilabs Drammen, Drammen, 11Haukeland University Hospital, Bergen, 12Department of Neurology, Akershus University Hospital, Lørenskog, 13Institute of Clinical Medicine, University of Oslo, Oslo, 14Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway Background: Low serum 25(OH)-vitamin D (25OH-vitD) and Epstein-Barr virus (EBV) are known risk factors for multiple sclerosis (MS). EBV infection is associated with an increased risk of developing MS, and MS disease activity is associated with antiEBV nuclear antigen 1 (EBNA-1) antibody levels. It has been shown that intrathecal production of anti-EBNA-1 by B-lymphocytes can be attenuated by stimulation with vitamin D. Due to seasonal variation in 25OH-vitD levels, we hypothesize that there is a seasonal variation in EBNA-1 antibody production, associated with 25OH-vitD levels. Objective: To study the association between anti EBNA-1 antibody levels and 25OH-vitD in a prospective cohort of patients with relapsing-remitting MS. Method: The study comprises 91 patients with relapsing-remitting MS, all participants in a randomized clinical trial (the OFAMS study). Repeated, paired measurements of 25OH-vitD and antiEBNA1 levels were obtained in 6 month intervals from baseline to month 24 . The association between EBNA-1 and 25OH-vitD levels was analysed using generalized linear models for hierarchical data in MPlus. A large proportion (70.0%) of EBNA-1 levels was above the upper detection limit for the quantitative chemiluminescent assay. A selection of 20 samples from this group was available for dilution and determination of exact EBNA-1 levels. The analyses of association between EBNA-1 and 25OH-vitD levels were therefore performed using both unadjusted values, and on a dataset where all values above the upper detection limit were replaced by the mean value of these 20 samples. Results: In the analysis of unadjusted anti-EBNA-1 levels there was a negative association with 25OH-vitD levels (B=-0.246, 95% CI [-0.470, -0.022], p =0.031). This association remained significant after adjusting for the patient’s age, gender, HLA DRB1*15 status, vitamin A and interferon β-1a treatment. Analysis of adjusted EBNA-1 levels did not change the results (B=-0.317, 95% KI [-0.564, -0.071], p =0.017). Conclusion: There is a weak, but significant and persistent negative association between anti-EBNA-1 antibody levels and 25OH-vitD levels. The results indicate that 25OH-vitD and EBNA-1 antibody levels are affected by a common, exogenous

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factor, or that the effect of vitamin D on MS disease may include modulation of anti-EBNA-1 antibody producing B-lymphocytes. Disclosure Stig Wergeland: nothing to disclose. Kjell-Morten Myhr: nothing to disclose. Kristin Løken-Amsrud: nothing to disclose. Antonie G. Beiske: nothing to disclose. Kristian Bjerve: nothing to disclose. Harald Hovdal: nothing to disclose. Søren Bakke: nothing to disclose. Finn Lilleås: nothing to disclose. Rune Midgard: nothing to disclose. Tom Pedersen: nothing to disclose. Silje Stokke Kvistad: nothing to disclose. Gro Njølstad: nothing to disclose. Trygve Holmøy: nothing to disclose. Trond Riise: nothing to disclose. Øivind Torkildsen: nothing to disclose. P398 Antibody response to individual EpsteinBarr virus proteins in multiple sclerosis J. Lindsey Neurology, University of Texas, Houston, TX, United States Epstein-Barr virus (EBV) is associated with multiple sclerosis (MS). One of the most consistent findings has been that antibodies to the EBV nuclear antigen-1 (EBNA-1) are increased in MS. Only a limited number of other EBV proteins have been investigated. Our previous work using Western blots demonstrated that most people have antibodies to many different EBV proteins, and suggested that antibodies were increased to some, but not all, EBV antigens. The objective of this work was to identify EBV proteins that are the targets of an increased antibody response in MS. We immunoprecipitated EBV proteins using either MS or control IgG, and identified the bound proteins using iTRAQ quantitative mass spectrometry. We compared the amounts bound by MS or control IgG. We then selected and produced single EBV proteins, and used quantitative immunoassays to compare the antibody response in 80 MS patients and 80 matched controls. Mass spectrometry identified 28 EBV proteins that were immunoprecipitated by MS or control IgG. Fifteen of these proteins were more concentrated in the MS immunoprecipitate. We selected 4 individual EBV proteins for further study. The antibody response to EBNA-1 was significantly increased in MS (p< 0.001), as was the antibody response to the small capsid protein BFRF3 (p=0.007). The antibody response to the EBV membrane glycoprotein gp350 was marginally increased in MS (p=0.059), but the antibody response to gp42 was not significantly different. We conclude that the antibody response is increased only to selected EBV antigens in MS patients. This finding may be relevant to the pathogenesis of MS. Disclosure Dr Lindsey has nothing to disclose.


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Environmental risk factors P399 Beneficial effect of smoking cessation on multiple sclerosis prognosis R. Ramanujam1,2, A.K. Hedström1, A. Manouchehrinia1, L. Alfredsson1, T. Olsson1, M. Bottai1, J. Hillert1 1Karolinska Institutet, 2The Royal Institute of Technology, Stockholm, Sweden Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, usually characterized by bouts and remissions, typically followed by a secondary progressive (SP) course. Smoking tobacco is a well-established risk factor for MS. However, it is less clear whether smoking after diagnosis is detrimental. This study investigated if the risk of conversion to secondary progressive MS (SPMS) is higher among those who continue smoking after MS diagnosis. Data from the GEMS (Genes and Environment in Multiple Sclerosis) study, consisting of prevalent patients from the Swedish National MS-Registry, was used for smokers at MS diagnosis including baseline characteristics and continuing smoking habits. To determine if smoking after diagnosis affects the time to SPMS, an accelerated failure time model incorporating both static and time varying covariates was created using all smokers at diagnosis (n=728). The optimized model illustrated that each additional year of smoking after diagnosis accelerated the time to conversion by 4.7% (p< 0.001). Kaplan-Meier plots demonstrated that those who continued to smoke continuously each year after diagnosis converted to SP faster than those who quit smoking, reaching secondary progression at 48 and 56 years of age, respectively. This study gives evidence that continued smoking is associated with an acceleration in time to SP and that those who quit fare better. We therefore propose that patients with MS should be advised to stop smoking once a diagnosis has been made, not only to lessen risks of co-morbidities, but also to avoid aggravating MS-related disability. Disclosure Dr. Ramanujam has nothing to disclose. Dr. Manouchehrinia has nothing to disclose. Dr. Hedström has nothing to disclose. Dr. Bottai has nothing to disclose. Dr. Alfredsson has nothing to disclose. Dr. Olsson reports grants from The Swedish research Council, grants from The Knut and Alice Wallenberg Foundation, grants from The AFA foundation, grants from The Swedish Brain Foundation, during the conduct of the study; grants from Biogen, grants from Novartis, grants from Genzyme, outside the submitted work. Dr. Hillert reports grants from The Bibbi and Nils Jensen Foundation, grants from The Swedish Research Council, grants from The Karolinska Institutet research funds, during the conduct of the study; grants and personal fees from BiogenIdec, grants and personal fees from Novartis, personal fees from TEVA, from Genzyme, outside the submitted work. P400 Vitamin D status does not influence disability progression of multiple sclerosis patients over three years follow-up A.-H. Muris1,2, J. Smolders2, L. Rolf1,2, L. Klinkenberg3, N. van der Linden3, S. Meex3, J. Damoiseaux3, R. Hupperts1,2

1School

for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, 2Academic MS Center Limburg, Orbis Medical Center, Sittard, 3Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands Introduction: The risk of developing multiple sclerosis (MS) as well as MS disease activity is associated with vitamin D (25(OH) D) status. The relationship between the main functional disability hallmark of MS, disability progression, and 25(OH)D status is less well established though, especially not in progressive MS patients. Methods: This retrospective 3-year follow-up study included 554 MS patients with a baseline 25(OH)D serum level and Expanded Disability Status Scale (EDSS) with a minimum follow-up of three years. Logistic regressions were performed to assess the effect of baseline 25(OH)D on relapse rate. Repeated measures linear regression analyses were performed to assess the effect on disability and disability progression. Results: Baseline deseasonalized 25(OH)D status was associated with subsequent relapse risk (yes/no), but only in the younger MS patients (⩽ 37.5 years; OR=0.872, per 10nmol/L 25(OH)D, p=0.041). Baseline 25(OH)D was not significantly associated with either disability or disability progression, irrespective of MS phenotype. Discussion and conclusion: Within the physiological range, 25(OH)D status appears to affect the occurrence of relapses in younger MS patients, but does not significantly diminish disability or disability progression. Whether high dose supplementation to supra physiological 25(OH)D levels prevents disability progression in MS should become clear from long term follow-up of supplementation studies. Disclosure AM, JS, LR, LK, NvdL, SM and JD declare that there is no conflict of interest. RH received honoraria for lectures and advisory boards and Research Grants from Merck, Biogen, Sanofi-Genzyme, Novartis and TEVA. P401 1α, 25-dihydroxy-vitamin D3 effects selectively activation and pro-inflammatory phenotype of different antigen-presenting cells L. Neubeck, J. Eisele, K. Thomas, T. Ziemssen Center of Neuroscience Carl Gutsav Carus Dresden, Dresden, Germany Objective: To evaluate the effect of 1α, 25-dihydroxy-vitamin D3 (Vit.D3) on different human antigen-presenting cells (APCs) of multiple sclerosis (MS) patients and healthy controls (HC). Background: Dendritic cells (DCs) as professional APCs play an important role in the pathology of MS. Matured DCs have the potential to activate naïve T cells to differentiate into pathological T cells. DCs can be divided into various subpopulations whereas 6-sulfo LacNAc+ (slan) DCs were previously identified to exert highly pro-inflammatory capabilities. Although Vit.D3 has already shown to demonstrate immune modulating properties and


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Poster Session I, 21(S11) to be linked with clinical disease activity, its ability to regulate the differentiation, maturation and function of DCs is not known in detail. Methods: Using in vitro assays, peripheral blood mononuclear cells (PBMCs) of HC were cultured with two different concentrations of Vit.D3 (10nM vs. 100nM). Using an ex vivo approach, PBMCs of MS patients were evaluated before and after Vit.D3 substitution. Surface and activation markers as well as cytokine release after stimulation with lipopolysaccharide (LPS) of slanDCs, BDCA1+ DCs and monocytes were investigated. Results: In HC PBMCs, Vit.D3 decreased the release of proinflammatory cytokines including IL-6, IL-12, IL-23 and TNF-α upon LPS stimulation in slanDCs and BDCA1+ DCs dose-dependently. The in vitro presence of Vit.D3 increased levels of antiinflammatory IL-10 of cultured BDCA1+ DCs. Vit.D3 also inhibited the release of IL-6, IL-23 and TNF-α in monocytes after LPS stimulation. The expression of activation marker CD83 was down regulated in slanDCs but not BDCA1+ DCs after Vit.D3 culture. CD150 expression in slanDCs and BDCA1+ DCs was increased by increasing Vit.D3 concentrations in vitro. In MS patients, slanDCs and BDCA1+ DCs demonstrated decreased levels of IL-6, IL-12 and IL-23 and a down-regulation of the activation and maturation marker CD83 after start of Vit.D3 substitution. Conclusion: Here we present first data of Vit.D3 effects on different APCs in vitro and ex vivo. These results suggest immunemodulating properties of Vit.D3 in MS, especially on the APC level. Further investigations are necessary to elucidate potential modulating effects on the APC depending T cell activation. Disclosure Dr. Katja Thomas has received honorarium from Novartis, Bayer and Biogen idec. Prof. Dr. T. Ziemssen is on the scientific advisory board for Bayer Healthcare, Biogen Idec, Novartis, Merck-Serono, Teva, Genzyme, and Synthon; has received speaker honorarium from Bayer Healthcare, Biogen Idec, Genzyme, MSD, GSK, Novartis, Teva, Sanofi, and Almirall; and has received research support from Bayer Halthcare, Biogen Idec, Genzyme, Novartis, Teva, and Sanofi. L. Neubeck and J. Eisele: Nothing to disclose. P402 Dietary fatty acids directly affect immune response in CNS autoimmunity via the small intestine A. Duscha1, S. Jörg2, J. Berg1, A. Hammer2, D.A. Akkad3, D.N. Müller4, R. Gold1, R.A. Linker2, A. Haghikia1 1Neurology, Ruhr-University Bochum, St. Josef Hospital, Bochum, 2Neurology, Friedrich-Alexander-University, Erlangen, 3Human Genetics, Ruhr-Universität Bochum, Bochum, 4Experimental and Clinical Research Center & Max-Delbrück Center, Berlin, Germany Background: With recent advances in the field of microbiotics, investigations of the interaction between the gut microbiome, host immune system, and nutrition have grown to include questions of autoimmunity. While the direct interaction between these factors has yet to be elucidated, dietary factors such as fatty acids (FA), molecules released by gut microbiota during fermentation of indigestible carbohydrates, have been shown to alter immune cell

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homeostasis and ameliorate disease course in various autoimmune models. Objective: Our study investigated the influence of FA on T cell differentiation and local immune responses in the gut under normal and autoimmune conditions in multiple sclerosis (MS) animal models, as well as on T cell differentiation and proliferation in the human system. Design and methods: Using both ex vivo and in vivo methodologies, we analyzed the effects of fatty acids of varying chain lengths on T cell differentiation in the small intestine of both healthy mice and mice afflicted with MOG experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We also investigated the effects of these molecules in the human system by analyzing human naïve T cell differentiation and proliferation in vitro. Results: Our results demonstrated opposing effects of dietary short chain fatty acids (SCFA) and medium- or long-chain FA (MCFA/LCFA) on T helper (Th) cells. Murine ingestion of MC and LCFA promoted differentiation of Th1 and Th17 cells and led to an impaired sequestration of intestinal Th1 and Th17 cells via p38 MAPK by 6-15%. Contrastingly, dietary SCFA enhanced Treg differentiation by 18% and expanded gut Treg by lipin-2/ JIP2-dependent suppression of the JNK1 pathway. Furthermore, in a model of T cell-mediated autoimmunity, LCFA and MCFA exacerbated EAE and increased pathogenic T cell populations by skewing the microbiome composition towards a pro-inflammatory Th1/Th17-inducing phenotype, while treatment with SCFA ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina propria-derived CD4+ CD25+ Foxp3+ Treg. In the human system, SCFA enhanced Treg differentiation (10%) and proliferation (12%) in vitro, paralleling results found in the murine system. Conclusions: Our results demonstrate a direct dietary impact on intestinal- and, subsequently, CNS-specific Th cell responses in extra-intestinal autoimmunity and may have therapeutic implications for autoimmune diseases like MS. Disclosure Alexander Duscha: nothing to disclose Stefanie Jörg: nothing to disclose Johannes Berg: nothing to disclose Anna Hammer: nothing to disclose Denis A. Akkad: nothing to disclose Dominik N. Müller: nothing to disclose Ralf Gold: nothing to disclose Ralf A. Linker: nothing to disclose Aiden Haghikia: nothing to disclose P403 Body mass index influence disease activity and interferon-beta treatment response in multiple sclerosis S.A. Stokke Kvistad1,2, K.-M. Myhr3,4,5, T. Holmøy6, J.S. Benth7,8, S. Wergeland9, K.I. Løken-Amsrud10, A.G. Beiske11, K.S. Bjerve12, H. Hovdal13, F. Lilleås14, R. Midgard15, T. Pedersen16, S.J. Bakke17, A.E. Michelsen18,19, P. Aukrust18,19,20, T. Ueland18,21, J.V. Sagen22,23, Ø. Torkildsen5,9,24 1Hormone Laboratory, 2Norwegian Multiple Sclerosis Competence Centre, Haukeland University Hospital, 3Department of Neurology, Norwegian Multiple Sclerosis


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Competence Centre, 4Department of Neurology, Norwegian Multiple Sclerosis Registry and Biobank, 5Department of Clinical Medicine, University of Bergen, KG Jebsen MS Reasearch Centre, Bergen, 6Akershus University Hospital/ Department of Neurology, 7University of Oslo, Instiitute of Clinical Medicine, 8Akershus University Hospital, Helse Sør-Øst Research Centre, Oslo, 9Department of Neurology, Haukeland University Hospital, Norwegian Multiple Sclerosis Competence Centre, Bergen, 10Department of Neurology, Innlandet Hosital Trust, Lillehammer, Lillehammer, 11Multiple Sclerosis Centre, Hakadal, 12Clinic of Laboratory Medicine, 13Department of Neurology, St.Olav Hospital, Trondheim University Hospital, Trondheim, 14Curato Oslo, Oslo, 15Department of Neurology, Molde Hospital, Molde, 16Unilabs Drammen, Drammen, 17Department of Neuroradiology, Oslo University Hospital, 18Research Institute of Internal Medicine, Oslo University Hospital, 19University of Oslo, Institute of Clinical Medicine, 20Section for Clinical Immunology and Infectious Diseases, Oslo University Hospital, 21Institute of Clinical Medicine, University of Oslo, Oslo, 22Department of Laboratory Medicine and Pathology, Haukeland University Hospital, Hormone Laboratory, 23Department of Clinical Science, University of Bergen, 24Department of Neurology, Haukeland University Hospital, Norwegian Multiple Sclerosis Registry and Biobank, Bergen, Norway Background: Obesity is a possible risk factor of multiple sclerosis (MS). Studies have reported an increased risk of MS in obese individuals, but so far the association between obesity and disease activity has not been explored. Objective: To study if there is an association between body mass index (BMI) and clinical and magnetic resonance imaging (MRI) disease activity in patients with relapsing-remitting MS (RRMS) before and during interferon beta 1a (IFNB) treatment. The association between BMI and serum levels of vitamin D and selected inflammation markers was also explored. Methods: Cohort study of 86 patients originally included in a multicenter, randomized, placebo-controlled trial of omega-3 fatty acids. (The OFAMS study). BMI was calculated at baseline, and patients were followed for two years with clinical scoring (relapses and disability status), 12 repeated MRI scans and nine serum measurements of 11 inflammation markers and 25-hydroxyvitamin D. No evidence of disease activity (NEDA) was defined as no evidence of clinical relapses, disability progression or new or enlarging T2 or T1 contrast enhancing MRI lesions. The patients were without any disease modifying therapy during the first six months, and all received INFB treatment during months 7-24. Results: There was no difference in clinical and MRI activity between patients stratified by BMI prior to INFB treatment, whereas during INFB-treatment, 80 % of overweight or obese patients (BMI⩾25) had MRI activity compared to 48 % in the group of normal weight patients (BMI< 25) (p=0.001). Including clinical disease activity, 24 % in the normal weight group obtained NEDA-status compared to only 13 % in the group of overweight and obese patients (p=0.05). These findings were consistent after adjusting for gender and HLA-DRB1*15 status. Two of the inflammation markers, pentraxin 3 (PTX3) and interleukin-1 receptor antagonist (IL1Ra) were correlated with BMI, but there was no correlation between BMI and vitamin D levels.

Conclusion: There was no association between BMI and disease activity before INFB-treatment. The numbers of patients that accomplished NEDA status during treatment was however significantly lower among overweight and obese patients, than among those with normal weight, indicating that BMI could affect INFB treatment response. Disclosure Silje Kvistad has received unrestricted research grants from Biogen and Novartis Kjell-Morten Myhr: Nothing to disclose Trygve Holmøy: Nothing to disclose Jūratė Šaltytė Benth:Nothing to disclose Stig Wergeland: Nothing to disclose Kristin I. Løken-Amsrud: Nothing to disclose Antonie G. Beiske: Nothing to disclose Kristian S. Bjerve: Nothing to disclose Harald Hovdal: Nothing to disclose Finn Lilleås: Nothing to disclose Rune Midgard: Nothing to disclose Tom Pedersen: Nothing to disclose Søren J. Bakke: Nothing to disclose Annika E. Michelsen: Nothing to disclose Pål Aukrust:Nothing to disclose Thor Ueland: Nothing to disclose Jørn V. Sagen: Nothing to disclose Øivind Torkildsen: Nothing to disclose P404 Oral succinate contained as a food additive exacerbates experimental autoimmune encephalomyelitis via increased IL-1β production K. Takata1, T. Okuno1, T. Koda1, J.A. Honorat1, A. LittlewoodEvans2, J.M. Carballido2, H. Mochizuki1, Y. Nakatsuji1 1Neurology, Osaka University Graduate School of Medicine, Osaka, Japan, 2Novartis Institutes for BioMedical Research, Basel, Switzerland Background: Food habit has recently drawn attention as a potential risk factor of multiple sclerosis (MS). Because succinate was reported to enhance the inflammation and the consumption of succinate as a food additive has been increasing, we hypothesized that the rapid increase in the prevalence of MS in Japan is partially attributed to the increase of succinate intake. Methodology: We investigated the effects of oral succinate intake on experimental autoimmune encephalomyelitis (EAE), an animal model of MS. CD4-positive T cells in intestinal lamina propria and in mesenteric lymph nodes (MLN) were analyzed by FACS, and cytokine production from explants of intestines was also assessed. In addition, we analyzed the effects of succinate on bone marrow dendritic cells and T cell differentiation. Principal findings: Oral administration of succinate exacerbated EAE, and significantly increased the antigen-specific production of IL-17 by T cells isolated from inguinal lymph nodes. Histological examination revealed an increased infiltration of inflammatory cells into the CNS. The number of CD4-positive IL-17-producing T cells was increased in intestinal lamina propria. The production of IL-1β by intestinal tissue explants was


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Poster Session I, 21(S11) significantly increased in the succinate-treated group. Conversely, the number of Treg cells in intestinal lamina propria and MLN was significantly decreased in the succinate-treated group. Succinate enhanced IL-1β production and Th17 cell differentiation in an IL-1β dependent manner in vitro. Feeding succinate to GPR91 deficient mice, during EAE induction, also resulted in an accelerated disease onset. This observation suggests that additional mechanisms than those involving the triggering of succinate in immune cells, such as gut microbiome, might be responsible for the observed phenomenon. Conclusions and significance: Oral administration of succinate aggravates EAE via increased IL-1β production. Our findings suggest that increased intake of succinate as a food additive may contribute to exacerbation of MS. Disclosure Kazushiro Takata: nothing to disclose Tatsusada Okuno: nothing to disclose Toru Koda: nothing to disclose Joseph Archie Honorat: nothing to disclose Amanda Littlewood-Evans: a relevant person of Novartis Institutes for Biomedical Research José M. Carballido: a relevant person of Novartis Institutes for Biomedical Research Hideki Mochizuki: nothing to disclose Yuji Nakatsuji: nothing to disclose P405 Interaction between smoking and HLA genotype in multiple sclerosis development A.K. Hedström1, I. Lima Bomfim2, H.B. Sondergaard3, A. Bang Oturai3, F. Sellebjerg3, M. Wendel Gustavsen4, H.F. Harbo4, D. Obradovic5, I. Kockum6, T. Olsson6, L. Alfredsson1 1Institute of Environmental Medicine, 2Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden, 3Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, 4Institute of Clinical Medicine, Department of Neurology, University of Oslo, Oslo University Hospital, Oslo, Norway, 5Department of Neurology, Military Medical Academy, Belgrade, Serbia, 6Neuroimmunology Unit, Department of Clinical Neuroscience and Center for Molecular Medicine, Karolinska Institutet at Karolinska University Hospital, Solna, Sweden Background: It has become increasingly clear that interactions between environmental influences and an individual´s genetic background contribute to MS development. We aimed to investigate whether the previously observed interaction between smoking and HLA genotype in the Swedish population could be replicated and extended to include other populations. Methods: We used 4 independent case-control studies from 4 different populations (Sweden, Norway, Denmark, and Serbia). Each study was analyzed separately. More detailed analyses were then performed by combining the studies into a larger dataset (3131 cases and 6085 controls). Cases and controls were classified according to their smoking status and HLA-DRB1 as well as HLA-A genotypes. Subjects with different genotypes and

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smoking habits were compared with regard to MS incidence, by calculating odds ratios with 95% confidence intervals employing logistic regression. The potential interaction between different genotypes, as well as between genotype and smoking, was evaluated by calculating attributable proportion due to interaction. Results: The interaction between smoking, HLA-DRB1*15 and HLA-A*02 was replicated in the Swedish, Danish, and Norwegian studies. By combining the Scandinavian datasets into one, we show that interactions take place between both HLA-DRB1*15 and HLA-A*02 regardless of smoking status, between HLA-DRB1*15 and smoking regardless of HLA-A*02 status, and between HLAA*02 and smoking regardless of HLA-DRB1*15 status. When each of the 3 interacting risk factors are considered without presence of the other 2 risk factors, smoking increases the risk of MS by a factor of 2.3, absence of HLA-A*02 increases the risk by a factor of 1.9, and HLA-DRB1*15 increases the risk by a factor of 3.5. However, there was a 15-fold increased risk of developing MS among smokers with both genetic risk factors, compared with subjects with none of the risk factors (OR 15.0, 95% CI 12.218.5), which indicates significant interaction on the additive scale (attributable proportion due to interaction 0.5, 95% CI 0.4-0.6, p< 0.0001). In the Serbian study, there was no association between HLA*02 and MS in the population. However, a strong interaction was observed between smoking and HLA-DRB1*15 with regard to MS risk (AP 0.5, 95% CI 0.2-0.8, p=0.003). Conclusions: The risk of developing MS associated with HLA genotypes is strongly influenced by smoking status and vice versa. Disclosure Dr. Hedström, Dr. Lima Bomfim, Dr Bach Sondergaard, Dr Wendel Gustavsen, and Dr. Obradovic report no disclosures. Dr. Bang Oturai has served on scientific advisory boards for Biogen Idec and Novartis; has received research support from Novartis and Biogen Idec; has received speaker honoraria from Biogen Idec, Novartis and TEVA; and has received support for congress participation from, Merck Serono, Biogen, Novartis and Genzyme. Dr. Sellebjerg has served on scientific advisory boards for Biogen Idec, Genzyme, Merck Serono, Novartis and Teva, served as consultant for Biogen Idec and Lundbeck; has received support for congress participation from Biogen Idec, Novartis and Teva; has received speaker honoraria from Biogen Idec, Genzyme, Merck Serono and Novartis. His laboratory has received research support from Biogen Idec and Novartis. Dr. Flinstad Harbo received unrestricted travel grants or speaker´s fees from Novartis, Biogen Idec and Sanofi and an unrestricted research grant from Novartis. Dr. Kockum received speaker´s fees from Merck-Serono, and is involved in a project sponsored by Biogen. Dr. Olsson served on scientific advisory boards and received speaker honoraria Novartis, Merck-Serono, Biogen Idec,TEVA and Genzyme; served as Co-editor of Current Opinion in Immunology; received from Novartis and Biogen; and receives research support from Novartis, Genzyme, Biogen Idec, the Swedish Research Council (07488), EU fp7 Neurinox, and CombiMS, the, and the Swedish Brain Foundation. Dr. Alfredsson receives research support from the Swedish Medical Research Council (K2013-69X-14973-10-4 and


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825-2012-5168) and Swedish Council for Health, Working Life and Welfare (Dnr 2012-0325). P406 Alterations of the human gut microbiome in multiple sclerosis S. Jangi1, R. Gandhi1, N. Li2, F. Von Glehn1, R. Yan3, K. Melo1, M. Mazzola1, B. Patel2, B. Glanz4, S. Cook4, F. Stuart4, J. Holden5, P. Kivisakk6, P. De Jager4, T. Chitnis4, R. Bakshi4, F. Quintana3, G. Gerber2, L. Bry2, H. Weiner1 1Brigham & Women’s Hospital, Partners MS Center, Harvard Medical School, 2Harvard Medical School, Brigham and Women’s Hospital, 3Brigham and Women’s Hospital and Harvard Medical School, 4Partners MS Center, Brigham and Women’s Hospital, Boston, 5University of Massachusetts Amherst, Amherst, 6Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, United States Background: The gut microbiome has been implicated in autoimmune disorders. We investigated the gut microbiome in 61 subjects with multiple sclerosis (MS) and 43 healthy controls. Methods and results: Following fecal sample collection from study participants, we extracted bacterial DNA and used Roche 454 and Illumina platforms for 16S rRNA sequencing to determine the composition of the gut microbiome. We found the phyla Euryarcheota andVerrucomicrobia were increased in MS subjects. At the genus level, Methanobrevibacterand Akkermansia were increased (BH adjusted p-value < 7.98 x 10-3 and < 9.37 x10-4 respectively) whereas Butyricimonas was decreased (BH adjusted p-value < 3.47 x 10-3). Additional genera were decreased in untreated patients compared to controls including Prevotella, Colinsella, and Slackia. Patients on disease modifying treatment had increased Prevotella and Sutterella and decreased Sarcina genera compared to untreated patients. Next, we performed gene expression profiling in circulating monocytes and T cells from MS patients and found that subjects with increased Methanobrevibacter or Akkermansia in stool samples also had increased gene expression within the same inflammatory gene module (p< .0056 and p< .011 respectively) including CCR2, STAT5, CASP1 and CASP3 in monocytes, suggesting both organisms may drive a similar inflammatory monocyte phenotype. Conversely, increased Butyricimonas was inversely correlated with the same gene module (p< .033) suggesting Butyricimonas may be associated with an immunoregulatory monocyte profile. We used antigen arrays to profile myelin antigen reactivities in subjects’ sera and found that MS patients with high abundance of Methanobrevibacter had increased reactivity to tetracosanoid acid (p< .0135), a cerebroside component found in the myelin sheath. Furthermore, MS subjects with antibody reactivity to lipids derived from Methanobrevibacter also had increased expression of TNF-a and IFN-g within T cells (p < 1.7 X 10-9), suggesting that reactivity to Methanobrevibacter may be linked to changes in T cell immunoreactivity. Finally, in a second cohort, we found that MS patients had elevated breath methane compared to controls, consistent with our observation of increased gutMethanobrevibacter in MS. Conclusions: We describe prominent alterations in the gut microbiome in MS which may be related to the underlying immunopathogenesis of the disease.

Disclosure Howard Weiner reports the following conflicts of interest/sources of funding: CONSULTANT Gerson Lehrman $1,000 Therapix $1,000 RESEARCH SUPPORT EMD Serono, Miragen, Sanofi, TEVA. Roopali Gandhi reports funding from Biogen, Novartis and Serono. Sushrut Jangi: nothing to disclose Ning Li: nothing to disclose Georg Gerber: nothing to disclose Lynn Bry: nothing to disclose James Holden: nothing to disclose Qing Liu: nothing to disclose Francisco Quintana: nothing to disclose Rohit Bakshi: nothing to disclose Kirsy Melo: nothing to disclose Parham Nejad: nothing to disclose Felipe von Glehn: nothing to disclose Maria Mazzola: nothing to disclose Bonnie Glanz: nothing to disclose Sandra Cook: nothing to disclose Fiona Stuart: nothing to disclose Phil DeJager: nothing to diclose

Neurobiology P407 c-Fos reporter reveals temporal, spatial and transcriptional astrocytic activity in experimental autoimmune encephalomyelitis (EAE), correlated with disease severity and modulated by S1P-signaling A. Groves, Y. Kihara, D. Jonnalagadda, J. Chun Scripps Research Institute, La Jolla, CA, United States Background: Fingolimod in multiple sclerosis binds to S1P1 receptors (S1PRs) on autoreactive lymphocytes and reduces their infiltration into the CNS. Fingolimod also has direct CNS effects via modulation of S1PRs on various CNS cell types. Objective: To assess the extent of astrocyte activation related to EAE clinical severity; characterize the temporal, spatial and transcriptional activity of astrocytes during EAE; and explore alterations by genetic removal of S1P1 signaling and fingolimod treatment. Method: Monophasic EAE was induced and doxycyline was removed at EAE onset, allowing c-Fos activated cells to express a semi-permanent GFP signal. Astrocyte activation was quantified and compared in untreated, fingolimod treated, and astrocyte specific S1P1 nulls by histology and flow cytometry. Activated astrocytes were visualized in the intact lower spinal cord, using tissue clearance techniques and advanced confocal microscopy, at different time points post-EAE onset to characterize temporal and spatial activity. Transcriptional change analysis was revealed using fluorescenceactivated cell sorting (FACS) of activated astrocytes and RNAseq. Results: In acute EAE (3-5 days post onset (dpo)), the clinical score of untreated controls was greater than fingolimod treated and nulls. Astrocyte activation of controls was also greater than fingolimod treated and nulls, correlating with disease severity in all groups. At 5 dpo, astrocytes comprise >90% of GFCs. Activated astrocytes 1 dpo in the intact lower spinal cord were seen as neuroanatomically discrete spheroid regions. At 3-5 dpo, discrete lesion sites enlarged to include peripherally activated astrocytes. Transcriptional analysis of EAE-activated astrocytes revealed changes in 3 groups.


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Poster Session I, 21(S11) Conclusions: The unbiased c-Fos reporter mouse predominately identifies astrocytes after EAE sign onset and correlates with clinical severity. Astrocyte-specific S1P1 removal and fingolimod administration reduces the number of activated astrocytes and size of the lesions, these changes track with clinical score amelioration. Activated astrocytes were identified as spheroid regions in the lower spinal cord and increases in activation were observed along the cord periphery during the development of EAE clinical scores. Distinct transcriptional changes in activated astrocytes that are altered by S1P receptor modulation implicate S1P1 dependent processes associated with amelioration of disease that are intrinsic to astrocytes. Disclosure Aran Groves has nothing to disclose. Yasuyuki Kihara has nothing to disclosure. Deepa Jonnalagadda has nothing to disclose. Jerold Chun received funding the the NIH and Novartis AG. P408 K2P channels: novel regulators of oligodendroglial cell functions S. Korr1,2, S. Albrecht1, S.G. Meuth2,3, T. Kuhlmann1, P. Ehling2,3 1Institute of Neuropathology, 2Department of Neurology, 3Institute of Physiology I, Neuropathophysiology, University Hospital Münster, Münster, Germany In multiple sclerosis (MS) decreased numbers of myelin forming oligodendrocytes and reduced differentiation of oligodendrocyte precursor cells (OPC) are key aspects hampering remyelination. Previous studies linked potassium channels to myelination, as unspecific channel blockers suppress maturation as well as proliferation of OPCs in mice. Here, we demonstrate the expression profile, conductive properties and the regulative involvement of distinct members of the two pore domain potassium (K2P) channel family in murine primary oligodendroglial lineage cells. For this purpose OPCs isolated from K2P-1 and K2P-2 deficient mice were subjected to different cell culture assays to examine proliferation, migration and differentiation as well as to qPCR- and patch clamp-analysis. For K2P-1 also the influence of channel ablation during postnatal myelination in vivo was determined. K2P-1 deficient OPCs exhibited a reduced proliferation capacity together with an earlier onset of differentiation in vitro, based on myelin gene expression and immunostaining. Assessment of developmental myelination in vivo corroborated the differentiation promoting effect of K2P-1 deficiency. Ablation of K2P-2 however led to enhanced migration of the OPCs and a later onset of myelin gene expression after induction of differentiation. Taken together, our results indicate a versatile modulation of precursor as well as differentiating oligodendroglial cell functions by distinct K2P channels, which could contribute to novel therapeutic opportunities for the treatment of MS.

Tanja Kuhlmann: nothing to disclose Petra Ehling: nothing to disclose P409 Are axon initial segments affected in multiple sclerosis ? A. Dilsizoglu Senol1, C. Lubetzki1,2, M. Davenne1 1Institut du Cerveau et de la Moëlle Epinière, 2AP-HP, Hôpital de la Pitié Salpêtrière, Paris, France The axon initial segment (AIS) and nodes of Ranvier respectively allow for the generation and propagation of action potentials (APs) along the axon, due to the aggregation of voltage-gated sodium (Nav) and potassium (Kv) channels in these domains. Depending on the Nav and Kv isoforms expressed at the AIS, the AIS length or its distance from the soma, neurons can modulate the neuron’s excitability properties. In multiple sclerosis (MS), as well as in experimental models of demyelination, loss of the myelin sheath is associated with a significant disorganization of nodes of Ranvier, which causes defects in the propagation of APs, and leads to clinical disability. Given the strong similarity between nodes and AISs in terms of molecular composition and the fact that both are flanked by the myelin sheath, added to recent findings that demyelinating lesions are prominent not only in white matter but also in grey matter areas, where AISs are found, we decided to analyze whether AISs might also be affected in MS mouse experimental models or MS post-mortem tissue. We undertook our analysis in a commonly used cuprizone-induced demyelination mouse model of MS. We measured the length and distance from the soma of AISs from the primary motor cortex in adult C57Bl/6 mice fed with cuprizone for 6 weeks. We did not find any statistically significant difference in AIS length or position compared to untreated mice. We also analyzed mice fed with cuprizone for 10 weeks, since complete demyelination is obtained only after five weeks of feeding. Again we did not find a significant difference. We thus concluded that AISs are not affected by demyelination per se. Since the cuprizone mouse model only partially recapitulates MS features, we also undertook the analysis of AISs in MS cortical lesions, where inflammation may be also and more prominently influential upon AISs. Interestingly, after both 6 and 10 weeks of cuprizone treatment, among the activated microglia found in cortical layers V and VI, we observed a subpopulation of microglia, which interacts with AISs. We then found that both activated and resting microglia actually interact with AISs and display different types of contact, with some microglial processes either extending along or engulfing the entire AIS. We also found these novel AIS-microglia interactions in human tissue. We are currently addressing the nature of these interactions, and their potential link with disease progression in MS. Disclosure Aysegul Dilsizoglu Senol: nothing to disclose Marc Davenne: nothing to disclose Catherine Lubetzki: nothing to disclose

Disclosure Sabrina Korr: nothing to disclose Stefanie Albrecht: nothing to disclose Sven G. Meuth: nothing to disclose

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P410 Neurodegenerative gene profiling in the central nervous system during experimental autoimmune encephalomyelitis


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N. Fissolo1, C. Matute1, S. Matías2, M. F-Bustamante1, Á. Sánchez2, S. Issazadeh-Navikas3, X. Montalban1, M. Comabella1 1Multiple Sclerosis Centre of Catalonia/Neuroimmunology Department, Vall d’Hebron University Hospital & VHIR, 2Unitat d’Estadística i Bioinformática, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain, 3Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark Background: Multiple Sclerosis (MS) is a disease with two components: an inflammatory component that prevails in the initial stages (relapsing-remitting), and a neurodegenerative component that is more prominent in the advanced stages of the disease (progressive). Currently, therapeutic strategies in MS are highly effective to reduce or even suppress the inflammatory component of the disease; however, current treatments have proven to be totally ineffective in those patients in whom the neurodegenerative component predominates. Despite numerous studies in this field, the mechanisms of neurodegeneration that take place during the course of the disease are not well understood. Here, we aimed to identify genes associated with the neurodegenerative process occurring during the different stages of the disease in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). Methods: Neurodegeneration was investigated using the chronic MOG35-55-induced EAE. Animals with MOG-induced EAE show an inflammatory phase on days 0-16 post-immunization (p.i.), and a neurodegenerative phase from day 16. C57BL/6 immunized either with MOG (EAE group) or PBS (control group) were sacrificed at different stages of the disease: 8, 36, 50 and 90 days. These time points were selected based on the extend of neurodegeneration in brain and spinal cord, determined with SMI 32+ neuronal staining. Gene expression profiling was determined in spinal cord tissue by using Affymetrix GeneChip® Mouse ST Array 2.1. Results: Gene expression profiling study in mice with EAE led to the identification of a number of differentially expressed genes relevant to the neurodegenerative process that takes place during the disease. Among the top differentially expressed pathways that were modulated over time between animals in the neurodegenerative phase vs. the inflammatory phase (adjusted p-values < 0.05), there was a high representation of genes involved in K+, Na+ and Ca+ channel activities, oxidative stress and glutamate signalling. Conclusions: These findings may help to better understand the neurodegenerative process occurring in the central nervous system of MS patients. Functional studies are currently underway to further investigate the implication of the modulated molecular pathways in the neurodegenerative process. Disclosure M Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, and Novartis X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall

Nicolás Fissolo, Clara Matute, Sara Matías, Marta F. Bustamante, Alex Sanchez, Shohreh Issazadeh-Navikas have nothing to disclose P411 NG2, expressed by immune and neural cells, displays multiple roles in development of experimental autoimmune encephalomyelitis G. Ferrara1, S. Morando1, M. Errede2, F. Girolamo2, F. Ivaldi1, N. Panini3, E. Erba3, R. Perris4, C. Bendotti3, T. Mennini3, L. Garzetti5, R. Furlan5, N. Kerlero de Rosbo1, D. Virgintino2, A. Uccelli1 1Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, 2Department of Basic Medical Sciences, Human Anatomy and Histology Unit, University of Bari School of Medicine, Bari, 3Department of Biochemistry and Molecular Pharmacology, Mario Negri Institute for Pharmacological Research, Milan, 4Division for Experimental Oncology 2, The National Cancer Institute Aviano, CRO-IRCCS, Aviano, 5Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy Nerve/glial-antigen 2 (NG2), expressed by oligodendrocyte progenitor cells (OPC), essential for remyelination, and by pericytes, crucial for blood-brain-barrier (BBB) integrity, could be implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). To understand its possible role, we induced EAE with MOG in NG2KO and wild-type (WT) mice. NG2KO mice developed milder EAE, with reduced demyelination and CD45+ infiltrates. Accordingly, NG2KO exhibited restoration of BBB integrity as supported by a tight-junctions proteins distribution similar to WT mice and greatly readjusted compared to what observed in WT EAE mice. In contrast to WT mice where OPC are significantly decreased at the late EAE phase, NG2KO displayed OPC numbers similar to those observed in WT mice. NG2 was expressed by invading macrophages and activated microglia in injured CNS. We found that it was also expressed on T cells and dendritic cells (DC) in naïve WT mice. Upon generation of MOGspecific encephalitogenic T cells, we observed that lack of NG2 associated with a shift towards a less inflammatory cytokine profile, whereby MOG-reactive NG2KO T cells produced significantly less IFN-γ, but more IL-4 and IL-10. We therefore addressed how the lack of NG2 affected DC responses. Analysis of MOGprimed lymph node cells for their intracellular expression of IL-12 showed that the proportion of IL-12-expressing CD11c+ DCs was significantly lower in EAE-induced NG2KO mice, indicating that NG2KO DCs skew MOG-specific T cell response to an antiinflammatory Th2 type. Chimera experiments confirmed the significant role of NG2 expressed by immune cells in EAE development as demonstrated by the observation that recipients of NG2KO bone marrow, but not of WT bone marrow, developed milder EAE regardless of their intrinsic WT or NG2KO genotype. All together these findings shows that NG2 expressed by immune cells, OPC and pericytes plays a complex and novel role in controlling development of neuroinflammation. Disclosure Ferrara G: Nothing to disclose


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Poster Session I, 21(S11) Morando S: Nothing to disclose Errede M: Nothing to disclose Girolamo F: Nothing to disclose Ivaldi F: Nothing to disclose, Panini N: Nothing to disclose Erba E: Nothing to disclose Perris R: Nothing to disclose Bendotti C: Nothing to disclose Mennini T: Nothing to disclose Garzetti L: Nothing to disclose Furlan R: Nothing to disclose Kerlero de Rosbo N: Nothing to disclose Virgintino D: Nothing to disclose Uccelli A: Nothing to disclose

Repairing mechanisms P412 Glia-axonal ribosome transfer in peripheral and central demyelination: a novel mechanism for axonal survival? G.J. Schenk1, A. Shakhbazau2, C. Hay2, J. Kawasoe2, R. Klaver1, V.W. Yong2, J.J.G. Geurts1, J. van Minnen2 1Anatomy and Neurosciences, VU University Medical Centre, Amsterdam, The Netherlands, 2Hotchkiss Brain Institute and Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Accumulation of ribosomes and translation machinery occurs in the axonal cytoplasm in response to nervous system injury. Glia cells were previously proven capable of transferring these polyribosomes to injured or diseased axons in different pathological contexts. Although this process, which may form a yet understudied survival signal, has been well-described for Schwann cells in the peripheral nervous system (PNS), evidence for the occurrence of glia to axon transfer of ribosomes in the central nervous system (CNS) is lacking. Here we investigate glia-axonal ribosome transfer in response to demyelination in both the PNS and CNS. In the PNS we show that adriamycin-induced demyelination in rodents has the potential to induce ribosome transfer to axons. We also monitor the glia-axonal ribosome supply by implantation of transgenic Schwann cells engineered to produce fluorescent ribosomes in this demyelination model. In the CNS severe disruption of oligodendrocyte-axon interaction is found in multiple sclerosis (MS), which is characterized by widespread demyelination and neurodegeneration. Given these hallmarks of MS, we investigated the presence of axonal ribosomes in mouse experimental autoimmune encephalomyelitis (EAE), a well-established immunological model for MS, and in human MS autopsy white matter brain material. We provide electron microscopic and confocal immunofluorescent evidence for increased axonal ribosome content in the spinal cords of EAE mice and in the MS brain compared to matching controls. In conclusion, our data strongly indicate that glia to axon transfer of ribosomes not only occurs in the PNS, but also in the CNS and that demyelination is a potent trigger in initiating this process. Glia to axon transfer of ribosomes may thus be a universal contributor to axonal survival during disease conditions in the brain, including MS. Disclosure Geert J. Schenk: Nothing to disclose

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Antos Shakhbazau: Nothing to disclose Curtis Hay: Nothing to disclose Jean Kawasoe: Nothing to disclose Roel Klaver: Nothing to disclose V. Wee Yong: Nothing to disclose Jeroen J.G. Geurts: Nothing to disclose Jan van Minnen: Nothing to disclose P413 Deficiency in the LINGO-1 signalling pathway enhances optic nerve regeneration in a knock out mouse optic nerve crush model G. Sheng, G. Huang, B. Yun, S. Mi Biogen, Cambridge, MA, United States Background: Leucine-rich repeat and immunoglobulin domaincontaining Nogo receptor-interacting protein-1 (LINGO-1) is a negative regulator of oligodendrocyte differentiation, myelination and remyelination. In previous experiments LINGO-1 antagonism improved functional recovery in animal models of central nervous system diseases and remyelination in experimental autoimmune encephalomyelitis models. Optic neuritis is often an early manifestation of multiple sclerosis and the associated demyelination and damage to the optic nerve can be modelled by optic nerve crush. Objective: To assess the effect of LINGO-1 deficiency on optic nerve regeneration following optic nerve crush in LINGO-1 knock out (KO) mice. Methods: The optic nerve of LINGO-1 KO (n=5) or wild type (WT) C57BL6/J (n=10) mice was crushed with number 5 forceps for 2 seconds approximately 1 mm behind the optic disc. 2 µg/µl Alexa 488 conjugated cholera toxin β subunit (CTB) was injected intravitreally 2 days before the mice were sacrificed, after which optic nerves were dissected and processed. To quantify regenerating retinal ganglion cell axons the numbers of CTB-labelled axons at 100, 250 and 500 µm from the crush site in 4 sections per animal were determined. The unpaired t test was used for data analyses. Results: There was a 2-fold increase in CTB-labelled regenerating axons in LINGO-1 KO compared with WT mice at all distances from the crush site 28 days after injury. The mean number of regenerating axons per section in LINGO-1 KO mice 100 µm from the crush site was 13.2 (standard error of the mean ±1.8; n=20) compared with 5.9 (±0.4) in WT mice (n=40; P< 0.0001); the corresponding values at 250 µm were 5.1 (±0.8) vs 2.1 (±0.3; P< 0.001), and 1.7 (±0.3) vs 0.4 (±0.1; P< 0.0001) at 500 µm. The estimated mean number of regenerating axons per nerve were 587.7 (±135.1; n=5) vs 237.2 (±21.5; n=10; P< 0.01) at 100 µm, 201.9 (±52.9) vs 78.9 (±13.6; P< 0.05) at 250 µm and 64.1 (±13.2) vs 13.7 (±2.4; P< 0.001) at 500 µm in LINGO-1 KO and WT mice, respectively. Conclusions: These results suggest that optic nerve regeneration is more prevalent in the absence of LINGO-1. This supports investigation of whether LINGO-1 blockade may increase axonal regeneration in the clinic. Disclosure Guoqing Sheng: Employee of Biogen and holds stock/stock options in Biogen. Guanrong Huang: Employee of Biogen and holds stock/stock options in Biogen.


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Bian Yun: Employee of Biogen and holds stock/stock options in Biogen. Sha Mi: Employee of Biogen and holds stock/stock options in Biogen. This study was funded by Biogen. Biogen provided funding for medical writing support in the development of this abstract. Becky Gardner (Excel Scientific Solutions, Horsham, UK) wrote the first draft of the abstract based on input from authors. The authors had full editorial control of the abstract, and provided their final approval of all content. P414 Inhibition of neurogenesis in a Marburg´s variant of multiple sclerosis C. Oreja-Guevara1, J. García-López2, R. Sánchez-Sánchez3, A. Orviz-García1, I. González-Suárez1, A. Rábano4, U. GómezPinedo2, J. Matías-Guiu1 1Neurology, 2Instituto de Neurociencias, University Hospital San Carlos, Madrid, 3Hospital Reina Sofía, Córdoba, 4Fundación Cien, Madrid, Spain Background: Studies in multiple sclerosis showed an increase in the differentiation and proliferation of oligodendrocyte precursor cells in the subventricular zone (SVZ) and the dentate gyrus of the hippocampus (DG) in the early inflammatory phase. Objective: To study the neurogenesis in the Marburg´s variant of multiple sclerosis Methods: We study the case of a 27 years old immunocompetent patient with a fulminant Marburg´s disease. The disease duration was 20 days. The patient´s postmorten sample was studied using conventional histological dying (H/E, luxol fast blue and oil-red stain) and immunochemical and immunofluorescence techniques. The neurogenic niches, SVZ and DG were analyzed with confocal microscopy using markers for proliferation (Ki67, PCNA), neuroblasts (TUJ1), stem cells (GFAPd, SOX2, PAX6, Musashi), astrocytes (GFAP, AQ4), oligodendrocytes (NG2, Olig), microglia and cellular infiltrates (IBA-1, CD68, MHCII) and cellular death (Tunel). Results: The neuropathological study showed extensive areas of inflammation with severe destruction of myelin, reactive astrocytosis and a generalized vasogenic edema. We found a 10-fold decrease in the number of Ki-67+ cells and PCNA in the SVZ in comparison with healthy controls, indicating an almost absent cell proliferation. Neural Stem Cells (NSC) GFAPδ+ were quantified by densitometry, showing a significative reduction of this cellular type in the Marburg’s SVZ (0.021±0.007129) compared to the healthy control’s SVZ (0.40±0.005847) (Image 2). Similarly, we identified a reduction of SOX2 stem cells in the patient (1.4 cells/ mm2) in comparison with healthy controls (13.4 cells/mm2) and a complete absence of PAX6 neural progenitors. A very low expression of Olig2, NG2 and Musashi1 was detected in the corpus callosum, DG and SVZ, indicating an almost complete absence of oligodendrocyte precursors. The patient’s tissue showed a strong increase of inflammatory cells (IBA-1 +, CD68+, MHCII+) with activation of the microglia. Conclusions: Cell proliferation was drastically decreased in the SVZ and in DG. Neurogenesis was not found despite the strong inflammatory response and the high level of cellular death associated to the pathology. The fulminant course of the case could be explained by the reduction of the neurogenesis and no differentiation of oligodendrocyte precursor cells.

Disclosure Celia Oreja-Guevara received honoraria for speaking and/or consultancy from Biogen, Genzyme, Bayer, Merck-Serono, Roche, Teva and Novartis. Aida Orviz-García received honoraria for speaking from Novartis Ines González-Suárez received honoraria for speaking from Biogen U Gómez-Pinedo: Nothing to disclosure J García-López: Nothing to disclosure R Sanchez-Sánchez: Nothing to disclosure A Ràbano: Nothing to disclosure Jorge Matias-Guiu: Nothing to disclosure

P415 Abnormalities of the main cortical and subcortical functional networks in MS patients M. Filippi1,2, P. Valsasina1, L. Vacchi1, V.M. Leavitt3, G. Comi2, A. Falini4, M.A. Rocca1,2 1Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 2Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy, 3Department of Neurology, Columbia University Medical Center, New York, NY, United States, 4Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy Background: Resting-state (RS) fMRI allows to map function of large-scale neuronal networks of the human brain without any influence of between-subject differences related to task performance. This is a critical issue in MS patients, who experience heterogeneous disease manifestations. RS fMRI studies performed so far in MS suggest that prominent RS functional connectivity (FC) changes occur in many RS networks and correlate with clinical and/or structural MRI measures. However, results of RS FC studies in MS are still controversial. Objectives: We explored abnormalities of RS FC within the main cortical/subcortical brain networks in a large cohort of MS patients with different clinical phenotypes and investigated their correlation with clinical status and cognitive performances. Methods: RS fMRI and neuropsychological evaluation were obtained from 202 MS patients (118 relapsing remitting [RR], 43 secondary progressive [SP], 28 benign [B] and 13 primary progressive [PP] MS) and 98 healthy controls. FC analysis was done by means of seed-voxel correlation with seven major cortical/subcortical hubs (ventral precuneus/posterior cingulate, inferior parietal cortex, cuneus, postcentral gyrus, cerebellum, thalamus, and amygdala). Between-group differences of RS FC and correlations between RS FC and clinical/neuropsychological scores were evaluated (SPM8). Results: Compared to healthy controls, MS patients showed significantly reduced RS FC in all networks. In subcortical networks, however, regions of increased RS FC were also identified in MS patients vs control subjects. Lower RS FC was found in SPMS vs RRMS patients in several regions of the sensorimotor network, while PPMS patients had significantly reduced RS FC compared to controls mainly in the visual, sensorimotor and cerebellar networks. Compared to cognitively preserved (CP) patients, those patients with cognitive impairment had significantly lower RS FC


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Poster Session I, 21(S11) in the default-mode network (DMN) and dorsal attention network (DAS) as well as higher RS FC between subcortical and frontotemporal regions. A higher EDSS score was correlated with lower RS FC in sensory, cognitive and subcortical networks, while a worse cognitive performance was associated with lower DMN and DAN RS FC. Conclusions: Widespread abnormalities of cortical/subcortical RS FC were found in MS. Decreased RS FC was clinically relevant, since it correlated with patients’ disability and cognitive impairment. Disclosure Partially supported by a grant from Italian Ministry of Health (GR-2008-1138784/GR-2009-1529671) and Fondazione Italiana Sclerosi Multipla (FISM2012/R/8, FISM2014/R/7). P. Valsasina, L. Vacchi, V. Leavitt and A. Falini have nothing to disclose. M. Filippi has received compensation for consulting services and/ or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis. G. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. M.A. Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed. P416 Effects of action observation therapy on rehabilitation of motor deficits of the dominant right upper limb in patients with MS: an exploratory study with structural and functional MRI M.A. Rocca1,2, S. Fumagalli1,3, P. Preziosa1,2, R. Gatti3, R. Messina1,2, F. Martinelli-Boneschi2, G. Pavan2, M. Comola2, G. Comi2, M. Filippi1,2 1Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 2Department of Neurology, 3Laboratory of Analysis and Rehabilitation of Motor Function, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy Background: Action Observation Therapy (AOT) facilitates motor system function, possibly through a modulation of mirror neuron system (MNS) recruitment. Aims: We used functional and structural magnetic resonance imaging (MRI) techniques to assess whether AOT modifies brain activations and regional gray matter (GM) volumes in healthy controls (HC) and multiple sclerosis (MS) patients with motor deficits of the right upper limb. The correlations between MRI measures and improvement at clinical scales after training were also explored. Methods: In this blind, randomized, controlled trial, 71 right-handed subjects (46 HC and 25 MS with right-upper limb motor impairment), were randomized into 4 groups: 2 experimental groups (HC-AOT n=23 and MS-AOT n=12) and 2 control groups (HC-C n=23 and MS-C n=13). The training lasted for two weeks and consisted of 10 sessions of 45 minutes. The experimental groups

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watched 3 videos, of 5 minutes each, of daily-life actions alternated by their execution with the right upper limb; the control groups performed the same actions, but watched landscapes videos. At baseline (t0) and after 2 weeks (w2), clinical measures were assessed and functional and structural MRI sequences were acquired. During functional MRI, subjects were asked to manipulate six common objects alternated with a neutral one, with the right (R) hand. Results: At w2, during R manipulation, we observed an increased activation of MNS areas in HC-AOT, the R middle temporal gyrus in HC-C, the R superior parietal lobule in SM-AOT and the R caudate nucleus in SM-C. At w2, during R manipulation, the AOT groups (both HC and MS) had significantly higher activation of MNS areas compared to the control groups. At w2, all groups showed a GM volume modifications, characterized by increased GM volume of the middle and inferior frontal gyri in HC-AOT; the hippocampus in HC-C; the inferior parietal lobule in MS-AOT and the cerebellum in SM-C. At w2, GM volume reduction was also found in the cerebellum and basal ganglia in HC and in temporo-parieto-occipital regions and cerebellum in MS patients. At w2, all subjects showed an improvement in clinical and functional tests, which were correlated with MRI changes. Conclusions: Structural and functional changes of motor network and MNS occur in HC and MS after AOT, which correlate with motor performance improvements. These findings might contribute to the development of new rehabilitative approaches for MS. Disclosure Partially supported by a grant from FISM (FISM2012R15) and Italian Ministry of Health (RF-2011-02350374). S. Fumagalli, P. Preziosa, R. Gatti, R. Messina, G. Pavan, M. Comola have nothing to disclose. F. Martinelli-Boneschi has received speaker honoraria and funding for travel from Sanofi-Aventis and Biogen-Dompè. M.A. Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed. G. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. M. Filippi has received compensation for consulting services and/ or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis.

Imaging P417 Contribution of MRI lesions in late onset multiple sclerosis Y. Beckmann, S. Türe, Ş. Arıcı, C. Uzunköprü Neurology, Katip Çelebi University Atatürk Training and Research Hospital, Izmir, Turkey Late onset multiple sclerosis (LOMS), defined as onset of multiple sclerosis (MS) after the age of 50 years, comprises 2.7-12% of MS patients. Currently, no specific criteria are recommended for LOMS and diagnostic magnetic resonance imaging (MRI) findings have not been sufficiently validated in LOMS despite


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differences in epidemiologic data and clinical courses between elderly and adult MS patients. Objectives: The objective of this study is to investigate the contribution of cerebral and spinal MRI characteristics of LOMS and compare them with adult onset MS (AOMS) patients. Methods: A cohort of 45 LOMS patients (range: 50-64 years, mean: 53.6 years) and 50 AOMS patients (20-34 years, mean: 31.2 years) were analyzed in a retrospective study. Number and regional distribution of T2w and contrast-enhancing T1w lesions at initial and follow-up MRIs were main outcome measures. Lesion dissemination in space (DIS) and dissemination in time (DIT) were also assessed. MRIs were taken within three weeks of initial symptom onset and the follow-up duration was twelve and 60 months. Results: In LOMS:MRI plaque locations were supratentorial in 63%, infratentorial in 37%, and spinal cord in 72%(63% in cervical, and 49% in thoracic) on admission. Contrast-enhancing lesions were seen in 27% of LOMS patients. Of 45 patients, 88% met MRI criteria of DIS and 66% had DIT. In AOMS: At initial, MRI lesions located supratentorial in 92%, infratentorial in 67%, and spinal cord in 49%(89% in cervical, and in 18% in thoracic spinal cord).Contrast-enhancing lesions were detected in 62% of LOMS patients.DIS was observed in 63% of patients and 48% of patients had DIT.Cerebral lesions were significantly less detected and spinal lesions were more common in LOMS patients when compared to AOMS patients. Conclusions: There are still many unanswered questions with regard to elderly patients with MS. We investigated characteristics of MRI lesions in LOMS and our data suggests that there are significant differences in lesion distribution and dissemination between elderly and adult onset MS patients. Disclosure No disclosure P418 Cannabis induced alterations in brain activation during a test of information processing speed in patients with MS B. Pavisian1, R. Staines2, A. Feinstein3,4 1Brain Imaging, Sunnybrook Research Institute, University of Toronto, Toronto, 2Kinesiology, University of Waterloo, Waterloo, 3Psychiatry, University of Toronto, 4Psychiatry, Sunnybrook Hospital, Toronto, ON, Canada Objective: To determine the functional brain correlates of information processing speed in MS subjects who smoke cannabis and those who are drug naive. Methods: Two neurologically and demographically matched samples of MS subjects were enrolled, those who smoked cannabis daily (n=20) and those who were cannabis naïve (n=19). All subjects completed the Brief Repeatable Battery of Neuropsychological Tests and underwent fMRI testing during which they were administered a modified version of the Symbol Digit Modalities Test (mSDMT). Results: The cannabis group responded slower in 9 of 11 blocks of the mSDMT (p < 0.001), showing a trend towards a slower response time (p < 0.08), but did not differ in the accuracy of

response (p < 0.18). Both groups displayed activation in a prefrontal cortex-parietal network associated with information processing speed. When compared to the cannabis naïve group, cannabis users showed less activation in the right (p = 0.009) and left (p = 0.001) thalami and increased activation in the anterior cingulate (p = 0.006). Conclusion: Regular cannabis use in MS subjects is associated with slower information processing speed and a pattern of cerebral activity that differs from cannabis naïve subjects, most notably in a bilateral reduction of thalamic activity. Disclosure Bennis Pavisian: Nothing to disclose Richard Staines: Nothing to disclose Anthony Feinstein: Has served on scientific advisory boards for Merck Serono and Avanir Pharmaceuticals; has received speaker honoraria from Merck Serono, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Biogen Idec; serves on the editorial boards of Multiple Sclerosis and the African Journal of Psychiatry; receives publishing royalties for The Clinical Neuropsychiatry of Multiple Sclerosis (Cambridge University Press, 2007); chairs the Medical Advisory Committee for the Multiple Sclerosis Society of Canada; conducts neuropsychiatric evaluation, cognitive testing, brain imaging in neuropsychiatry in his clinical practice; and receives research support from the Canadian Institute of Health Research, the Multiple Sclerosis Society of Canada and Teva Pharmaceutical Industries Ltd. P419 Changes in connectivity of cognitive networks and thalamic volume in RRMS: an fMRI/DTI study M. Cerghet1,2, S. Nejad-Davarani3, L. Li3, Q. Jiang3 1Henry Ford Hospital, 2Wayne State University, 3Neurology, Henry Ford Hospital, Detroit, MI, United States Objectives: Cognitive dysfunction is present in at least half of patients with Multiple Sclerosis. The purpose of this study was to examine functional connectivity abnormalities in patients with multiple sclerosis (MS) using resting state fMRI (rsfMRI). Methods: Conventional MRI, rsfMRI and diffusion tensor imaging (DTI) data was acquired from 10 patients with relapsingremitting multiple sclerosis (RRMS) and 20 healthy controls. Crosscorrelation of the resting state average signal among the voxels in each brain region of the five cognitive networks: default mode network (DMN), attention, verbal memory, memory, and visuospatial working memory network, was calculated. Voxelwise analyses were used to investigate fractional anisotropy (FA) of white matter tracts. The normalized gray matter (GM), white matter and thalamus volumes were calculated. Results: Compared to controls, significant deficit in MS patients at each of five networks, attention (p=0.026), DMN (p=0.004), verbal memory (p< 0.001), memory (p=0.001), visuospatial working memory (p=0.003) was found. Significant reduction (p=0.034) in the normalized GM volume and asymmetry in thalamus volume (p=0.041) was detected in MS patients compared to controls. Conclusion: Wide spread of functional abnormalities are present within different cognitive networks in patients with RRMS,


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Poster Session I, 21(S11) suggesting that DMN may not be sufficient for measurement of MS cognitive impairment. Larger and longitudinal studies should ascertain whether rsfMRI of cognitive networks and changes in GM and thalamus volume can be used as tools for assessment of cognition in clinical trials in MS.

completely agreed on 24 cases (2 of them presenting new T2 lesions). Conclusion: The use of subtraction imaging increases MS lesion sensitivity detection by enhancing the contrast of new lesions when compared to stable disease. Moreover, it helps to better determine lesion growth.

Disclosure Mirela Cerghet: Nothing to disclose P420 Evaluating the sensitivity of subtraction imaging for the detection of new T2 multiple sclerosis lesions when using visual analysis, semiautomatic and automatic approaches M. Cabezas1, J.F. Corral1, A. Oliver2, X. Lladó2, C. Auger1, J. Sastre-Garriga1, M. Tintoré1, D. Pareto1, X. Montalban1, A. Rovira1 1Section of Neuroradiology and MR Unit (Department of Radiology), Vall d’Hebron University Hospital, Barcelona, 2VICOROB Group, Department of Computer Architecture and Technology, University of Girona, Girona, Spain Background: Lesion volume change assessment is crucial in monitoring multiple sclerosis (MS) progression. Subtraction imaging, which cancels stable disease, provides enhanced sensitivity to characterize lesions by separately identifying new, enlarging, and resolving MS lesions. Aim: To evaluate the effect of employing subtraction imaging for the detection of new T2 lesions, using both semiautomatic and fully automatic approaches. We aim to demonstrate a higher sensitivity of subtraction imaging compared to visual analysis of the original images. Methods: This study included 40 consecutive patients with a clinically isolated syndrome scanned with a 3T magnet at two different time points: the first within 3 months and the second 12 months after the onset of symptoms. Each scan included transverse T2-FLAIR, PD, T2 and T1 images. We evaluated and compared three different procedures to detect new T2 lesions: 1) expert visual analysis with semiautomatic segmentation to delineate lesions, 2) expert visual analysis with semiautomatic segmentation after applying subtraction and co-registration; and 3) fully automated segmentation based on deformable registration and subtraction imaging. To assess the improvement of subtraction imaging, we compared approaches 2 and 3 with traditional visual analysis. Moreover, we also compared the results from both subtraction approaches. Results: Using visual analysis on original images, 32 new lesions were found. Instead, 60 lesions were detected when employing subtraction imaging either with semiautomatic or automatic tools. Few lesions were missed when using subtraction imaging (7 and 4 for approaches 2 and 3). There was also a higher number of true detections when comparing both subtraction approaches (36 new lesions between approaches 2 and 3 against 26, and 29 when comparing both to visual analysis), a lower number of false detections (25 between approaches 2 and 3 against 34 when comparing both to visual analysis) and a highest overlap in terms of the Dice similarity coefficient (a value of 0.59 against 0.50, and 0.53 when compared to visual analysis), suggesting a higher correlation between subtraction imaging approaches. All three procedures

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Disclosure Mariano Cabezas has nothing to disclose. Juan F. Corral has nothing to disclose. Arnau Oliver has nothing to disclose. Xavier Lladó has nothing to disclose. Cristina Auger has received speaking honoraria from Novartis and Genzyme. Jaume Sastre-Garriga has received compensation for consulting services and speaking honoraria from Merck-Serono, BiogenIdec, Teva, Sanofi-Aventis and Novartis. Mar Tintoré has received compensation for consulting services and speaking honoraria from Bayer-Schering, Merck-Serono, Biogen-Idec, Teva, Sanofi-Aventis, and Novartis. Deborah Pareto has received speaking honoraria from Novartis and Genzyme. Xavier Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall. Alex Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, and has received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Bracco, MerckSerono, Teva Pharmaceutical Industries Ltd, OLEA Medical, Stendhal, Novartis and Biogen Idec. P421 Elevated brain temperature is associated with worse fatigue in multiple sclerosis patients V.M. Leavitt1, A. Kangarlu2, C.S. Riley1, F. Liu3, J.F. Sumowski4 1Neurology, 2Psychiatry, Columbia University Medical Center, 3New York State Psychiatric Institute, New York, NY, 4Neuropsychology & Neuroscience, Kessler Foundation, West Orange, NJ, United States Fatigue is a pervasive and debilitating symptom of multiple sclerosis (MS). Our current ability to effectively treat MS fatigue is hindered by a poor understanding of its pathophysiology and likely multiple underlying etiologies. We recently reported endogenously elevated body temperature and its association to worse fatigue in RRMS patients. Elevated brain temperature was also recently reported in 108 RRMS patients compared to 103 healthy controls (Hasan et al, 2015). In a preliminary study, we extend our temperature hypothesis of fatigue by investigating the association of elevated brain temperature and fatigue in MS. Methods: 14 MS patients (11 female) served. Disease subtypes were 9 RRMS, 3 SPMS, 2 PPMS. Average age was 54.5 ± 9.8 years. Average body temperature was 36.8°C (98.2°F). Brain temperature was non-invasively measured with magnetic resonance spectroscopy (MRS) in a 3.0T Siemens Skyra scanner. MRS


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thermometry permits measurement of brain temperature with accuracy of ±0.1°C. The investigator who calculated brain temperature was blinded to all demographic/clinical data of all participants (i.e., age, phenotype, fatigue status). Fatigue was measured with the Fatigue Severity Scale (FSS). Results: Average brain temperature was 37.4°C (99.32°F); average body temperature was 36.8°C (98.31°F). Higher brain temperature was associated with worse fatigue (r=.319). Higher body temperature was also associated with worse fatigue (r=.276). Also, the relationship between body temperature and fatigue was at least partially mediated by brain temperature. Summary: Our current understanding and treatment of MS fatigue is limited, but our previous and current findings support elevated brain/body temperature as a candidate underlying mechanism for fatigue in MS. Cooling therapies to treat MS fatigue (i.e., aspirin, cooling garments) have shown efficacy in a small number of studies; however, these investigations did not consider endogenous temperature elevations as a target or explanation for treatment efficacy. Greater understanding/acknowledgment of elevated brain temperature and its consequences for patients with MS will support novel cooling treatments for fatigue. Brain temperature may be a sensitive outcome variable to consider for use in clinical trials. Disclosure Funding for this study was provided through grant support from the National Multiple Sclerosis Society to VML (RG4810A) and from the NIH to JFS (R00HD060765). VM Leavitt reports no disclosures. A Kangarlu reports no disclosures. F Liu reports no disclosures. CS Riley has received financial compensation on an advisory board in a consulting capacity from Biogen Idec, Novartis, Teva Neuroscience, and Genzyme Sanofi. JF Sumowski reports no disclosures. P422 N-acetylaspartate and creatine decrease with myelin damage in relapsing multiple sclerosis E.L. MacMillan1, J.J. Schubert1, I.M. Vavasour1, E. Vianna2, A. Dzyakanchuk2, Y. Yoo3,4, R. Tam3,4, S.H. Kolind1, A.L. Traboulsee1 1Department of Medicine (Neurology), Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada, 2F. Hoffmann-La Roche Ltd., Basel, Switzerland, 3UBC MS/MRI Research Group, 4Department of Radiology, The University of British Columbia, Vancouver, BC, Canada Background: Brain magnetic resonance imaging (MRI) offers a noninvasive measure of myelin content through the myelin water fraction (MWF). Magnetic resonance spectroscopy (MRS) measures total creatine (tCr = creatine + phosphocreatine), which shuttles energy produced in the mitochondria to areas of need, and N-acetylaspartate (NAA), which shuttles acetyl-coenzyme A groups from neuronal mitochondria to myelin and oligodendrocytes. While MWF, NAA and tCr have separately been shown to be lower in patients with relapsing forms of multiple sclerosis (RMS) than in controls, these measures have yet to be obtained within the same cohort. Given the roles of tCr and NAA in mitochondrial

function and myelin production, we hypothesized that tCr and/or NAA would correlate with myelin content in the brain. Objective: To determine whether the levels of NAA and tCr in normal-appearing white matter are correlated with MWF in RMS patients and healthy controls (HC). Methods: 26 patients recruited for an MRI substudy of a Phase III, randomised, double-blind study of ocrelizumab (OCR) vs interferon (IFN)-β-1a in RMS patients (OPERA II, NCT01412333) and 44 age- and gender-matched HC were scanned at 3T. MRS was measured from a 6.5x4.5x1.8cm3 white matter voxel and fit with LCModel v6.3. NAA, N-acetyl-aspartylglutamate, tCr, choline, myo-inositol and glutamate concentrations were calculated relative to the water peak and corrected for voxel compartmentation and relaxation. MWF was measured using a 32 echo gradient and spin echo imaging sequence to sample the water T2 decay curve, which was modelled with multiple exponential components. MRS voxels were mapped to MWF maps to extract the mean MWF in the voxel. Wilcoxon rank sum was used to test group differences, and Spearman’s rank was used to assess relationships between MWF and metabolite levels. Results: tCr (r2=0.24; P=0.01) and NAA (r2=0.16; P=0.05) both positively correlated with the mean voxel MWF in the MS group. There were no correlations between MWF and any metabolite in the HC group or when both MS and HC were included. Conclusions: The presence of positive, though weak, relationships between tCr and NAA with myelin content in the MS cohort suggests that decreased mitochondrial function, as evidenced by reduced tCr and NAA, may be linked to loss of myelin in RMS patients. These measures will be followed longitudinally in the OPERA trials, which will assess the efficacy and safety of OCR vs IFN-β-1a in RMS patients. Disclosure Erin L MacMillan is supported by a Post-Doctoral fellowship from the Multiple Sclerosis Society of Canada and has acted as a consultant for F. Hoffmann-La Roche Ltd. Julia J Schubert has nothing to disclose. Irene M Vavasour has received research support from F. Hoffmann-La Roche Ltd. and Teva Canada Innovation. Eduardo Vianna is an employee of F. Hoffmann-La Roche Ltd. Anna Dzyakanchuk is an employee of F. Hoffmann-La Roche Ltd. Youngjin Yoo has nothing to disclose. Roger Tam has nothing to disclose. Shannon H Kolind has nothing to disclose. Anthony L Traboulsee has received grant support from F. Hoffmann-La Roche Ltd. and Sanofi Genzyme; is a steering committee member for F. Hoffmann-La Roche Ltd.; and has been a consultant for Biogen, Chugai, EMD Serono, F. Hoffmann-La Roche Ltd., Medimmune, Sanofi Genzyme, Teva Neuroscience. P423 Consistency of grey matter volume measurement in multiple sclerosis:comparison of FSL, FreeSurfer and SPM V. Popescu1, M.M. Schoonheim2, A. Versteeg1, N. Chaturvedi3, M. Jonker3, R. Xavier de Menezes3, F. Gallindo-Garre3, B.M.J. Uitdehaag4, F. Barkhof1, H. Vrenken1,5 1Radiology and Nuclear Medicine, 2Anatomy and Neurosciences, 3Epidemiology and Biostatistics, 4Neurology, 5Physics and Medical Technology, VU University Medical Centre, Amsterdam, The Netherlands


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Poster Session I, 21(S11) Background: Studies disagree on the location of grey matter (GM) atrophy in the multiple sclerosis (MS) brain. Aim: To examine the consistency between FSL, FreeSurfer, SPM for GM atrophy measurement (for volumes, patient/control discrimination, and correlations with cognition). Materials and methods: 127 MS patients and 50 controls were included and cortical and deep grey matter (DGM) volumetrics were performed. Consistency of volumes was assessed with Intraclass Correlation Coefficient/ICC. Consistency of patients/ controls discrimination was assessed with Cohen’s d, t-tests, MANOVA and a penalized double-loop logistic classifier. Consistency of association with cognition was assessed with Pearson correlation coefficient and ANOVA. Voxel-based morphometry (SPM-VBM and FSL-VBM) and vertex-wise FreeSurfer were used for group-level comparisons. Results: The highest volumetry ICC were between SPM and FreeSurfer for cortical regions, and the lowest between SPM and FreeSurfer for DGM. The caudate nucleus and temporal lobes had high consistency between all software, while amygdala had lowest volumetric consistency. Consistency of patients/controls discrimination was largest in the DGM for all software, especially for thalamus and pallidum. The penalized double-loop logistic classifier most often selected the thalamus, pallidum and amygdala for all software. FSL yielded the largest number of significant correlations. DGM yielded stronger correlations with cognition than cortical volumes. Bilateral putamen and left insula volumes correlated with cognition using all methods. Conclusion: GM volumes from FreeSurfer, FSL and SPM are different, especially for cortical regions. While group-level separation between MS and controls is comparable, correlations between regional GM volumes and clinical/cognitive variables in MS should be cautiously interpreted. Disclosure V. Popescu was supported by the Dutch MS Research Foundation grant 10-718 and the Du Pre grant of the MS International Federation. M.M. Schoonheim was supported by the Dutch MS Research Foundation grant 08-650. F. Barkhof serves on the editorial boards of Brain, European Radiology, Radiology, Multiple Sclerosis Journal and Neuroradiology and serves as a consultant for BayerSheringPharma, Sanofi-Aventis, Biogen-Idec, Teva, MerckSerono, Novartis, Roche, Synthon, Jansen Research and Genzyme. B. M. J. Uitdehaag has received consultation fees from Biogen Idec, Novartis, Merck-Serono, and Danone Research. H. Vrenken receives research support from the Dutch MS Research Foundation, grant numbers 05-358c, 09-358d and 10-718, has received research grants from Novartis and MerckSerono, and has received speaker’s honorarium from Novartis; all funds paid directly to his institution. The MS Center Amsterdam is funded by the Dutch MS Research Foundation program grant 98-358, 02-358b, 05-358c, 09-358d. P424 Evaluation of two automated lesion segmentation and filling pipelines for brain tissue segmentation of multiple sclerosis patients

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S. Valverde1, A. Oliver1, E. Roura1, D. Pareto2, J.C. Vilanova3, L. Ramió-Torrentà4, J. Sastre-Garriga5, X. Montalban5, À. Rovira2, X. Llado1 1University of Girona, Girona, 2Section of Neuroradiology and MR Unit (Department of Radiology), Vall d’Hebron University Hospital, Barcelona, 3Girona Magnetic Resonance Center, 4Multiple Sclerosis and Neuro-immunology Unit, Dr. Josep Trueta University Hospital, Girona, 5Neurology / Neuroimmunology Department, Multiple Sclerosis Centre of Catalonia (Cemcat), Vall d’Hebron University Hospital, Barcelona, Spain Background: The presence of white matter (WM) multiple sclerosis (MS) lesions can significantly affect the accuracy of tissue segmentation algorithms. Even though several automated lesion segmentation and lesion filling tools have been proposed, an extensive analysis of fully automated tissue segmentation pipelines incorporating both automated lesion segmentation and lesion filling has not been performed yet. Aim: To analyze the effect of manual or automated lesion annotations on the computation of WM and gray matter (GM) tissue volume employing SPM8 or FAST segmentation methods. The study includes two different automated lesion segmentation and filling tools (LST and SLS). Methods: Seventy clinically isolated syndrome patients were scanned in a 3.0 T system (Trio, Siemens). Image acquisition protocol included 3D T1-w sagittal, 2D FLAIR and PD/T2-w sequences. Manual annotations were performed by a trained technician over PD/T2 images. For each automated pipeline, we calculated the % difference in GM and WM volume obtained from: a) T1-w images where manual annotated lesion masks were used to refill lesions before tissue segmentation; b) T1-w images where lesions were automatically segmented on the FLAIR modality and filled after. Moreover, we also evaluated the % differences between the previous estimations and those obtained with original T1-w images containing lesions. Results: Differences in total and normal-appearing tissue volume between manually annotated and SLS/LST were small (< 0.20%) for both GM and WM, and independently of the segmentation method. Differences did not increase in images with higher lesion load (9-18ml) and did not correlate with lesion load (p>0.43). In contrast, for images segmented without lesion filling, differences were significantly higher for GM (0.25%, p< 0.05) and WM (0.39%, p< 0.05) when FAST was used, but not for SPM8 (p>0.30), while the differences in normal-appearing tissue were only significant when SPM8 was used (GM: -0.2%, p< 0.002; WM: 0.3%, p< 0.02). Observed values in total tissue in SPM8 and normal-appearing in FAST were produced by a canceling effect between the differences in lesion regions and the effects of these lesions on normal-appearing tissue. Conclusion: Differences between tissue volumes computed using manual annotations for lesion filling and using fully automated LST and SLS were not statistically significant, independently of the tissue segmentation employed. Disclosure S. Valverde: Nothing to disclose A. Oliver: Nothing to disclose E. Roura: Nothing to disclose


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D. Pareto: D Pareto has received speaking honoraria from Novartis J.C. Vilanova: Nothing to disclose Ll. Ramió-Torrentà: Nothing to disclose J. Sastre-Garriga: J Sastre-Garriga has received compensation for consulting services and speaking honoraria from Merck-Serono, Biogen-Idec, Teva, and Novartis. X. Montalban: X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi, Teva Pharmaceuticals, and Almirall. À. Rovira: Dr. Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, and has received speaker honoraria from Novartis, Bayer, Genzyme, Bracco, Teva Pharmaceutical Industries Ltd, OLEA Medical, Stendhal, Novartis and Biogen Idec. X. Lladó: Nothing to disclose P425 Manual segmentation of MS cortical lesions using MRI: a comparison of three MRI reading protocols J. Maranzano, D.A. Rudko, D.L. Arnold, S. Narayanan Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada Background: To date, double inversion recovery (DIR) has been put forth as the MRI pulse-sequence of choice for segmenting and scoring cortical lesions (CLs) in multiple sclerosis (MS) patients. Recently however, other MRI pulse-sequences, such as magnetization-prepared rapid gradient echo (MPRAGE), magnetization transfer ratio (MTR) and phase-sensitive inversion recovery (PSIR) have been employed, because of their higher contrast-tonoise and signal to noise ratios. Objective: To determine the relative utility of DIR for CL identification in a multimodal approach, by comparing three different MRI reading protocols that employed different combinations of MRI pulse-sequences. Methods: 25 relapsing remitting (RR) and 3 secondary progressive (SP) MS patients were imaged at 3 T at baseline and two-year time points. In each imaging session, four primary MR images were collected, including: double inversion recovery (DIR), dualecho, fast spin echo for proton density and T2-weighted images (PD/T2), fluid-attenuated inversion recovery (FLAIR) and T1-weighted gradient-recalled echo images. Lesions affecting the cortex were segmented manually using three unique lesion identification protocols: Protocol 1 (P1) used all the available images. Protocol 2 (P2) used all the available images except for DIR. Protocol 3 (P3) used only DIR. All manual segmentations were performed according to the recently presented consensus recommendations for cortical lesion identification. Results: 643 CLs were identified with P1 (mean 22.96), 633 with P2 (mean 22.6) and 280 with P3 (mean 10). Intra-class correlation (ICC) coefficients on CL counts were calculated between scoring methods, yielding the following results: P1 vs P2 = 0.97, P1 vs P3 = 0.50, P2 vs P3 = 0.49. A non-parametric Wilcoxon signed-rank test between the counts obtained with the different reading methods showed : P1 vs P2, p = 0.93; P1 vs P3, p = 4.46 x 10-5; P2 vs P3, p = 1.72 x 10-5.

Conclusion: MRI CL segmentation can be efficiently performed using a multimodal approach that includes 3D T1-weighted and FLAIR images acquired with 1 mm isotropic voxel size, supported by conventional T2-weighted and proton density images with 3 mm thick slices. This multimodal approach is superior to a segmentation relying on DIR alone. Inclusion of DIR in the multimodal reading protocol did not significantly improve the lesion identification rate. Disclosure Josefina Maranzano: Nothing to disclose David A. Rudko: Nothing to disclose Douglas L. Arnold reports personal fees from Acorda, Biogen Idec, Genzyne, Hoffman-La Roche, Innate Immunotherapeutics, MedImmune, Mitsubishi Pharma, Novartis, Receptos, Sanofi Aventis and Teva outside the submitted work, and is an employee and stockholder in NeuroRx. Sridar Narayanan has received personal compensation for consulting activities from NeuroRx Research

P426 T2 and T2* relaxometry as a detector of USPIO enhancement in CIS patients A. Kerbrat1, B. Combes2, A. Maarouf3, E. Bannier2, J.-C. Ferré4, A. Tourbah3, I. Berry5, J.-P. Ranjeva6, C. Barillot2, G. Edan1 1Neurology, CHU Rennes, 2Rennes 1 University, INRIA, VISAGES Team (UMR 746), Rennes, 3Neurology, CHU Reims, Reims, 4Radiology, CHU Rennes, Rennes, 5CHU Toulouse, Toulouse, 6Aix-Marseille University, CNRS, CRMBM UMR 7339, Marseille, France Background: Assessing lesions activity is crucial for MS diagnosis and treatment, especially at disease onset. Gadolinium-enhanced T1-weighted images are usually used to measure this activity. Ultrasmall super paramagnetic iron oxide (USPIO) enhancement has been recently proposed as a specific marker of macrophages activity within lesions. However, image contrast due to USPIO enhancement is weak on T1-weighted images and the resulting labeling task is error prone. Due to its paramagnetic properties, the presence of USPIO in a biological tissue should be associated to a significant reduction of its resulting T2 and T2* relaxation times. Objective: To assess lesions activity in CIS patients using T2 and T2* relaxometry maps, before and after USPIO infusion; and to compare the results with visual analysis of USPIO- and gadolinium-enhanced T1-weighted images. Methods: Fourteen CIS patients were included in this prospective mono-centric MRI study (3T Verio). T2 and T2* relaxometry images were acquired before and 24 hours after USPIO infusion (SHU555C). Three experts visually labeled Gadolinium- and USPIO-Enhanced lesions on T1-SE images. T2 and T2* pre and post-USPIO quantitative and difference maps were calculated. The joint T2 and T2* post minus pre USPIO difference maps were then visually assessed for the 14 patients. A lesion was labeled as USPIO positive if T2 and T2* values difference maps showed a significant signal decrease. Results: Visual analysis of the relaxometry difference maps allowed identifying 34 lesions as potentially USPIO positive while 18 were detected as gadolinium positive and 7 as USPIO


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Poster Session I, 21(S11) positive on T1 weighted images. All these 7 lesions were detected as USPIO positive using the relaxometry difference maps. Eleven out of the 18 gadolinium positive lesions were detected as USPIO positive using the relaxometry difference maps. According to USPIO and T2/T2* relaxometry results compared to gadolinium alone, 4 patients were re-classified as having active MS lesions (10 vs 6 patients, respectively). Conclusion: T2 and T2* relaxometry sequences combined with USPIO appear as potential sensitive markers of active MS lesions. These results are preliminary to the design of an automated method able to detect USPIO presence and its concentration in MS lesions. Disclosure Anne Kerbrat: Nothing to disclose Benoit Combes: Nothing to disclose Adil Maarouf: Nothing to disclose Elise Bannier: Nothing to disclose Jean Christophe Ferré : Nothing to disclose Ayman Tourbah: A Tourbah has received in the last year, consulting and lecturing fees, travel grants and research support from Medday, Biogen Idec, Sanofi-Genzyme, Novartis, MerckSerono, Teva Pharma, and Roche. Isabelle Berry: I Berry has performed in the last year, clinical trials for Medday, Biogen Idec, Sanofi-Genzyme, Novartis, MerckSerono, Teva Pharma, and Roche Jean-Philippe Ranjeva: nothing to disclose Christian Barillot: Nothing to disclose Gilles Edan: G Edan reports grants and personal fees from Merck Serono, grants and personal fees from Teva Pharma, personal fees from Biogenidec, grants and personal fees from Novartis, personal fees from Sanofi. P427 Differentiating neuromyelitis optica from other causes of longitudinally extensive transverse myelitis on spinal magnetic resonance imaging Y. Pekcevik1,2, C.H. Mitchell1, M.A. Mealy3, G. Orman1, I.H. Lee1,4, S.D. Newsome5, C.B. Thompson6, C.A. Pardo7, P.A. Calabresi8, M. Levy9, I. Izbudak1 1Division of Neuroradiology, The Russell H. Morgan Department of Radiology and Radiological Sciences, Division of Neuroradiology Johns Hopkins Hospital, Baltimore, MD, United States, 2Department of Radiology, Tepecik Training and Research Hospital, Izmir, Turkey, 3Johns Hopkins Hospital Transverse Myelitis & Multiple Sclerosis Centers, Baltimore, MD, United States, 4Chungnam National University, Department of Radiology, Korea, Daejeon, Republic of Korea, 5Department of Neurology, Division of Neuroimmunology and Neuroinfectious Disease, Johns Hopkins Hospital, 6Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, 7Department of Neurology and Pathology, Division of Neuroimmunology and Neuroinfectious Disorders, Johns Hopkins University School of Medicine, 8Department of Neurology, Johns Hopkins Hospital, 9Department of Neurology, Neuromyelitis Optica Clinic, Johns Hopkins Hospital, Baltimore, MD, United States

Background: Longitudinally extensive transverse myelitis (LETM) is defined as a hyperintense spinal cord lesion extending

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over three or more vertebral levels. Although spinal cord magnetic resonance imaging (MRI) findings of neuromyelitis optica (NMO) have been described, there is limited data available about findings that help differentiate NMO from other causes of LETM. Objective: We aim to investigate the spinal MRI findings of LETM that help differentiate NMO at acute stage from multiple sclerosis and other causes of LETM. Methods: The spine MRI of 160 patients with a radiologic diagnosis of LETM between 2002 and 2012 were retrospectively reviewed. After exclusion, 94 patients with LETM were enrolled in the study (48 patients with serum NMO-IgG positive NMO and 46 patients with other etiologies). Bright spotty lesions (BSL), the lesion distribution and location were evaluated on axial T2-weighted images. The “BSL” defined as lesion similar or higher in signal intensity than CSF. Brainstem extension, cord expansion and T1 darkness and lesion enhancement were noted. The“T1 dark” defined as the signal intensity of the lesion approaching that of CSF on T1 weighted images. Brain MRI of the patients during LETM was also reviewed. Results: Patients with NMO had a greater amount of BSL and T1 dark lesions (p < 0.001 and 0.003, respectively). The lesions in NMO patients were more likely to involve greater than half of the spinal cord cross-sectional area, to enhance and be located centrally or both centrally and peripherally in the cord. Of 62 available brain MRIs, 14 of the 27 NMO patients had findings that may be specific to NMO. Conclusion: Certain spinal cord MRI features are more commonly seen in NMO patients and obtaining brain MRI during LETM may support diagnosis. Disclosure Dr. Yeliz Pekcevik, Dr. Charles H.Mitchell, Dr. Gunes Orman, Dr. In Ho Lee, Carol B. Thompson have nothing to disclose. Maureen A. Mealy received honoraria from the International Organization of Multiple Sclerosis Nurses and from EMD Serono. Dr. Scott Newsome has received consultant fees from BiogenIdec, Genzyme, and Novartis and research support from BiogenIdec and Novartis. Dr. Carlos A. Pardo Villamizar, support from Bart McLean Fund for Neuroimmunology Research and Project Restore. Dr. Michael Levy receives research support from NIH, Guthy Jackson Charitable Foundation, Viropharma, Acorda, Sanofi, NeuralStem and Genentech, and serves as a consultant for Chugai Pharmaceuticals, GlaxoSmithKline and Medimmune. Dr. Calabresi has received personal compensation for consulting or serving on scientific advisory boards from; Merck, Vertex, Vaccinex, and Abbvie; and has received research funding from companies Biogen-IDEC, Novartis and Medimmune. Dr. Izlem Izbudak received research support from Bayer for reading MR angiography images. There are no direct financial or other conflicts of interest in relation to the current publication. P428 A pipeline for detecting new multiple sclerosis lesions on longitudinal brain magnetic resonance imaging M. Cabezas1, A. Oliver2, X. Lladó2, C. Auger1, J. SastreGarriga1, D. Pareto1, X. Montalban1, A. Rovira1 1Section of Neuroradiology and MR Unit (Department of Radiology), Vall d’Hebron University Hospital, Barcelona,


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Group, Department of Computer Architecture and Technology, University of Girona, Girona, Spain Background: The presence of new T2 lesions in follow-up MRI scans is an accepted biomarker to evaluate treatment efficacy in MS. However, this task is commonly applied visually or semiautomatically and is prone to inter- and intra-observer errors as well as labour intensive. Automatic tools for new T2 lesion detection would therefore be highly desirable. Aim: To develop and test in a relevant clinical cohort an automated approach to detect new T2 MS lesions from serial brain MRI images. Materials and methods: The study sample is made up of 36 patients with a clinically isolated syndrome (CIS), selected according to the presence of new T2 lesions in follow-up MRI scans. In this sample, new T2 lesion volume range was 12.53 to 7563.08 mm3 and new lesions mean was 5. All patients were scanned with a 3T magnet at two different time points: the first within 3 months and the second 12 months after the onset of symptoms. Each MR scan includes transverse T2-FLAIR, PD-w, T2-w and T1-w images. A new pipeline introducing a novel postprocessing approach based on deformation fields computed using Demons non-rigid registration was compared to a ground truth of visual semiautomatic annotations of new T2 lesions provided by expert neuroradiologists. This new approach studies the deformation between timepoints to determine changes in lesions. The automated pipeline includes several steps: common MRI pre-processing, co-registration between the baseline and follow-up images, automatic computation of a threshold on the white matter region of the 3D subtraction and a final post-processing step that combines the individual lesion masks for each image and applies rules based on intensity, lesion size and deformation fields to reduce the number of false positives. Concordance measures were applied. Results: Using the T2-FLAIR image to detect new lesions we obtained: 70.93% of true positive (TP) fraction and 17.80% of false positive (FP) fraction, with a mean true positive detection of 3 new lesions and a Dice similarity coefficient (DSC) of 0.68. Using the PD-w and T2-w images the TP fraction and FP fraction increased to 71.67% and 37.68%, respectively with a decrease in the DSC to 0.62. Conclusion: Our novel approach provides a low rate of FP and a high rate of TP with acceptable DSC and looks promising for further validation in other clinically relevant samples. Disclosure Mariano Cabezas has nothing to disclose. Arnau Oliver has nothing to disclose. Xavier Lladó has nothing to disclose. Cristina Auger has received speaking honoraria from Novartis and Genzyme. Jaume Sastre-Garriga has received compensation for consulting services and speaking honoraria from Merck-Serono, BiogenIdec, Teva, Sanofi-Aventis and Novartis. Deborah Pareto has received speaking honoraria from Novartis and Genzyme. Xavier Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of

clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall. Alex Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, and has received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Bracco, MerckSerono, Teva Pharmaceutical Industries Ltd, OLEA Medical, Stendhal, Novartis and Biogen Idec. P429 Periventricular lesion burden in multiple sclerosis correlates with cortical thinning M. Jehna1, L. Pirpamer2, M. Khalil2, S. Fuchs2, S. Ropele2, C. Langkammer2, A. Pichler2, F. Stulnig2, H. Deutschmann1, F. Fazekas2, C. Enzinger1,2 1Department of Radiology, 2Department of Neurology, Medical University of Graz, Graz, Austria Objective: It has been suggested recently that cortical pathology in multiple sclerosis (MS) may at least partly be caused by factors in the cerebrospinal fluid (CSF). We thus hypothesised that MS related tissue changes in compartments close to the CSF such as periventricular lesions might correlate with cortical pathology. Methods: We investigated a cohort of 160 patients, comprising 91 with a clinically isolated syndrome (CIS) and 69 with relapsing-remitting MS (RRMS) (mean age: CIS: 31.4+/-9.0; RRMS: 33.0+/-8.7 years, mean disease duration: CIS: 7.2+/-15 months; RRMS: 8.0+/-6.5 years, median EDSS: CIS: 1, 0-3.5; RRMS: 1.25, 0-4) with 3.0T MRI. MS lesions were segmented semi-automatically on FLAIR images. To quantify periventricular lesion load (PV-LL), we generated ventricle masks and dilated them by a voxel factor of three. Lesions within the dilated ventricle margin were classified as periventricular. Cortical thinning was assessed via cortical mean thickness (CMT) and compared to data from 58 healthy controls (HC) (mean age: 29.1+/-7.4 years). Results: Compared to HC, CIS and (even more so) RRMS patients demonstrated significantly reduced CMT. Even after controlling for ventricular volume and total lesion load, increased periventricular lesion occupancy (percentage of PV-LL) significantly correlated with decreased CMT in RRMS (r=-0.295, p=0.015) but not in CIS (r=0.032, p=0.768) patients. Interpretation: The correlation between increased periventricular lesion burden and decreased CMT suggestive of subpial cortical pathology supports the concept that common CSF-mediated factors might play a role in the accumulation of brain damage in MS subgroups, particularly in patients with relapsing-remitting inflammation. Disclosure Dr. Jehna reports no disclosures. Mr. Pirpamer, MSc reports no disclosures. Dr. Khalil has received funding for travel and speaker honoraria from Bayer Schering Pharma, Novartis Genzyme, Merck Serono, Biogen Idec, and Teva Pharmaceutical Industries. Dr. Fuchs reports no disclosures. Dr. Ropele reports no disclosures. Dr. Langkammer reports no disclosures. Dr. Pichler reports no disclosures.


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Poster Session I, 21(S11) Ms. Stulnig reports no disclosures. Dr. Deutschmann reports no disclosures. Dr. Fazekas serves on scientific advisory boards for BayerSchering, Biogen Idec, Genzyme, Merck Serono, Pfizer, Novartis and Teva Pharmaceutical Industries Ltd.; serves on the editorial boards of Cerebrovascular Diseases, Multiple Sclerosis, the Polish Journal of Neurology and Neurosurgery, Stroke, and the Swiss Archives of Neurology and Psychiatry; and has received speaker honoraria and support from Biogen Idec, Bayer Schering, Merck Serono, Novartis, Pfizer, Sanofi-Aventis, Shire and Teva Pharmaceutical Industries Ltd. Dr. Enzinger has received funding for travel and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis Genzyme and Teva Pharmaceutical Industries Ltd./ sanofi-aventis; research support from Merck Serono, Biogen Idec., and Teva Pharmaceutical Industries Ltd./sanofi-aventis; serving on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Genzyme, Merck Serono, Novartis, and Teva Pharmaceutical Industries Ltd./sanofiaventis; academic editor for PLOSOne. P430 Grey/white matter ratio at diagnosis, and the risk of 10-year multiple sclerosis progression M. Moccia1, M. Quarantelli2, R. Lanzillo1, S. Cocozza3, A. Carotenuto1, B. Carotenuto2, B. Alfano2, A. Prinster2, M. Triassi4, R. Palladino5, A. Brunetti3, V. Brescia Morra1 1Department of Neuroscience, Federico II University, 2Institute of Biostructure and Bioimaging, Italian National Research Council, 3Department of Advanced Biomedical Sciences, 4Department of Public Health, Federico II University, Napoli, Italy, 5Department of Primary Care and Public Health, Imperial College, London, United Kingdom Objectives: Grey and white matters are both affected in multiple sclerosis (MS), but poorly correlate among each other. This is possibly due to the heterogeneous pathological substrates of the disease, with preponderance of inflammatory demyelinating aspects in relapsing-remitting (RR), and of neurodegenerative components in secondary progressive (SP). Therefore, the present study aims to investigate the relationship between grey and white matter in a population of newly diagnosed RRMS subjects, with longterm MS-related outcomes. Methods: The present 10-year retrospective longitudinal study included 134 RRMS subjects that performed MRI at the time of diagnosis with acquisition of T1-weighted volumes for segmentation purposes. In particular, the ratio between grey and white matter was subsequently calculated. The occurrence of clinical relapses, the reaching of Expanded Disability Status Scale (EDSS) 4.0, and the SP conversion were recorded during a mean followup period of 10.1±1.8 years (from 7.1 to 13.2). Results: During the study period, 54 subjects (40.3%) reached EDSS 4.0, and presented reduced grey/white matter ratio, as compared to subjects not reaching EDSS 4.0 (1.270±0.156 and 1.343±0.185, respectively) (p< 0.001). At the same time, 29 subjects (21.6%) converted to SP, and presented reduced grey/white matter ratio, as compared to subjects not converting to SP (1.241±0.149 and 1.334±0.179, respectively) (p< 0.001). In particular, subjects with higher grey/white matter ratio at diagnosis

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had a 90% reduced rate of reaching EDSS 4.0 (p=0.004; hazard ratio=0.077; 95% confidence interval=0.013-0.453), and of SP conversion, as compared to subjects with lower grey/white matter ratio (p=0.004; hazard ratio=0.026; 95% confidence interval=0.002-0.313). However, the grey/white matter ratio was not associated with the annualized relapse rate (p=0.413; coefficient=-0.129; 95% confidence interval=-0.441-0.182), or with the rate of experiencing a relapse (p=0.327; hazard ratio=0.591; 95% confidence interval=0.168-2.074). Conclusions: The ratio of grey/white matter is a predictor of disability progression and of SP conversion in newly diagnosed RRMS subjects, suggesting that different pathological substrates are present from the early phases of MS, and highlighting the importance of appropriate MRI techniques at MS diagnosis. Disclosure Marcello Moccia: Nothing to disclose. Mario Quarantelli: Nothing to disclose. Roberta Lanzillo: She has received honoraria from Bayer Shering, Biogen, Merck-Serono, Teva and Novartis for lectures or scientific boards. Sirio Cocozza: Nothing to disclose. Antonio Carotenuto: Nothing to disclose. Barbara Carotenuto: Nothing to disclose. Bruno Alfano: Nothing to disclose. Anna Prinster: Nothing to disclose. Maria Triassi: Nothing to disclose. Raffaele Palladino: Nothing to disclose. Arturo Brunetti: Nothing to disclose. Vincenzo Brescia Morra: He has received honoraria from Bayer Shering, Biogen, Merck-Serono, Teva, Genzyme and Novartis for lectures or scientific boards.

P431 A serial 10-year follow-up study of early relapsing-remitting MS patients: exploring longterm value of different MRI brain volumetric outcomes in predicting disability progression R. Zivadinov1,2, T. Uher1,3, J. Hagemeier1, M. Vaneckova4, D.P. Ramasamy1, M. Tyblova4, N. Bergsland1,5, Z. Seidl4, M.G. Dwyer1, J. Krasensky4, E. Havrdova3, D. Horakova3 1Buffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, 2MR Imaging Clinical Translational Research Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States, 3Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, First Faculty of Medicine and General University Hospital, Prague, 4Department of Radiology, 1st Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic, 5IRCCS “S.Maria Nascente”, Don Gnocchi Foundation, Milan, Italy Background: We previously showed in a study cohort with serial yearly MRI that cortical, central and thalamic atrophy were associated with development of confirmed disability progression (CDP) over a period of 5 years. However, no studies have explored


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the evolution of brain atrophy in relation to development of CDP on serial yearly MRI scans over a longer 10-year period. Objectives: We explored the association of different MRI brain volumetric measures and CDP development. Methods: 180 RRMS patients, who started treatment with intramuscular interferon beta-1a (30 µg/week) received yearly clinical and 1.5T assessments on the same MRI scanner over 10 years. At 10-year follow-up, they were divided into those with (100) or without (76) CDP (48 weeks), by standard treatment trial criteria. The number of available MRI scans at various time points were: baseline (178), months 12 (176), 24 (155), 36 (160), 48 (158), 60 (161), 72 (157), 84 (154), 96 (157), 108 (154) and 120 (152). Changes in whole brain (WB), cortical, gray matter (GM), white matter (WM), and lateral ventricle (LV) volumes were calculated via a direct method on 3D-T1 scans between all available time points. Longitudinal linear mixed effect and regression models, adjusted for age, sex and treatment change, were fit to the data in order to describe the temporal association between development of CDP and evolution of brain volume measures. Results: At 10 years, the greatest effect size on percentage decreases from baseline, in MS patients with CDP compared to those without, was detected for WB (d=0.55, -7.5% vs. -5.2%, p < 0.001), LV (d=0.51, +40.5% vs. +21.8%, p < 0.001), cortical (d=0.49, -7.7% vs. -6.2%, p = 0.001) and GM (d=0.40, -7.1% vs. -5.8%, p = 0.006) volumes. In patients who developed CDP at 10 years and those who did not, mixed effect models showed significant interactions between CDP status and percentage changes over time for WB and LV (p < 0.001), cortical (p = 0.02) and GM (p = 0.04) volumes. LV volume was the best independent predictor of changes in GM (R2 = 0.43, p < 0.001), cortical (R2 = 0.38, p < 0.001) and WB (R2 = 0.21, p < 0.001) volumes. Conclusions: Whole brain atrophy and enlargment of lateral ventricles are strongly associated with development of CDP on serial yearly MRI assessments over a period of 10 years. Given the simplicity of LV assessment on lower quality images, assesment of LV may become a useful brain atrophy outcome for clinical routine. Disclosure The study is an investigator-initiated study that was supported by Czech Ministries of Education and Health [NT13237-4/2012, PRVOUK-P26/LF1/4, RVO-VFN64165/2012]. The MRI acquisition part of the study was supported by Gedeon Richter and Biogen Idec. The MRI analysis part was supported in part by Biogen Idec. Financial relationships/potential conflicts of interest: Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health. Dr. Uher received financial support for conference travel and honoraria from Biogen Idec, Novartis, Merck Serono and Genzyme. Drs. Hagemeier, Ramasamy and Bergsland have nothing to disclose. Dr. Tyblova received compensation for travel and honoraria from Biogen Idec, Sanofi Aventis, Teva and Merck Serono.

Drs. Seidl, Vaneckova, and Krasensky received financial support for research activities from Biogen Idec. Dr. Dwyer has received personal compensation from Claret Medical and EMD Serono, and research grant support from Novartis. Dr. Havrdova received speaker honoraria and consultant fees from Biogen Idec, Merck Serono, Novartis, Genzyme and Teva, as well as support for research activities from Biogen Idec and Merck Serono. Dr. Horakova received compensation for travel, speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck Serono, Bayer Shering, and Teva, as well as support for research activities from Biogen Idec. P432 Cerebral microbleeds in multiple sclerosis. A case-control study R. Zivadinov1,2, D.P. Ramasamy1, P. Polak1, J. Hagemeier1, C. Magnano1, M.G. Dwyer1, N. Bertolino1, B. Weinstock-Guttman3, C. Kolb3, R.R. Benedict3, D. Hojnacki3, M.E. Haacke4,5,6, F. Schweser1,2 1Buffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 2MR Imaging Clinical Translational Research Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 3Jacobs Multiple Sclerosis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, 4Department of Radiology, Wayne State University, Detroit, MI, United States, 5School of Biomedical Engineering, McMaster University, Hamilton, ON, Canada, 6Shanghai Key Laboratory of Magnetic Resonance, East China Normal University, Shanghai, China Background: Cerebral microbleeds (CMBs) appear as small, round or ovoid hypo-intense lesions on gradient-recalled echo (GRE) T2*-weighted or susceptibility-weighted imaging (SWI) MRI. Their presence has been associated with traumatic brain injury, Alzheimer’s and Parkinson’s disease and aging. CMB number and lesion burden is associated with cognitive decline. No previous studies assessed CMBs in patients with multiple sclerosis (MS). Objectives: To assess CMBs in MS and clinically isolated syndrome (CIS) patients and explore their association with clinical outcomes. Methods: In a prospective study, 445 MS patients (283 relapsingremitting, 120 secondary-progressive and 41 primary-progressive), 55 CIS patients, 51 patients with other neurologic diseases (OND) and 177 healthy controls (HCs) were assessed by 3T MRI and clinical examinations. The CMBs were examined on SWI scans using Microbleed Anatomical Rating Scale (MARS). MARS is assessing CMBs in infratentorial (brainstem and cerebellum), deep (basal ganglia, thalamus, internal and external capsule, corpus callsoum and deep and periventruclar white matter) and lobar (frontal, parietal, temporal and occipital) regions. The number and volume of definite CMBs was determined. Parametric and non-parametric statistics was used to determine differences between the study groups.


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Poster Session I, 21(S11) Results: The mean age (47.7 yrs for MS, 47.1 yrs for HCs and 49.1 yrs for OND) and sex were not different between the study groups, except for younger age in CIS patients (38.9 yrs). More MS patients had CMBs compared to HCs (11.5% vs. 5.4%, p=0.024). MS patients also showed significantly higher number (0.14 vs. 0.06, p=0.038) and volume (8.2mm3 vs. 2.4 mm3, p=0.049) of CMBs compared to HCs. There were no significant CMB positivity, frequency or volume differences between OND (11.8%) and MS patients or between CIS (9.1%) patients and HCs (p>0.05). Considering subjects ⩾50 yrs of age, MS patients (n=206) showed significantly higher CMB frequency compared to HCs (n=81; 21.2% vs. 8%, p=0.01). In subjects < 50 yrs of age, MS patients (n=239) showed similar CMB frequency compared to HCs (n=96; 4.6% vs. 3.1%, p=0.764). In MS patients both number and volume of CMBs was associated with increased age (p< 0.001) and level of disability, as measured (p< 0.003). Conclusions: Frequency of CMBs is increased in MS patients compared to age- and sex-matched HCs, but comparable to ONDs. CMBs are associated with more advanced disability in MS patients. Disclosure Financial relationships/potential conflicts of interest: Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health. Deepa P. Ramasamay, Paul Polak, Jesper Hagemeier, Christopher Magnano, Nicola Bertolino and Ferdinand Schweser have nothing to disclose. Michael G. Dwyer has received consultant fees from Claret Medical and EMD Serono. Bianca Weinstock-Guttman received honoraria as a speaker and as a consultant for Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis and Acorda. Dr Weinstock-Guttman received research funds from Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis, Acorda. Channa Kolb has received speaker honoraria from Novartis, Genzyme and Biogen-Idec. Ralph R.H. Benedict has acted as a consultant or scientific advisory board member for Bayer, Biogen Idec, Actelion, and Novartis. He receives royalties from Psychological Assessment Resources, Inc. He has received financial support for research activities from Shire Pharmaceuticals, Accorda and Biogen Idec. David Hojnacki has received speaker honoraria and consultant fees from Biogen Idec, Teva Pharmaceutical Industries Ltd., EMD Serono, Pfizer Inc, and Novartis. Mark E. Haacke is the president of Magnetic Resonance Innovations, Inc. P433 Patterns of decreased cortical surface-based magnetization transfer ratio in multiple sclerosis D.A. Rudko, J. Maranzano, D.L. Arnold, S. Narayanan Neurology and Neurosurgery, McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada

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Background: Magnetic resonance imaging (MRI) visualizes only a fraction of the disease burden visible in postmortem multiple sclerosis (MS) studies. In particular, standard MR images obtained at clinically accessible field strengths are unable to detect sub-pial cortical gray matter pathology. The goal of this study was to evaluate the utility of surface-based cortical magnetization transfer ratio (csMTR), acquired using 3T MRI, as a method to detect subpial gray matter demyelination in MS. Methods: 21 MS patients (17 RRMS, 4 SPMS), as well as corresponding matched controls, were recruited from the MS Clinic of the Montreal Neurological Institute. All subjects were imaged using a 3T MRI scanner. Based on the T1-weighted anatomical MR images, cortical surface meshes were generated along the inner (75% depth from pial surface), middle (50% depth) and outer (25% depth) cortical boundaries. csMTR values, representative of cortical myelination, were then smoothed along the three surfaces using a 2D geodesic blurring kernel. Group differences in csMTR between MS patients and controls were evaluated at each cortical depth along the cortical surface meshes by employing a general linear mixed model. Results: The largest areas of decreased csMTR were along the outer cortical boundary in the left and right precentral and postcentral gyri/sulci, superior temporal sulci, middle temporal gyri/sulci, parahippocampal gyri and in the cuneus. The total area of decreased csMTR was 17.61% on the outer surface, 7.91% along the middle and 5.25% along the inner cortical boundaries. The mean difference between the inner and outer csMTR in MS patients (mean ΔMTR=2.03% units) exceeded that found in controls (mean ΔMTR=1.66% units). This difference was also correlated with EDSS in our cohort (p< 0.05 corrected for multiple comparisons). Importantly, the correlation with EDSS remained significant after covarying for white matter lesion load, baseline normalized brain volume, age and global cortical thickness. The area of decreased csMTR relative to controls was larger in cortical sulci compared to gyri (sulcal area of significantly decreased csMTR=6267 mm2, gyral area of significantly decreased csMTR=4533 mm2). Conclusion: The pattern of regional decrease of csMTR in MS patients was consistent with post-mortem descriptions of the distribution of sub-pial lesions. Our results support the hypothesis that csMTR may be a sensitive quantitative biomarker of sub-pial demyelination in MS. Disclosure This work was supported by a research grant from the Canadian Institutes of Health Research, MOP # 84367. Dr. Rudko has no conflicts of interest to disclose. Dr. Maranzano has no conflicts of interest to disclose. Dr. Arnold reports personal fees from Acorda, Biogen Idec, Genzyne, HoffmanLa Roche, Innate Immunotherapeutics, MedImmune, Mitsubishi Pharma, Novartis, Receptos, Sanofi Aventis and Teva outside the submitted work, and is an employee and stockholder in NeuroRx. Dr. Narayanan has received personal compensation for consulting activities from NeuroRx Research. P434 Magnetic resonance spectroscopy of the hippocampus is not correlated with memory performance in early and late stages of multiple sclerosis


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W. Köhler1, P. Bublak2, J. Faiss3, M. Fischer1, F. Hoffmann4, A. Kunkel3, M. Schwab2, E. Stadler5, U.K. Zettl6, M. Sailer5, for HIPPOCOMS Study Group 1Klinik für Neurologie und Neurologische Intensivmedizin, Fachkrankenhaus Hubertusburg, Wermsdorf, 2FriedrichSchiller-Universität, Jena, 3Asklepios Fachkliniken Brandenburg GmbH, Teupitz, 4Krankenhaus Martha-Maria Halle-Dölau gGmbH, Halle, 5Universitätsklinik für Neurologie, Magdeburg, 6Universitätsklinikum Rostock, Rostock, Germany Background: In multiple sclerosis (MS) memory deficits are frequent. Some studies found these to be correlated with hippocampal atrophy, others with functional data of the hippocampus. Thus, it is not clear if memory impairment in MS relates to focal hippocampus damage or to broader network dysfunctions. Previous studies utilised magnetic resonance imaging and functional magnetic resonance imaging. We investigated hippocampal damage by using an alternative method, i.e., MRS quantifying the extent of axonal dysfunction and demyelination in the hippocampus of MS patients and its correlation to memory performance. Goals: To investigate correlations between metabolic changes in the hippocampus and memory performance in MS patients. Methods: Nineteen MS-patients were recruited from two centres and assigned to two groups: EarlyMS (N=8) with disease durations of less than 2 years, and lateMS (N=11) with disease durations of 12 or more years. Patients were tested by five memory tests (AVLT, RCFT, DCS, VLT, NVLT) and underwent 3 Tesla single voxel MRS in three regions: left and right hippocampus, intersection of corpus callosum and fornix (reference-voxel). The assessed metabolites ratios of N-Acetylaspartate (NAA) / Creatine (Cr) and Choline (Cho) / Creatine (Cr) were compared between regions and groups and correlated with age-corrected memory performance. Results: NAA/Cr (1.0 ± 0.18 vs. 1.5 ± 0.22) and Cho/Cr (0.34 ± 0.05 vs. 0.39 ± 0.05) were reduced in bilateral hippocampi compared to the reference-voxel (p< .001). Minor differences between earlyMS and lateMS were found in NAA/Cr of the right hippocampus (1.11 ± 0.18 vs. 0.93 ± 0.14; p< .05) and in NAA/Cr of the reference-voxel (1.69±.17 vs. 1.44±.19; p< .01), but not for Cho/Cr. In both groups, correlations between MRS and memory performance were not significant. Highest correlations were found for right Hippocampus NAA/Cr in lateMS (r=.37, p=.26), and reference-voxel Cho/Cr in earlyMS (r= -.63, p=.09). Conclusions: Biochemical changes measured by MRS indicate early axonal loss in both hippocampi but these changes do not explain memory deficits in MS. Disclosure This study is supported by: Merck Serono GmbH, Germany, a division of Merck KGaA, Darmstadt, Germany. Köhler, Faiss, Hoffmann, Sailer, Schwab, Zettl: Received institutional research grants and personal honoraria as speaker from Biogen Idec, Bayer, Genzyme, Merck Serono, Novartis, Sanofi and TEVA. Kunkel: Received travel support from biogen. Bublak, Fischer, Stadler: nothing to disclose.

P435 Visualizing and characterizing cortical gray matter lesions in MS with 7T MRI L. Jonkman1, R. Klaver1, L. Fleysher2, M.D. Steenwijk3, J.A. Koeleman1, T.-P. de Snoo1, F. Barkhof3, M. Inglese4, J.J. Geurts1 1Department of Anatomy and Neurosciences, VU Medical Center, Amsterdam, The Netherlands, 2Department of Radiology, Mount Sinai School of Medicine, New York, NY, United States, 3Department of Radiology and Nuclear Medicine, VU Medical Center, Amsterdam, The Netherlands, 4Department of Radiology, Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY, United States

Background: Cortical gray matter (GM) demyelination is frequent and clinically relevant in MS. Unfortunately, many GM lesions go undetected on conventional MRI and not much is known about their quantitative MR properties. Some quantitative characteristics of GML have been reported between lesional and non-lesional tissue, but differences between cortical lesion types have so far not been found. Ultra-high field MRI and specific MRI sequences may facilitate improved visualization and characterization of GM lesions due to higher signal-to-noise and better spatial resolution. Objective: (i) to determine the sensitivity of 7T MRI T2 and T2* sequences for the detection of histopathologically verified GML. (ii) to quantify potential differences in GML types and normal-appearing GM (NAGM) by magnetization transfer ratio (MTR) and qR2* maps, and between GML and NAGM for diffusion tensor imaging (DTI). Methods: Coronal brain sections of 15 MS patients were formalin-fixed and scanned on a 7T Bruker Biospec MRI. Scan protocol included T2, T2*, MTR, qR2* (inplane 0.1x0.1x1mm) and DTI (2x2x1mm) sequences. GML were scored on T2 and T2*. Histopathology was performed with proteolipid protein (PLP) and GML were identified. MR images were matched to histopathology and sensitivity of T2 and T2* sequences were evaluated. Subsequently, histopathologically verified lesions were drawn as regions of interests (ROIs), MTR, qR2* and DTI maps were coregistered to the T2-weighted images, and mean ROI values were obtained and statistically analyzed. Results: We identified 98 GML. Prospectively, T2 and T2* detected 28% and 16% of GML (p=0.054). Retrospectively this increased to 83% and 82%. Quantitatively, 74 GML and 45 areas of NAGM were analyzed; lesion types III and IV showed lower MTR values than type I/II lesions and NAGM (0.001>p< 0.05). Type IV lesions showed lower qR2* values than lesion type II (p< 0.05), and lesion type III and IV showed lower qR2* values than NAGM (p< 0.001). For DTI analysis, 48 GML and 39 areas of NAGM were analyzed; GML had a higher FA than NAGM (p = 0.02). Conclusion: At 7T post-mortem MRI, T2 and T2* were equally capable at detecting up to ~85% of GML. A priori observer training could possibly increase prospective lesion detection. Furthermore, qMRI differences between some cortical GML types were found. Lastly, GML have a higher FA than NAGM. A histopathological analysis to pathologically explain this increase will be presented at the meeting.


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Poster Session I, 21(S11) Disclosure Laura E Jonkman has nothing to disclose Roel Klaver has nothing to disclose Lazar Fleysher has nothing to disclose Martijn Steenwijk has nothing to disclose Jan A Koeleman has nothing to disclose Teun-Pieter de Snoo has nothing to disclose Frederik Barkhof serves on the editorial boards of Brain, European Radiology, Neuroradiology, Multiple Sclerosis journal and Radiology and serves as a consultant for Bayer-Schering Pharma, Sanofi-Aventis, Biogen-Idec, Teva, Novartis, Roche, Synthon BV, Jansen Research. Matilde inglese serves on the editorial board of MS International, Journal of World Radiology Frontiers in Aging Neuroscience, and the Scientific Advisory Board of the Italian MS Society and has served as a consultant for Celgene Cellular Therapeutics and Vaccinex, Inc. MI has received research grant support from NIH, NMSS, Novartis Pharmaceuthicals and Teva Neurosciences. Jeroen JG Geurts is an editor for Multiple Sclerosis Journal, associate editor for BMC Neurology, and serves on the editorial boards of Neurology and MS International; he is a member of the scientific advisory board of the Dutch MS Research Foundation, of the MS Society of Canada and a scientific steering committee member of the International Progressive MS Alliance; he has served as a consultant for MerckSerono, Novartis, Biogen Idec, Genzyme and Teva Pharmaceuticals. P436 Periventricular venous density is normal in neuromyelitis optica - preliminary data from a 7T MRI study S. Schumacher1, F. Pache1,2, J. Behrens1, P. Dusek2,3, L. Harms4,5, K. Ruprecht4,5, P. Nytrova2, S. Chawla6, T. Niendorf7,8, I. Kister9, F. Paul1,4,5, Y. Ge6, J. Würfel1,10, T. Sinnecker1,11 1NeuroCure Clinical Research Center, Universitätsmedizin Berlin, Berlin, Germany, 2Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic, 3Institute of Neuroradiology, Universitätsmedizin Göttingen, Göttingen, 4Clinical and Experimental Multiple Sclerosis Research Center, Charité Universitätsmedizin Berlin, 5Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany, 6Department of Radiology, NYU School of Medicine, New York, NY, United States, 7Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine, 8Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany, 9Multiple Sclerosis Care Center, Department of Neurology, NYU School of Medicine, New York, NY, United States, 10Medical Image Analysis Center, Universitätsspital Basel, Basel, Switzerland, 11Department of Neurology, Asklepios Fachklinikum Teupitz, Teupitz, Germany Background: Vascular involvement in multiple sclerosis (MS) perivascular cuffing and thickened vein walls were described decades ago. Recently, a reduced (periventricular) venous density was reported in MS, and intra-lesional venous shrinking was suggested as an in vivo marker following inflammation. Vascular abnormalities on 7T MRI images have not been investigated in neuromyelitis optica (NMO).

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Objective: To compare periventricular venous density in NMO, healthy controls and MS using ultra-high field (7T) MRI. Methods: 18 patients with NMO (18 female; age mean±SD, range: 48±15, 22-71 years), 18 relapsing remitting MS patients (13 female; age mean±SD, range: 41±9, 20-53 years), and 18 healthy controls (7 female; age mean±SD, range: 44±14, 20-70 years) were investigated at 7T MRI including T2*-weighted (T2*w) and fluid-attenuated inversion recovery (FLAIR) imaging to calculate the periventricular venous area (PVA in mm2) by a blinded investigator. Results: In total, we detected 131 white matter lesions in 18 NMO patients, 368 white matter lesions were visualized in MS patients, and 139 white matter lesions were depicted in HC. We did not observe any differences in periventricular venous density measured by PVA in NMO (mean±SD, range: 132,33±24,08, 97-176 mm2) versus HC (Mann-Whitney U test, p=0.171; mean±SD, range: 143,33±27,30, 88-196 mm2). Contrarily, PVA was significantly reduced in MS (Mann-Whitney U test, p=0.019; mean±SD, range: 118,81±29,63, 61-170 mm2) compared to HC as described previously. Conclusions: The periventricular venous system appeared - in contrast to MS - normal in NMO. This discrepancy underlines differences in the underlying pathogenesis between NMO and MS. Disclosure This work was supported by an investigator-initiated grant from the Guthy-Jackson Charitable Foundation, the German Research Foundation (DFG Exc 257 to Friedmann Paul) and the German Ministry for Education and Research (Competence Network Multiple Sclerosis to Friedemann Paul,Klemens Ruprecht and Florence Pache). Above that Klemens Ruprecht received research support from Novartis as well as speaking fees and travel grants from Bayer Healthcare, Biogen Idec, Merck Serono, Sanofi/Genzyme and Teva. Sophie Hahndorf: nothing to disclose Janina Behrens: nothing to disclose Petr Dusek: nothing to disclose Lutz Harms: nothing to disclose Petra Nytrova: nothing to disclose Sanjeev Chawla: nothing to disclose Thoralf Niendorf: nothing to disclose Ilya Kister: nothing to disclose Yulin Ge: nothing to disclose Jens Wuerfel: nothing to disclose Tim Sinnecker: nothing to disclose P437 Accurate and reliable atrophy measurement on clinical quality FLAIR scans M.G. Dwyer1, D.P. Ramasamy1, J. Durfee1, R. Zivadinov1,2 1Buffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 2MR Imaging Clinical Translational Research Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States Background: Brain atrophy is a critical component of MS in all stages of the disease. It is strongly related to disability, but has not been widely used because it is too complex to assess in a clinical


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setting. Although excellent tools exist for measuring atrophy in research labs, they require high-resolution T1 scans, customized workstations, and extensive technical expertise - making them largely unavailable to local neurologists. They may also fail with severe atrophy or require special pre-processing to handle pathology. Therefore, a more clinically-relevant method for atrophy measurement would be a significant boon for general clinical research. Objectives: Develop and validate a robust, publicly available, web-based measure of atrophy for clinical-quality FLAIR images. Methods: We focused on lateral ventricular volume (LVV) because it reflects both gray and white matter atrophy and has clear borders even on low-quality scans. We compiled a real-world dataset of 100 3mm FLAIR scans from 62 MRI centers, balanced for field strength, lesion load, and level of atrophy. This dataset was used to develop and tune an LVV quantification algorithm with specific attention to common issues. An MS-specific, multi-site FLAIR template and a probabilistic ventricular atlas were created. Individual FLAIR images were pre-processed with Fourier-based upsampling, lesion-attenuating Winsorization, histogram matching, and peri-ventricular constrained warping. Template-based masking was used to exclude misclassified cisterns and 3rd/4th ventricle, and to include choroid plexus. Final refinement and quantification was performed using level-set evolution. For validation, hi-res T1 and low-res FLAIR images were used (n=100). Gold-standard LVV measures were created by manual segmentation on hi-res T1. These were compared to the automated results of our algorithm running on low-res FLAIR images. We also assessed scan/re-scan reliability for 5 subjects. Finally, a publicly available, HIPAA-compliant web-based cloud server was created, capable of running the algorithm directly from PACS- or CD-based DICOM images. Results: Correlation between hi-res gold standard volumes and automated volumes (from low-res FLAIR) was r=0.96 (p < 0.001). Scan-rescan coefficient of variation was 1.61%. Processing time via the cloud server is approximately 12 minutes per scan. Conclusions: Atrophy measurement via LVV is feasible, accurate, reliable, and accessible on clinical quality scans. Disclosure The study was funded by an investigator initiated grant from Novartis. Financial Relationships/Potential Conflicts of Interest: Michael G. Dwyer has received personal compensation from Claret Medical and EMD Serono, and research grant support from Novartis. Deepa P. Ramasamay and Jacqueline Durfee have nothing to disclose. Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health.

P438 MR frequency shifts in new MS lesions of CIS patients over 2 years V. Wiggermann1,2, I. Ibs3, S.M. Schoerner4, E. Hernández Torres2,5, L. Metz6, G. Vorobeychik7, D.K.B. Li8,9, A. Traboulsee9, A. Rauscher2,5,10

1Physics

and Astronomy, 2Pediatrics, University of British Columbia, Vancouver, BC, Canada, 3University of Osnabrueck, Osnabrueck, 4Technical University of Dortmund, Dortmund, Germany, 5UBC MRI Research Centre, Vancouver, BC, 6Clinical Neurosciences, University of Calgary, Calgary, AB, 7Fraser Health MS Clinic, Burnaby, 8Radiology, 9Medicine (Neurology), 10Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada Background and goals: Frequency shift (FS) imaging demonstrated potential for quantitative assessment of tissue damage due to multiple sclerosis (MS) lesion formation1–3. Heterogeneity of FS between lesions reflects variable degrees of demyelination and tissue matrix destruction2. Clinically isolated syndrome (CIS) patients experience demyelinating events suggestive of MS. Assessing MR FS longitudinally in this pre-MS cohort may illuminate the time line of axonal loss and demyelination in new MS lesions. Methods: 73 CIS patients in a randomized, placebo controlled, double-blind Minocycline trial received a baseline MRI and up to 5 follow-up MRI (month 3,6,12,24) following treatment initiation. Multi-gradient echo (GRE), proton density (PD), FLAIR and contrast-enhanced T1-weighted images were acquired at 3T (Philips Achieva, GRE: 5 echoes, TR/TE/ΔTE=48/20/6ms, reco. voxelsize=0.38x0.38x1.2mm3). Gadolinium(Gd)-enhanced and T1-hypointense lesions were identified on T1-Gd scans. Lesions that appeared without Gd-enhancement but at subsequent FLAIR scans were classified as new T2-lesions. Normal appearing white matter (NAWM) and diffusely abnormal white matter (DAWM) were defined on PD. Average FS for each region were computed from the GRE phase by homodyne filtering and scaling to the Larmor frequency at 3T at 23ms. A linear mixed-effects model was applied in R. Results: 30 Gd-lesions and 19 new T2-lesions appeared over the course of the study. The lesions´ frequency increased significantly (p=0.0001) from 6 months prior to 3 months post-enhancement, with a rapid increase around the time of lesion formation. FS remained elevated but exhibited no significant changes beyond 3 month post-enhancement or new appearance. FS in non-lesion tissue and in black holes remained constant over 1yr (p>0.4, 0.73±0.31ppb in black holes, -0.005±0.025ppb in DAWM and -0.715±0.140ppb in NAWM). Discussion: We demonstrated that FS in new MS lesions remain elevated for up to 12 months. Beyond 12 months, insufficient data preclude definite conclusions. While another study showed normalization of MR FS 5 years after lesion formation4, our results indicate that this normalization does not occur within the first 12 months. Conclusion: Lesion formation in CIS leads to increases in the MR resonance frequency that persist for at least 1yr after lesion appearance. References: 1He and Yablonskiy, 2009 2Yablonskiy et al., 2012 3Wiggermann et al., 2013 4Wiggermann et al., ISMRM 2014, #0892 Disclosure This study was funded by the MS Society of Canada. VW is recipient of an MS Society of Canada Graduate Student Award.


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Poster Session I, 21(S11) EHT receives support from CONACyT. II, SMS, GV and LM have nothing to disclose. DKBL consults and receives honoria from Roche, Nuron Therapeutics, Novartis, Opexa, Vertex Pharmaceuticals, SanofisAventis, Genzyme, Perceptive, Merck Serono. AT receives support from CIHR, MS Society of Canada and Genzyme and honoria from Roche, EMD Serono, Teva Neuroscience, Biogen, Novartis and Chugai. AR is recipient of a CIHR New Investigator Award and imaging advisory board member of F. Hoffman La-Roche (unrelated to MS). P439 Differential neurodegenerative mechanisms in thalamus throughout multiple sclerosis stages: a multimodal quantitative 3 T and 7 T MRI study C. Louapre1,2, S.T. Govindaraja1, C. Giannì1,2, C.A. Treaba1,2, J.A. Sloane3, R.P. Kinkel4, C. Mainero1,2 1A. A. Martinos Center for Biomedical Imaging, Charlestown MA, 2Harvard Medical School, 3Beth Israel Deaconness Medical Center, Boston, MA, 4University of California San Diego, San Diego, CA, United States Background: Thalamic degeneration occurs early in multiple sclerosis (MS), in association with clinical disability. Underlying pathological mechanisms include demyelination, inflammation, iron accumulation, neurodegeneration. Goal: To investigate the interplay between different pathological processes in thalamus throughout MS stages: i) neurodegeneration (atrophy); ii) demyelination and changes in iron content by quantitative T2* (q-T2*); iii) regional q-T2* changes as function of distance from ventricles to test the hypothesis of an outside-in pathogenesis. To assess the relation between heterogeneous thalamic pathology and clinical metrics. Methods: Thirty-eight MS patients (9 early MS ⩽ 3 years disease duration, 16 RRMS, 13 SPMS) underwent 7T T2* imaging to obtain q-T2* maps and segment white matter (WM) lesions; 3T T1-weighted acquisitions for FreeSurfer cortical surface reconstruction, and FIRST-FSL thalami segmentation. T2* maps were registered on 3T T1 images to compute mean thalamic q-T2*, and within concentric thalamic bands originating from the CSF/thalamus interface. Differences in thalamic volume, global q-T2* and laminar q-T2* in MS vs controls, and across MS subgroups were tested using linear regression adjusted for age, gender and intracranial volume. The contribution of thalamic volume and q-T2* to Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT) scores was determined by stepwise multilinear regression. Results: Thalamic volume was decreased in MS subjects (~18%, p< 10-8), and in each MS subgroup (p=0.006 in early MS, p< 10-6 in RRMS, p< 10-11 in SPMS) vs controls and was strongly associated with global WM lesion load (p< 10-15). We found no difference in global thalamus q-T2* in early and RRMS relative to controls; SPMS exhibited longer thalamic q-T2* (~11%, p< 10-5), consistent with demyelination and/or iron loss. T2* changes in SPMS were uniformly distributed within the thalamus without a gradient towards the CSF or WM. Focal thalamic lesions were

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seen in 2 early, 5 RR and 10 SPMS. In all MS, EDSS was predicted by thalamic volume (p=0.005) and thalamic q-T2* (p=0.02), while SDMT by thalamic volume (p< 10-4). Conclusion: Thalamic neurodegeneration occurs from the earliest MS stages, independently from local demyelination. This suggests an early neurodegenerative process originating either primarily within the thalamus or secondary to distant WM lesions, later being associated with local demyelination. Disclosure Study funding National MS Society (NMSS 4281-RG-A1 and NMSS RG 4729A2/1), the Claflin Award, NIH R01NS078322-01-A1 STG, CAT, JAS, CM: No disclosure. CL has received a fellowhip from ARSEP foundation. CG has received a fellowship from FISM 2012/B/4. RP reports personal fees from Genzyme; A Sanofi Corp, personal fees from Biogen Idec, grants from Acclerated Cure Project, personal fees from Novartis, outside the submitted work. P440 2D MR spectroscopy can identify molecules differentiating MS from healthy controls K. Ribbons1, S. Quadrelli2, J. Lechner-Scott1,3, O. Al-Iedani4, J. Arm4,5, C. Mountford2, S. Ramadan4 1Hunter Medical Research Institution, Newcastle, NSW, 2Institute of Health & Biomedical Innovation, University of Technology, Translational Research Institute, Brisbane, QLD, 3Neurology, John Hunter Hospital, Newcastle, 4School of Health Sciences, Faculty of Health and Medicine, University of Newcastle, Callaghan, 5Radiological Imaging Services, Hunter New England Local Health District, Newcastle, NSW, Australia Introduction: MS diagnosis is increasingly reliant on MR but routine imaging is not specific for MS. New MR modalities like spectroscopy might add to the specificity of diagnosis and could potentially identify new biomarkers. Methods: One-dimensional (1D) and two-dimensional (2D) localised correlation spectroscopy (L-COSY) MRS was acquired from the posterior cingulate gyrus (PCG) using a 3T Prisma MRI scanner. MRS was performed on 11 RRMS participants receiving immunomodulatory treatment (n=8) or no treatment (n=3) with a mean EDSS of 2.0. Comparisons were made with a healthy age and gender-matched control group (n=8). Data was acquired from a 3x3x3 cm3 voxel. 1D profiles were analysed with LCModel (v6.2-2B) using water normalization. Felix 2007 software was used for the processing and analysis of the 2D L-COSY data. The creatine methyl resonance (3.02-3.02ppm) was used as the internal chemical shift reference and cross-peak volume ratios were normalized to water. Average peak volumes were calculated for each assigned metabolite and compared using a Mann-Whitney test (non-normal distribution) using Stata ADDIN EN.CITE StataCorp2013233(StataCorp 2013)2332339StataCorpStata Statistical Software: Release 13Release 132013TXCollege Station(StataCorp 2013). Results: L-COSY identified two metabolites, not detectable by 1D MRS, a diagonal peak at 1.33ppm and a cross peak at 3.83.33ppm, which can be tentatively assigned to glucose and/or glycerol. Compared to healthy controls the MS group had 76%


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(P=.032) increase in the 1.33ppm peak and 22% increase (P=.02) in glycerol/glucose. With 1D spectroscopy, we identified a statistically significant increase in aspartate (+8%, P=0.013), N-acetylaspartate (+2%, P=0.048), and lipid+macromolecues (+7%, P=0.04) in MS patients compared to control. Conclusion: In vivo spectroscopy has the potential to play an important role in biomarker discovery in MS disease. L-COSY is adding significantly to 1D spectroscopy in identifying biochemical changes in the central nervous system of MS patients. Disclosure K Ribbons, S Quadrelli, O. Al- Iedani, J Arm, C Mountford, S Ramadaan declare no conflicts. J Lechner-Scott has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment and also clinic support as well as research grants from Bayer Health Care, Biogen Idec, CSL, Genzyme Sanofi, Merck Serono and Novartis. This study was supported by grants from Biogen and Novartis.

P441 A longitudinal study of spinal cord lesion load in progressive multiple sclerosis D. Plantone1, H. Kearney1, M. Yiannakas1, F. De Angelis1, A.J. Thompson1,2, D. Miller1,2, O. Ciccarelli1,2 1NMR Research Unit, UCL Institute of Neurology, 2NIHR University College London Hospitals Biomedical Research Centre, London, United Kingdom Background: Previous MRI studies failed to find any strong correlation between clinical disability and the number of cord lesions seen on sagittal images.We have recently demonstrated that a quantitative measure of upper cervical cord lesion load(UCLL) from high in-plane resolution,axial phase sensitive inversion recovery(PSIR)images is associated with physical disability in MS at a single time point. Objectives: To measure UCLL in a progressive MS cohort at one year follow up and its association with physical disability. Methods: We recruited 18 secondary progressive(SP)(age 54,0+7,7;10F)and 13 primary progressive(PP)MS(age 52,5+10,7; 3F)patients.Physical disability was estimated at baseline and follow up using the expanded disability status scale(EDSS).All subjects had 3TMRI of their cervical cord at both time points. Scanning protocol included 3D-PSIR imaging, acquired in the axial plane,covering C2-C4,with a resolution of 0.5x0.5x3mm3. Lesions were seen as hypointense areas and outlined using a semiautomated method.To measure differences between MS and controls and changes from baseline to follow up we performed a t-test and calculated univariate correlations with disability using Spearman’s rank correlation. Results: At baseline SPMS patients had a higher UCLL than PPMS(p=0.03).After one year,although UCLL was still higher in SPMS than PPMS, this difference was not significant (p=0.06) and there was a significant increase of UCLL in both SPMSn(p< 0.001) and PPMS (p=0.007). In all patients together, a significant positive correlation was seen between UCLL and EDSS at baseline (p=0.004;R=0.53) and after one year (p=0.012;R=0.46). Thirteen of the 31 patients deteriorated clinically with an increase

in their EDSS (defined as an increase of 1.0 if baseline EDSS⩽5.0;0.5 if baseline EDSS>5.0); these patients exhibited a greater increase in UCLL during the year (UCLL increase: 0.171mm 3±0.163;27.4%,vs0.075mm 3±0.085;12.2%;p=0.02) compared with the 18 clinically stable patients. A significant positive correlation was seen between the change of UCLL and the change of EDSS in the whole cohort of patients(p=0.009;R=0.48). Conclusion: This longitudinal study demonstrated that the increase in cervical cord lesion load may be an important mechanism leading to progression of physical disability in progressive MS.The detection of significant change within one year suggests that this quantitative measure of cervical cord lesion load may be a sensitive endpoint in future trials in progressive MS. Disclosure Domenico Plantone: Nothing to disclose. Hugh Kearney: Nothing to disclose. Marios Yiannakas: Nothing to disclose. Floriana De Angelis: Nothing to disclose. In the past year, Alan Thompson has received honoraria and support for travel for consultancy from Biogen Idec and MedDay, honorarium for consultancy from Eisai, and honoraria and support for travel for lecturing from Serono Symposia International Foundation and Novartis. He received support for travel from the MS International Federation as Chair of their Medical and Scientific Advisory Board, from the International Progressive MS Alliance, as chair of their Scientific Steering Committee and from the National MS Society (USA) as member of their Research Programs Advisory Committee. He receives an honorarium from SAGE Publishers as Editor-in-Chief for Multiple Sclerosis Journal. David H Miller has received honoraria through payments to his employer, UCL Institute of Neurology, for Advisory Committee and/or Consultancy advice in multiple sclerosis studies from Biogen Idec, GlaxoSmithKline, Novartis, Merck, Chugai, Mitsubishi Pharma Europe and Bayer Schering Pharma. He has also received compensation through payments to his employer for performing central MRI analysis of multiple sclerosis trials from GlaxoSmithKline, Biogen Idec, Novartis, Apitope and Merck. O. Ciccarelli receives research grant support from the Multiple Sclerosis Society of Great Britain and Northern Ireland, the Department of Health Comprehensive Biomedical Centre, the International Spinal Cord Research Trust (ISRT) and the Engineering and Physical Sciences Research Council (EPSRC); she serves as a consultant for Novartis, Biogen and GE and payments are made to UCL Institute of Neurology. The Queen Square MS Centre at UCL Institute of Neurology is supported by the UK MS Society and UCL-UCLH Biomedical Research Centre. P442 Changes in cervical cord MRI metrics in a one-year followup study in early primary progressive multiple sclerosis N. Cawley1, C. Tur1, K. Abdel-Aziz1, T. Schneider1, B.S. Solanky1, C.A.M. Wheeler-Kingshott1, D.H. Miller1,2, A.J. Thompson1,2, O. Ciccarelli1,2 1Queen Square MS Centre, UCL Institute of Neurology, 2NIHR University College London Hospitals Biomedical Research Centre, London, United Kingdom


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Poster Session I, 21(S11) Introduction: There is a pressing need to develop imaging biomarkers in progressive MS that detect clinically relevant changes over time for use in neuroprotective clinical trials. We aimed to determine if spinal cord advanced imaging techniques,including q-space imaging (QSI),single voxel 1H-MR spectroscopy (MRS) and upper cervical cord cross sectional cord area (UCCA) showed significant changes over 1-year and if these changes are associated with disability progression over that time period. Methods: 24 patients with PPMS (13F, mean age 50.8yrs (SD 8.8),median EDSS 5),and 26 healthy controls (21F, mean age 42.1yrs (SD 12.3)) were studied at baseline.20 patients (10F) with PPMS and 18 healthy controls (13F) were followed-up at 1-year. All subjects underwent MRS, QSI and UCCA of the cervical cord at 3T at baseline and 1 year follow-up. Patients were clinically assessed with the expanded disability status scale (EDSS), grip strength, 9-hole peg test (9-HPT) and timed 25-foot walk test (TWT). Multiple regression models were used to assess changes in the clinical scores, differences in imaging measures between groups, and the association between MRI measures and clinical scores, always correcting for age and gender. Results: Patients progressed clinically over 1-year in the EDSS (median EDSS 6 (p< 0.001), z-TWT (p < 0.01) and z-9HPT (p< 0.008).All QSI-derived indices of perpendicular diffusivity, tNAA and UCCA measures were significantly different between patients and controls at 1-year follow-up (p values between 0.048-0.0001), however, only UCCA showed a significant change (decrease) from baseline: -2.86 (95% CI -4.35, -1.37). Patients had a greater decrease in tNAA and a greater increase in Creatine (Cr) over 1 year than controls, but these differences did not reach statistical significance. In patients, greater increases in Cr were associated with greater decreases in z-TWT (RC: -0.07 [95% CI: -0.16, -0.15], p< 0.001);greater decreases in tNAA showed a borderline association with greater decreases in z-TWT (RC 0.07 [-0.005, 0.14], p< 0.063). Conclusion: These findings demonstrate that among all MRI metrics, UCCA shows the greatest and most significant changes,indicating that development of atrophy in the spinal cord may be the most sensitive marker of axonal loss.However,changes in Cr (and to a less extent tNAA) seemed more sensitive to clinical decline, suggesting gliosis is an early pathological process in MS and may also be involved in disability progression. Disclosure Niamh Cawley-no disclosures. Carmen Tur-received a McDonald Fellowship (from the Multiple Sclerosis International Federation) in 2007, and has received an ECTRIMS post-doctoral research fellowship in 2015. She has also received honoraria and support for travelling from BayerSchering, Teva, Merck-Serono and Serono Foundation, Biogen, Sanofi-Aventis, Novartis, and Ismar Healthcare. Khaled Abdel-Aziz-no disclosures. Torben Schneider-no disclosures. Bhavana Solanky-no disclosures. C.A.M. Wheeler-Kingshott-serves as a consultant for Biogen and receives research support from the UK MS Society, UCL/UCLH NIHR BRC, EPSRC, ISRT, Wings for Life, New Zealand Brain Research Centre, Novartis, and Biogen. Professor David Miller-has received honoraria from Biogen Idec, Novartis, GlaxoSmithKline, and Bayer Schering, and research grant support for doing MRI analysis in multiple

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sclerosis trials sponsored by GlaxoSmithKline, Biogen Idec, and Novartis. Professor Alan Thompson-In the past year, Alan Thompson has received honoraria and support for travel for consultancy from Biogen Idec and MedDay, honorarium for consultancy from Eisai, and honoraria and support for travel for lecturing from Serono Symposia International Foundation, Novartis, TEVA and Remedica. He received support for travel from the MS International Federation as Chair of their Medical and Scientific Advisory Board, from the International Progressive MS Alliance, as chair of their Scientific Steering Committee and from the National MS Society (USA) as member of their Research Programs Advisory Committee. He receives an honorarium from SAGE Publishers as Editor-in-Chief for Multiple Sclerosis Journal. Professor Olga Ciccarelli-serves as a consultant for Biogen and General Electric and receives research support from the UK MS Society, UCL/UCLH NIHR BRC, and EPSRC. P443 Spinal cord atrophy as a primary outcome measure in primary progressive multiple sclerosis neuroprotective trials N. Cawley1, K. Abdel-Aziz1, T. Schneider1, D. Altmann1, C.A.M. Wheeler-Kingshott1, D.H. Miller1,2, A.J. Thompson1,2, O. Ciccarelli1,2 1Queen Square MS Centre, UCL Institute of Neurology, 2NIHR University College London Hospitals Biomedical Research Centre, London, United Kingdom Background: Spinal cord involvement in multiple sclerosis (MS) often results in progressive locomotor disability mainly due to axonal loss. Spinal cord atrophy reflects axonal loss but its measurements using MRI has been limited by poor reproducibility and responsiveness. In order to detect small changes longitudinally in upper cervical cord cross sectional cord area (UCCA), a highly reproducible method is required. We report a novel reproducible measure of UCCA in MS. The aim of this study is to measure spinal cord atrophy in a primary progressive MS (PPMS) cohort at one year follow-up, and to determine sample sizes required to demonstrate reduction of spinal cord atrophy as an outcome measure in a placebo-controlled trial for PPMS. Methods: We recruited 26 patients (11F, 15M) with PPMS, mean age 51.9yrs (SD 9.6) and 18 healthy controls (13F, 5M), mean age 42.4yrs (SD 12.6). Patients had a median EDSS of 5.0 at baseline. The 3T magnetic resonance imaging (MRI) protocol included an axially acquired fast field echo (FFE) sequence (0.5 x 0.5 x 5mm3) at both time points. Upper cervical cord cross sectional cord area was measured using the active surface model (ASM). Unpaired and paired t-tests were used to measure the differences between MS patients and controls and changes from baseline to follow-up. Sample sizes for given treatment effects and power were calculated using parameters estimated from the sample. Results: At baseline MS subjects had a smaller UCCA than controls (76.29mm2 +/- 9.33 vs 81.80mm2 +/- 8.13, p = 0.025). There was a significant progression of clinical disability in MS patients (p = 0.0001) and a significant decrease (p = 0.0001) in UCCA in patients over one year (2.77mm2 +/- 2.32). For a 12-month treatment trial, the minimum sample size per arm required to detect a 50% treatment effect, at 80% power was 55.


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Conclusion: Over a 12 month follow-up period, PPMS subjects had a significant decrease in UCCA when compared to controls. A reduction in UCCA was not detected in healthy controls. Spinal cord atrophy is a feasible and responsive outcome measure for placebo-controlled neuroprotective trials in PPMS. Disclosure Niamh Cawley - no disclosures. Khaled Abdel-Aziz - no disclosures. Torben Schneider - no disclosures. Dan Altmann - no disclosures. Claudia Wheeler-Kingshott - serves as a consultant for Biogen and receives research support from the UK MS Society, UCL/ UCLH NIHR BRC, EPSRC, ISRT, Wings for Life, New Zealand Brain Research Centre, Novartis, and Biogen. Professor David Miller-has received honoraria from Biogen Idec, Novartis, GlaxoSmithKline, and Bayer Schering, and research grant support for doing MRI analysis in multiple sclerosis trials sponsored by GlaxoSmithKline, Biogen Idec, and Novartis. Professor Alan Thompson- In the past year, Alan Thompson has received honoraria and support for travel for consultancy from Biogen Idec and MedDay, honorarium for consultancy from Eisai, and honoraria and support for travel for lecturing from Serono Symposia International Foundation, Novartis, TEVA and Remedica. He received support for travel from the MS International Federation as Chair of their Medical and Scientific Advisory Board, from the International Progressive MS Alliance, as chair of their Scientific Steering Committee and from the National MS Society (USA) as member of their Research Programs Advisory Committee. He receives an honorarium from SAGE Publishers as Editor-in-Chief for Multiple Sclerosis Journal. Professor Olga Ciccarelli-serves as a consultant for Biogen and General Electric and receives research support from the UK MS Society, UCL/UCLH NIHR BRC, and EPSRC. P444 Evidence of progressive demyelination and neurodegeneration in chronic MS lesions: DTI study A. Klistorner1,2, C. Yiannikas2, J. Parratt2, C. Wang2, Y.T. Liu2, S.L. Graham1, M.H. Barnett2 1Macquarie University, 2Sydney University, Sydney, NSW, Australia Background: While acute inflammatory demyelination is a major cause of axonal loss in MS, chronic inflammation in the existing lesions and diffuse inflammatory changes in NAWM may also contribute to progressive axonal damage. Diffusion tensor imaging (DTI) is sensitive technique used to assess the microstructural organisation of white matter tracts. Earlier studies linked axial diffusivity (AD) to axonal loss and radial diffusivity (RD) with myelin content. However, both parameters can potentially (and sometimes paradoxically) be affected by crossing, branching, merging or kissing fibers. We recently demonstrated that using optic radiation (OR) tract-specific analysis partially alleviates this problem. Aims: To evaluate longitudinal changes of diffusivity indices in lesional and non-lesional white matter in optic radiation of the MS patients in an attempt to gain better understanding of the evolution of the disease.

Method: 34 RRMS subjects (age: 40.9+/-12.5, disease duration: 5.4+/-3.0 y), who demonstrated T2 FLAIR lesions within the OR were enrolled. OR was identified using probabilistic tractography. Voxel-based analysis of AD and RD within lesions and nonlesional (i.e. not traversing lesions) fibers was performed. Result: 28 patients had lesions in both ORs, therefore, total of 62 ORs were analysed. Since in several patients lesions occupied the entire cross-section of the OR, non-lesional fibers were analysed only in 49 ORs. Average OR lesion volume was 608+/-575 mm3. Both RD and AD demonstrated much higher values within the lesions compare to non-lesional fibers (p< 0.001 for both). There was moderate, but significant (p< 0.001) increase of lesional AD and RD during follow-up period (1.58+/-0.16 vs 1.61+/-0.16 and 0.93+/-0.12 vs 0.96+/-0.13 respectively). AD also demonstrated increase in non-lesional OR fibers, albeit on a much lesser scale (1.182+/-0.05 vs 1.193+/-0.06, p< 0.001), while increase of RD did not reached level of significance (0.746+/-0.05 vs 0.751+/0.05, p=0.06). The largest relative increase was observed in lesional RD (2.4%), followed by lesional AD (1.7%), with non-lesional fibers showing 1.0% and 0.6% increase for AD and RD respectively. Conclusion: Significant increase of AD and RD in chronic lesions suggests ongoing inflammatory and demyelinating activity accompanied by axonal loss. In addition, small, but significant increase of AD in non-lesional fibers indicates ongoing neurodegenerative changes in NAWM. Disclosure Study was funded by NMSS garnt and “Save Neuron” grant from Novartis Alexander Klistorner-nothing to disclose Con Yiannikas-nothing to disclose John Parratt-nothing to disclose Chenyu Wang-nothing to disclose Michael H Barnett-nothing to disclose Yeying Tina Liu-nothing to disclose Stuart L Graham-nothing to disclose

P445 An Argentinian cohort of individuals with radiologically isolated syndrome M.I. Gaitán, M.C. Ysrraelit, M.P. Fiol, J. Correale Neurology, FLENI, Buenos Aires, Argentina Background: Subjects with MRI abnormalities suggestive of multiple sclerosis (MS) were recently defined as individuals with Radiologically Isolated Syndrome (RIS). Clinical demographics and predictors of radiological or clinical progression were described mostly from European and North America cohorts. Objective: The aim of this study was to describe radiological and clinical demographics of a single center cohort in South America. Methods: Radiological data was obtained from subjects fulfilling the 2009 criteria for RIS. Individuals were scanned in a 1.5 or 3T scanner. A radiologist and an MS specialist read images. An MS specialist performed clinical evaluation and ordered complementary studies. Results: The cohort consisted of 24 subjects, 3 male and 21 female, mean age 40 years old (range 25-60). Baseline brain MRI


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Poster Session I, 21(S11) was performed for the following reasons: headache (10), endocrine disorders (4), seizures (2), peripheral vertigo (2), non-specific symptoms (2), essential tremor (2), transient global amnesia (1), neurofibromatosis control (1). Longitudinal imaging data were acquired for 20 individuals and the mean follow up time was 3.5 years. MRI dissemination in time occurred in 90% of the subjects and the mean time to radiological progression was 2.5 years. All the subjects that presented enhancing lesions on the initial MRI, developed dissemination in time. Only three patients evolved with a clinically define relapse, interestingly, all of them experienced an acute transverse myelitis as first clinical event. The mean conversion time was 2.5 years. All of the three cases that converted to clinical disease had enhancing lesions in the initial brain MRI. Lumbar punctures were performed in 14 out of 24 subjects, oligoclonal bands were positive in 85% of the cases and 83% of this group developed new MRI lesions. Eleven patients underwent visual evoked potentials, 64% of them had a prechiasmatic defect. Seven out of 18 subjects with cervical MRI had spine lesions, 71% of them had future radiological progression. Discussion: As in other studies the most frequent reason of initial brain MRI was headache, also, enhancement in the first brain MRI was predictor of disease clinical conversion and radiological progression. The percentage of radiological progression was higher than in other reports and the percentage of clinical conversion was lower. This study may contribute to improve the understanding of the natural course and evolution of RIS. Disclosure This study was supported by Raul Carrea Institute of Neurology, FLENI. Dr. Gaitan has received reimbursement for developing educational presentations from Merck-Serono Argentina, Genzyme Argentina and Novartis Argentina and travel/ accomodations stipends from Biogen-Idec Argentina, Teva-Tuteur Argentina and Merck-Serono Argentina. Dr. Ysrraelit has received reimbursement for developing educational presentations and travel/accomodations stipends from Merck-Serono Argentina, Biogen-Idec Argentina, Genzyme Argentina, Bayer Inc, Novartis Argentina and TEVA-Tuteur Argentina. Dr. Fiol has received reimbursement for developing educational presentations from Merck-Serono Argentina, Biogen-Idec Argentina, Genzyme Argentina, Bayer Inc and Novartis and travel/accomodations from Merck-Serono Argentina, BiogenIdec Argentina, Genzyme Argentina, Bayer Inc, Novartis and TEVA-Tuteur Argentina. Jorge Correale is a board member of Merck-Serono Argentina, Biogen-IdecLATAM, and Merck-Serono LATAM, and Genzyme global. Dr. Correale has received reimbursement for developing educational presentations for Merck-Serono Argentina, MerckSerono LATAM, Biogen-Idec Argentina, Genzyme Argentina, and TEVA-Tuteur Argentina as well as professional travel/ accommodations stipends. P446 Cognitive correlates of the brain functional connectome abnormalities in pediatric patients with multiple sclerosis M. Filippi1,2, E. De Meo1, L. Moiola2, A. Ghezzi3, P. Veggiotti4, R. Capra5, M.P. Amato6, L. Vacchi1, A. Fiorino2, L. Pippolo3,

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M.C. Pera4, M. Copetti7, G. Comi2, A. Falini8, M.A. Rocca1,2 1Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 2Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, 3Multiple Sclerosis Center, Ospedale di Gallarate, Gallarate, 4Fondazione ‘Istituto Neurologico Casimiro Mondino’, Pavia, 5Multiple Sclerosis Center, Spedali Civili of Brescia, Brescia, 6Department of Neurology, University of Florence, Florence, 7Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, 8Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy Background: Up to 10% of MS patients experience their first attack during childhood. Objectives: To investigate abnormalities of functional organization of large-scale brain networks (connectome) using restingstate (RS) fMRI and graph theory in pediatric MS patients and their contribution to cognitive impairment. Methods: Fifty-four pediatric MS patients and 27 age- and sexmatched healthy controls (HC) were studied. Patients with abnormal performance in ⩾3 tests of a neuropsychological battery for children were classified as cognitively impaired (CI). Functional connectivity between 160 cortical and subcortical brain regions was estimated using a bivariate correlation analysis. Betweengroup differences of global and local network connectivity metrics were investigated. Results: Global network metrics (network degree, global efficiency, hierarchy, path length and assortativity) did not differ between pediatric MS patients and HC as well as between cognitively preserved (CP) and CI MS patients. Compared to HC, MS patients showed limited differences in hub distribution with the formation of hubs (not present in HC) in the left cerebellar lobule VI and supplementary motor area and the loss of one hub in the left medial frontal gyrus (MFG). Compared to HC, CP MS patients harboured additional hubs in the left middle temporal gyrus and occipital lobe. Conversely, CI MS patients lost hubs in the right precuneus, right occipital lobe, bilateral thalamus and cerebellum crus I. They also showed additional hubs in the left precuneus and right superior temporal gyrus. Compared with HC and CI, CP MS patients showed a decreased nodal degree of the left MFG, bilateral insular regions and right caudate nucleus. They also showed increased nodal degree in the right superior parietal, pre- and postcentral gyri. The direct comparison between CP and CI MS patients showed a decreased nodal degree of the left MFG in the first group. Conclusions: The global topology of functional network organization is relatively preserved in pediatric MS patients. Functional abnormalities of local network reorganization play a major role in determining cognitive impairment in these patients. Disclosure Partially supported by a grant from Italian Ministry of Health (GR-2009-1529671) and Fondazione Italiana Sclerosi Multipla (FISM2011/R/19). E De Meo, L Moiola, P Veggiotti, L Vacchi, A Fiorino, L Pippolo, MC Pera, M Copetti, and A Falini have nothing to disclose. A Ghezzi has served on scientific advisory boards for Merck Serono, Biogen Idec Teva Pharmaceutical Industries Ltd; has


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received speaker honoraria from Merck Serono, Biogen Idec, Bayer Schering Pharma, and Novartis, Serono Symposia International; served as a consultant for Novartis; and receives research support from Sanofi-Aventis, Biogen Idec, and Merck Serono. R Capra received consulting fees from Novartis, Merck Serono, BiogenIdec and lecture fees from Bayer, BiogenIdec, Genzyme, and Sanofi-Aventis. MP Amato serves on scientific advisory boards for Biogen-Idec, Merck Serono, Bayer Schering and Sanofi Aventis and receives research support and honoraria for speaking from Biogen-Idec, Merck Serono, Bayer Schering and Sanofi Aventis. M. Filippi has received compensation for consulting services and/ or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis. G. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. M.A. Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed. P447 Volume estimation of subcortical grey matter structures in multiple sclerosis: comparison between NeuroQuant® and FIRST D. Pareto1, F.X. Aymerich1,2, J. Sastre-Garriga3, C. Auger1, M. Tintoré3, X. Montalban3, À. Rovira1 1Section of Neuroradiology and MR Unit (Department of Radiology), University Hospital Vall d’Hebron, 2Automatic Control (ESAII), Universitat Politècnica de CatalunyaBarcelona Tech (UPC), 3Multiple Sclerosis Centre of Catalonia (Cemcat), Department of Neurology-Neuroimmunology, University Hospital Vall d’Hebron, Barcelona, Spain Background: Volume estimation of subcortical grey matter structures is becoming a field of interest in multiple sclerosis (MS). The goal of this study was to compare volume estimations for subcortical structures obtained with the NeuroQuant® and FIRST in a cohort of clinically isolated syndrome (CIS) patients. Material and methods: 115 CIS patients were analyzed. Structural images were acquired on a 3.0 T system using a sagittal 3D T1-weighted gradient-echo (MPRAGE) sequence (TR=2300 ms, TE=3000 ms, voxel size=1.0x1.0x1.2mm3). Volumes for subcortical structures were obtained with Neuroquant® and FIRST -following the described methodology; total intracranial volumes were also obtained. The Intraclass Correlation Coefficient (ICC) between the two estimated volumes (NeuroQuant® and FIRST) was calculated for each of the following structures: (right and left) thalamus, caudate, putamen, pallidum, hippocampus and amygdala. The total intracranial volume was also considered. For each structure, the percentage difference of the volume calculated with FIRST in relation to the volume estimated by NeuroQuant® was also calculated. Results: The ICC was below 0.45 for the following structures: pallidum (ICC left=0.25, ICC right=0.27), amygdala (ICC left=0.29, ICC right=0.35) and total intracranial volume

(ICC=0.44). The ICC ranged between 0.45 and 0.65 for the caudate (ICC left=0.46, ICC right=0.61) and thalamus (ICC left=0.55, ICC right=0.64); and it was higher than 0.65 for the hippocampus (ICC left=0.67, ICC right=0.76) and putamen (ICC right=0.79, ICC left=0.83). FIRST estimated volumes were systematically lower than the volumes obtained with NeuroQuant®, except for the pallidum (both right and left), where FIRST volumes were on average 70% higher than NeuroQuant® volumes. FIRST underestimations ranged between 1% and 12% for (both right and left) thalamus, caudate, putamen, hippocampus and total intracranial volume; and between 20% and 28% for right and left amygdala. Conclusions: Structures showing largest disagreement between the two methods were the smallest ones (pallidum and amygdala). For the other subcortical grey matter regions, the agreement on the estimated volumes was moderate to strong. Disclosure Novartis supported software analysis. Deborah Pareto has received speaking honoraria from Novartis and Genzyme. F. Xavier Aymerich has nothing to disclose. Jaume Sastre-Garriga has received compensation for consulting services and speaking honoraria from Merck-Serono, BiogenIdec, Teva, Sanofi-Aventis and Novartis. Cristina Auger has received speaking honoraria from Novartis and Genzyme. Mar Tintoré has received compensation for consulting services and speaking honoraria from Bayer-Schering, Merck-Serono, Biogen-Idec, Teva, Sanofi-Aventis, and Novartis. Xavier Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall. Alex Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, and has received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Bracco, MerckSerono, Teva Pharmaceutical Industries Ltd, OLEA Medical, Stendhal, Novartis and Biogen Idec.

P448 Patterns of regional gray matter and white matter atrophy progression contributing to clinical deterioration in MS: a 5-year tensor-based morphometry study P. Preziosa1,2, M.A. Rocca1,2, E. Pagani1, S. Mesaros3, J. Drulovic3, M. Filippi1,2 1Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 2Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy, 3Clinic of Neurology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia Background: Irreversible tissue loss occurs from the earliest phases of MS and is correlated with clinical disability and cognitive impairment. Objectives: To investigate the regional patterns of gray matter (GM) and white matter (WM) atrophy progression over a


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Poster Session I, 21(S11) five-year follow up in MS patients and their association with clinical and cognitive deterioration. Methods: Clinical (EDSS and phenotype changes), neuropsychological (Rao’s battery) and brain MRI (dual-echo and 3D T1-weighted sequences) assessment were performed at baseline (T0) and after 5 years (Y5) from 66 MS patients with the main disease clinical phenotypes and 10 controls. At T0 and Y5, measures of brain lesion volume and regional brain atrophy were obtained. Tensor-Based Morphometry (TBM) and SPM12 was used to assess longitudinal changes of GM and WM volumes in MS patients after 5 years and according to the presence of neurologic deterioration, phenotype modification and cognitive worsening. Results: At Y5, 36/66 (55%) MS patients showed a significant disability worsening, 14/66 (21%) evolved to a worse clinical phenotype and 18/63 (29%) had a worsening of cognitive functions. At baseline, compared to controls, MS patients showed a widespread pattern of GM and WM atrophy. At Y5, MS patients developed further GM atrophy of several deep GM nuclei including the thalami, putamen and caudate nuclei, as well as of several fronto-temporo-parieto-occipital regions and the cerebellum. Progression of atrophy of the main WM tracts was also detected. Compared to stable MS patients, those with clinical and cognitive worsening showed a left-lateralized pattern of GM and WM atrophy, involving the thalamus, caudate nucleus and putamen, several fronto-temporo-parieto-occipital regions, the cerebellum and the majority of WM tracts. Conclusions: GM and WM atrophy of relevant brain regions occurs in MS after 5 years. A different vulnerability of the two brain hemispheres to irreversible structural damage may be among the factors contributing to clinical and cognitive worsening in these patients.

the gold standard. This is due to the fact that not all lesions are correctly identified employing automated techniques. Objectives: Aim of this study was to develop a method for MS lesion segmentation based on Dual-Echo MRI sequence and a priori information. This ensures an improved classification of lesions and a considerable gain in time required for the segmentation. Methods: Brain dual-echo MRI acquired on a 3.0 T Philips Achieva scanner was obtained in 10 MS patients used for the training set and 20 MS patients used for the validation (lesion load 0.3÷9 ml). Lesions were identified by an expert neurologist on the Proton Density-weighted (PD-w) images with marker points, and these were used to expand the segmentation of lesions constrained by intensity similarity and edge detection. An intensity threshold was defined for each marker using a curve extracted after a training process on manual segmented lesions. A new half-way contrast image was obtained averaging the PD-w and the T2-W image, to take advantage of both images tissue contrasts, and this was high-pass filtered to enhance lesion edges. Finally a more robust threshold was estimated using lesion values distribution to refine the segmentation according to these new threshold values. The segmentation obtained was compared to the manual one. Results: These results are the mean metrics evaluated for all patients: Dice Similarity Coefficient (DSC) = 0.8, Mean Square Error (MSE) = 0.2 ml, True Positive Fraction (TPF) = 0.9, False Positive Fraction (FPF) = 0.1 and False Negative Fraction (FNF) = 0.2. Conclusions: Lesion segmentation performed with this method revealed high similarity with the ground truth. FPF and FNF indicated low misclassification of lesions. Moreover process time was drastically reduced of about 96 minutes for the maximum lesion load considered.

Disclosure

Disclosure

P. Preziosa, E. Pagani, S. Mesaros, J. Drulovic have nothing to disclose. M.A. Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed. M. Filippi has received compensation for consulting services and/ or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis.

This study has been partially supported by the “INNI” grant from FISM (zFISM-13-S-1). L. Storelli, P. Preziosa, E. Pagani have nothing to disclose. M.A. Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed. M. Filippi has received compensation for consulting services and/ or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis.

P449 A method for segmentation of multiple sclerosis lesions on magnetic resonance images L. Storelli1, M.A. Rocca1,2, P. Preziosa1,2, E. Pagani1, M. Filippi1,2 1Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 2Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy Background: The identification and segmentation of focal hyperintense lesions on Magnetic Resonance Images (MRI) are essential steps in multiple sclerosis (MS) patients. Despite many automatic methods for MS lesion segmentation have been proposed in the last 15 years, manual segmentation is still considered

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P450 MSmetrix: accurate untrained method for longitudinal lesion segmentation S. Jain1, D.M. Sima1, A. Maertens1, S. Van Huffel2, F. Maes3, D. Smeets1 1R&D, icometrix, 2Department of Electrical Engineering-ESAT, STADIUS Center for Dynamical Systems, Signal Processing and Data Analytics, 3Department of Electrical Engineering-ESAT, PSI Medical Image Computing, KU Leuven, Leuven, Belgium We describe the untrained MS lesion segmentation method MSmetrix and its results on the longitudinal MS lesion segmentation challenge organised at the ISBI 2015 conference. The organisers provided 5 training and 15 test datasets, consisting of


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T1-weighted, T2-weighted, FLAIR and PD-weighted MRIs of MS patients scanned 3-5 times with an interval of approximately one year on a 3T MR scanner. Competing methods were evaluated independently by the organisers based on expert segmentations with respect to accuracy and ability to track lesion evolution. MSmetrix takes as input 3D T1-weighted and 3D FLAIR brain images acquired from an MS patient. The images are preprocessed and co-registered before executing the main loop of the algorithm consisting of three iterated steps: brain segmentation, lesion segmentation, and lesion filling. The T1-weighted image is segmented into grey matter (GM), white matter (WM) and cerebrospinal fluid (CSF) using a probabilistic model and the expectation-maximisation algorithm. Lesion segmentation is then performed using the FLAIR image with GM, WM and CSF segmentations as priors. The lesion segmentation is used to fill in the lesions in the T1-weighted image with WM intensities. These three steps are repeated until there is no significant change in the lesion segmentation. Unlike training based methods, MSmetrix makes no prior assumptions on the lesion size or shape and is scanner independent. We applied MSmetrix on the test datasets of the ISBI challenge without prior tuning on the training datasets. MSmetrix´s normalised Dice score relative to inter-rater metrics was 0.94, which was the same as the winning (trained) method. The average linear correlation of changes in lesion volumes between successive time points for MSmetrix was 0.33, which was the highest correlation after the winning method (0.55). These results illustrate that MSmetrix is an accurate untrained method for longitudinal MS lesion segmentation, requiring only 3D T1 and 3D FLAIR and outperforming other state-of-the-art untrained methods.

Methods: Three-dimensional (3D) T1-weighted magnetization prepared rapid gradient echo (MPRAGE) scans of 51 healthy subjects were included into this study. Each subject was scanned twice on two different scanner platforms at 1.5 T and 3 T field strengths (total=4 scans) within a period of a few weeks. In total, 204 images were downloaded from the Alzheimer´s Disease Neuroimaging Initiative (ADNI) repository. The data was acquired at 50 different imaging centers. The two scans were acquired back-to-back during a single imaging session. Since no atrophy is expected the percentage volume change between the two scans can be used as a measure of error. For each patient intrascanner (1.5 T vs. 1.5 T and 3 T vs. 3 T scan) and inter-scanner errors (first 1.5 T vs. first 3 T scan) were determined. Results: The 5%-, 50%- and 95%-percentiles of the absolute errors for total brain volume in the intra-scanner setting were [0.05, 0.24, 1.28] for SPM12, [0.16, 1.93, 14.38] for SIENAX, and [0.01,0.15, 0.9] for SIENA. The minimum percentage volume difference necessary to detect a significant (p=0.05) volume change between two measurements in the same subject is therefore 1.28% for SPM12, 14.38% for SIENAX, and 0.9% for SIENA. The 5%, 50% and 95% percentiles of the absolute errors for total brain volume in the inter-scanner setting were [0.21, 1.74, 5.44] for SPM12, [0.61, 4.96, 19.67] for SIENAX, and [0.20,1.57,4.97] for SIENA. Conclusions: SIENA appears better suited than SPM12 for longitudinal measurements in the intra-scanner setting. SPM12 has a much lower variability than SIENAX and hence might be better suited for cross-sectional measurements. All methods feature a significantly higher variability when baseline and follow-up scans were acquired on different devices with different field strengths.

Disclosure

Disclosure

Saurabh Jain: nothing to disclose Diana M Sima: nothing to disclose Anke Maertens: nothing to disclose Sabine Van Huffel: nothing to disclose Frederik Maes: nothing to disclose Dirk Smeets: nothing to disclose

Roland Opfer: nothing to disclose Timo Kepp : nothing to disclose Per Suppa: nothing to disclose Lothar Spies: nothing to disclose Christine Eggert: nothing to disclose S. Schippling has received research grants from Biogen Idec, Bayer Healthcare and Genzyme and consulting/speaker fees from Bayer Healthcare, Biogen Idec, Merck Serono, Novartis Pharma, TEVA and Genzyme/Sanofi-Aventis.

P451 Assessing intra- and inter- scanner variability of automated brain volumetry using SPM12, SIENA, and SIENAX R. Opfer1, T. Kepp1, P. Suppa1, L. Spies1, C. Egger2, S. Schippling2 1jung diagnostics GmbH, Hamburg, Germany, 2Department of Neurology, University Hospital Zurich, Zurich, Switzerland Background: Brain volume and brain volume loss measures are newly recognized biomarkers of neurodegeneration in multiple sclerosis (MS). Statistical Parametric Mapping (SPM), SIENA and its cross-sectional version SIENAX are well established tools to quantify brain volume as well as brain volume changes. Objectives: To compare intra- and inter-scanner variability of SPM12, SIENA, and SIENAX. For each tissue compartment and each method the impact of measurement variability on longitudinal volumetric studies was assessed. Minimum percentage volume differences necessary to detect a significant volume change between two measurements in the same subject were determined.

P452 Functional network imbalance underlies severity of cognitive impairment in multiple sclerosis M.M. Schoonheim1, T.M. Wassenaar1, A.J.C. Eijlers1, K.A. Meijer1, B.M.J. Uitdehaag2, F. Barkhof3, A.M. Wink3, J.J.G. Geurts1 1Anatomy and Neurosciences, 2Neurology, 3Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands Background: Cognitive dysfunction in multiple sclerosis (MS) is highly prevalent, but still poorly understood. Previously we have shown a cognitively relevant network imbalance in MS using eigenvector centrality mapping (ECM). In this study, we expanded on these results by dividing the group into different severities of cognitive impairment.


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Poster Session I, 21(S11) Objective: To identify regions with altered functional network centrality that relate to different severities of cognitive impairment in early MS. Method: An early inception cohort of 162 MS patients (six years post-diagnosis, 108 women) and 48 matched healthy controls (HC, 29 women) underwent resting-state fMRI scanning. Eigenvector centrality mapping (ECM) was applied to quantify the centrality of brain regions. Cognitive testing included an expanded brief repeatable battery (BRB-N). Patients were subdivided into three cognitive groups: severely cognitively impaired (SCI, scoring < -2 SD on at least two domains, n=30), mildly cognitively impaired (MCI, scoring between -1.5 and -2 SD on at least two domains, n=21) and cognitively preserved (CP, scoring better than MCI, n=111). Differences in ECM values between MS groups and controls were assessed by permutation-based cluster wise testing, correcting for age, sex and education. Results: All MS groups displayed decreased centrality compared to HCs in posterior parts of the brain corresponding to the ventral stream. This area included only occipital parts in CP, but were more widespread (i.e. more laterally and anteriorly) in MCI, and involved the hippocampus only in SCI. Additional decreases in centrality were seen in the right precentral gyrus and bilateral postcentral gyri in respectively MCI and SCI. Areas with increased centrality were observed in MCI and SCI only. Both groups showed increases in centrality in the posterior cingulate, left frontal pole and right frontal operculum. MCI only showed additional bilateral thalamic increases in centrality. In SCI, increases were additionally seen in the right frontal pole, precuneus, bilateral angular gyri and the right inferior frontal gyrus. Conclusion: Decreased centrality was seen in all MS groups, but was more extensive in groups with cognitive dysfunction, involving the hippocampus only in SCI. Similarly, increased centrality was seen in MCI and was most extensive in SCI. No additional changes were found in CP. These findings support the hypothesis of a more severe network imbalance in patients with cognitive dysfunction. Disclosure Dr. Schoonheim is sponsored by the Dutch MS Research foundation, grant nr 13-820, and has served as a consultant for Genzyme, Novartis and Excemed. Mr. Wassenaar has nothing to disclose. Mr. Eijlers is sponsored by the Dutch MS Research foundation, grant nr 14-358e. Ms. Meijer has nothing to disclose. Prof. Uitdehaag has served as a consultant for Biogen Idec, Novartis, MerckSerono, and Danone Research. Prof. Barkhof serves on the editorial boards of Brain, European Radiology, the Journal of Neurology, Neurosurgery & Psychiatry, Neurology, Multiple Sclerosis and Neuroradiology and has served as a consultant for Bayer-Shering Pharma, Sanofi-Aventis, Biogen-Idec, TEVA pharmaceuticals, Genzyme, Merck-Serono, Novartis, Roche, Synthon, Jansen Research and Lundbeck. Dr. Wink has nothing to disclose. Prof. Geurts is an editor for Multiple Sclerosis Journal, associate editor for BMC Neurology, and serves on the editorial boards of Neurology and MS International; he is a member of the scientific advisory board of the Dutch MS Research Foundation, of the MS Society of Canada and a scientific steering committee member of

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the International Progressive MS Alliance; he has served as a consultant for MerckSerono, Novartis, Biogen Idec, Genzyme and Teva Pharmaceuticals. P453 Evaluation of [18F]GE-180 PET imaging in relapsingremitting multiple sclerosis patients: a first-in-human study W. Trigg1, C. Buckley1, K. Heurling1, P. Sherwin1, D. Brooks1, S. Sridharan2, R. Hinz2, J. Crouch3, M. Lawlor3, S. Amodeo3, R. Paulseth3, K. Gulenchyn3 1Imaging R and D, GE Healthcare, Amersham, 2University of Manchester, Manchester, United Kingdom, 3St Joseph’s Hospital, Hamilton Health Sciences, Hamilton, ON, Canada Introduction: Multiple sclerosis (MS) is characterised by demyelination, but it is known from pathology studies that inflammation, evidenced by infiltrating immune cells and activated microglia in normal appearing white matter (NAWM), is also present at different disease stages. The effects of inflammation on MS progression are not yet understood; positron emission tomography (PET) offers the opportunity to monitor these effects and thus aid patient stratification and guide therapy selection, adding to the information already available from MRI techniques. The 18 kDa translocator protein (TSPO) is upregulated in activated microglia, which are present in inflammatory lesions and NAWM in MS. [11C]-(R)-PK11195 is a TSPO-PET ligand which is known to show localisation and extent of inflammation in many brain diseases, including MS, but suffers from a poor signal to noise ratio (SNR) and short (20 minutes) half-life. [18F]GE-180 is a novel TSPO-PET ligand which has shown improved SNR and lower non-specific binding than [11C]-(R)-PK11195 in preclinical models. Here, we present initial results from a phase 1 study in relapsing-remitting MS (rrMS) and healthy control subjects (HVs). Methods: HVs and rrMS subjects were assessed for binding status. One non-binder in each group was included. Subjects underwent T1 pre and post gadolinium enhanced MRI scans and T2 scans additionally. 90 minute dynamic [18F]GE-180 PET scans were performed typically within 1 month. PET and T1 pre-contrast MR images were co-registered in the software package PMOD, and the Hammers atlas was applied to acquire standardised uptake values (SUVs) for regions of interest (ROIs). Selected areas of T2 hyperintensity were defined manually to give MS lesion SUVs. A cortical composite grey matter (GM) region was chosen as reference for SUVRs. Results: No Gd-enhancing lesions were identifiable from T1 post-contrast MRIs. With [18F]GE-180, whole WM uptake (SUVRGM) was slightly higher in rrMS than HVs, while a lesionrich periventricular (PV) area yielded SUVRs which were approximately 10% higher in rrMS than HVs. PET-defined lesions in rrMS showed an elevation of 20 - 40% compared to HVs. Conclusion: Preliminary results suggest that [18F]GE-180 is able to identify areas of inflammation in PET images which are nonGd-enhancing in T1. Disclosure The data presented are from a GE Healthcare sponsored phase 1 clinical trial.


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William Trigg, Chris Buckley, Kerstin Heurling, David Brooks and Paul Sherwin are or were employees of GE Healthcare. Sujata Sridharan receives partial funding for her PhD studies from GE Healthcare and is Supervised by Rainer Hinz who has nothing to disclose. MaryLou Lawler, Janet Crouch, Karen Gulenchyn, Shelley Amodeo and J.E. Rick Paulseth are employees of Hamilton Health Sciences where the studies were carried out. The studies were funded by GE Healthcare. P454 Use of cortical thickness to detect localized damage in the somatomotor cortex in MS: relation with clinical disability M. Tonietto1,2, M. Calabrese1, E. Silvestri2, A. Morra3, M. Castellaro2, S. Monaco1, A. Bertoldo2 1Department of Neurological and Movement Sciences, University of Verona, Verona, 2Department of Information Engineering, University of Padova, 3Neuroradiology Unit, Euganea Medica, Padova, Italy Background: Cortical pathology in MS can be either diffuse or localized and it is associated with clinical disability. Cortical thickness (CT) is often used to quantify diffuse cortical damage by calculating the mean across whole brain or across regions. Objectives: In this study we tested various descriptive statistic measures of CT in the somatomotor cortex and we investigated their relationship with clinical disability. Methods: 3D-T1 weighted MPRAGE (1mm3 isotropic resolution) was acquired on 102 MS patients (41±9 y) using a Philips Achieva 1.5T MRI scanner. Images were analysed using the ANTs cortical thickness pipeline which provided CT maps. Somatomotor cortex was parcel into 8 regions: left and right precentral gyrus (lPreCG, rPreCG), supplementary motor area (SMA), left and right inferior postcentral gyrus (lInfPostCG, rInfPostCG), left and right superior postcentral gyrus and paracentral lobule. For each region, mean, median, standard deviation, mean of the 1st percentile (m1%) and maximum of CT were calculated. The Kurtzke pyramidal Functions Score (pFS) was used to evaluate the motor disability. Patients showed a pFS of 1.3 ± 1.0 (range 0 - 4). Correlation between descriptive statistic measures of CT with pFS were assessed using partial correlation controlling for age. Regression analysis was performed to evaluate the percentage of explained pFS variance for each measure. Results: Mean and median CT showed similar values and they were inversely correlated with pFS only in the SMA (R=-0.35, p=0.0004), while m1% CT was inversely correlated with pFS for all the 8 brain regions considered with correlation coefficients ranging from r=-0.21 (p=0.037) in the lInfPostCG to r=-0.34 (p=0.0006) in the rPreCG. Other measures were not correlated with pFS. When entered in a regression analysis, mean CT explained 13% of pFS variance (p=0.002), m1% CT 15% (p=0.001) and their combination 23% (p=0.0002), indicating that their contribute to motor disability is mostly independent. Similar results were obtained using the mean of the 5th percentile of CT. Conclusions: m1% CT of somatomotor cortex, is a predictor of clinical disability in MS mostly independent from mean CT. This might be explained as mean CT is related with diffuse cortical damage while m1% CT might be expression of more localized

cortical damages (i.e. focal lesions in the normal appearing grey matter). Future studies will tell if m1% CT can be an earlier predictor of clinical disability than mean CT. Disclosure MT, ES, AM, M Castellaro, SM, AB: nothing to disclose M Calabrese: has received consulting and/or lecture fees and/ot travel grants from Bayer Schering, Biogen Idec, Genzyme, Novartis and Teva P455 Abnormal cerebral venous haemodynamics in patients with MS S. Kolbe, J. Vilsten Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, Australia Background and aims: Cerebral veins within white matter are a common site of peripheral immune cell infiltration in MS. These veins display a unique blood oxygen level dependent (BOLD) signal that is highly correlated across the white matter and can be identified using functional MRI and spatial independent components analysis (ICA). This preliminary study aimed to characterise the haemodynamics of the cerebral veins in healthy controls (HC) and people with MS. We hypothesised that inflammatory mediated changes in the vascular endothelium could lead to abnormal venous haemodynamics. Methods: 16 patients (7m/9f, age=22-54yrs, dd=3-5yrs) and 13 HC (6m/7f, age=26-42) were imaged at 3T using a BOLDweighted echo planar imaging sequence during rest (440x1.4s repetitions, voxel size=2.5x2.5x2.5mm3), and a T2-weighted sequence for lesion identification. White matter regions displaying BOLD signal characteristics of cerebral veins (narrow peak power band 0.06< 0.08Hz) were identified in HC using spatial ICA (MELODIC, FSL). IC maps were registered to standard space and averaged to create a probabilistic anatomical atlas of the venous signal. This map was then used to sample venous BOLD signals from all subjects. BOLD signals were normalised to Z-scores and analysed using multi-taper power spectral decomposition in MATLAB®. Average power in the peak frequency range for patients was compared to HC using a Student’s t-test, and to logarithmically transformed lesion volume using Pearson correlation analysis. Results: In HC, white matter venous BOLD signals displayed a phasic pattern with a narrow peak power (mean±SD=0.074± 0.008Hz). This signal did not correlate with arterial BOLD signals. In patients, average power in the peak range (2.51±0.66) was significantly lower than for HC subjects (3.20±0.76, p=0.015) and did not correlate with lesion volume (R=-0.18). Conclusions: These results indicate that MS is associated with dysregulated BOLD signal dynamics in deep cerebral veins that are not associated with total inflammatory lesion load. Future studies should assess this phenomenon in relation to the spatial distribution of lesions. Disclosure Scott Kolbe: salary support from the National Health and Medical Research Council of Australia (#APP1054147) Julian Vilsten: nothing to disclose


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Poster Session I, 21(S11) P456 Hippocampal-DMN disconnectivity in MS is related to WM lesions and contributes to clinical symptoms L. Vacchi1, M.A. Rocca1,2, E. Pravatà1,3, P. Valsasina1, M. Radaelli2, B. Colombo2, C. Gobbi4, G. Comi2, A. Falini5, M. Filippi1,2 1Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 2Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy, 3Department of Neuroradiology, 4Department of Neurology, Neurocenter of Southern Switzerland, Civic Hospital, Lugano, Switzerland, 5Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy Background: The hippocampus is part of the default-mode network (DMN) and is functionally hit early in the course of MS. Objectives: We hypothesized that white matter focal lesions may contribute, through a disconnection mechanism, to hippocampal dysfunction and hippocampal-related clinical deficits in MS. To test this, we assessed the relationship between abnormalities of hippocampal resting state (RS) functional connectivity (FC) with brain T2 lesion volumes and presence and severity of depression. Methods: Structural and RS fMRI images were acquired from 69 cognitively intact MS patients and 42 matched healthy controls (HC). In patients, depression was quantified using the MontgomeryAsberg Depression Rating Scale. Hippocampal RS FC was assessed using a seed-voxel approach. SPM8 was used for between-group comparisons and analysis of correlation between RS FC abnormalities with clinical and structural MRI variables. Results: Compared to HC, MS patients experienced a significant atrophy of the whole brain and left hippocampus (p< 0.001) as well as a distributed pattern of decreased RS FC between the hippocampi and several cortical-subcortical regions. Reduced hippocampal RS FC with the DMN was strongly correlated to higher T2 lesion volume as well as to disease duration, severity of depression and disability. Conclusions: In cognitively preserved MS patients, brain focal WM lesions influence the functional integration of the hippocampus to other brain regions of the DMN, leading to a disconnection syndrome. Such a disruption of hippocampal RS FC contributes to the occurrence of depression and to clinical disability. Disclosure This work has been supported by a grant from Italian Ministry of Health (GR-2008-1138784) and Fondazione Italiana Sclerosi Multipla (FISM2012/R/8). L Vacchi, E. Pravatà, P. Valsasina, M. Radaelli, B. Colombo, C. Gobbi, A. Falini have nothing to disclose. M.A. Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed. G. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. M. Filippi has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and

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receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis.

P457 Phase-sensitive inversion recovery improves the detection of cerebellar cortical lesions and discloses their correlation with disability in multiple sclerosis A. Favaretto1, A. Lazzarotto1, D. Poggiali1, G. Rolma2, F. Causin2, F. Rinaldi1, P. Perini1, P. Gallo1 1Multiple Sclerosis Centre - Veneto Region (CeSMuV), Department of Neurosciences, 2Neuroradiology Unit, University of Padova, Padova, Italy Background: Cerebellar pathology plays a major role in determining physical and cognitive disability in multiple sclerosis (MS). The demonstration of cortical lesions (CL) in the cerebellum by magnetic resonance imaging (MRI) is hampered by technical and anatomical constrains. Thus, the correlation between MRI-detectable focal lesions in the cerebellar cortex and the accumulation of cerebellar-related disability remains undefined. Objective: To investigate the occurrence of cerebellar CL and white matter lesions (WML) and their correlation with cerebellarrelated disability by combining double inversion recovery (DIR) and phase-sensitive inversion recovery (PSIR) images. Material and methods: 40 MS patients [10 clinically isolated syndrome (CIS)/early relapsing-remitting (eRRMS, < 3 years of disease duration), 24 RRMS, 6 secondary progressive (SPMS)], having a wide range of disability (Expanded Disability Status Scale, EDSS) and disease duration, were enrolled in the study. DIR and PSIR images were obtained with a 3T MRI (Philips). Results: CL could be detected in 26/40 (65%) patients by DIR (5/10 CIS/eRRMS, 15/24 RRMS, 6/6 SPMS) and in 31/40 (77.5%) patients by PSIR (7/10 CIS/eRRMS, 18/24 RRMS, 6/6 SPMS). PSIR disclosed a significantly higher number of CL compared to DIR in the whole cohort (+87.2%, p< 0.0001) and in RRMS and SPMS patients (+90%, p=0.0008; +82.1%, p=0.002). WML were detected only in 48% of the patients and 17% had CL but not WML. A strong correlation was found between the number of CL and the cerebellar functional system score of EDSS with both DIR (r=0.69, p< 0.0001) and PSIR (r=0.72, p< 0.0001). The correlation analysis between WML and CL observed by PSIR resulted low (r=0.54; p= 0.003) confirming the relative independence of grey matter and white matter cerebellar lesions. By comparing PSIR and DIR images we observed that DIR failed to detect some CL, especially small lesions located near the sigmoid sinus, some purely intracortical lesions and CL with mild hyperintense signal. PSIR also showed a better morphological characterization of both CL and WML. Conclusions: We demonstrate that cerebellar CL can be disclosed by means of PSIR in the majority of MS patients, including those at clinical onset with no symptom/sign of cerebellar dysfunction, and strongly correlate with the cerebellar EDSS. Thus, the observation of CL in the cerebellum of MS at clinical onset might be useful for prognostic and therapeutic aims. Disclosure Dr. Alice Favaretto has received honoraria from Novartis, Teva and Almirall.


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Dr. Andrea Lazzarotto has nothing to disclose. Dr. Davide Poggiali has nothing to disclose. Dr. Giuseppe Rolma has nothing to disclose. Dr. Francesco Causin has nothing to disclose. Dr. Francesca Rinaldi has received honoraria from Biogen Idec, MerkSerono and Teva. Dr. Paola Perini has has received honoraria from Biogen Idec/ Elan, Merck Serono, Sanofi-Aventis and Teva; has been a consultant for Biogen Idec, Merck Serono and Teva. Prof. Paolo Gallo has received honoraria from Bayer Schering, Biogen Idec/Elan, Merck Serono, Novartis, Sanofi-Aventis and Teva; has been a consultant for Bayer Schering, Biogen Idec, Genzyme, Merck Serono and Novartis; has received research support from Bayer, Biogen Idec/Elan, Merk Serono, Genzyme and Teva; and has received research grant from the University of Padova, Veneto Region of Italy, the Italian Association for Multiple Sclerosis, the Italian Ministry of Public Health. P458 The role of spinal cord MRI as an adjunct to brain MRI at 3T in defining “no evidence of disease activity” in patients with multiple sclerosis S. Tummala1, T. Singhal2, V.V. Oommen1, F. Khalid1, G. Kim1, R. Bakshi3 1Laboratory for Neuroimaging Research, Brigham & Women’s Hospital, Harvard Medical School, 2Neurology, Brigham and Women’s Hospital, Harvard Medical School, 3Laboratory for Neuroimaging Research, Brigham & Women’s Hospital, Partners MS Center, Harvard Medical School, Boston, MA, United States Background: Approved disease modifying therapies (DMTs) for multiple sclerosis (MS) are only partially effective. There is an interest in monitoring patients for “no evidence of disease activity” (NEDA) to guide DMT management decisions, such as switching between agents. While surveillance brain MRI is commonly used as a tool to define NEDA, the role of routine spinal MRI is unknown. Objective: Evaluate the diagnostic yield of brain and spinal cord 3T MRI in the evaluation of NEDA over a one year period. Methods: This was a longitudinal study of 61 consecutive patients [3 clinically isolated syndromes, 56 relapsing-remitting, 2 secondary progressive, 50 (82%) women, age (mean±SD) 44.1±8.6 years, disease duration 10.5±9.1 years, Expanded Disability Status Score 1.5±1.6]. During the observation period, 56 patients (92%) were receiving DMT [monotherapy with intramuscular interferon-beta (IFNB)-1a (n=20), subcutaneous IFNB-1a (n=11), IFNB-1b (n=1), glatiramer acetate (n=20), natalizumab (n=2), or mycophenolate mofetil (n=1), or dual therapy with IFNB-1a and mycophenolate mofetil (n=1)]. The MRI protocol (3T GE Signa) included T2-weighted fluid-attenuated inversion recovery (FLAIR) images of the brain and T2-weighted fast spin echo images of the cervical and thoracic spine. Follow-up MRI was performed at 12.4±1.3 (range 9.7-15.2) months. NEDA was defined as the absence of new or enlarging T2 lesions at follow-up. Results: Thirty-nine patients (64%) had NEDA by brain MRI, only one of whom (3%) had spinal activity. Thus, thirty-eight (62%) had NEDA by brain and spine MRI. Fifty-five (90%) had

NEDA by spinal cord MRI, 17 (31%) of whom had brain activity. Five (8%) had brain and spine MRI changes, and 17 (28%) had brain MRI changes only. Of the 22 (36%) with brain MRI changes, 5 (23%) had spine MRI changes. Conclusions: In this cohort, we showed a low diagnostic yield of spinal cord MRI as an adjunct to brain MRI at 3T in monitoring MS patients for NEDA over one year. Disclosure Dr. Bakshi received consulting fees from AbbVie, Alkermes, Biogen, Novartis, and Questcor and research support from Biogen, Merck-Serono, Novartis, Genzyme and Teva. The other authors have nothing to disclose. Study supported by: Grant #RG3705A1 from the National Multiple Sclerosis Society (R. Bakshi).

P459 Prediction of conversion to secondary progression phase in multiple sclerosis M. Castellaro1, A. Bertoldo1, A. Morra2, S. Monaco3, M. Calabrese3, O. Doyle4 1Department of Information Engineering, University of Padova, 2Neuroradiology Unit, Euganea Medica, Padova, 3Department of Neurological and Movement Sciences, University of Verona, Verona, Italy, 4Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom Background: Multiple Sclerosis (MS) is characterized by two clinical phases. Relapsing-Remitting (RR) MS patients are known to convert to secondary progressive (SP) at a rate of 66% after 15 years. While most of the therapies are active in the RR phase, the SP phase is characterized by relentless disability accumulation. Early prediction of the conversion to the SP phase would be helpful to take adequate countermeasures when these are still incisive. Objectives: In this study, we used machine learning to assess if brain-imaging data can be used to make individual predictions regarding the conversion to SP. Methods: 70 MS patients, 35 SPMS and 35 RRMS, were retrospectively enrolled in the study. Inclusion criteria included the same imaging protocol on a Philips Achieva 1.5T MRI scanner.; being RRMS at the time of MRI examination and having at least 4 years of follow up after the MRI. RRMS patients were also selected to match both gender and age of SPMS. The protocol consisted of 3D-T1 weighted MPRAGE and Diffusion Tensor Imaging (DTI) with 15 directions at a b-value of 800 s mm−2. 3D-T1 images were analysed using the Advanced Normalization Tools (ANTs) cortical thickness (CT) script and provided voxelwise CT maps co-registered to the MNI Atlas. Fractional Anisotropy (FA), Mean Diffusivity (MD) and Mode of the anisotropy (MO) maps obtained with FSL were normalized to the FA template. FA template was then thresholded to obtain the most superficial WM boundary (FA between 0.2 and 0.3). This modest border of WM was used for prediction because it could reflect the damage of leuco-cortical MS lesion.


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Poster Session I, 21(S11) To predict subsequent conversion from baseline scans, Gaussian process classifiers were trained and tested on each modality using 10-fold cross-validation. Predictive performance of the classifiers was assessed using area under the receiver operator characteristic curve (AUC) with AUC of 1 indicating a perfect classifier and 0.5 a classifier randomly guessing. Results: Prediction of transition to SP from RR was achieved with an AUC of 0.5 for CT, 0.67 for FA, 0.71 for MD and 0.72 for MO. Conclusions: We found that, for a linear classifier, the DTI metrics have a higher predictive power than the CT data. The MD and MO limited to the most superficial WM resulted in the highest predictive performance suggesting that these metrics are potentially useful in predicting conversion to SP from RR. Disclosure Castellaro Marco: nothing to disclose Calabrese Massimiliano: has received consulting and/or lecture fees and/or travel grants from Bayer Schering, Biogen Idec, Genzyme, Novartis and Teva Morra Aldo: nothing to disclose Bertoldo Alessandra: nothing to disclose Doyle Orla: nothing to disclose P460 FMRI correlates of sustained attention in pediatric multiple sclerosis M.A. Rocca1,2, E. De Meo1,2, L. Moiola2, A. Ghezzi3, P. Veggiotti4, R. Capra5, M.P. Amato6, L. Vacchi1, A. Fiorino2, L. Pippolo3, M.C. Pera4, G. Comi2, A. Falini7, M. Filippi1,2 1Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 2Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, 3Multiple Sclerosis Center, Ospedale di Gallarate, Gallarate, 4Fondazione ‘Istituto Neurologico Casimiro Mondino’, Pavia, 5Multiple Sclerosis Center, Spedali Civili of Brescia, Brescia, 6Department of Neurology, University of Florence, Florence, 7Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy Background: A large proportion of patients with pediatric MS has cognitive deficits, with a prominent involvement of linguistic abilities in addition to memory, attention and executive functions. Previous resting state (RS) functional connectivity (FC) studies have shown that in pediatric MS patients, cognitive dysfunction is associated to structural and functional abnormalities of posterior core regions of the default mode network. In addition, cognitively impaired pediatric MS patients showed decreased RS FC of the precuneus of the working memory network. Objectives: To assess fMRI abnormalities during a sustained attention task in pediatric MS patients and their correlations with cognitive dysfunction. Methods: fMRI scans were acquired in 58 pediatric MS patients and 14 matched healthy controls (HCs) during the Conners’ Continuous Performance Test (CPT). Patients with ⩾ 2 abnormal tests at neuropsychological evaluation were classified as cognitively impaired (CI). Results: Twenty patients were CI. With increasing task demand, all participants showed activations of bilateral parietal regions,

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middle frontal gyrus, supplementary motor area (SMA), right lingual gyrus and precuneus. Compared to HC, MS patients had an increased activation of left insula, anterior cingulate cortex and right inferior frontal gyrus, and a reduced activation of right precuneus and paracentral lobule. Compared to HC and CI, CP MS patients showed increased activation of left thalamus, inferior temporal and lingual gyri. Compared to the other two groups, CI MS patients had increased recruitment of the bilateral superior medial frontal gyrus, left SMA and right inferior frontal gyrus and cerebellum. They also experienced a reduced activation of the right postcentral gyrus (PCG). Better performance during CPT correlated with increased activity if the right precuneus and PCG, while worse CPT performance correlated with increased activity in frontal regions. Conclusions: During and attentive task, CI and CP pediatric MS patients recruited different brain area with increasing task demand. The increased fMRI activity in frontal regions seen in CI MS patients is likely to be a maladaptive mechanism, associated with cognitive impairment. Disclosure Partially supported by a grant from Italian Ministry of Health (GR-2009-1529671). E. De Meo, L. Moiola, P. Veggiotti, L. Vacchi, A. Fiorino, L. Pippolo, M.C. Pera, A. Falini have nothing to disclose A Ghezzi has served on scientific advisory boards for Merck Serono, Biogen Idec Teva Pharmaceutical Industries Ltd; has received speaker honoraria from Merck Serono, Biogen Idec, Bayer Schering Pharma, and Novartis, Serono Symposia International; served as a consultant for Novartis; and receives research support from Sanofi-Aventis, Biogen Idec, and Merck Serono.R Capra received consulting fees from Novartis, Merck Serono, BiogenIdec and lecture fees from Bayer, BiogenIdec, Genzyme, and Sanofi-Aventis. MP Amato serves on scientific advisory boards for Biogen-Idec, Merck Serono, Bayer Schering and Sanofi Aventis and receives research support and honoraria for speaking from Biogen-Idec, Merck Serono, Bayer Schering and Sanofi Aventis. M.A. Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed. G. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. M. Filippi has received compensation for consulting services and/ or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis. P461 7T MP2RAGE for detection of cortical lesions V.V. Sethi, B.E. Dewey, P. Sati, D.S. Reich TNU, NINDS, NIH, Bethesda, MD, United States Background: Cortical gray matter lesions (CGML) are integral to the pathogenesis of multiple sclerosis(MS) but suboptimally detected, particularly the subpial . We investigate MP2RAGE ultra-high resolution, isotropic acquisitions at 7T, together with a


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surface-based analysis technique to map T1 values(T1), to improve the detection & distribution of CGML. Methods: 10 patients (progressive MS) & 2 healthy controls(HC) provided informed consent & underwent 7T imaging( Siemens Magnetom, 32-channel receive coil,single channel volume transmit coil(Nova Medical)). 4 back-to-back MP2RAGE sequences were acquired axially(0.5x0.5x0.5mm, α1/α2 4°/5°, TI1/TI2 0.8/2.7sec, TR 6 sec, in 10.5 min). Images were coregistered & using the transform, the inline T1 map images were aligned & a voxel-wise median image was created. CGML were marked on the median uniform image using JIM v7.0; lesions were classified as IC(intracortical), LC(leukocortical) and juxtacortical(JC; lesions abutting but not entering the cortex). Lesion volume(LV) was computed & masks overlaid on surface-reconstructed T1 maps (3 patients). Results: Pure subpial lesions were not visible, but the superficial components of Type II & Type IV lesions were clearly visible. Intracortical lesion subtypes(Type II, IV) and CGML abutting but not entering the WM were identified. The mean(SD) LV(cu.mm) was 151(209), 413(328) & 229(337) for IC, LC, and JC lesions respectively; controls had no JC lesions, IC &LC LV was 7(3) & 189(135) respectively. For patients, lesional T1(msec) was progressively higher(abnormal) from the cortical surface towards WM; lower in IC lesions(1802(31)) vs. LC(1999(211))(p< 0.05), & JC(2057(246)(p< 0.05). For HC, T1 was 1739(113) & 1756(104) for IC & LC lesions. Reconstructed cortical T1 maps showed a frontotemporal CGML distribution. Marked CGML colocalized with regions of apparent T1 abnormality. Conclusions: Ultra-high resolution MP2RAGE(NEX=4) detects CGM abnormalities, allowing identification of some subtypes of intracortical lesions. Controls showed no JC lesions and a paucity of IC lesions, suggesting that findings in patients were in many instances not artifactual. A combination of MP2RAGE and T1 mapping can help define the topographical distribution of CGML at varying cortical depths. Further work will study the relationship between T1 value patterns, lesion subtypes, and measures of clinical disability. Separate, short acquisitions improve patient compliance and decrease artifacts. Disclosure Varun V Sethi: nothing to disclose. Blake E Dewey: nothing to disclose. Pascal Sati: nothing to disclose. Daniel S Reich: nothing to disclose. P462 Improved framework for tractography reconstruction of the optic radiation E. Martinez-Heras1, F. Varriano2, V. Prĉkovska1, C. Laredo3, M. Andorrà1, E.H. Martinez-Lapiscina1, A. Calvo4, E. Lampert1, P. Villoslada1, A. Saiz1, A. Prats-Galino2, S. Llufriu1 1Center of Neuroimmunology, Service of Neurology, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 2Laboratory of Surgical NeuroAnatomy (LSNA), Facultat de Medicina, 3Comprehensive Stroke Center, Department of Neuroscience, Institut d Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 4Medical Imaging Platform, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

Background: The optic radiation (OR) is one of the major components of the visual system and a key structure at risk in white matter diseases such as multiple sclerosis (MS). However, it is challenging to perform track reconstruction of the OR using diffusion MRI due to a sharp change of direction in the Meyer’s loop and the presence of kissing and crossing fibers along the pathway. Objectives: We aimed to provide a highly precise and reproducible framework for tracking the OR from thalamic and visual cortex masks. Methods: The framework combined the generation of probabilistic streamlines by high order fiber orientation distributions estimated with constrained spherical deconvolution and an automatic post-processing based on anatomical exclusion criteria (AEC) to compensate for the presence of anatomically implausible streamlines. Specifically, those ending in the contralateral hemisphere, cerebrospinal fluid or grey matter outside the visual cortex were automatically excluded. We applied the framework to two distinct high angular resolution diffusion-weighted imaging (HARDI) acquisition protocols on one cohort, comprised of ten healthy volunteers and five MS patients. Results: Compared with histological mask, the OR reconstruction into a template (OR-TCT) was highly precise (percentage of voxels within the OR-TCT correctly defined as OR), ranging from 0.71 to 0.83. The sensitivity (percentage of voxels in histological reference mask correctly defined as OR in OR-TCT) ranged from 0.65 to 0.81 and the accuracy (measured by F1 score) was 0.73 to 0.77 in healthy volunteers. When AEC was not applied the precision and accuracy decreased. The absolute agreement between both HARDI datasets measured by the intraclass correlation coefficient was 0.73. Conclusion: This improved framework allowed us to reconstruct the OR with high reliability and accuracy independently of the acquisition parameters. Moreover, the reconstruction was possible even in the presence of tissue damage due to MS. This framework could also be applied to other tracts with complex configuration. Disclosure Eloy Martínez-Heras: nothing to disclose. Federico Varriano: nothing to disclose. Vesna Prčkovska: nothing to disclose. Carlos Laredo: nothing to disclose. Magí Andorrà: nothing to disclose. Elena H. Martinez-Lapiscina: nothing to disclose. Anna Calvo: nothing to disclose. Erika Lampert: nothing to disclose. Pablo Villoslada: received compensation for advisory from Roche, Novartis and Bionure Incorporation. Albert Saiz: received compensation for advisory and speaking from Bayer-Schering, MerckSerono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd and Novartis. Alberto Prats: nothing to disclose. Sara Llufriu: nothing to disclose. P463 Microstructural thalamic and cortico-thalamic correlates of cognitive impairment in pediatric multiple sclerosis M.A. Rocca1,2, E. De Meo1,2, L. Moiola2, A. Ghezzi3, P. Veggiotti4, R. Capra5, M.P. Amato6, L. Vacchi1, A. Fiorino2,


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Poster Session I, 21(S11) L. Pippolo3, M.C. Pera4, M. Copetti7, G. Comi2, A. Falini8, M. Filippi1,2 1Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 2Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, 3Multiple Sclerosis Center, Ospedale di Gallarate, Gallarate, 4Fondazione ‘Istituto Neurologico Casimiro Mondino’, Pavia, 5Multiple Sclerosis Center, Spedali Civili of Brescia, Brescia, 6Department of Neurology, University of Florence, Florence, 7Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, 8Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy Background: A large proportion of pediatric MS patients experience cognitive deficits. Objectives: We assessed the role of microstructural abnormalities of thalamic connectivity defined regions and their cortical connections to cognitive impairment in pediatric MS patients. Methods: Using a 3.0 T scanner, dual-echo, 3D T1-weighted and diffusion tensor (DT) MRI scans were acquired from 44 pediatric MS patients and 26 gender- and age-matched healthy controls (HC). Patients underwent an extensive neuropsychological assessment. Thalamic connectivity defined regions (CDRs) were segmented on the basis of their cortical connectivity using Diffusion Tractography-Based Parcellation. Betweengroup differences of CDRs and cortico-thalamic tract DT MRI metrics were assessed using Mann-Whitney test. The relationships of DT MRI metrics of thalamic CDR and cortico-thalamic tract with neuropsychological and conventional MRI measures were tested using the Spearman’s Rank correlation coefficient. A random forest analysis was run to identify the best imaging predictor of global cognitive impairment and deficits of specific cognitive domains. Results: Thalamic volume did not differ between pediatric MS patients and HC. The analysis of DT MRI abnormalities of the thalamus showed that, compared to HC, MS patients had lower factional anisotropy (FA) and higher mean diffusivity (MD) of the temporal-CDR (T-CDR) bilaterally, and higher FA of the right occipital-CDR (O-CDR). Compared to HC, MS patients also showed: 1) decreased FA of the bilateral occipital (O-T) and temporal (T-T) cortico-thalamic tracts and left frontal (F-T) tract; and 2) increased MD of all right tracts and left F-T, O-T, posterior parietal (PP-T) and T-T tracts. The best predictor of global cognitive performance was MD value in the right PP-T tract. Impairment of attention/information processing speed domain was predicted by right PP-T tract MD, followed by MD of the right motor cortico-thalamic tract and left T-CDR; visual spatial memory impairment was mainly associated to MD of the right T-CDR. Finally verbal fluency was associated with MD of the right PP-T followed by FA of the T-CDR. Conclusions: A cortico-thalamic disconnection and microstructural abnormalities in the thalami contribute to explain cognitive impairment in pediatric MS patients. Disclosure Partially supported by a grant from Italian Ministry of Health (GR-2009-1529671) and Fondazione Italiana Sclerosi Multipla (FISM2011/R/19 & FISM 2012/R/8).

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E. De Meo, L. Moiola, P. Veggiotti, L. Vacchi, A. Fiorino, L. Pippolo, M.C. Pera, M. Copetti, A. Falini have nothing to disclose. A Ghezzi has served on scientific advisory boards for Merck Serono, Biogen Idec Teva Pharmaceutical Industries Ltd; has received speaker honoraria from Merck Serono, Biogen Idec, Bayer Schering Pharma, and Novartis, Serono Symposia International; served as a consultant for Novartis; and receives research support from Sanofi-Aventis, Biogen Idec, and Merck Serono.R Capra received consulting fees fromNovartis,Merck Serono, BiogenIdec and lecture fees fromBayer, BiogenIdec, Genzyme, and Sanofi-Aventis. MP Amato serves on scientific advisory boards for Biogen-Idec, Merck Serono, Bayer Schering and Sanofi Aventis and receives research support and honoraria for speaking from Biogen-Idec, Merck Serono, Bayer Schering and Sanofi Aventis. M.A. Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed. G. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. M. Filippi has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis. P464 White and grey matter network evolution in patients with early relapsing-remitting multiple sclerosis V. Fleischer1, A. Gröger2, A. Droby2, P. Kolber2, E. Reuter2, F. Zipp2, S. Groppa2 1Focus Program Translational Neurosciences (FTN), Rhine Main Neuroscience Network (rmn2), Department of Neurology, University Medical Center of the Johannes-Gutenberg University Mainz, 2Focus Program Translational Neurosciences (FTN), Rhine Main Neuroscience Network (rmn2), Department of Neurology, University Medical Center of the JohannesGutenberg University Mainz, Germany, Mainz, Germany Background and aim: The pathology of multiple sclerosis consists of inflammatory demyelination and neuronal injury, which occur early in the disease; yet, remission phases indicate repair. Whether and how the central nervous system maintains and regains its homeostasis and how brain networks respond to diffuse inflammatory processes in the very early phase of the disease is not known. The goal of this study was to characterise the reorganization of white and grey matter networks from onset. Methods: 138 relapsing-remitting multiple sclerosis patients (93 females; mean age 33.9±10.3 years) were investigated using 3T MRI and classified into six groups by disease duration (< 6 months, 6-12 months, 12-18 months, 18-24 months, 24-48 months and 48-96 months). Network reorganization was analysed with the aid of graph theoretical approaches based on the connectivity pattern derived from diffusion tensor imaging with probabilistic tractography for white matter and from voxelbased morphometry and the regional volume correlation matrix for grey matter.


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Results: In the first year of the disease, white matter networks were found to evolve to a structure of increased modularity [F(5, 137) = 2.562, p < 0.05], i.e. with specialized local communities and strong internal connections but sparse long-range paths. Furthermore, we observed changes in regional connectivity, as shown by increased local efficiency [F(5, 137) = 3.058, p < 0.05] and clustering ([F(5, 137) = 2.466, p < 0.05] but no clinical decline. The analysis of grey matter networks showed a complementary increase in modularity (r = 0.85, p < 0.05). This modified connectivity pattern mainly involved the cerebellum, cingulum and temporo-parietal region. As the disease progresses, the pattern of WM and GM dynamics diverges. Conclusion: Our data suggest that network functionality in patients with relapsing-remitting multiple sclerosis is maintained at the beginning of the disease through a structural adaptation with increased modular connectivity and long-range disconnection like in maturation. Modularity could become a promising marker of ongoing disease dynamics. Grey and white matter network analysis provides important connectivity fingerprints of the early disease course and might be applied in clinical practice and therapeutic trials. Disclosure Vinzenz Fleischer: nothing to disclose Adriane Gröger: nothing to disclose Amgad Droby: nothing to disclose Pierre Kolber: nothing to disclose Eva Reuter: nothing to disclose Frauke Zipp has received research grants from Teva, Merck Serono, Novartis and Bayer as well as consultation funds from Teva, Merck Serono, Novartis, Bayer Healthcare, Biogen Idec Germany, ONO, Genzyme, Sanofi-Aventis and Octapharma. Her travel compensation has been provided for by the aforementioned companies Sergiu Groppa: nothing to disclose P465 23Na-MRI reveals sodium accumulation in skin of patients with relapsing-remitting multiple sclerosis K. Huhn1, P. Linz2, F. Pemsel1, A. Waschbisch1, D.-H. Lee1, C. Kopp1, M. Uder3, J. Titze4, D.N. Müller5, R.A. Linker1 1Department of Neurology, 2Interdisciplinary Centre for Clinical Research, Nikolaus-Fiebiger-Centre for Molecular Medicine, 3Department of Radiology, Friedrich-Alexander-University, Erlangen, Germany, 4Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, United States, 5Experimental and Clinical Research Center, Charité, Berlin, Germany Background: Nutritional factors like sodium chloride intake may play an important role in the pathogenesis of multiple sclerosis (MS). Recently, a high-salt diet was shown to induce pathogenic Th17 cells thus worsening the disease course in an animal model of MS. To further investigate the relation between systemic salt load and autoimmune inflammation in MS in vivo, we analysed sodiumchloride accumulation in the skin and calf muscles by sodium magnetic-resonance-imaging (23Na-MRI) techniques in relapsingremitting MS (RRMS) patients versus healthy controls (HC).

Methods: 23Na-MRI of skin and muscle of the calf was applied using specific sodium coils and post-processing techniques. The first set of experiments comprised 10 male patients with relapsing-remitting MS (RRMS) independently of immunmodulatory therapy and 10 healthy controls (HC) matched for age. Sodium concentrations (in mM) and water content (in arbitrary units (A.U.)) were calculated correlating signal intensities of tissue with those of standard solutions. Statistics were performed using Mann-Whitney test with p < 0.05 or p < 0.01 as levels of significance. Results: All 20 subjects had similar body weight (mean ± SD: MS 76.8 ± 4.1 kg; HC 74.9 ± 9.8 kg) and levels of systolic blood pressure (MS 127.1 ± 7.8; HC 123.3 ± 10.9 mmHg; p = 0.413). 23Na-MRI of the skin showed increased sodium accumulation (18.8 ± 2.1 mM vs. 16.8 ± 2.0; p < 0.05, tissue signal relative to standard) and higher water content (0.10 ± 0.03 A.U. vs. 0.07 ± 0.01; p < 0.01) in RRMS patients as compared to HC. No difference between both groups was seen upon comparing sodium and water concentrations in triceps surae and peroneal muscles. Conclusion: 23Na-MRI revealed a higher sodium accumulation in the skin but not in calf muscles of MS patients. At the date of presentation, analyses will comprise another set of 20 individuals to further elucidate the association between salt load and salt driven autoimmune inflammation in RRMS. Disclosure The study was supproted by a grant of Novartis Pharma. KH, PL, FP, AW, DHL, CK, MU, JT, DM and RL: nothing to disclose. P466 Sodium (23Na) MRI of acute and chronic tissue changes in multiple sclerosis P. Eisele1, S. Konstandin2,3, M. Griebe1, K. Szabo1, M.E. Wolf1, A. Alonso1, A. Ebert1, C. Rossmanith1, M.G. Hennerici1, L.R. Schad2, A. Gass1 1Department of Neurology, Universitätsmedizin Mannheim, 2Computer Assisted Clinical Medicine, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, 3MR-Imaging and Spectroscopy, Faculty 01 (Physics/Electrical Engineering), University of Bremen, Bremen, Germany Background: Sodium magnetic resonance imaging (MRI) is a new technique that is sensitive to demonstrate tissue damage in multiple sclerosis (MS) indicated by increased sodium concentration. Recently several studies have characterised acute MS lesions with conventional and diffusion-weighted MRI (DWI). In particular it has been shown that early lesions may show a transient reduction of the apparent diffusion coefficient (ADC). We were interested in sodium abnormalities in particular in the early phases of lesion development. Objectives: To quantify total sodium concentration (TSC) in acute and chronic MS lesions with a focus on hyperacute lesions with reduced diffusion. Methods: 23Na MR and 1H MR imaging was performed in 69 MS patients and 10 healthy controls (HC) on a clinical 3T whole-body scanner (Magnetom TIM Trio, Siemens Healthcare, Erlangen,


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Poster Session I, 21(S11) Germany). Quantitative assessment of TSC and ADC levels within lesions, normal-appearing white matter (NAWM) and normalappearing grey matter (NAGM) was performed. In 6 patients serial MRI was performed (on admission, after 3-5 days, after 7-10 days, and after four weeks). Results: TSC in the NAWM and the NAGM in MS patients was significant higher compared to HC (NAGM: 37,84 ± 3,61 mM vs 32,76 ± 0,90 mM, p-value < 0,01; NAWM: 28,55 ± 1,90 mM vs 22,60 ± 1,57 mM, p-value < 0,01). In MS lesions, TSC was significant higher in T1 hypointense lesions (43,96 ± 4,97 mM), than in T1 isointense lesions (34,93 ± 3,72 mM) while contrast-enhancing lesions (51,62 ± 5,37 mM) showed the highest sodium levels. Acute lesions with reduced diffusion showed TSC (29,82 ± 1,52 mM) at the level of the NAWM. On follow-up MRI, in lesions with reduced diffusion subsequent increase of ADC and TSC values occurred along with signs of the development of vasogenic edema and contrast-enhancement, while TSC values in initially contrast-enhancing lesions remained stable. After four weeks, TSC values decreased along with resolution of contrast-enhancement and vasogenic edema. Conclusions: Our data demonstrate that sodium MRI is a sensitive marker of tissue damage and blood brain barrier (BBB) integrity. It is interesting to note that acute lesions showed near normal sodium signal at the time of ADC reduction and the highest values along with the opening of the BBB. This information on the evolution of early MS lesions could be a differentiating feature that might also be considered in therapeutic decision making. Disclosure Dr. Eisele has received travel expenses from Bayer Health Care. Dr. Konstandin reports no disclosures. Dr. Griebe reports personal fees from Biogen Idec. Prof. Szabo has received financial support for research from Merck Serono. Dr. Wolf reports personal fees from Biogen Idec. Dr. Alonso reports no disclosures. Dr. Ebert reports no disclosures. Christina Rossmanith reports no disclosures. Prof. Hennerici reports no disclosures. Prof. Schad reports no disclosures. Prof. Gass has received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Bayer Schering, Biogen Idec, Merck Serono, Novartis and TEVA Neurosciences. P467 Topography of metabolic abnormalities over the entire brain using voxel-wise statistical mapping of fast 3D-MRSI Proof of concept on multiple sclerosis M. Donadieu1, Y. Le Fur1, A. Maudsley2, A. Lecocq1, S. Gherib1,3, E. Soulier1, S. Confort-Gouny1, F. Pariollaud1,3, M.-P. Ranjeva1,3, J. Pelletier1,3, M. Guye1, W. Zaaraoui1, B. Audoin1,3, J.-P. Ranjeva1 1CRMBM-CEMEREM, UMR CNRS 7339 Aix Marseille Université, Marseille, France, 2Department of Radiology, Miller School of Medicine University of Miami, Miami, FL, United States, 3Department of Neurology, Timone University Hospital, Marseille, France

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Objectives: Voxel-based whole brain metabolic statistical mapping is applied to characterize, for the first time throughout the entire brain, the topography of brain metabolic abnormalities in multiple sclerosis (MS). Methods: Weighted mean combination of two 3D echo planar spectroscopic imaging (EPSI) acquired in the AC-PC and the AC-PC+15° axial planes was performed to obtain high quality metabolite maps covering the whole brain for five metabolites: N-acetyl aspartate (NAA), glutamate-glutamine (Glx), creatinephosphocreatine (tCr), choline (Cho) and myo-inositol (m-Ins). After spatial normalization, maps from 16 Relapsing-Remitting MS patients (median disease duration=5.1 years, range [3.3-13.5]; median EDSS=1, range [0-4]) and 16 matched controls were compared using statistical mapping analyses to determine the topography of metabolic abnormalities. Probabilistic demyelinated T2 lesion maps and grey matter (GM) atrophy maps were generated. Results: In patients, significant decreases in NAA and Glx reflecting neuronal dysfunction were observed in prefrontal regions, motor system, bilateral thalami and mesial temporal lobes. Diffuse increases in m-Ins reflecting glial activation were observed inside the white matter in temporal-occipital lobes, both in demyelinated lesions and in the normal appearing white matter. Increases in tCr associated to increase in glial cell activation were observed in the occipital lobe, both in white and grey matter. Significant decrease in Cho levels was observed in the orbitofrontal regions colocalized with GM atrophy and NAA decreases. Conclusion: We first demonstrate the ability to map non-invasively over the whole brain - from vertex to cerebellum - the metabolic abnormalities associated to MS using 3D-EPSI, opening a new window onto the non-invasive characterization of the topography of pathological processes. Disclosure The first author (MD) is the recipient of a PhD grant (CIFRE) supported by Siemens France and the French Ministry of Research and Technology (ANRT)

P468 Regional microstructural white matter damage is proportional to fatigue in multiple sclerosis A. Bisecco1,2, A. d’Ambrosio1, G. Caiazzo2, R. Sacco1, R. Docimo1, S. Bonavita1,2, M. Cirillo2,3, F. Esposito2,4, G. Tedeschi1,2, A. Gallo1,2 1Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Napoli, 2MRI Center ‘SUN_FISM’, Neurological Institute for Diagnosis and Care ‘Hermitage Capodimonte’, 3Neuroradiology Service, Department of Radiology, Second University of Naples, Naples, 4Department of Medicine and Surgery, University of Salerno, Baronissi, Italy Background: Fatigue affects a large proportion of patients with multiple sclerosis (MS). Structural magnetic resonance imaging (MRI) studies have provided discordant results on the correlation between the presence and severity of fatigue and MRI measures of brain damage. Objectives: Aim of this study was to assess the spatial distribution of microstructural white matter (WM) damage in MS and its relationship with fatigue in relapsing remitting (RR) MS patients.


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Methods: Sixty non-depressed RRMS patients and 30 sex, age and education-matched healthy controls (HC) underwent a MRI protocol including diffusion tensor imaging (DTI). MS patients were evaluated by a neurological examination and the Fatigue Severity Scale (FSS). Tract-based-spatial-statistics (TBSS) was applied for voxel-wise analysis of fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD). Significant differences were reported at a threshold of 0.05. Results: Thirty MS patients were fatigued (F-MS). Compared to HC, MS patients had decreased FA and increased MD/RD of the majority of skeleton voxels. In the comparison with HC, F-MS patients showed more extensive WM damage than NF-MS patients for all DTI indices. The following tracts were electively damaged in F-MS patients: frontal and occipital U-fibers, right external capsule, left uncinate fasciculus, forceps minor, left superior longitudinal fasciculus, bilateral cingulum and pons. We found no differences in direct comparison between F-MS and NF-MS patients for DTI measures and T2-lesions distribution. Significant correlations were found between FSS score and 1) FA abnormalities of bilateral corona radiata, bilateral cingulum, right anterior thalamic radiation, corpus callosum, forceps minor, right superior longitudinal fasciculus, right cerebral peduncle and midbrain; 2) RD abnormalities of the right superior longitudinal fasciculus, right inferior front-occipital fasciculus, forceps minor, bilateral cingulum and thalamus. Conclusions: F-MS patients show more widespread microstructural WM damage than NF-MS patients. The correlation between FSS score and FA/RD abnormalities in several clinically-relevant tracts supports the role of demyelination in the development of this disabling symptom. The involvement of cognitive-relevant structures such as the cingulum and forceps minor only in F-MS patients and the correlation of their FA/RD values with FSS score also supports the contribution of cognition to fatigue in MS. Disclosure A. Bisecco reports no disclosures; A. dÁmbrosio reports no disclosures; G. Caiazzo reports no disclosures; R. Sacco reports no disclosures; R. Docimo reports no disclosures; S. Bonavita received speakers honoraria from Biogen Idec, Novartis, and Merck-Serono; M. Cirillo reports no disclosures; F. Esposito reports no disclosures; G. Tedeschi has received compensation for consulting services and/or speaking activities from Bayer Schering Pharma, Biogen Idec, Merck Serono, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck Serono, and Fondazione Italiana Sclerosi Multipla; A. Gallo received speakers honoraria from Biogen Idec, Novartis, and Merck-Serono. P469 Quantitative histological validation of NODDI MRI indices of neurite morphology in multiple sclerosis spinal cord F. Grussu1, T. Schneider1, R.L. Yates2, M. Tachrount3, C. Tur1, J. Newcombe4, H. Zhang5, D.C. Alexander5, G.C. DeLuca2, C.A.M. Wheeler-Kingshott1 1NMR Research Unit, Department of Neuroinflammation, Queen

Square MS Centre, UCL Institute of Neurology, University College London, London, 2Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, 3Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, 4NeuroResource, UCL Institute of Neurology, 5Department of Computer Science and Centre for Medical Image Computing, University College London, London, United Kingdom Introduction: Neurite orientation dispersion and density imaging (NODDI) is a recent diffusion magnetic resonance imaging (MRI) method mapping neurite morphology, potentially able to detect specific features of tissue microstructure changes in multiple sclerosis (MS). Objectives: To investigate the validity and specificity of NODDI in MS via comparison of its metrics to quantitative histology. Methods: MRI Two samples of formalin-fixed post-mortem MS spinal cord (one lumbar, secondary progressive MS, expanded disability status scale (EDSS) 10, length 2cm; one thoracic, primary progressive MS, EDSS 7, length 3.5cm) were scanned at 9.4T. MRI images were analysed to derive NODDI free water fraction (FWF), neurite density index (NDI) and orientation dispersion index (ODI, 0 for parallel, 1 for dispersed neurites) and diffusion tensor imaging (DTI) fractional anisotropy (FA), axial, radial and mean diffusivities (AD, RD, MD). FA quantifies the spatial anisotropy of diffusion; AD/RD the amount of diffusion parallel/orthogonal to the main diffusion direction; MD the average amount of diffusion. Histology Sections from the lumbar case were stained for axons and myelin. Digital processing of their images provided circular variance (CV, spread of neurite orientations) and myelin staining intensity (MSI). Statistics Univariable linear regression models identified associations between mean values of histology and MRI metrics within manually drawn regions of interest. Results: Metrics In both cases, NDI, ODI and FA were hypointense in white matter (WM) focal lesions (FLs) compared to surrounding WM, whereas FWF, AD, RD, MD hyperintense. In the lumbar case, CV was hypointense in WM FLs, where MSI showed demyelination. NDI and MSI were hypointense in grey matter (GM) FLs compared to GM. Statistics For NODDI, higher CV was strongly associated with higher ODI (p< 0.001); higher MSI with higher NDI (p< 0.001) and weakly with lower ODI (p=0.02). For DTI, higher CV was associated with lower FA (p=0.03); higher MSI with higher FA (p=0.01) and lower AD (p=0.003), RD (p=0.01), MD (p=0.01). Conclusions: NODDI metrics in post-mortem MS spinal cord agree with histology. While pathological decreases in neurite orientation dispersion and myelin can be selectively detected with NODDI ODI and NDI, the two cause opposite effects on DTI FA, a conventional but non-specific index of tissue integrity. In conclusion, NODDI provides sensitive and specific promising biomarkers of tissue injury in MS. Disclosure F.Grussu and T.Schneider are joint first authors. G.C. DeLuca and C.A.M. Wheeler-Kingshott are joint senior authors.


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Poster Session I, 21(S11) The following is disclosed: ● F. Grussu is supported by a Grand Challenge PhD studentship (University College London). ● T. Schneider is an employee of Philips Healthcare UK since 1st Jan 2015. ● R.L. Yates is supported by a Medical Research Council (MRC) PhD studentship (University of Oxford). ● M. Tachrount: nothing to disclose. ● C. Tur received a McDonald Fellowship (from the Multiple Sclerosis International Federation) in 2007, and has received an ECTRIMS post-doctoral research fellowship in 2015. She has also received honoraria and support for travelling from Bayer-Schering, Teva, Merck-Serono and Serono Foundation, Biogen, Sanofi-Aventis, Novartis, and Ismar Healthcare. ● J. Newcombe: nothing to disclose. ● H. Zhang receives research funding from EPSRC, MRC, UK MND Association, US CHDI Foundation and Horizon2020. ● D.C. Alexander receives research funding from EPSRC, MRC, UK MND Association, US CHDI Foundation and Horizon2020. ● G.C. DeLuca is supported by a Goodger Scholarship (University of Oxford) and the NIHR Biomedical Research Centre, Oxford. He has also received honoraria and travel expenses as an invited speaker for Bayer Schering and travel expenses from Biogen Idec, Genzyme, and Novartis. ● C.A.M. Wheeler-Kingshott receives research funding from EPSRC, UK MS Society, Horizon2020, Biogen Idec, Novartis, Wings for Life. P470 MRI anisotropy improves with remyelination in a mouse model of MS M.K. Ansari, Y. Zhang University of Calgary, Calgary, AB, Canada Background: Remyelination is a critical repair process in MS. With resheath of the injured axons, remyelination promotes nerve conduction and thereby helps patients regain lost functions. However, the MRI property of remyelination is not well characterized, signifying an urgent need in clinical trials of repair agents. Recently, using a new image processing method named structure tensor analysis, tissue coherency is shown to be greater in histological images with greater myelin content. The goal here was to validate if and how tissue alignment changes in MRI with de- and remyelination that occurs sequentially in mice spinal cords. Methods: We imaged 10 mice at a 9.4T scanner. Demyelination was induced using a chemical toxin in the dorsal column of mice spinal cords at cervical 5-6. MRI was done at day 0 (before injury), and at days 7 and 28, which corresponds to periods of intact myelin, de- and re-myelination in histology. We acquired standard T2 MR images with matrix 256x256, slice thickness 0.75mm, and 7 slices/scan. Structure tensor analysis was applied to each lesion area in the MRI, with tissue coherency (anisotropy), energy (trace of major directions), and angular entropy (complexity) computed. Variable difference was assessed using mixedeffect modeling.

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Results: We found completely distinct features of tissue directionality between de- and re-myelinated lesions. Tissue energy was significantly higher in lesions with remyelination than with demyelination. Tissue coherency was 29% higher, and angular entropy 123% lower in remyelinated lesions than in demyelinated ones, although not reaching significant. Between remyelinated lesions and intact myelin, there was no significant difference in any outcome. Conclusions: This study suggests that remyelination leads to improved alignment in tissue microstructure that can be detected using MRI. This may be related to the mechanisms of remyelination, which occurs only after the clearance of interfering pathologies such as myelin debris. Structure tensor analysis may become a new measure of remyelination in MS lesions with further validation. Disclosure Mohammad Ansari has no conflict of interest to declare. Yunyan Zhang is funded by the MS Society of Canada, Natural Sciences and Engineering Research Council of Canada, and Alberta Innovates-Health Solutions, Canada.

P471 The yearly rate of relative thalamic atrophy (2D- and 3D-yrRTA) differentiates CIS from controls M. Menéndez González1,2, D. Pareto3, A. Fernández-Oliveira1, J.F. Corral3, P.D. García-López1, J. Sastre-Garriga4, X. Montalbán4, A. Rovira3 1Morphology Department, Universidad de Oviedo, Oviedo, 2Neurology Unit, Hospital Álvarez-Buylla, Mieres, 3Section of Neuroradiology and MR Unit (Department of Radiology), 4Department of Neurology / Neuroimmunology, Centre de Esclerosi Múltiple de Catalunya (Cemcat); Vall d’Hebron University Hospital, Barcelona, Spain Background: Segmentation-based techniques applied to volumetric (3D) T1-weighted images are the gold standard for morphometry assessment of brain structures. However, these techniques are not widely available in clinical practice since they require the use of specific automated softwares, while planimetric measures (2D) are more feasible. In clinically isolated syndrome (CIS) changes in subcortical GM have been already reported and, indeed, several studies found an association between grey matter (GM) atrophy and the risk of conversion to clinically definite MS. Among all GM structures, the thalami seem to be consistently affected in MS, according to most studies. The yearly rate of Relative Thalamic Atrophy (yrRTA) compares the extent of thalamic atrophy -representing specific GM atrophy- with the extent of ventricular enlargement -representing unspecific, global brain atrophy- measured in brain MRI studies performed at two different time-points. The yrRTA can be computed using both planimetric (2D) and automated segmentation-based volumetric (3D) measurements. Goals: The aim of this study was to compare the 2D- and 3D-yrRTA in controls and patients with CIS in two serial MRI examinations. We also aimed to assess the correlation between the 2D and the 3D-yrRTA. Methods: A sample of 82 subjects (mean age: 32.5, age range: 20 to 50 years; 36 males and 48 females) including 34 healthy subjects


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and 48 patients with CIS was evaluated. We computed the yrRTA using volumetric (NeuroQuant®) and planimetric measures on T1-weighted images following a previously described protocol. Then we compared results between groups using the Kuskall-Wallis test and between methodologies using Inter-Class Correlation Coefficient (ICC). Results: Mean time to first follow-up MRI was 9.85 months (range: 3.20-20.57 months). The mean 2D-yrRTA in controls was 37.075 while the mean 2D-yrRTA in CIS was 10.74 (p=0.02). The mean 3D-yrRTA in controls was 34.26 while the mean 3D-yrRTA in CIS was 12.17 (p=0.04). The ICC for 2D- and 3D-yrRTA was 0.89 (0.84-0.93). Conclusions: Both 2D- and 3D-yrRTA differentiate patients with CIS from controls. Further studies are needed to determine the value of the yrRTA for assessing the risk of conversion to definite MS in patients with CIS. Planimetric approaches might be useful for estimating deep gray matter atrophy in patients with CIS and MS when more technically demanding automated segmentation techniques are not available. Disclosure Manuel Menéndez-González as received compensation for consulting services and speaking honoraria from Novartis and Bayer. Deborah Pareto has received speaking honoraria from Novartis and Genzyme. Aníbal Fernández-Oliveira: nothing to disclose. Juan Francisco Corral: nothing to disclose. Pablo David García-López: nothing to disclose. Jaume Sastre-Garriga has received compensation for consulting services and speaking honoraria from Merck-Serono, BiogenIdec, Teva, Sanofi-Aventis and Novartis. Xavier Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall. Alex Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, and has received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Bracco, MerckSerono, Teva Pharmaceutical Industries Ltd, OLEA Medical, Stendhal, Novartis and Biogen Idec. This project was funded by Novartis.

P472 Leptomeningeal enhancement on delayed acquisition, post-contrast 7 Tesla MRI in multiple sclerosis D.M. Harrison1,2, K. Wang3, J. Fiol2, W. Royal1, J. Hua4, I. Izbudak5 1Neurology, University of Maryland School of Medicine, 2Neurology, 3Johns Hopkins University School of Medicine, 4F.M. Kirby Research Center for Functional Neuroimaging, Kennedy Krieger Institute, 5Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States Background: Leptomeningeal inflammation is an increasingly recognized histopathologic finding in multiple sclerosis (MS).

Recent investigations into the use of post-contrast fluid attenuated inversion recovery (FLAIR) MRI to detect meningeal inflammation in MS report varying results. We aimed to investigate 7 Tesla (7T) MRI to detect leptomeningeal inflammation in MS. Methods: 14 participants with MS and 2 healthy volunteers (HV) underwent whole-brain 7T MRIs. Magnetization-prepared FLAIR (MPFLAIR) (0.7mm3 resolution) was acquired pre-contrast and approximately 25 minutes after gadolinium injection. Images were co-registered and a digital subtraction image was created. Areas of hyperintensity on the subtraction image were identified by 2 independent reviewers and marked if confirmed as post-contrast hyperintensity in the leptomeningeal space. Consensus was achieved in tandem with a third reviewer. Results: A total of 39 foci of leptomeningeal enhancement were noted in 12 (86%) cases with MS. The median number of foci was 2.5 (range 0 - 8) with 9 (64%) MS cases having >1 enhancement focus. Three patterns of enhancement were seen: focal nodules (18 foci, 46%), amorphous spreading/filling in the subarachnoid space (14 foci, 36%), and linear hyperintensities appearing adherent to pia (7 foci, 18%). One HV had 3 foci (all were nodular) and the other had none. MS subjects having >1 enhancing focus were older (48.1 years, SD (5.6)) than those with 0 or 1 (34.0 years, (SD 12.1), p = 0.01). Non-significant trends were also noted for a longer disease duration and higher proportion of male gender in those with > 1 enhancing focus. No significant association was found between enhancing foci and disability scores. Discussion: Gadolinium enhancement was seen on post-contrast MPFLAIR in an overwhelming majority of MS cases. This is in contrast to two prior publications at 3T in which this finding was seen either very rarely or up to 25%. This difference may be due to elevated hyperintensity of gadolinium at 7T, finer resolution, or the time delay of acquisition used. Further work is needed to determine if this apparent increase in sensitivity visualizes previously undescribed normal variation versus pathology indicative of leptomeningeal inflammation. Given proposed links between intrathecal inflammation and progressive MS, our finding of more enhancing foci in older males (a high risk group for disability progression) also warrants further investigation. Disclosure Dr. Harrison has received consulting fees from Mallinckrodt Pharmaceuticals, Genzyme, and EMD Serono. Dr. Harrison receives research funding from EMD Serono and NIH/NINDS K23NS072366. Mr. Wang has no financial disclosures or funding to report. Ms. Fiol has no financial disclosures or funding to report. Dr. Hua has no financial disclosures or funding to report. Dr. Royal has no financial disclosures to report. Dr. Royal receives research funding from NIMH, NIDA, Biogen-Idec, Teva, EMD Serono, Genzyme, Novartis, Mallinckrodt, MedImmune and Alexion. Dr. Izbudak has no financial disclosures to report. Dr. Izbudak receives research funding Seimens and Biogen-Idec. P473 Changes in the normal appearing white matter in neuromyelitis optica measured by MRI at 7T field strength I.-J. Chou1,2,3, R. Tanasescu1,4, O.E. Mougin5, C.R. Tench1, B. Gran1, W.P. Whitehouse2, P.A. Gowland5, C.S. Constantinescu1


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of Clinical Neuroscience, 2Division of Academic Child Health, University of Nottingham, Nottingham, United Kingdom, 3Paediatric Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, 4Department of Neurology, Neurosurgery and Psychiatry, Carol Davila University of Medicine and Pharmacy, Colentina Hospital, Bucharest, Romania, 5Sir Peter Mansfield Magnetic Resonance Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, United Kingdom Background: There is currently limited knowledge of in vivo MRI quantitative changes in the damaged substrates within the white matter lesions and normal appearing white matter (NAWM) in neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD). Methods: We acquired T1 relaxation time and magnetisation transfer ratio (MTR) maps for the brain of patients with NMO/ NMOSD, MS and healthy subjects using high-resolution magnetic resonance imaging at 7T to compare intracranial lesions and NAWM. Results: We prospectively investigated 36 participants: 14 patients with NMO/NMOSD and 12 patients with MS in remission status compared to 10 healthy controls. Lesion count and volume were significantly higher in MS patients than NMO/NMOSD patients and healthy controls. Comparing to healthy controls, MS lesions had significant deviation of T1 relaxation time and MTR than NMO/NMOSD lesions did. The height of NAWM histogram peak of both T1 relaxation time and MTR in NMO/NMOSD patients were significantly lower than that in healthy subjects and not different from that in MS patients. Conclusions: Abnormal values in T1 relaxation time and MTR suggests that NMO/NMOSD lesions had more myelin and less water content than that in MS lesions. Similar to MS NAWM, the decreased peak heights of NAWM histograms indicate that at least some of the NAWM in patients with NMO/NMOSD is indeed abnormal. Disclosure I-Jun Chou: nothing to declare Radu Tanasescu: nothing to declare Olivier E. Mougin: nothing to declare Christopher R. Tench: nothing to declare Bruno Gran: nothing to declare William P. Whitehouse: nothing to declare Penny A. Gowland: nothing to declare Cris S. Constantinescu: nothing to declare P474 Intensity of initial demyelinating event associated with lower subsequent MWF in new MS lesions E. Monohan, W. Vargas, P. Sneha, A. Raj, T. Vartanian, N. Nealon, J. Perumal, T.D. Nguyen, S.M. Hurtado Rua, S.A. Gauthier Weill Cornell Medical College, New York, NY, United States Objectives: Multiple sclerosis (MS) is characterized pathologically by focal demyelination with variable degrees of remyelination. Investigating the potential of myelin repair strategies in Multiple Sclerosis (MS) requires both a quantitative tool to

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measure myelin content in-vivo and an understanding of myelin dynamics during lesion evolution. The objective of this study is to measure the longitudinal change in myelin water fraction (MWF), a MRI biomarker of myelin, in new MS lesions and to identify factors that influence their subsequent myelin content. Methods: Twenty-four MS patients were scanned with wholebrain Fast Acquisition with Spiral Trajectory and T2prep (FAST-T2) MWF mapping at baseline and median follow up of 6 months. Eleven healthy controls (HC) confirmed the reproducibility of FAST-T2 in white matter regions of interests (ROIs) similar to a lesion size. A random-effect-model was implemented to determine the association between baseline clinical and lesion variables and the subsequent MWF. Results: ROI-based measurements in HCs were highly correlated between scans [mean r = 0.893(.764 - .967)]. In MS patients, 38 gadolinium enhancing (Gd+) and 25 new non-enhancing (Gd-) T2 hyperintense lesions (5.7 months, ± 3.8) were identified. Significant improvement in MWF was seen in Gd+ lesions (0.035 ± 0.029, p< 0.001) as compared to Gd- lesions (0.006 ± 0.017, p=0.065). In the model, higher baseline MWF (p< 0.001) and the presence of Gd (p< 0.001) was associated with higher subsequent MWF. Conclusions: FAST T2 provides a clinically feasible method to quantify MWF change in new MS lesions. The observed influence of baseline MWF, which represents a combined effect of both resolving edema and myelin change within acute lesions, suggests that the extent of initial inflammation impacts final myelin recovery. Disclosure Elizabeth Monohan: nothing to disclose. Wendy S. Vargas, MD has served on an advisory board for Teva Pharmaceuticals and received grant support from the National Multiple Sclerosis Society and Teva Pharmaceuticals. Sneha Pandya: nothing to disclose. Ashish Raj, PhD: nothing to disclose. Thanh D. Nguyen, PhD: nothing to disclose. Timothy Vartanian, MD, PhD is a speaker for Teva Neuroscience and Genzyme, has received honoraria for advising Genzyme, and has received grant support from the National Multiple Sclerosis Society, Biogen Idec, and Mallinckrodt pharmaceuticals. Nancy Nealon, MD: nothing to disclose. Jai Perumal, MD is a speaker for Biogen Idec, Teva Neuroscience, Genzyme, and Acorda and has consulted for Biogen Idec and Genzyme. Sandra M. Hurtado Rúa, PhD: nothing to disclose. Susan A. Gauthier DO, MPH has received honoraria for advising Genzyme and Teva Neuroscience and has received grant support from the National Multiple Sclerosis Society, Biogen Idec, Novartis Pharmaceuticals, Mallinckrodt pharmaceuticals, Genzyme, and EMD Serono. P475 Disrupted blood flow modulation in functional brain networks in multiple sclerosis measured with hypercapnia MRI Y. Ge1, O. Marshall1, L. Pape1, H. Lu2, I. Kister1, R.I. Grossman1 1New York University School of Medicine, New York City, 2Johns Hopkins University School of Medicine, Baltimore, NY, United States


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Introduction: The aim of this study was to assess CVR deficits or impaired modulation of cerebral blood flow (CBF) using hypercapnia (5% CO2) MRI within several well-established functional networks in patients with multiple sclerosis (MS). Methods and materials: Nineteen MS patients (9 male, 10 female, 42.8±10.2 years old) and 19 healthy controls (13 male, 6 female, 39.6±12.9 years old) were recruited for this study. Hypercapnia MRI was performed at 3T with a multi-array head coil. CVR was measured with percent CBF changes normalized by end tidal CO2 (EtCO2) increase from breathing room air (ie. normocapnia) to breathing a mixture of 5% CO2, 21% O2, and 74% N2 (ie. hypercapnia). EtCO2 levels, which are equivalent to blood CO2 levels, were monitored and recorded throughout the experiment on a MEDRAD system. Specifically, CBF was measured using pseudocontinuous ASL perfusion MRI. Image processing was conducted using SPM to generate CBF and CVR maps. A well-established brain functional network classification was used to generate 10 networks (http:// www.brainnexus.com/resources/resting-state-fmri-templates). The percent CBF change in each network per EtCO2 change was used to determine network CVR values. These values were compared between patient and control groups using a two-sample t-test, with a p< 0.05 considered significant after Bonferroni correction. Results: Compared to the control group, the MS group showed a decrease in CVR within each of the 10 networks, with significant decreased CVR in 7 functional networks after Bonferroni correction. Average CVR and their comparison P values for each network between patients and controls are as follows: DMN (3.3±1.4 % vs 4.8±1.5% CBF/mmHg EtCO2; p=0.003), executive (3.7±1.1 vs 5.2±1.6%; p=0.002), anterior cingulate/precuneus (3.4±1.2 vs 5.4±1.6%; p=0.0001), salience (3.9±1.3 vs 5.8±1.9%; p=0.001), inferior frontal gyrus/middle temporal (3.5±0.9 vs 5.2±1.6%; p=0.0003), and motor (3.7±1.2 vs 5.6±1.6%; p=0.003) networks. The auditory, parietal association, supplemental motor, and visual networks didn’t reach significant difference after the Bonferonni correction between the two groups. Discussion: We found a significantly decreased CVR in multiple functional network regions in MS, suggesting an impaired cerebral blood modulation that can lead to neurovascular coupling disturbance and subsequent neuronal dysfunction. Such CVR impairment seem to primarily affect cognitive than somatosensory networks in MS.

Background: A hurdle to developing treatment for progressive multiple sclerosis (PMS) is the absence of a predictive biomarker. One aim of the Secondary and Primary pRogressive IbudilastNeuronext Trial for MS (SPRINT-MS) is to evaluate advanced imaging biomarkers for PMS. High Angular Resolution Diffusion Imaging (HARDI) provides quantitative metrics of tissue microstructure that are candidate biomarkers. The technical demands of HARDI make it difficult to ensure uniform performance at multiple sites, leading to prohibitively large sample sizes. Goal: To develop a HARDI acquisition and quantitative quality assurance (QA) procedures to limit variability across multiple imaging sites. Methods: An acquisition that was uniform across scanners in terms of spatial resolution and diffusion gradient profiles was developed. The QA procedure includes a monthly scan of an agar phantom developed by the Biomedical Informatics Research Network at each of 27 sites within NeuroNEXT, an infrastructure established by the National Institutes of Health to facilitate phase II trials of therapy for neurological disease. Only 3 tesla Siemens and GE scanners are used. Scans were also acquired at baseline on healthy subjects under a protocol approved by a central internal review board. Images were evaluated based on gross artifact, eddy current distortion and signal to noise ratio (SNR). A receiver operating characteristic (ROC) analysis was developed to determine acceptable stability of SNR. Results: Phantom measurements have proved invaluable for detecting gross scanner artifact, guiding repairs and sparing patients from the burden of a repeat scan. SNR from healthy controls was markedly higher on the Siemens Skyra (~60) than on the other imaging platforms (~30). ROC analysis suggests that the Skyra imagers can sustain a large drop in SNR (~30%) before a 10% drop in sensitivity in diffusivity measurements, while the other scanners can only sustain a drop of SNR of ~10% before exhibiting similar loss of sensitivity. Eddy current distortion was lowest among the Siemens Trio scanners. Conclusions: A cross-platform HARDI acquisition and QA protocol has been developed to characterize variability in a multicenter trial. The use of the protocol to limit variability is currently underway. Support by National Institute of Health (U01NS082329), National Multiple Sclerosis Society (RG-5184-A-6) and Medicinova Disclosure

This work was supported by NIH R01 Grants, NS029029-20S1 and NS076588 from National Institute of Health (NIH) and a research grant (RG4707A). This work was also performed under the rubric of the Center for Advanced Imaging Innovation and Research (CAI2R, www.cai2r.net), a NIBIB Biomedical Technology Resource Center (NIH P41 EB017183).

Dr. Sakaie received salary support from Novartis and Biogen. Dr. Fox has received consultant fees from Biogen Idec, GlaxoSmithKline, Novartis, Questcor, Teva, and Xenoport; grant and research support from Novartis. Dr. Lowe may receive future financial benefits from the Cleveland Clinic for inventions or discoveries commercialized through Autonomic Technologies, Inc., CardioNomic, IntElect Medical, Inc and Siemens Medical. Drs. Zhou and Debbins report no disclosures.

P476 Quality assurance of advanced imaging in a multicenter trial of ibudilast therapy for progressive multiple sclerosis X. Zhou1, K. Sakaie1, J.P. Debbins2, R.J. Fox3, M.J. Lowe1 1Cleveland Clinic, Cleveland, OH, 2Barrow Neurological Institute, Phoenix, AZ, 3Cleveland Clinic, Neurological Institute, Cleveland, OH, United States

P477 Prediction of executive functions in multiple sclerosis based on structural and functional MRI - insights from a multicentre study M. Loitfelder1, M.A. Rocca2, M. Filippi2, T. Yousry3, O. Ciccarelli3, G. Tedeschi4,5, S. Ropele1, F. Fazekas1, C. Enzinger1, on behalf of the MAGNIMS Network

Disclosure


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Poster Session I, 21(S11) 1Department

of Neurology, Medical University of Graz, Graz, Austria, 2Vita-Salute San Raffaele University, Milan, Italy, 3UCL Institute of Neurology, London, United Kingdom, 4Second University of Naples and Institute of Diagnosis and Care ‘Hermitage-Capodimonte’, 5Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Division of Neurology, Second University of Naples, Naples, Italy Background: Deficits in information processing speed (IPS) and executive function (EF) are frequent in multiple sclerosis (MS). MRI surrogate markers of the cognitive status of patients are a matter of current research. In this context, T2 lesion load and thalamic volume have shown predictive value. Next to morphological markers, information from functional MRI (fMRI), especially on thalamic activation, recently gained interest as potential predictor. In a multi-centric study, we here explored whether a combined use of structural and functional markers could predict IPS/EF status. Method: 26 relapsing-remitting MS patients and 32 healthy controls (HC) from 4 MAGNIMS centres underwent (f)MRI including a go/no-go task and neuropsychological assessment. Subtests of the Brief Repeatable Battery of Neuropsychological Tests, the Wisconsin Card Sorting Test and the performance with the fMRI paradigm were used as estimates of IPS/EF. Activation of the thalamus and the inferior frontal gyrus (pars triangularis), thalamic volume, T2 lesion load, and age were used as predictors for IPS/EF function in regression models. Results: Compared to HC, patients showed increased activation in a frontoparietal network including both thalami and decreased thalamic (p< .001), grey matter (p=.016) and total brain volume (p=.016). Thalamic volume (beta=0.606, p=.001) together with thalamic activation (beta=-0.410, p=.022) best predicted IPS/EF and explained 52.7% of the variance. Conclusion: Thalamic volume and activation, together, best predicted cognitive status in yet cognitively normal RR-MS patients. This highlights the potential of a combined use of functional and morphological parameters in the prediction of cognitive status in MS. Disclosure Authors have nothing to disclose. P478 Signal abnormalities on susceptibility-weighted MR imaging in patients with clinically isolated syndromes and in subjects with incidental focal white matter lesions A. Rovira, C. Auger, G. Arrambide, M. Tintore, X. Aymerich, M. Alberich, E. Huerga, X. Montalban, D. Pareto Vall d’Hebron University Hospital, Barcelona, Spain Background and purpose: Identifying MRI biomarkers that can differentiate MS patients from subjects with incidental focal abnormalities is of great clinical relevance. The aim of this study is to analyze the value of SWI in differentiating clinically isolated syndrome (CIS) patients, from asymptomatic young adults demonstrating brain focal white matter lesions.

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Methods: 32 with CIS (mean age 35 years; 59% females), and 21 subjects demonstrating incidental brain MR imaging focal white matter lesions (control group) (mean age 43 years, 90% females) were included in the study. Subjects were scanned at 3.0T by using SWI and T2WI. In all subjects an observer, blinded to clinical information, assessed the presence and topography of focal high signal intensity lesions in the brain and spinal cord, the fulfillment of the criteria for dissemination in space (DIS), and the presence of intralesional susceptibility signal (ISS) loss on SWI sequence. Results: Patients with CIS had less T2 lesion volume than control group (3.7 cm3 vs 4.5 cm3), although the difference was non-significant (p=0.09). Juxtacortical, infratentorial, periventricular and spinal cord lesions were present in 91%, 91%, 100% and 72% of CIS patients, while only in 14%, 19%, 43% and 0% in the control group. DIS was demonstrated in all CIS patients, while only demonstrated in three of the control group (14%). ISS loss was observed only in 4 patients in the control group, although only one showed more than 20% of the T2 visible lesions with this signal abnormality. ISS were observed in all CIS patients (all but two with more than 20% of the T2 lesions with this signal abnormality). The presence of ISS was sensitive for CIS (100%) and achieved a high specificity (81%) and accuracy (92%) for differentiating them from controls, although similar results were obtained when considering fulfillment of DIS criteria (sensitivity 100%; specificity 85%). Combining the presence of ISS with the McDonald 2010 criteria for DIS achieved 100% of specificity and accuracy in differentiating patients with CIS from subjects with incidental white matter abnormalities. Conclusions: Intralesional susceptibility signal (ISS) changes on SWI are constantly present in CIS patients, and were highly specific in differentiating these patients from subjects showing incidental white matter abnormalities. Combination of presence of ISS loss and current McDonald criteria for DIS improves diagnostic specificity and accuracy. Disclosure Alex Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, and has received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Bracco, MerckSerono, Teva Pharmaceutical Industries Ltd, OLEA Medical, Stendhal, Novartis and Biogen Idec. Cristina Auger has received speaking honoraria from Novartis and Genzyme Georgina Arrambide has received travel expenses for scientific meetings from Merck-Serono Mar Tintore has received compensation for consulting services and speaking honoraria from Bayer-Schering, Merck-Serono, Biogen-Idec, Teva, Sanofi-Aventis, and Novartis Manel Alberich has nothing to disclose Elena Huerga has nothing to disclose. Xavier Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall. Deborah Pareto has received speaking honoraria from Novartis and Genzyme.


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P479 Efficiency of FLAIR* at 1.5T, 3T, and 7T for detecting perivenular lesions in multiple sclerosis (MS) L. Vuolo1,2, B. Dewey2, P. Sati2, L. Massacesi1, D.S. Reich2 1University of Florence, Florence, Italy, 2National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States Background: FLAIR* is a new MRI technique that combines the advantages of T2-FLAIR for detecting MS lesions and of T2* weighting for detecting parenchymal veins. FLAIR* can be used at clinical field strengths (1.5T and 3T) and ultra-high-field strength (7T) to generate high-isotropic-resolution whole-brain images. Objective: To evaluate the efficiency of FLAIR* imaging in detecting perivenular distribution of lesions at different magnetic field strengths. Methods: 10 MS patients underwent 1.5T MRI. Moreover, an additional 9 MS patients underwent 3T MRI followed by 7T MRI within 8-13 months. FLAIR* images were obtained as previously described. 3T-FLAIR* was acquired both before and after injection of gadolinium-based contrast agent. A single expert simultaneously evaluated the images, reporting the total number of lesions and classifying the lesions as perivenular if intralesional hypointense signal was noted in at least 2 perpendicular planes and if it was completely surrounded by hyperintense signal in at least 1 plane. Results: Of the 265 lesions detected on 1.5T, 243 (81%) were perivenular. Of the 411 lesions detected on 3T and 7T, 375 (91%), 380 (93%) and 402 (98%) perivenular lesions (PVLs) were reported, respectively, on 3T-FLAIR* pre-gad, 3T-FLAIR* postgad and 7T-FLAIR*. Therefore, 7T-FLAIR* was slightly more sensitive in detecting the PVLs than 3T-FLAIR* pre-gad (p=0.02) and 3T-FLAIR* post-gad (p=0.02), and the administration of contrast agent only marginally increased the number of PVLs (p=0.04) detected at 3T. We were not able to directly compare 1.5T versus 3T and 7T. Conclusions: This study demonstrates that FLAIR* acquired at 3T, even in the absence of contrast agent, captures nearly all (93%) of the PVLs seen at 7T. Impressively, even at 1.5T, the proportion of PVLs is high (81%). Therefore, this study supports the usefulness of FLAIR* imaging on clinical scanners and paves the way for multicenter trials to assess its diagnostic utility.

Background: In Multiple Sclerosis (MS) small foci of leptomeningeal enhancement in post gad FLAIR scans have been described and proposed as an in vivo marker of meningeal inflammation and of compartmentalization of the immune response in the CNS. However these data were obtained in a research setting with 3D-FLAIR sequences acquired in high field magnets and delaying acquisition beyond 10 minutes after gadolinium injection. In this study, prevalence of leptomeningeal enhancement foci at low field in a routine diagnostic setting was evaluated. Methods: Inclusion criteria: MS patients (n=242; 205 relapsing remitting MS, 84%; 37 secondary chronic progressive MS) that underwent MRI scan with a standardized protocol, between January 2013 and January 2015. MRI protocol: magnet 1.5T (Philips), included an axial FLAIR (thickness: 4mm) acquired 2 minutes after gadolinium injection. A single expert blinded to clinical data evaluated the images and reported presence, site and location of leptomeningeal enhancement foci. Results: Out of the 242 MS patients, 28 (11%) showed at least one focus of leptomeningeal enhancement. The enhancement was more observed in 8/37 cases in SP MS ( 21%) than in 20/205 RR MS (10%). Disease duration and age were positively related to the presence of leptomeningeal enchantment. In addition a trend for higher EDSS in positive patients was observed. Conclusion: This study confirms that leptomeningeal enhancement is a common finding in MS patients even in a routine diagnostic setting. However the prevalence of foci observed in this study was lower, suggesting that the delay of the scan acquisition after the gadolinium injection is critical. Despite the difference in the overall prevalence, the different frequency in the RR and in the SP patients observed was consistent with that previously reported. The higher prevalence in progressive patients is consistent with the pathological findings about leptomeningeal foci observed in MS patients. Disclosure AR received honoraria for talking from Biogen-Itec, Teva, Novartis, Genzyme LM has received financial support for participating in multicentric clinical trials from Biogen, Novartis and Teva and travel expenses for attending meetings from Biogen, Novartis, Teva, Genzyme and Merck Serono. LV, BF, CM, EM: nothing to disclose

Disclosure LV, BD, PS, DSR: nothing to disclose LM: has received financial support for participating in multicentric clinical trials from Biogen, Novartis and Teva and travel expenses for attending meetings from Biogen, Novartis, Teva, Genzyme and Merck Serono. The Intramural Research Program of the National Institute of Neurological Disorders and Stroke supported this study.

P480 Leptomeningeal enhancement analysis in diagnostic clinical setting L. Vuolo, A.M. Repice, C. Mechi, E. Magnani, B. Forci, L. Massacesi University of Florence, Florence, Italy

P481 Cortical lesions in pediatric-onset multiple sclerosis: a preliminary 7 tesla view R. Datta1,2, V. Sethi3, A.T. Waldman1,2, S. Narula1,2, B.E. Dewey3, P. Sati3, D.S. Reich3, B.L. Banwell1,2 1Neurology, Children’s Hospital of Philadelphia, 2Neurology, University of Pennsylvania, Philadelphia, PA, 3Translational Neurology Unit, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States Background: Cortical lesions (CLs) in multiple sclerosis (MS) patients are underappreciated on conventional 1.5 tesla (T) magnetic resonance imaging (MRI), and visualization of CLs in adults


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Poster Session I, 21(S11) with relapsing and particularly secondary progressive MS has relied on 3T MRI and utilization of specialized sequences. CLs have been reported to occur rarely in pediatric MS patients, suggesting that accrual of cortical pathology occurs with longer disease duration and progressive disease. Ultra high field MR provides a novel window into cortical pathology, and application of 7T MRI in pediatric MS patients provides insight into whether cortical pathology is a feature of MS onset in childhood. Methods: In this pilot project, 8 pediatric-onset MS patients cared for at the Children’s Hospital of Philadelphia were imaged on a single 7T MRI scanner. CLs were annotated on the T1-weighted MPRAGE images (0.7 mm isotropic resolution) by one observer and then adjudicated by a second experienced rater. CL were characterized as leucocortical (LC) - affecting white matter and gray matter (GM) or intracortical (IC) - within the GM cortex. Total CLs, age at onset, age at scan, disease duration, total relapses and Expanded Disability Status Scale (EDSS) score were recorded. None of the patients had secondary progressive disease at the time of scan. CLs were required to involve four or more voxels (inplane) in two consecutive slices and to be hypointense to the surrounding GM. Results: A total of 996 (mean=125±53SD, median=121) CLs {LC lesions=774 (mean=97±41SD, median=96); IC lesions=222 (mean=28±14SD, median=25)} were detected in 8 pediatric-onset MS patients (3 female, mean age at scan 21yrs±3.5SD, mean age of disease onset 15yrs±2.3SD, mean disease duration 5.3yrs±3.4SD). The median EDSS was 1.75 (range, 0-3.5). Discussion: Leucocortical and intracortical lesions appear to be prominent in adolescents and young adults with pediatric-onset relapsing-remitting MS. Development of standardized and quantifiable MRI intensity measures are required to reduce subjectivity in the identification of these lesions. Nonetheless, the marked hypointensity of many of the CL identified in the present cohort lends confidence that cortical pathology is present in pediatriconset MS, occurs early, and is detectable prior to clinically progressive disease. Disclosure Nothing to disclose P482 MTR-derived pial and subpial abnormalities in the spinal cord of RRMS patients: a two-year follow-up study F. De Angelis1, C. Tur1, H. Kearney1, M.C. Yiannakas1, D. Plantone1, D.H. Miller1,2, O. Ciccarelli1,2 1UCL Institute of Neurology, London, UK, 2NIHR University College London Hospitals Biomedical Research Centre, London, United Kingdom Background: In multiple sclerosis (MS), cortical -especially subpial- demyelination has been associated with brain meningeal inflammation and disease progression. We previously showed that patients with progressive MS had lower MTR in the outer spinal cord (SC) -an area corresponding to the expected location of the pia mater and subpial regions- when compared with early MS patients. We also found that early MS had lower MTR in this region than healthy controls (HC). In this study, in the same cohort of patients, we investigated 1) the differences between patients

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and HC in the MTR-derived pia mater at 2 years of follow-up (2yFU), and changes of this MRI parameter over time in the patient cohort; 2)the associations between MTR and clinical changes over the 2yFU. Methods: 15 relapsing-remitting MS (RRMS) patients (12F, mean age 41 [SD 9.1] yrs) and 9 HC (2F, 42 [9.2] yrs) were scanned at 3T and clinically assessed using expanded disability status scale (EDSS) and MS functional composite at baseline and at 2yFU. The structural imaging protocol included a high-resolution 3D fat-suppressed fast field-echo (3D-FFE) and a 3D phasesensitive inversion recovery (3D-PSIR). MTR was acquired using a 3D slab-selective FFE sequence with 2 echoes. MT-on/-off images were registered to the 3D-FFE, and MTR maps were calculated. Masks of the white and grey matter were created. Following removal of the 2 outermost voxels from the white matter mask, we recorded the MTR of the cord outline. We measured SC mean cross-sectional area from 3D-PSIR image centred at C2/ C3 intervertebral disc. Linear regression models adjusting for age and gender were used to estimate differences between patients and controls in MTR measures, and the association between MTR and clinical changes over time. Results: At 2yFU, patients had lower MTR in the outer SC regions than HC (difference [95%CI]: -1.77 [-3.43; -0.10], p=0.038); however, there was no evidence of a difference in the change of the MTR of the outer SC between groups (p=0.592). Although patients with EDSS increase over the follow-up had a decrease in MTR values of the outer SC, this was not significantly different from zero (change: -0.29 [-1.64;1.07], p=0.656). Conclusions: These results confirm our previous finding of RRMS having lower MTR in regions involving the pia mater and subpial area in the SC than HC, suggesting that the role of SC meningeal inflammation in MS requires to be further explored even at a early stage of the disease. Disclosure F. De Angelis, H. Kearney, M. C. Yiannakas, and Domenico Plantone have nothing to disclose. O. Ciccarelli receives research grant support from the Multiple Sclerosis Society of Great Britain and Northern Ireland, the Department of Health Comprehensive Biomedical Centre, the International Spinal Cord Research Trust (ISRT) and the Engineering and Physical Sciences Research Council (EPSRC); she serves as a consultant for Novartis, Biogen and GE and payments are made to UCL Institute of Neurology. D.H. Miller has received honoraria through payments to his employer, UCL Institute of Neurology, for Advisory Committee and/or Consultancy advice in multiple sclerosis studies from Biogen Idec, GlaxoSmithKline, Novartis, Merck, Chugai, Mitsubishi Pharma Europe and Bayer Schering Pharma. He has also received compensation through payments to his employer for performing central MRI analysis of multiple sclerosis trials from GlaxoSmithKline, Biogen Idec, Novartis, Apitope and Merck. The Queen Square MS Centre at UCL Institute of Neurology is supported by the UK MS Society and UCL-UCLH Biomedical Research Centre. C. Tur received a McDonald Fellowship (from the Multiple Sclerosis International Federation) in 2007, and has received an ECTRIMS post-doctoral research fellowship in 2015. She has also received honoraria and support for travelling from Bayer-Schering,


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Teva, Merck-Serono and Serono Foundation, Biogen, SanofiAventis, Novartis, and Ismar Healthcare. P483 Local increases in metabolite levels predict lesion formation and lesion severity in relapsing-remitting multiple sclerosis A.M. Klauser1, O.T. Wiebenga2, A.J.C. Eijlers1, M.M. Schoonheim1, B.M.J. Uitdehaag3, F. Barkhof2, P.J.W. Pouwels4, J.J.G. Geurts1 1Department of Anatomy & Neurosciences, 2Department of Radiology and Nuclear Medicine, 3Department of Neurology, 4Department of Physics and Medical Technology, VU University Medical Center, Amsterdam, The Netherlands Background and purpose: Not all white matter (WM) damage in multiple sclerosis (MS) appears on conventional magnetic resonance imaging (MRI) scans and relatively little is known about the local processes that take place in new lesions before becoming visible on a conventional T2 weighted scan. In this longitudinal study, the absolute concentrations of total N-acetylaspartate (tNAA), total creatine (tCr), choline-containing compounds (Cho), myo-inositol (Ins), and glutamate (Glu) were quantified both before and after lesion appearance on MRI. Materials and methods: Three groups of relapsing-remitting MS patients receiving either natalizumab (n=29), standard therapy (interferon beta-1b or glatiramer acetate, n=19) or no treatment (n=11) were scanned four times, with six month intervals. Imaging included MR spectroscopic imaging (MRSI) within a single 80x100x15 mm slab above the corpus callosum, T2-weighted imaging and diffusion tensor imaging (DTI). Only patients with newly formed T2 lesions appearing in the MRSI slab were selected for further analysis. Metabolite concentrations at all time points were determined for normal-appearing white matter (NAWM), grey matter (GM) and for the areas of the newly formed lesions. Results: In 12 patients (5 receiving standard therapy, 7 untreated) a total of 16 new lesions developed within the MRSI slab during the study period. Glutamate increased 1.0 mM (19%, p=0.039) in WM areas where new lesions developed on subsequent T2 scans. In these same areas, higher Cho and tCr increases during lesion formation were negatively correlated with increases in radial diffusivity (RD) and mean diffusivity (MD) within the same lesions (rho>0.69, p< 0.01). This was confirmed by performing a median split on RD increases in lesions during lesion formation to create a ‘mild’ and a ‘severe’ group of lesions: mild lesions could be predicted by a higher increase in Cho (p=0.01) and tCr (p=0.02) compared to more severe lesions. Conclusions: Our findings suggest that early metabolite changes have predictive value for the appearance and severity of new lesions. Glutamate levels increased before lesions appeared on T2-weighted MRI, possibly reflecting local inflammatory processes and/or early axonal dysfunction. In lesions retrospectively classified as ‘mild’ a higher increase of choline and creatine was found during lesion formation. This may be a reflection of early, more proficient remyelination, with subsequent restricted damage within lesions. Disclosure Study supported by: Biogen and the Canadian MS Society. Dr. Klauser: nothing to disclose.

Mr. Wiebenga: nothing to disclose. Mr. Eijlers is sponsored by the Dutch MS Research foundation, grant nr 14-358e. Dr. Schoonheim is sponsored by the Dutch MS Research foundation, grant nr 13-820, and has served as a consultant for Genzyme, Novartis and Excemed. Prof. Uitdehaag has served as a consultant for Biogen Idec, Novartis, MerckSerono, and Danone Research. Prof. Barkhof serves on the editorial boards of Brain, European Radiology, the Journal of Neurology, Neurosurgery & Psychiatry, Neurology, Multiple Sclerosis and Neuroradiology and has served as a consultant for Bayer-Shering Pharma, Sanofi-Aventis, Biogen-Idec, TEVA pharmaceuticals, Genzyme, Merck-Serono, Novartis, Roche, Synthon, Jansen Research and Lundbeck. Dr. Pouwels: nothing to disclose. Prof. Geurts is an editor for Multiple Sclerosis Journal, associate editor for BMC Neurology, and serves on the editorial boards of Neurology and MS International; he is a member of the scientific advisory board of the Dutch MS Research Foundation, of the MS Society of Canada and a scientific steering committee member of the International Progressive MS Alliance; he has served as a consultant for MerckSerono, Novartis, Biogen Idec, Genzyme and Teva Pharmaceuticals. P484 Longitudinal study of venous oxygenation in multiple sclerosis with advanced MRI Y. Ge1, S. Chawla1, J.-C. Brisset1, H. Lu2, P. Storey1, M. Sadowski1, R.I. Grossman1 1New York University School of Medicine, New York City, 2Johns Hopkins University School of Medicine, Baltimore, NY, United States Introduction: T2-relaxation-under-spin-tagging imaging (TRUST) is a novel MRI technique for in vivo non-invasive estimate of cerebral venous oxygenation (Yv), which is a global index of brain oxygen metabolism and neuronal health. Previous studies have shown decreased oxygen utilization in multiple sclerosis (MS). The aim of this study was to evaluate the changes in Yv using TRUST MRI at an interval of approximately 2 years in MS. Methods: A total of 21 healthy subjects and age matched 17 patients with relapsing remitting MS (with sporadic episodes of attacks) were recruited and followed-up in this study. All MS patients underwent two scans at 3T MRI system at an interval of approximately 2 years. Axial TRUST slices on lower superior sagittal sinus (SSS) were acquired using single-shot echo planar imaging sequence with four different T2-weightings (eTE of 0, 40, 80 and 160ms), corresponding to 0, 4, 8 and 16 refocusing pulses in the T2-preparation (τCPMG =10 ms). For each eTE, four pairs of tag and control images were acquired to improve SNR. Data were processed using in-house MATLAB scripts. After pairwise subtraction between control and tag images, four voxels with highest blood signals in the SSS were chosen for T2 fitting. The T2 values were then converted to venous oxygenation via a wellestablished calibration plot for each subject. The T2 and Yv were compared between controls and MS patients. Two tailed paired t-tests were performed to evaluate the changes in the Yv between the baseline and follow-up periods in MS patients.


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Poster Session I, 21(S11) Results: Compared to healthy controls, MS patients at baseline showed significantly elevations in T2 (68.24±10.64ms vs 59.65±7.13ms, p=0.01) and Yv (62.1±6.25% vs 58.2±4.08%, p=0.03). Compared to baseline, MS patients showed a significant increase in T2 at approximately 2-year follow-up time point (68.24±10.64ms vs. 95.46±18.46ms, p< 0.001). Similarly, a significant increase in Yv was also observed at follow-up (62.1±6.25% vs. 74.82±6.51%, p< 0.001) in MS patients. Discussion: Our results suggest that MS patients consume less oxygen and this oxygen underutilization becomes more prominent with disease progression. This impairment of oxygen consumption in MS may have a profound impact on the underlying mechanism of progressive neurodegeneration associated with cellular energy failure, likely due to the chronically high level of nitric oxide in MS that can inhibit the oxygen uptake in mitochondrial aerobic respiratory chain. Disclosure This work was supported by NIH R01 Grants, NS029029-20S1 and NS076588 from National Institute of Health (NIH) and a research grant (RG4707A). This work was also performed under the rubric of the Center for Advanced Imaging Innovation and Research (CAI2R, www.cai2r.net), a NIBIB Biomedical Technology Resource Center (NIH P41 EB017183). P485 Neuroplastic cerebral grey and white matter changes following constraint-induced movement therapy for chronic hemiparetic MS: randomised controlled trial V.W. Mark1,2,3, E. Taub2, M. Haddad2, A. Barghi2, B. Womble2, G.R. Cutter4, D. Morris5, M.H. Bowman2, S. McKay2, T. Adams6, G. Uswatte2,5 1Physical Medicine and Rehabilitation, 2Psychology, 3Neurology, 4Biostatistics, 5Physical Therapy, 6University Hospital Health Club, University of Alabama at Birmingham, Birmingham, AL, United States Background: Chronic MS with minimal relapses does not have well-developed treatment for its associated disability. Its relentless CNS degeneration is associated with irreversible functional decline. Therefore, therapies that can improve both disability and CNS structure in other neurological diseases should be evaluated as potential treatment for MS. Constraint-Induced Movement therapy (CIMT) can improve real-world paretic arm use as well as increase cortical grey matter on structural MRI in stroke and cerebral palsy. However, whether a progressive neurological disorder such as MS could respond similarly has not been evaluated with respect to these concurrent clinical and neuroimaging outcomes. Objective: Evaluate concurrent changes in cerebral grey and white matter structure and real-world arm function in chronic MS following either CIMT vs. a control intervention with similar expectancy to benefit. Methods: 20 adults with chronic minimally or non-relapsing MS and reduced use of the more paretic arm were randomised to CIMT vs. a program of Complementary and Alternative Medicine (CAM) techniques (aquatherapy, yoga, massage, relaxation techniques) for 3.5 h/day x 10 consecutive weekdays. 3 Tesla structural MRI was obtained pre- and post-treatment. Cortical changes were assessed with Voxel-Based Morphometry; white matter

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changes with Fractional Anisotropy (FA) on Diffusion Tensor Imaging. Changes in real-world arm use were assessed with the Motor Activity Log (MAL). Results: Patients had equal expectancy to improve in either treatment assignment. Groups did not differ in pretreatment arm use on the MAL. The CIMT group had significantly larger increases than the CAM group in bilateral sensorimotor cortices [F(1,17) > 9.0, p’s < 0.007]. On whole-brain analysis, only the CIMT group had significantly increased cortical grey matter (p’s < 0.03). Only the CIMT group showed significantly increased FA in white matter regions (p < 0.05). On the MAL there was a very large treatment effect in favor of CIMT [F(1,17) = 31.3, p < 0.001]. Conclusions: CIMT can counteract the degenerative grey and white matter CNS changes of MS at least over the course of treatment, with a parallel real-world improvement in paretic arm use. Similar changes did not occur following a dose-matched alternate treatment with identical expectancy to benefit. Further research should evaluate the retention and generalizability of such changes for this relentlessly progressive neurodegenerative disorder. Disclosure Mark VW: nothing to disclose. Taub E: nothing to disclose. Haddad M: nothing to disclose. Barghi A: nothing to disclose. Womble B: nothing to disclose. Cutter GR: is on the Consultation & Advisory Boards for Alexion, Allozyne, Consortium of MS Centers, Diogenix, Klein-Buendel Incorporated, Genzyme, Medimmune, Novartis, Nuron Biotech, Receptos, Spiniflex Pharmaceuticals, Somahlution, Teva pharmaceuticals, and Xenoport; is the Corporate President for Pythagoras, Inc.; and is on the Data & Safety Monitoring Boards for Apotek, Biogen-Idec, Cleveland Clinic, Glaxo Smith Klein Pharmaceuticals, Gilead Pharmaceuticals, Modigenetech/Prolor, Merck/Ono Pharmaceuticals, Merck, Neuren, PCT Bio, Revalesio, SanofiAventis, Teva, Vivus, NHLBI, NINDS, NMSS, and NICHD. Morris D: nothing to disclose. Bowman MH: nothing to disclose. McKay S: nothing to disclose. Adams T: nothing to disclose. Uswatte T: nothing to disclose. P486 Early structural changes in relapsing remitting multiple sclerosis patients with depression J.I. Rojas, L. Patrucco, F. Sanchez, J. Miguez, E. Cristiano Centro de Esclerosis Múltiple de Buenos Aires, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina Some studies suggest an inflammatory mechanism associated with depression in MS. We investigated the association of structural damage and depression in MS patients. Methods: A prospective study including patients with RRMS, with less than three years of disease onset, EDSS ⩽3 and no history of depression were included. Patients were classified in depressed (D-MS) and non-depressed (nD-MS) based on the clinical assessment for depression and Beck Depression Index Scale at inclusion. Brain dual-echo, high-resolution T1-3D weighted and DT MRI scans were acquired from MS patients and healthy controls (HC).


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Between-group differences of GM and WM volumes were assessed using SIENAX and FIRST software (p< 0.05). Tract-based spatial statistics was used to define the regional distribution of DT MRI abnormalities in WM (FMRIB’s Diffusion Toolbox). Results: 65 individuals, 20 HC, 22 nD-MS and 23 D-MS patients were included. No differences in demographics and clinical variables were observed. In D-MS patients a decrease in total brain volume (p < 0.01), gray matter volume (< 0.01) and an increase in T2 lesion load (p < 0.01) were observed compared with nD-MS. No differences in white matter volume as well as in overall fractional anisotropy (FA) and axial diffusivity values between groups were observed. Conclusion: Patients with D-MS had a more diffuse and focal structural damage than nD-MS. Measures derived from different MR modalities, is a promising approach to improve the understanding of the pathophysiology of depression in MS. Disclosure Authors declare no conflict of interest

OCT P487 A prospective optical coherence tomography study evaluating the effect of glatiramer acetate on changes in retinal nerve fiber layer thickness in patients with relapsing-remitting multiple sclerosis over 24 months R. Zivadinov1,2, R. Melia1, J. Hagemeier1, J. Carl1, M.G. Dwyer1, D. Hojnacki3, C. Colb3, B. Weinstock-Guttman3 1Buffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, 2MR Imaging Clinical Translational Research Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, 3Jacobs Multiple Sclerosis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States Background: The retina is the only place where a tissue layer made up of axons can be imaged directly so quantification of the retinal nerve fiber layer thickness (RNFLT) and total macular volume (TMV) on optical coherence tomography (OCT) have been proposed as potential surrogate markers for the assessment of axonal degeneration in multiple sclerosis (MS). Objectives: To explore whether treatment with glatiramer acetate (GA) may decrease accumulation of axonal loss, as detected by changes in OCT measures in patients with relapsing-remitting (RR) MS compared to a reference population of healthy controls (HCs). Methods: This was a prospective, single-blinded, longitudinal, 24-month OCT study in 60 RRMS patients who started treatment with 20 mg/day of GA, as compared to 40 age- and sex-matched HCs. Subjects underwent clinical and OCT examinations at baseline and at follow-up. Analyses were conducted between all eyes and eyes with or without history of neuritis (ON) before enrollment or during the follow-up. Results: At baseline the average RNFLT was significantly lower in MS patients for total (86.5 vs. 92.3 microns, p=0.007) and temporal inferior quadrant (126.9 vs. 142.6 microns, p< 0.001),

compared to HCs. The baseline TMV was also decreased in MS patients compared to HCs (p=0.005). Over 24 months, MS patients with ON affected eyes lost 1.6 microns of average total RNFLT, compared to 0.8 in MS patients with unaffected eyes and 0.5 in HCs (p=NS). The highest loss was observed for the average temporal inferior RNFLT quadrant in MS patients with affected eyes (6.8 microns), followed by patients with unaffected eyes (4.7 microns) and HCs (4.4 microns) (p=NS). Conclusions: MS patients treated with GA over 24 months did not significantly deteriorate in OCT measures. These findings suggest that treatment with GA can stabilize accumulation of axonal loss in the retina. Disclosure Study disclosures: The study was funded by an investigator initiated grant from Teva Pharmaceuticals. Financial relationships/potential conflicts of interest: Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health. Rebecca Melia, Jesper Hagemeier and Jillian Carl have nothing to disclose. Michael G. Dwyer has received consultant fees from Claret Medical and EMD Serono. Channa Kolb has received speaker honoraria from Novartis, Genzyme and Biogen-Idec. David Hojnacki has received speaker honoraria and consultant fees from Biogen Idec, Teva Pharmaceutical Industries Ltd., EMD Serono, Pfizer Inc, and Novartis. Bianca Weinstock- Guttman received honoraria as a speaker and as a consultant for Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis and Acorda. Dr Weinstock-Guttman received research funds from Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis, Acorda. P488 Anti-viral antibodies levels are not associated with OCT measures B. Weinstock-Guttman1, K. Kavak1, Z. Younus2, B. Teter1, M. Nadeem1, K. Zakalik1, R. Zivadinov3, S.A. Sanai1, C. Kolb1, M. Ramanathan4 1Neurology, 2SUNY University at Buffalo, 3BNAC, Neurology, 4Pharmaceutical Sciences, SUNY University at Buffalo, Buffalo, NY, United States Objective: To investigate the association between blood antiviral antibodies levels (viral capsid antigen [VCA], EpsteinBarr nuclear antigen [EBNA], and Cytomegalovirus [CMV]) and Optical coherence tomography (OCT) measures in a prospective cohort of RRMS patients with a disease duration ⩽ 5 years. Background: Retinal Nerve Fiber Layer Thickness (RNFLT) was shown to be strongly associated with visual but also neurological disability and with MRI measures of brain atrophy in MS cohorts. Presence of anti-CMV and high anti-EBV antibodies levels were associated with more destructive MRI metrics.


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Poster Session I, 21(S11) Methods: Data of 138 MS patients were analyzed. The OCT measures were calculated based on either (1) the affected eye for patients with a unilateral history of ON (2) the average of affected eyes for patients with a bilateral history of ON or (3) the average of both eyes for patients without a history of ON. Blood measures were divided into quartiles. One way Analysis of Variance (ANOVA) tests were carried out to investigate possible associations between anti-viral levels and OCT measures. Results: RNFLT was significantly lower among patients with a history of ON (38.8% of cohort) compared to those without (83.4±16.8 vs 91.3±12.6 respectively, p=.006). Macular volume of those with a history of ON was 8.3 (SD=.48) compared to 8.4 (SD=.47) for those with no history of ON (p=.096). Total macular volume was significantly associated with CMV positivity; those who were CMV positive had significantly lower total macular volume compared to patients who were CMV negative (16.7±.78 vs 17.0±.80 respectively, p=.037) although significance was lost after adjusting for ON status. There were no significant differences between VCA and EBNA levels with either ON status or OCT measures. Conclusion: High levels of anti-viral antibodies do not show a significant relation to the destructive process measured by OCT suggesting a different underlying pathology from the MRI metrics (lesion load and atrophy). Disclosure Bianca Weinstock-Guttman has participated in speaker´s bureaus and served as a consultant for Biogen Idec, Teva Neuroscience, EMD Serono, Novartis, Genzyme & Sanofi, Acorda Therapeutics, Inc. and Genentech. Dr. Weinstock-Guttman also has received grant/research support from the agencies listed in the previous sentence as well as Questcor Pharmaceuticals, Inc., and Shire. She serves in the editorial board for BMJ Neurology, Journal of International MS and CNS Drugs Dr. Murali Ramanathan received research funding the National Multiple Sclerosis Society and the Department of Defense. He received compensation for serving as an Editor from the American Association of Pharmaceutical Scientists. He also receives revenue from a self-published textbook. These are unrelated to the research presented in this report. Katelyn Kavak Nothing to disclose Barbara Teter Nothing to disclose Zilfa Younus Nothing to disclose Muhammad Nadeem Nothing to disclose Karen Zakalik Nothing to disclose Shaik Ahmed Sanai Nothing to disclose, Channa Kolb has received speaker honoraria from Novartis, Genzyme and Biogen-Idec. Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health. P489 Longitudinal reduction of total macular volume in relapsing and remitting multiple sclerosis: indicative of ongoing neurodegeneration

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A.S. Loughran-fjeldstad1, N.G. Carlson2, L.J. Cook3, J.W. Rose1,2 1Neurology, University of Utah, 2Neurovirology, VA SLC HSC, GRECC, 3Pediatrics, University of Utah, Salt Lake City, UT, United States Background: Optical coherence tomography (OCT) is a noninvasive imaging technique that can quantify thickness of the retinal layers and subsequent the total macular volume (TMV). OCT has become increasingly important in monitoring neurodegeneration of the CNS associated with autoimmune diseases, including Multiple Sclerosis (MS). Objective: To examine TMV in Relapsing-Remitting MS (RRMS) patients with and without a history of optic neuritis (ON) over three 6 month intervals for evidence of neurodegeneration. Methods: TMV measurements were completed using spectral domain OCT in 117 patients with no prior history of ON (MS Unaffected) and in 37 patients with a history of bilateral ON (MS Affected). One eye was randomly selected from each participant. All patients were free from relapse or ON at least 6 months prior to participating in these studies. Results: TMV was significantly reduced in the MS Affected (8.1 ± 0.4 mm3) eyes compared with the MS Unaffected (8.4 ± 0.04 mm3) eyes at baseline (p < 0.0001). However, over time there were no significant changes in TMV in the MS Affected group (p > 0.05). In contrast, the MS Unaffected eyes showed a significant decrease over time between visit 1 (8.40 ± 0.04 mm3) and visit 3 (8.36 ± 0.04 mm3) (p = 0.0001), and between visit 2 (8.38 ± 0.04 mm3) and visit 3 (p = 0.008), but not between visit 1 and visit 2 (p = 0.06). Conclusions: No significant differences in TMV were observed in the eyes of the MS Affected group over the three measurements suggesting that affected eyes reach a steady state following ON. However, the significant changes observed in TMV in the MS Unaffected group are indicative of ongoing progressive neurodegeneration. Therefore, OCT measures of TMV in unaffected eyes may be of particular value in longitudinal studies of RR-MS and progressive forms of MS for clinical trials. Disclosure Anette S. Loughran-Fjeldstad: Nothing to disclose. Noel G. Carlson: Nothing to disclose. Larry J. Cook: Nothing to disclose. John W. Rose: Nothing to disclose. P490 Microcystic macula edema in myelin oligodendrocyte glycoprotein (MOG-) antibody-associated relapsing optic neuritis J. Havla1, O. Outteryck1,2, F. Schmidt3, M. Spadaro1, E. Meinl1, R. Hohlfeld1,4, T. Kuempfel1 1Institute of Clinical Neuroimmunology, Munich, Germany, 2Université Lille Nord de France, Lille, France, 3Department of Neurology, Ingolstadt, 4Munich Cluster for Systems Neurology (SyNergy), Munich, Germany Introduction: Patients with antibodies to myelin-oligodendrocyte glycoprotein (MOG abs) can display a wide spectrum of clinical phenotypes. While antibodies to cell-bound MOG were initially detected in pediatric patients, MOG abs were recently


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also observed in patients with seronegative neuromyelitis optica (NMO), NMO spectrum disease and relapsing optic neuritis (ON). Optical coherence tomography (OCT) data in patients with MOG abs positive ON are scarce. Peripapillar retinal nerve fiber layer (pRNFL) edema is usually seen in acute anterior ON. Rarely, microcystic macular edema (MME) shows the proportion of focal retinal inflammation or neurodegeneration. Case description: In this 53 yo male patient without immunosuppressive pre-treatment, severe ON of both eyes occurred in 01/2015. Initially, his visual acuities were reduced to cloudy vision (OD) and 20% (OS) with retrobulbar pain. CSF showed pleocytosis (9 cells/µl), elevated albumin levels (1260 mg/l), but no oligoclonal bands. Brain MRI (without specific optic nerve imaging) and spinal cord MRI were unremarkable. Past medical history revealed recurrent ON: bilateral 1987; 1994/1999 episodes with retrobulbar pain, OS 2001 (vision OD 100%, OS 40%). Acute ON was suspected by external physicians and (1) a steroid pulse therapy (5 g) was initiated, followed by (2) plasma exchange (PLEX, 5 cycles). MOG abs were measured for the first time and tested positive (aquaporin-4 abs negative). After PLEX, he improved only marginally and presented to us in 3/2015. We performed the first OCT (visual acuity OD 0.3, contrast vision 2.5%chart: 0/60) and detected bilateral MME in macular volume scan besides severe bilateral pRNFL atrophy. Another course of steroids (5 g) was given. In 04/2015 brain MRI showed signs of ongoing ON with extensive gadolinium (Gd)-enhancement along both optic nerves. Compatible with those findings the MME increased in number and expansion (but no edema in pRNFL). Repeated MOG abs testing revealed highly anti-MOG reactivity. Another course of PLEX was initiated, and immunosuppressive therapy with azathioprine recommended. Conclusion: Here we describe the first case of MME in MOG abs positive recurrent ON with Gd-enhancement of both optic nerves which correlated with high anti-MOG reactivity in serum. We assume that MME in this patient reflects severe inflammation of the anterior visual pathways, and may thus serve as an outcome parameter in MOG abs associated ON. Disclosure JH received speaker honoraria, travel expenses, and personal compensations from Merck Serono, Bayer Healthcare and Novartis Pharma. TK has received travel expenses and personal compensations from Bayer Healthcare, Teva Pharma, Merck Serono, Novartis, Sanofi Aventis, Genzyme and Biogen Idec, Inc. as well as grant support from Bayer-Schering AG and Novartis Pharma. RH has received travel expenses, speaker honoraria and personal compensations from Bayer Healthcare, Teva Pharma, Merck Serono, Novartis, Sanofi Aventis, Genzyme and Biogen Idec, Inc. as well as grant support from Novartis, Teva Pharma, BiogenIdec, Merck-Serono, Bayer Healthcare und Sanofi-Aventis. RH is supported by the DFG (DFG CRC TRR128, Z2) and BMBF (KKNMS). OO, EM, MS and FS declare that they have no competing interests. P491 Evaluation of choroidal vascular changes in patients with multiple sclerosis using enhanced depth imaging optical coherence tomography

E. Esen1, S. Sızmaz1, M. Demirkiran2, T. Demir2, İ. Ünal3, N. Demircan1 1Ophthalmology, 2Neurology, 3Biostatistics, Çukurova University, Adana, Turkey Background and objective: The aim of this study is to evaluate the choroidal thickness (CT) in patients with multiple sclerosis (MS) using enhanced depth imaging optical coherence tomography and to assess its correlation with retinal nerve fiber layer (RNFL) thickness, disease duration and disease disability. Patients and methods: In this study 68 eyes of 34 MS patients and 60 eyes of 30 healthy subjects were enrolled. All participants underwent optical coherence tomography scanning for RNFL and CT measurements. Choroidal thickness was measured at fovea and at six extrafoveal points. Results: The mean CT measurements in MS patients were significantly thinner than those of healthy controls at all measurement points (p< 0.001). Among MS patients, CT values revealed no significant difference between 32 eyes with ON and 36 eyes without ON. Average subfoveal CT did not correlated with RNFL and expanded disability status scale (EDSS) scores, but reduced CT was associated with longer disease duration (r= -0.28, p=0.019) in MS patients. Conclusion: Choroidal thickness decreases in MS patients when compared with healthy controls. The decreased CT might provide evidence to support potential role of vascular dysregulation in the pathophysiology of MS disease. Disclosure Ebru Esen: Nothing to disclose Selçuk Sızmaz: Nothing to disclose Turgay Demir: Nothing to disclose Meltem Demirkiran: Nothing to disclose İlker Ünal: Nothing to disclose Nihal Demircan: Nothing to disclose P492 Optical coherence tomography in multiple sclerosis patients: correlation with MR spectroscopy M. Siger, K. Dziegielewski, J. Nawrocki, K. Selmaj Medical University of Lodz, Lodz, Poland Goal of the study: To assessed the correlation between retinal nerve fibre layer thickness (RNFL) and normal appearing white matter damage analyzed by proton magnetic resonance spectroscopy (H-MRS). Methods: Twenty two relapsing-remitting MS patients and 8 healthy control subjects were subjected to RNFL thickness measurement by optical coherence tomography and brain H-MRS. Proton magnetic spectroscopy was performed in NAWM in left and right centrum semiovale. N-acetyl-aspartate (tNAA), choline-containing compounds (tChol), creatine (Cr), myo-inositol (mIn), glutamine and glutamate compounds (Glx) were estimated. Results: There was a correlation between reduction of average RNFL thickness and lower tNAA concentration of NAWM in MS N-ON patients (p=0.02, r= 0.6). Sectoral analysis showed that in the same group of patients there was a correlation between RNFL


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Poster Session I, 21(S11) thickness in the temporal quadrant and decreased concentrations of tNAA (p=0.01, r= 0.6). Conclusion: Our results suggest that RNFL changes indicate white matter damage exceeding the visual pathway thus making RNFL potential marker for neuro-axonal damage especially in MS N-ON patients. Disclosure Siger M: Nothing to disclose Dziegielewski K: Nothing to disclose Nawrocki K: Nothing to disclose Selmaj K: Nothing to disclose P493 Relationships between brain atrophy and structure of optic nerves in multiple sclerosis S. Sivertseva1, E. Kochkina1, I. Dolgova2, I. Proskuryakova1, O. Dolgova2, A. Boyko3 1MSCH ‘Neftyanik’, 2Tyumen Regional Ophthalmic Clinic, Tyumen, 3Pirogov’s Russian National Research Medical University, Moscow City Multiple Sclerosis Center, Moscow, Russian Federation Objective: To assess associations between retinal nerve fiber layer (RNFL) thickness and brain atrophy using bicaudate ratio (BCR), and to evaluate relationship these measures to clinical disability in patients with relapsing-remitting multiple sclerosis (MS). Methods: Thirty-one patients with a mean age of 34,1±11,69 years were enrolled (32,3% patients with previous history of optic neuritis). All patients underwent 1,5-tesla brain magnetic resonance imaging (MRI) with intravenous contrast, detailed ophthalmological examination, optical coherence tomography, multifocal visual evoked potentials (mfVEP). Disability was assessed according to the Expanded Disability Status Scale (EDSS). Brain atrophy was estimated using MRI with bicaudate ratio (BCR), which was calculated by dividing the minimum intercaudate distance by brain width at the same level. Results: Average RNFL thickness was 81,6±14,03 µm, in generally, this parameter was decreased in 57,1% including visually asymptomatic patients. Average EDSS score was 2,5±0,87. There were 93,5% patients with delayed latency of the mfVEP and 83,9% with abnormalities in ophtalmoscopy. Average BCR in percentage was 11,8±3,21%. There were correlations between disease duration and BCR(r=0,417, p=0,022), EDSS score and BCR (r=0,452, p=0,012). There was negative correlation between BCR and average RNFL thickness (r = -0,386; p = 0,032), BCR and changes in ophtalmoscopy (r = -0,396; p = 0,030). Conclusions: Our study demonstrated association between brain atrophy and damage of retinal axons in patients with MS. We conclude that RNFL and BCR are seems to be predictors of disability in relapsing-remitting MS. Disclosure S.A. Sivertseva: nothing to disclose; E.E. Kochkina: nothing to disclose; I.A. Proskuryakova: nothing to disclose; I.G. Dolgova: nothing to disclose; A.N. Boyko: nothing to disclose;

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P494 A comprehensive analysis of the optic pathway, from retina to cortex, discloses no correlation between white matter inflammation and neurodegeneration in very early multiple sclerosis L. Federle, M. Puthenparampil, L. Cacciaguerra, S. Zywicki, D. Poggiali, F. Rinaldi, P. Perini, P. Gallo Multiple Sclerosis Centre of Padua, Neurological Clinic of Padua, Department of Neuroscience, University of Padua, Padova, Italy Introduction: The optic pathway was suggested to be a prototype system to investigate trans-synaptic degeneration in multiple sclerosis (MS). Objectives: To investigate possible relationships between white matter (WM), cortical and retinal damage in a very early phase of MS. Material and methods: The study included 43 patients with clinically isolated syndrome or very early relapsing remitting MS (CIS/eRRMS; mean disease duration 2.8±2.5 months) and 31 matched healthy controls (HC). Patients were divided into optic neuritis positive (ON+, n.9) or ON- (n.34) on the base of clinical presentation. MRI examination included 3D Fast Field Echo (3DT1) and 3D Fluid Attenuated Inversion Recovery (3D-FLAIR) sequences. Global cortical thickness (gCTh), pericalcarin CTh (V1-CTh) and white matter volume (WMV) were analysed by means of Freesurfer on 3D-T1 sequences. Optic radiation morphology (OR) and volume (ORV) were reconstructed on the base of the Jülich’s Atlas. White matter lesion volume (WMLV), OR-WMLV and percent WM damage (WMLV/WMV=WMLV% and OR-WMLV/ORV=ORWMLV%) were obtained by 3D-FLAIR image segmentation. The optic coherence tomography (OCT) included the analysis of macular volume (MV), global peripapillary retinal nerve fiber layer (g-RNFL) and the 6 fundus oculi’s sectors (temporal, T-RNFL; temporal superior, TS-RNFL; nasal superior, NS-RNFL; nasal, N-RNFL; nasal inferior, NI-RNFL, temporal inferior, TI-RNFL). The retina of both eyes was analyzed. The eyes of ON+ were further divided into affected (aON+) or not (naON+). Results: Compared to HC, both ON+ and ON- had a reduced CTh in many cortical areas. While no difference in CTh was found between ON- and ON+, ON+ had higher OR-WMLV, OR-WMLV%, WMLV and WMLV% than ON-. No correlation between gCTh or V1-CTh and OR-WMLV or OR-WML% was observed in both groups. Compared to HC and ON- eyes, aON+ presented a significant thinning of T-RNFL (p< 0.0001) and TI-RNFL (p< 0.0001). While in HC g-RNFL positively correlated to all RNFL sectors, in ON- this correlation was significantly reduced for all sectors but T-RNFL. The multivariate analysis failed to disclose any correlation between OCT data and MRI WM and cortex parameters. Conclusions: No relationship between WM, cortical and retinal damage in both ON+ and ON- CIS/eRRMS patients was demonstrated. The observation of an early involvement of the RNFL in ON- merits to be further investigated as possible marker of primary rather than trans-synaptic neurodegeneration in MS. Disclosure Dr. Lisa Federle has received funding for travel from Merck Serono, Biogen Idec, Sanofi-Aventis, and Bayer Schering Pharma and honoraria from Genzyme, Teva and Almirall.


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Dr. Marco Puthenparampil has received funding for travel from Teva, Merck Serono, Biogen Idec, and Novartis. Dr. Laura Cacciaguerra has nothing to disclosed. Dr. Sofia Zywicki has nothing to disclosed. Dr. Davide Poggiali has nothing to disclosed. Dr. Francesca Rinaldi has received honoraria from Biogen Idec, MerkSerono and Teva.Dr. Paola Perini has has received honoraria from Biogen Idec/Elan, Merck Serono, Sanofi-Aventis and Teva; has been a consultant for Biogen Idec, Merck Serono and Teva. Prof. Paolo Gallo has received honoraria from Bayer Schering, Biogen Idec/Elan, Merck Serono, Novartis, Sanofi-Aventis and Teva; has been a consultant for Bayer Schering, Biogen Idec, Genzyme, Merck Serono and Novartis; has received research support from Bayer, Biogen Idec/Elan, Merk Serono, Genzyme and Teva; and has received research grant from the University of Padova, Veneto Region of Italy, the Italian Association for Multiple Sclerosis, the Italian Ministry of Public Health. P495 Prospective study of retinal nerve fibre layer thickness in alemtuzumab treated multiple sclerosis patients A.-L. Nguyen1, J. Lam1, Y. Zhao1, R. Carruthers1, A. Javed2, S. Krolczyk3, A. Traboulsee1, ICAMMS IST 1University of British Columbia, Vancouver, BC, Canada, 2University of Chicago Medicine, Chicago, IL, 3Genzyme, a Sanofi company, Boston, MA, United States Background: Retinal nerve fibre layer (RNFL) thickness is emerging as a biomarker for axonal loss and may reflect more global atrophy in multiple sclerosis (MS). RNFL thickness, measured by optical coherence tomography (OCT), is reduced in MS patients with and without a history of optic neuritis. To date, treatment for RRMS has not been shown to affect progressive RNFL thinning, which is previously reported as -2.0µm/year in treated patients. Alemtuzumab is a humanized monoclonal antibody against CD52 that has been highly effective in RRMS at preventing relapses, disability progression and new MRI lesions and in slowing brain atrophy. We hypothesize that the neuroprotective benefits of alemtuzumab will be evident on the prevention of RNFL thinning. Objectives: To measure the mean change in RNFL thickness in MS patients treated with alemtuzumab over a 2-year period. Methods: This was a prospective single centre open label study of RRMS patients treated with up to 2 courses of alemtuzumab and followed up over a 2-year period. Patients with and without a prior history of optic neuritis were included. The Heidelberg Spectralis SD-OCT was used to obtain the mean RNFL thickness at baseline and at 6-month intervals. Results: 22 patients were analysed (mean age=34y, 20F:2M, mean disease duration=5y). The overall mean change in RNFL thickness was +1.8µm (95% confidence interval -0.5, 4.1; p=0.12). Median baseline EDSS was 3.2 (range 0-5) and at 2 years was 2.0 (range 0-5.5), with a median change in EDSS of -0.5. Conclusion: In contrast to the published natural history of progressive RNFL thinning in RRMS, this treated cohort did not demonstrate a measurable decline over two years. The findings of this study suggests that alemtuzumab may target mechanisms that promote neuroprotection on retinal axons.

Disclosure A Nguyen: received grant support from Novartis for her fellowship. J Lam: nothing to disclose. Y Zhao: nothing to disclose. R Carruthers: lectures for Genzyme, Teva, Biogen; clinical trials with Biogen, Roche, Genzyme, Novartis, Biogen, Teva, MedImmunue, Chugai. A Javed: received consulting fees from Bayer, Teva, Novartis, Mallinckrodt, Genzyme, Biogen. S Krolczyk: employed at Genzyme no other conflicts. A Traboulsee: received grant support from Hoffman la Roche and Sanofi Genzyme; steering committee membership for Hoffman la Roche; consultancy for Biogen, Chugai, EMD Serono, Hoffman la Roche, Medimmune, Sanofi Genzyme, Teva Neuroscience. Source of funding: Genzyme. P496 Leber;s hereditary optic neuropathy & untreated remitting relapsing MS share multicolor OCT findings: potential biomarker for mitochondrial flavoprotein biosynthesis and for electron transport chain activation R.C. Sergott1,2, M.L. Moster1,2, OCT 1Neuro-Ophthalmology, Wills Eye Hospital, 2Neurology, Thomas Jefferson University, Philadelphia, PA, United States Background: MultiColor OCT [MC] provides a topographic map of the retina using 3 different wavelengths of light to image the outer, mid, and inner retina, MC is a different imaging paradigm compared to spectral domain OCT. Method and results: MC images of patients with acute LHON, a disorder of single point mutations of mitochondrial DNA and carriers of LHON mutations demonstrated green, instead of, red retinas, in a halo pattern in the paramacular area. This observation appears to indicate enhanced mitochondrial activity or possibly mitochondrial biogenesis due to increased production of flavoproteins [FP], a key component of mitochondrial metabolism and the electron transport chain since FP can be excited in the blue wavelength of light (488nm) and emits florescence in the green wavelength range (approx. 533nm). MC images of 10 patients with LHON and LHON carriers were compared to patients with untreated MS . Similar findigns were found not only in the retinas but also in the retinal vascular system. In 15 patients whose MS was clinicallly inactive as defined by clinical status and MRI findings, the MC results were normal. In contrast, 7/10 paitents with a non-ophthalmic exacerbationsof MS demonstarted a greeen retinal signal. Green retinal signals were not observed in 15 age and gender matched controls. However, similar,signals were observed with Alzheimer´s, Parkinson´s and multisystem atrophy, other diseases believed to have a potential mitochodrial component in pre-apoptotic cellular pathophysiology. Discussion: Therefore, the green signature of MC is not specific for a single disease but rather a final common pathway for many neuro-ophthalmic degenerative conditions, inlcuidng MS. The green retinal signature may evolve into a biomarker for mitochondrial metabolic activty of FP in MS and pre-apoptotic cell death, a pathway which has been demonstrated in age-related macular


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Poster Session I, 21(S11) degeneration, diabetic retinopathy, and retinal degenerative syndromes. MC-OCT adds another dimension to the pathologic changes occuring within the afferent visual system in MS, a disease that with pathological evidence of mitochondrial DNA abnormalities and LHON, a disease with known mitochondrial DNA mutations. Disclosure Robert C. Sergott, MD has served as a consultant and speaker for Heidelberg Engineering, Biogen-Idec, EMDSerono, Teva, Genzyme, Merck, Johnson & Johnson, Mallinckrodt, Lundbeck, and Glaxo Smith Kline. Mark L Moster, MD, has served as a consultant and speaker for Biogen-Idec, Teva, Genzyme, and Accorda. P497 Patterns of OCT changes in optic neuritis C. Maggiore1, R. Khan2, A. Petzold1 1Neuro-Ophthalmology, 2IT Service, Moorfields Eye Hospital NHS Trust, London, United Kingdom Background: Multiple sclerosis (MS) is an inflammatory/degenerative disease and continuous attempts of improvement of noninvasive imaging techniques to evaluate the degree of degeneration are ongoing. Optical coherence tomography (OCT) assessment of the thickness of the peripapillary retinal nerve fiber layer (pRNFL) and segmented macular layers are measure of the bi-directional axonal damage, and consequently cascaded neuronal degeneration, after an episode of acute optic neuritis (ON). In addition, focal swelling of the inner nuclear layer and outer retinal layers have been observed and related to pathology, namely microcyst formation and cytotoxic oedema. The possibility to distinguish between MSON and MSON mimics is relevant for patient management. The aim of this study was to investigate patterns of early and late retinal changes in a range of optic neuropathies. Methods: A retrospective review of 76 patients investigated for suspected optic neuritis. Spectral domain OCT scans were segmented using an automated 11-layer algorithm. Results: The average age of the patients was 40 years with a female:male ratio of 2.5:1. The patients were classified in healthy controls (n=17), MS associated ON (MSON, n=42), and other inflammatory optic neuropathies (n=17). Different patterns of qualitative and quantitative changes were observed in inner and outer retinal layers. In contrast to MSON other optic neuropathies frequently had more severe atrophy of the inner retinal layers compared to healthy controls. Conclusion: This study confirms earlier data on more severe inner retinal layer atrophy in patients with MSON mimics. Likewise atrophy in the macular region presents earlier than pRNFL atrophy permitting to bypass the limitations of a swollen optic disc and related pseudo-atrophy in the first weeks following optic nerve inflammation, independent of aetiology.

P498 OCT characteristics at baseline in the SPRINT-MS/ NN 102 phase II trial of ibudilast in progressive MS R.A. Bermel1, J. Yankey2, C. Novalis3, J. Schneebaum3, P. Kaiser1, C. Coffey2, M.E. Cudkowicz4, T. Gleason5, A. Goodman6, E.C. Klawiter4, K. Matsuda7, M.M. McGovern4, E. McNeil8, R. Naismith9, R.J. Fox1 1Cleveland Clinic, Cleveland, OH, 2University of Iowa, Iowa City, IA, 3Digital Angiography Reading Center, Great Neck, NY, 4Massachusetts General Hospital, Boston, MA, 5Patient Advocate, Seattle, WA, 6University of Rochester Medical Center, Rochester, NY, 7Medicinova Inc, San Diego, CA, 8National Institute of Neurological Disorders and Stroke, Bethesda, MD, 9Washington University in St Louis, St. Louis, MO, United States Objective: To report baseline optical coherence tomography (OCT) characteristics of all enrolled subjects in a phase II trial of ibudilast in progressive MS (PMS). Background: There are no effective therapies for the treatment of PMS, and the optimal outcome metric for phase II trials in PMS is unknown. OCT is a potential outcome measure because of its ease of acquisition and its relative specificity for axonal integrity, but there is a paucity of experience implementing OCT in multicenter trials in PMS. Design and methods: NN 102/SPRINT-MS is a phase II trial of ibudilast in primary and secondary PMS utilizing the NINDSsponsored NeuroNEXT clinical trial network. The trial will evaluate the safety, tolerability, and activity of ibudilast with whole brain atrophy as primary outcome measure and peripapillary retinal nerve fiber layer thickness (RNFL) as a key secondary outcome measure. Approximately 250 subjects (from 28 US sites) will be randomized 1:1 to ibudilast 100mg/d or placebo. Each site will provide spectral domain (SD) OCT at 5 visits over the 96 week study duration, using either the Zeiss Cirrus or Heidelberg Spectralis instrument. OCT is being coordinated through a central OCT reading center, with specifications on agreement among certified graders who select from multiple individual scans at each time point. Results: As of May 1, 2015, the study has completed enrollment, with randomization expected to be complete by June 2015. Of those that have been randomized, 164 have baseline measurements available in the OCT dataset, with 126 subjects scanned using a Cirrus machine and 38 subjects using a Spectralis machine. Mean RNFL in the Cirrus group is 81.7uM (SD ± 11.4) in the right eye, 80.5uM (SD ± 12.2) in the left eye, and in the Spectralis group 85.1uM (SD ± 15.2) in the right eye and 83.9 (SD ± 15.7) in the left eye. Ganglion cell layer-inner plexiform layer thickness in the Cirrus group was 70.5uM (n=119, SD ± 10.3) in the right eye and 69.9uM (n=117, SD ± 10.2) in the left eye. Baseline characteristics of the full trial cohort will be presented. Conclusions: The NN102/SPRINT-MS demonstrates the feasibility of a multicenter trial in PMS to employ SD-OCT at all sites, coordinated by a central reading center, and allow two different acquisition platforms. Disclosure

Disclosure Cosimo Maggiore: nothing to disclose Ratna Khan: nothing to disclose Axel Petzold: nothing to disclose

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Supported by National Institutes of Health (U01NS082329 to Cleveland Clinic), National Multiple Sclerosis Society (RG-5184-A-6), Medicinova (through the National Institutes of Health), and individual grants from the National Institutes of Health


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to the Clinical Coordinating Center, Data Coordinating Center and each of the NeuroNEXT sites. RAB: has received consulting fees from Biogen, Novartis, Genentech, Genzyme, and Mallinkrodt. JY: nothing to disclose CN: is an employee of the Digital Angiography Reading Center (DARC). JS: is an employee of the Digital Angiography Reading Center (DARC). PK: nothing to disclose. CC: has received personal compensation for activities with ZZ Biotech, LLC as a consultant. MC: has received consultant fees from Trophos, GSK, BiogenIdec, Teva; served as site PI for clinical trials sponsored by Biogen-Idec and Neuraltis. TG: nothing to disclose. AG: has received personal compensation from Acorda Therapeutics, Actelion, Biogen-Idec, Genzyme-sanofi, GW Pharma, Mylan, Novartis, Teva, and Vaccinex for consulting services; financial support for research activities from Acorda Therapeutics, Avanir, Biogen Idec, EMD Serono, Genzymesanofi, Novartis, Ono, Roche, Sun, Takeda, and Teva; served as a site PI for a multi-center clinical trial by Roche. EK: has received consulting fees from Biogen Idec and Mallinckrodt Pharmaceuticals and research funding from Roche and Atlas5d. KM: is an employee of Medicinova MM: nothing to disclose EM: nothing to disclose RN: has received consulting and speaking fees from Acorda, Bayer, Biogen, Genentech, Genzyme, EMD Serono, Novartis, Questcor, Teva; served as Associate Editor, Journal Watch Neurology; served as site PI in a clinical trial sponsored by Acorda. RJF: has received consultant fees from Biogen Idec, GlaxoSmithKline, Novartis, Questcor, Teva, and Xenoport; grant and research support from Novartis. P499 Reduced corneal nerve fiber and dendritic cell density in patients with multiple sclerosis J. Mikolajczak1, H. Zimmermann1, E.M. Kadas1, A. Kheirkhah2, R. Muller2, A. Ren2, H. Prüß3, F. Paul1, P. Hamrah2, A.U. Brandt1 1Charité - Universitätsmedizin Berlin, NeuroCure Clinical Research Center, Berlin, Germany, 2Ocular Surface Imaging Center, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States, 3Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany Background: Multiple Sclerosis (MS) is the most common autoimmune disorder of the central nervous system. Previous studies suggest a mild affection of the peripheral nervous system (PNS) in some patients as well. The corneal subepithelial nerve plexus (SNP) is densely innervated by axons of the trigeminal nerve. As a part of the PNS, the SNP can easily be examined using in-vivo confocal microscopy (IVCM), which allows non-invasive imaging of small nerve branches and dendritic cells (DC). IVCM has been successfully used to show abnormalities in nerve quality and quantity in various herpes infections and diabetes.

Objective: To investigate the SNP in patients with MS and healthy controls (HC) and to identify differences in SNP and DC density as a possible sign of PNS affection in MS. Methods: Twenty-seven patients with relapsing-remitting MS (RRMS) (19 female, mean age 42.7 ± 9.3 years) and 20 age and sex matched HC were investigated with IVCM using a Heidelberg Engineering Retina Tomograph with Rostock Cornea Module. Using composite images, total nerve density and dendritic cell density were analyzed. Results were tested for a correlation with MS clinical severity described by the multiple sclerosis functional composite (MSFC) and expanded disability status scale (EDSS), visual acuity and retinal optical coherence tomography parameters. Measurements were analyzed using generalized estimating equation models (GEE). Results: Total nerve density was significantly reduced in RRMS compared to HC (16,3 ± 4,8 vs. 19,5 ± 5,3 µm/mm², GEE p=0.013). RRMS patients showed fewer dendritic cells (30.7 ± 27.2 vs. 71.5 ± 64.3 cells/mm², GEE p=0.007). There was a correlation of reduced total nerve density with disease duration (B=24.1, p=0.048) and lower MSFC score (B=1697, p=0.0013). Conclusion: The corneal nerve plexus is altered in patients with MS and thus allows investigation of disease pathology at the interface between central and peripheral nervous system. Corneal nerve density turnover is thought to be regulated by the trigeminal nerve, which could be a potential mechanism for the observed effect. Reasons for the reduced number of dendritic cells remain elusive, but might be founded in immunomodulatory therapy. Disclosure JM received speaking fees unrelated to this study from TEVA. HZ received speaking fees unrelated to this study from TEVA. EMK reports no conflicts of interest. RM reports no conflicts of interest. AR reports no conflicts of interest. HP reports no disclosures. FP received research support from the German Ministry for Education and Research (Competence Network Multiple Sclerosis), the Guthy Jackson Charitable Foundation and National Multiple Sclerosis Society, research grants and speaker honoraria from Bayer, Teva, Genzyme, Merck, Novartis, MedImmune and is member of the steering committee of the OCTIMS study (Novartis). PH reports no conflicts of interest. AUB reports no conflicts of interest. AUB received consulting fees unrelated to this study from Biogen, Novartis, Teva, Nexus, and Motognosis. AUB received funding unrelated to this study for research from Novartis, Biogen, BMWi and BMBF.

Neurophysiology P500 Asymptomatic subjects differ less from their twin siblings with multiple sclerosis, than from healthy controls in cognition. A Finnish twin cohort study H. Kuusisto1, T. Vahvelainen2, P. Hämäläinen3, T. Luukkaala4, I. Elovaara5,6 1Kanta-Häme Central Hospital, Hämeenlinna, 2Tampere University Hospital, Tampere, 3Masku Neurological Rehabilitation Centre, Masku, 4Science Center, Pirkanmaa Hospital District, 5Tampere School of Public Health, University of Tampere, 6Medical School, Tampere University, Tampere, Finland


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Poster Session I, 21(S11) Background: Cognitive impairment develops in some MS patients at any time during the course of the disease regardless of whether the patients have neurological disability or not. Underlying causes for the MS related cognitive decline are yet poorly understood but both genetic and environmental risk factors have been proposed. Objectives: To assess whether the cognitive performance differs between subjects with multiple sclerosis (MS) and their asymptomatic co-twins. Methods: Nineteen twin pairs discordant for MS recruited from the Finnish Twin Cohort were studied neurologically and with a comprehensive neuropsychological test battery. Control group included twenty age and education matched healthy subjects. Results: Compared with the control subjects, the asymptomatic co-twins of MS patients performed significantly less well in tests of naming, verbal reasoning, visuospatial performance, processing speed, attention, verbal memory and learning. The twins with MS performed significantly less well than their co-twins only in the SDMT evaluating processing speed, in visual learning and in word fluency. Conclusions: In the present sample subjects genetically susceptible for MS showed cognitive deficits typical for MS in the absence of actual disease. Disclosure Hanna Kuusisto, Tarja Vahvelainen, Päivi Hämäläinen, Tiina Luukkaala and Irina Elovaara have nothing to disclose. P501 Differences between oVEMP and cVEMP in the correlation with the brainstem and cervical spinal cord MRI in multiple sclerosis M. Krbot Skoric1, T. Gabelic1, L. Crnosija2, I. Adamec1, E.S. Papathanasiou3, M. Habek1,2 1University Hospital Centre Zagreb, 2School of Medicine, University of Zagreb, Zagreb, Croatia, 3Clinical Neurophysiology Laboratory, Clinic B, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus Background: Vestibular evoked myogenic potentials (VEMP) are a good measure of brainstem involvement of multiple sclerosis (MS). The aim of this study was to correlate VEMP results with the conventional MRI of the brainstem and the cervical spinal cord. Methods: This retrospective study on prospectively collected data, included 98 patients with relapsing-remitting MS. Cervical VEMPs (cVEMPs) and ocular VEMPs (oVEMPs) were analyzed individually and in the form of a VEMP score. Brainstem and cervical spinal cord (CSC) MRI 1.5 T was performed. Results: cVEMP score was lower in patients with CSC lesions compared to patients without CSC lesions (rank 56,94/median 2 vs. rank 45,72/median 0, p=0.047). This was reflected by the fact that patients with CSC lesions had higher left cVEMP amplitudes compared to patients without CSC lesions (1,7261 vs. 1,4028, p=0.027), and that patients with lesions in the midbrain had prolonged N23 latencies of the cVEMP response compared to patients without midbrain lesions (24,714 vs. 22,695, p=0.008). To exclude

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possible influence of brainstem lesions on the cVEMP results, we performed the analysis only on patients without brainstem lesions and found that patients who have lesions in the CSC (and no brainstem lesions) have higher right cVEMP amplitudes compared to patients without CSC lesions (and no brainstem lesions) (1,9785 vs. 1,5840, p=0.047). On the other hand, oVEMP score was higher in patients with brainstem lesions present, however with borderline significance (rank 54,97/median 3 vs. rank 44,25/median 2, p=0.058), and VEMP score was higher in patients with the lesion in the pons (rank 55,52/median 5 vs. rank 42,32/median 3, p=0.023). VEMP score also positively correlated with the brainstem functional score of the EDSS (rs=0,227, p=0.024). Conclusions: These results indicate different influence of demyelination and axonal degeneration on the cVEMP and oVEMP, possibly identifying heterogeneity of underlying MS pathophysiology. Disclosure Magdalena Krbot Skoric: Nothing to disclose Tereza Gabelic: Nothing to disclose Luka Crnosija: Nothing to disclose Ivan Adamec: Nothing to disclose Eleftherios S. Papathanasiou: Nothing to disclose Mario Habek: Nothing to disclose P502 Analysis of upper limb movement in multiple sclerosis subjects during common daily actions A. Tacchino1, L. Pellegrino2, G. Stranieri2, E. Tiragallo2, G. Brichetto3, M. Coscia4, M. Casadio2 1Italian Multiple Sclerosis Foundation, Genova, 2DIBRIS, University of Genoa, 3Italian Multiple Sclerosis Foundation, Genoa, Italy, 4Bertarelli Foundation, Lousanne, Switzerland Upper limb impairments prevent to perform both simple tasks, as moving an object, and ADL (e.g. eating, dressing and grooming) in about 65% of people with MS (PwMS)1, usually characterized by compromised muscle activation patterns, reduction in muscle strength, loss of coordination, tremor and fatigue. Thus, behavioral measures could improve the understanding of MS motor control alterations facilitating the design of novel rehabilitative treatments. Here, we proposed simple exercises to investigate and characterize upper limb motor performance and muscle activity in PwMS. The subjects were seated in front of a table with the right hand in the right corner. At the “Go!” they had to grasp an object in front of them, bring it to their mouth, place the object in its original position and return her/his hand to the starting position. The objects were: (i) two black varnished bottles filled at different levels (287 and 785 g); (ii) a plastic glass; (iii) a spoon placed in an empty plate. Both (ii) and (iii) were empty or filled with water. The subjects had to perform the task in the most natural way possible. 10 trials for each condition were performed. We recruited at Italian Multiple Sclerosis Society (Genoa, Italy) 7 healthy subjects (HS)


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(age: 49±14 ys) and 7 RR PwMS (age: 50±13 ys) without relapses in the last three months and absence of neurological signs and symptoms at upper limbs (4 with low impairment, EDSS< =2; 3 with moderate impairment, EDSS>2). All subjects were righthanded and their movements were evaluated with kinematics (markers placed on right acromion, left acromion, C7, sternum, elbow, wrist, metacarpus) and electromyography (right triceps brachii long and lateral head, biceps brachii short and long head, brachialis, brachioradialis, infraspinatus, latissimus dorsi, upper trapezius, rhomboideus and pectoralis major, anterior, medial and posterior deltoid, extensor and flexor carpi radialis). The most impaired PwMS significantly reduced movement smoothness with respect to HS and low impaired PwMS and high correlation was found with the self-reported disability degree (Abilhand). All PwMS showed abnormalities in the muscular functions principally during the object lifting phase. A more extensive analysis of kinematic and electromyography should be performed and results verified on a larger population and other ADL. 1) Santello M, Lang CE. Front Hum Neurosci. 2015 6;8:1050.

responders was higher considering the stretch reflex (56%) vs. the NRS (39%) and MAS (42%). There was a low concordance in response between the three measures (stretch reflex, NRS and MAS). Responders by the stretch reflex were taking a significantly higher number of puffs, while no differences were found in the responders by the other scales. Conclusions: The significant reduction of the stretch reflex during the tested therapy confirms its efficacy not only on symptoms related to spasticity but on spasticity itself. The low concordance between neurophysiological, subjective and clinical responders can be related to the different aspects of muscle hypertonia assessed by the three methods, as the stretch reflex provides selective measure of spasticity, while NRS and MAS also measure nonreflex hypertonia. The dose-response relationship might suggest that THC:CBD spray may be particularly effective when higher doses are tolerated. Disclosure The study have been supported with an unrestricted grant from Almirall S.A.

Disclosure Authors have nothing to disclose P503 THC:CBD oromucosal spray effect on spasticity assessed with stretch reflex in multiple sclerosis L. Marinelli1, L. Mori1, S. Canneva1, F. Colombano1, A. Currà2, F. Bandini3, E. Capello1, G. Abbruzzese1, C. Trompetto1 1Department of Neurosciences, University of Genova, Genova, 2Department of Medical-Surgical Sciences and Biotechnologies, A. Fiorini Hospital, Terracina, 3Department of Neurology, San Paolo Hospital, Savona, Italy Background: Patients with multiple sclerosis (MS) often develop spasticity, which is an exaggerated stretch reflex due to increased spinal excitability. However, non-reflex components of muscle hypertonia may coexist with spasticity. They can be difficult to distinguish during clinical evaluation and do not benefit from anti-spastic medications. Commonly used anti-spastic drugs determine side effects which are particularly relevant for MS patients, often already suffering by weakness, fatigue and cognitive symptoms. Nabiximols (THC:CBD) is an association of THC and CBD cannabinoids administered by oral puffs and absorbed via a transmucosal route. The spray effect on spasticity and related symptoms have been demonstrated in large studies adopting numeric rating scale (NRS) as main outcome measure. Aim & methods: This study is the first to assess the effect of THC:CBD spray on MS spasticity directly recording the stretch reflex using surface electromyography in limb muscles before start and after 1 month of treatment. Results: We recruited 57 MS patients and could record the stretch reflex in 36 (mean age 54, range 31-79, 21 females). Fifteen patents stopped THC:CBD before the re-evaluation because of nonsevere side effects mostly referred as dizziness, sleepiness and nausea. The THC:CBD spray caused a significant reduction of stretch reflex amplitude, as well as significant reductions of NRS and modified Ashworth scale (MAS) scores. The number of

P504 Evaluating optic neuritis with visual evoked potentials, which one is more sensitive black white pattern or red-white and red-black pattern stimuli? E. Acar, A. Soysal, M. Ozerden, Z. Ozdemir, K. Nilufer Neurology Department, Bakirkoy Research and Training Hospital for Psychiatry, Neurology and Neurosurgery, Istanbul, Turkey Background: Desaturation of bright colours, especially red,is reported by optic neuritis(ON) patients on affected eye during attack and recovery period in multiple sclerosis patients. In the literature, there are alot of study reporting P100 latency abnormalities by using black-white pattern shift visual evoked potentials (PSVEP) on ON cases. Objective: In this study, we would like to evaluate if redblack or red-white PSVEP is more sensitive than black-white for detecting ON. Material and methods: Thirty-six multiple sclerosis(MS) patients and 33 sex and age matched normal controls included the study. PSVEP with black-white (BW), red-white (RW) and redblack (RB) checker-board stimuli was recorded. VEP results of three different stimuli compared each other on MS patients and controls. Results: P100 latencies with RB stimuli was longer than BW and RW stimuli in MS patients (130.6±20.5, 120.3±16.5, 121.0±19.7, respectively) and control groups (114.6±6.7; 107.3± 4.4, 107.6±4.9, respectively). Cut-off values according to Roc analyses were found 113.5 for WB, 111.5 for RW and 120.5 for RB stımuli. We compared the patıents according to ON history; sensitivity and specificity were 77%-%60 for RB, %77-%67 for RW and % 84-50 for RB. In control group (66 eye) 3 for WB, 11 for RW and 12 for RB found to have pathology. Conclusion: Our study shows the value of BW PSVEP however in challenging cases where diagnosis is warranted promptly for treatment desicions, RB stimuli PSVEP seems to be more sensitive for detecting ON pathology in MS patients and might be helpful for


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Poster Session I, 21(S11) detecting subclinical ON. It should also be noted that RBVEP has a low specifity and futher longterm studies are needed. Disclosure Nothing to disclose P505 Intracortical inhibition in multiple sclerosis: relation to clinical subtype, motor disability, and cortical damage J.C. Nantes1,2, J. Zhong2,3, S.A. Holmes1,2, S. Narayanan3,4, Y. Lapierre4, L. Koski2,3 1Integrated Program in Neuroscience, McGill University, 2Research Institute of the McGill University Health Centre, 3Neurology and Neurosurgery, McGill University, 4Montreal Neurological Institute and Hospital, Montreal, QC, Canada Background: Inhibitory cortical activity influences motor learning and may impact to recovery after neurological damage. Multimodal research combining biomarkers of intracortical inhibition and brain damage with disability assessment could shed light on pathophysiological and adaptive neural processes affecting people with multiple sclerosis (MS). This study aimed to assess the extent to which transcranial magnetic stimulation (TMS)-based biomarkers of intracortical inhibition are related to clinical subtype, motor disability, and cortical damage of people with MS. Methods: After excluding for comorbidities and medications impacting neurotransmitter activity, participants included 36 persons with MS (subtypes: 22 relapsing remitting (RRMS), 6 primary progressive (PPMS), 8 secondary progressive (SPMS)) and 18 healthy controls (HC). TMS-based metrics included short-interval intracortical inhibition (SICI) and cortical silent period (CSP), each representing a distinct form of intracortical inhibition. SICI data was transformed such that higher values indicate greater inhibition. Disability was assessed with the Multiple Sclerosis Functional Composite (MSFC), which includes a measure of dominant upper limb function (nine-hole peg test (9HPT)). Cortical thickness and cortical magnetization transfer ratio (MTR) (markers of atrophy and demyelination, respectively) were measured. Results: Analysis of covariance found that age- and sex-adjusted SICI (HC: 68±6%, RRMS: 64±5%, PPMS: 61±10%, SPMS: 36±9%, F3,48= 3.24, p = 0.03), but not CSP (HC: 81±8ms, RRMS: 70±8ms, PPMS: 86±15ms, SPMS: 81±14ms, F3,48= 0.45, p > 0.05), differed based on clinical subtype. Post-hoc tests found SPMS participants had low SICI compared to all other groups (ps < 0.05). Among all MS participants, worse 9HPT performance was related to longer CSP (β = 0.44, p < 0.01), but not to SICI (p > 0.05). Lower cortical MTR correlated with shorter CSP duration among participants with a progressive MS course (rs= 0.57, p < 0.05), but not among RRMS or HC participants (ps > 0.05). Cortical thickness and intracortical inhibition were not correlated in any group (ps > 0.05). Conclusions: While SICI varies with MS subtype, CSP is more specifically related to upper limb motor impairment. Cortical demyelination may interfere with intracortical inhibition, and should therefore be considered when interpreting and clinically implementing TMS-based metrics, particularly for people with a progressive form of MS.

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Disclosure This study was supported by the Canadian Institutes of Health Research (grant number: MOP-119428) and The Research Institute of the McGill University Health Centre (fund numbers: 9967, 4857). Julia Nantes: Julia Nantes receives personal funding from the Vanier Canada Graduate Scholarship program to support her PhD studies; no other disclosures. Jidan Zhong: Nothing to disclose. Scott Holmes: Scott Holmes receives personal funding through a McGill University Faculty of Medicine studentship (F.S.B. Miller Fellowship); no other disclosures. Yves LaPierre: Dr. Yves Lapierre has received support as a consultant, membership on advisory councils, and grants from the pharmaceutical industry. Sridar Narayanan: Dr. Narayanan has received personal compensation for consulting activities from NeuroRx Research. Lisa Koski: Lisa Koski received the grants that funded this study (see above); no other disclosures. P506 Step initiation under dual-tasking in patients with clinically isolated syndrome (optic neuritis) suggestive of multiple sclerosis G. Brecl Jakob1, T. Remšak2, S. Šega1, A. Horvat Ledinek1, U. Rot1 1Department of Neurology, 2Department of Neurology, Unit for Neurorehabilitation, University Medical Centre Ljubljana, Ljubljana, Slovenia Background: Balance and cognition are affected by multiple sclerosis (MS). Dual task paradigm is used to study interference of motor and cognitive functions. Anticipatory postural adjustments (APAs) prior stepping have been linked to postural instability in elderly and subjects with neurological disorders. We studied step initiation (SI) by measuring APAs in patients with clinically isolated syndrome (optic neuritis-ON) suggestive of MS in relation to dual-tasking to investigate possible motor-cognitive interference in the earliest stages of the disease. Methods: We prospectively included 14 patients (age 34.3±18.7; EDSS 1±1, number of MRI lesions: min. 0, max >30, median 10) within 3 month from suffering unilateral ON. The required corrected visual acuity for inclusion was ⩾0.8. Additionally, 35 age, height and weight matched control subjects were included. APAs were studied using center of pressure (COP) measures. Step lengths, maximal medio-lateral (m-l) and antero-posterior (a-p) amplitudes of COP shift during APAs were measured in three conditions: SI alone, SI+Brooks’ (Br) spatial memory task and SI+2back verbal memory task (2B). Repeated measures ANOVA was used to analyze the data. An extensive neuropsychological battery was used to examine baseline attention, psychomotor speed, verbal memory and executive functions in patients. Results: Step lengths were shorter in patients (p=0.01) and were not affected by dual tasking (p=0.26). Patients exhibited smaller a-p APA amplitudes than healthy subjects (p< 0.01). Bigger a-p amplitudes with 2B compared to SI alone were observed in both groups (p< 0.05) with no effect of BR. A trend towards smaller m-l amplitudes in patients (p=0.09) was observed. Additionally m-l


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amplitudes were affected significantly by dual tasking (p< 0.001), however post-hoc analyses showed that healthy subjects increased m-l amplitudes while performing 2B (p=0.001) but not with BR (p=0.28). This was not observed in patients (p=0.99 and p=0.4). The cognitive performance of most of the patients was comparable to the healthy population norms. Only three patients performed worse on some measures of psychomotor speed and executive function. Conclusion: Postural control might be impaired in the earliest stages of MS where there is little or no clinical (motor and cognitive) disability observed. Additionally, patients and healthy subjects might respond differently to concurrent cognitive tasks that occupy distinct domains of working memory. Disclosure Gregor Brecl Jakob: Nothing to disclose Tamara Remšak: Nothing to disclose Saša Šega: Nothing to disclose Alenka Horvat Ledinek: Nothing to disclose Uroš Rot: Nothing to disclose

Neuropsychology P507 Emotional valence improve retrieval of autobiographical memory in multiple sclerosis N. Derache1,2, A. Mondou1, P. Piolino3, G. Defer1, B. Desgranges2 1Department of Neurology, Caen University Hospital, 2Laboratoire de Neuropsychologie, Inserm-EPHE-UCBN U1077, Caen, 3Institut de Psychologie de l’Université Paris Descartes, CNRS FRE 3292, Paris, France Background: Autobiographical memory (AM) is the ability to remember past events from one’s own life implying emotional processing. Concerning AM in MS, few studies found discussed results. Different studies, showed that emotion in MS patient could be altered, particularly the recognition of emotion. Objective: The aim of this study was to evaluate autobiographical memory in multiple sclerosis and to specify the role of emotion on its dysfunction. Methods: AM was evaluated in 30 MS-patients and 30 healthy controls matched for age, sexe, education and global intellectual efficiency using an emotional adaptation of the TEMPau (Episodic test of the past AM) task. Memory scores (free and cued) between group (MS patient vs healthy control), life period (0-17 years, 18-30 years and the last 12 months) and the emotional valence (positive/ negative or neutral) were compared using analyses of variance (ANOVA). We also looked for correlations between executive (verbal fluency, SDMT, letter-number sequences) and emotional. Results: MS-patients (19 females; mean age: 43.84 years +/7.91; mean EDSS:2+/-1.36; disease duration: 7.36+/-4.73; mean Mattis score: 139.4+/-4.99) had significantly reduced scores at free recall of AM compared to healthy controls (p< .001), whatever period or emotional valence. For cued recall, there was no difference for scores concerning AM retrieval with emotional valence (positive/negative) between the two groups whereas we found a significant reduced score for neutral memory in MS-patient group (p< .001). Executive performances of MS

patients were significant reduced compared to healthy control and correlated to AM scores. Conclusion: MS-patient had altered performance of AM retrieval probably related to an executive dysfunction. Alteration of AM in MS concerns all period of the individual life and is influenced by the emotional nature of the memory. It could be interesting to take account of emotion to improve performance of memory in MS-patient. Disclosure Derache: Nothing to disclose Mondou: Nothing to disclose Piolino: Nothing to disclose Defer: Nothing to disclose Desgranges: Nothing to disclose P508 The prevalence of bipolar disorders and impact on quality of life in a cohort of patients with multiple sclerosis I. Berrios Morales, A. Jun-O’Connell, A. Butala, A. Ahlawat, N. Henninger, K. Deligiannidis, N. Byatt, C. Ionete Neurology, University of Massachusetts School of Medicine, Worcester, MA, United States Background: Patients with multiple sclerosis (MS) are at increased risk of suffering from mood disorders, such as depression, which may adversely affect treatment compliance, outcome, functional status and an overall quality of life. However, little is known about the prevalence of bipolar disorder among MS patients and whether it affects quality of life. Objectives: The goals of our study were: (1) to assess the prevalence of bipolar disorders among MS patients evaluated at a tertiary care academic center using standardized psychiatric diagnostic screening tools; and, (2) to assess the quality of life among MS patients with and without bipolar disorder. Methods: Cross-sectional IRB approved study. After obtaining informed consent, MS patients were screened for bipolar disorder by trained physicians using the Mood Disorder Questionnaire (MDQ). The patients that scored positive on the MDQ underwent the Structured Clinical Interviews for DSM Disorders (SCID) to confirm the diagnosis. The medical records of all screened patients (n=153) were then reviewed. Mann-Whitney U test and Fisher’s Exact test were used for comparison of continuous and categorical variables, respectively. Two-sided p< 0.05 was considered significant. Results: Of the 16 MS participants that screened positive on the MDQ, 10 were identified as having met criteria for a diagnosis of bipolar disorder based on the SCID. Participants with bipolar disorder had a family history of bipolar disorder more frequently (p< 0.001) and their physical and mental quality of life scores were lower (p=0.009, p=0.001 respectively) than that of patients without bipolar disorder. Conclusions: This study demonstrated higher than expected prevalence of bipolar disorders in patients with MS, as compared to prior epidemiological data. MS patients with bipolar disorder had an overall lower quality of life (physical and mental component) as compared to MS patients without bipolar disorder. This study


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Poster Session I, 21(S11) added new evidence of association between MS and psychiatric co-morbidities and suggested more attention from the clinicians to this important aspect of quality of life in MS patients. Disclosure Idanis Berrios Morales, MD: Nothing to disclose Adalia Jun-OĆonnell, MD: Nothing to disclose Ankur Butala, MD: Nothing to disclose Aditi Ahlawat, BS: Nothing to disclose Kristina M. Deligiannidis, MD, Research/grant support: National Institutes of Health (NIH); Worcester Foundation for Biomedical Research; Forest Research Institute; University of Massachusetts Medical School; Assumption College; Cummings School of Veterinary Medicine at Tufts University; Michigan Institute for Clinical and Health. No conflicts of interest related to this project. Nancy Byatt, DO, MS, MBA, FAPM, Research/grant support: National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant KL2TR000160. No conflicts of interests related this project. Nils Henninger, MD: Nothing to disclose Carolina Ionete, MD, PhD: Has received research support from Biogen Idec and Genzyme. She has received compensations for consulting and advisory boards from Genzyme and TEVA. P509 Evidence of attentional impairment using virtual driving simulation in multiple sclerosis A. Mondou1, L. Courtin2, D. Chevanne1, N. Derache1, M.-L. Bocca2, G. Defer1 1Neurology Department, Caen University Hospital, 2Unit U1075 COMETE UCBN, INSERM, Caen, France Background: Detection of attentional disorders in complex situation related to daily life activities in Multiple Sclerosis (MS) patients, needs better “adapted tools” other than classical cognitive assessment. Objective: Investigate the usefulness of the virtual reality assessment of attention in MS, especially to evaluate vigilance and divided attention using driving simulation. Method: Eleven RRMS patients (10 female, mean age : 41,18±7,95 yrs, mean EDSS : 1,95±0,91, mean disease duration : 8,70±3,86 yrs) and 11 healthy matched controls performed a monotonous driving task (no traffic, repetitive landscape) with and without a divided attention condition. In comparison, a more traditional cognitive assessment of attentional functions, including Symbol Digit Modalities Test (SDMT) and Test of Attentional Performance (TAP) were administered. Statistical non-parametric Mann-Withney U test were used to compare performances in both groups in the two types of tasks. Results: Patients have worse performance than controls in monotonous driving condition, especially for the Standard Deviation of Lateral Position (SDLP, p < .05) of the vehicle trajectory. In driving simulation with divided attention condition, the driving performance was also impaired for the SDLP (p ⩽ .01) and probably relates to the Standard Deviation of fixed goal Speed (SDS, p < .005). However, in traditional attentional evaluation, there is no

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difference between MS patients and controls except for the SDMT score (p < .005). Discussion/conclusion: MS patients experienced difficulties in maintaining the trajectory and the speed of the simulated vehicle which may be indicative of attentional difficulties, especially vigilance and divided attention. These impairments were not objectified by the classical cognitive assessment outside the SDMT, as a more general measure of cognitive slowing. Driving simulation seems an interesting tool to assess the fluctuation of vigilance and the difficulties of divided attention in MS patients. The correlations with the cognitive complaint and other confounding factors such as mood disorders and fatigue will be presented during the meeting. Disclosure A. Mondou: Nothing to disclose. L. Courtin: Nothing to disclose. D. Chevanne: Nothing to disclose. N. Derache: Nothing to disclose. ML. Bocca: Nothing to disclose. G. Defer: Nothing to disclose. P510 Mood and multiple sclerosis M. Ponzio1, A. Tacchino1, P. Zaratin1, M.A. Battaglia2, G. Brichetto1 1Department of Research, Italian Multiple Sclerosis Foundation, Genoa, 2Department of Life Science, University of Siena, Siena, Italy Introduction: Many people with multiple sclerosis (PwMS) experience difficulties in mood. Recognizing factors associated with experienced anxiety and depression in MS can help to identify patients at risk suggesting specific assessment and treatment. This study aims to identify factors associated with experienced anxiety and depression in PwMS. Methods: Data, derived from the project “A New Functional Profile to Monitor the Progression of disability in MS”, were collected on consecutive outpatients or in-home rehabilitation patients attending the North Italy Rehabilitation units of Italian Multiple Sclerosis Society. We analyzed the first visit data (before to any rehabilitation treatment) during which clinical and demographic data and several clinical scales were collected. Here, The Anxiety and Depression subscales of the Hospital Anxiety and Depression Scale (HADS) were the primary outcome. Participants who scored ⩾8 on the two subscales were considered to be experiencing clinically significant levels of anxiety and depression. After a univariate analysis, logistic regression models were used to investigate whether the factors that were significantly different between the two groups predicted whether or not participants experienced anxiety and depression. Collinearity was assessed for each logistic regression models. Results: A total of 555 PwMS were included in the analysis. The 41.6% and 25.4% of the sample reported clinically significant anxiety and depression, respectively. The results of the final logistic regression models showed that sex (OR 0.38, 95%CI 0.220.65), EDSS score (OR 0.84, 95%CI 0.75-0.94), Life Satisfaction Index (LSI) (OR 0.87, 95%CI 0.82-0.93) and two subscale of


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Modified Fatigue Impact Scale (MFIS), cognitive (OR 1.06, 95% CI 1.03-1.09) and psychosocial (OR 1.17, 95%CI 1.04-1.30) subset respectively, were associated with anxiety status. Again LSI (OR 0.78, 95%CI 0.73-0.84) and cognitive (OR 1.07, 95%CI 1.04-1.10) and psychosocial (OR 1.18, 95%CI 1.04-1.33) MFIS subset respectively, were associated with depression status. Conclusion: Our results showed that the prevalence of anxiety is higher than depression in PwMS, as some studies have suggested (1). Besides, subjects with lower life satisfaction level and with cognitive and psychosocial fatigue were more likely experiencing clinically significant levels of anxiety and depression. 1. Janssens AC et al. Acta Neurol Scand 2003;108:389-395. Disclosure Ponzio M, Tacchino A, Zaratin P, Battaglia MA and Brichetto G have no conflicts of interest to declare P511 Characteristics of verbal fluency in patients with relapsing-remitting multiple sclerosis E. Tyburski1, A. Potemkowski1, M. Chęć1, A. Sołtys1, A. Sokołowski2, M. Kowalewski3, A. Samochowiec1 1Department of Psychology, University of Szczecin, Szczecin, 2Faculty of Psychology, University of Warsaw, Warsaw, 3Centre of Rehabilitation for MS Patients, Borne Sulinowo, Poland Background: Verbal fluency engages different psychological and neurological mechanisms. A number of attempts were made to explain the factors modifying the level of patients’ performance. Both semantic fluency and phonetic fluency deficits are observed in patients with multiple sclerosis (MS). Data from different studies provide the basis for a discussion on the nature of cognitive and executive dysfunctions determining the reduced level of verbal fluency. Moreover, little is known about abstract fluency in patients with MS. Objectives: 1) to determine the level of individual types of verbal fluency in patients with relapsing-remitting MS and 2) to assess the factors related to the level of different types of verbal fluency. Methods: 35 patients with relapsing-remitting MS and 35 healthy volunteers were involved in the study. The groups did not differ in terms of age, years of education and sex. Three versions of the Verbal Fluency Test (VFT) were administered: a) semantic (animals), b) phonemic (words beginning with the letter k) and c) abstract (sharp objects). In statistical analyses the authors applied Student’s t test, the parametric repeated measures analysis of variance test with appropriate post hoc tests as well as parametric r and non-parametric rs correlation coefficients. Results: The study revealed the differences between patients with MS and healthy subjects in the performance in all three tasks (p < 0.001). The clinical group demonstrated differences in the types of verbal fluency (p < 0.001). Post hoc analyses indicated that patients with MS performed best in semantic fluency (p < 0.001). No differences were shown in the level of phonemic and abstract fluency. Age, years of education and reduced mobility of patients were not related to the level of their performance in verbal fluency tasks. However, the study demonstrated a negative correlation between

the time after diagnosis and the level of phonemic fluency (rs = -0.41, p < 0.05) and abstract fluency (rs = -0.38; p < 0.05). Conclusions: The study revealed the presence of verbal fluency disturbances in patients with relapsing-remitting MS. The most reduced level of performance was observed in abstract and phonemic fluency. Psychological mechanisms underlying the disturbances were diversified. It is possible that semantic memory dysfunctions determined the lower results in semantic fluency task more than executive functions. It was the other way round in the case of the phonemic variant. Disclosure E. Tyburski: the research was supported by 504-3000-240764/2011 (Faculty of Humanities, University of Szczecin), A. Potemkowski: nothing to disclose, M. Chęć: nothing to disclose, A. Sołtys: nothing to disclose, A. Sokołowski: nothing to disclose, A. Samochowiec: nothing to disclose. P512 Relationships among subjective trait and state measures of fatigue and cognitive fatigue on an attention task A.K. Roth1, D.R. Denney1, S.G. Lynch2 1University of Kansas, Lawrence, 2University of Kansas Medical Center, Kansas City, KS, United States Background: Fatigue is one of the most common complaints among multiple sclerosis (MS) patients. It has been assessed at both the trait level (i.e., fatigue over the past week or month) and the state level (i.e., current fatigue). A related concept, cognitive fatigue, has been operationalized as a worsening in performance over time as an individual works on a repetitive task. Mixed findings exist regarding the relationship between subjective and objective measures of fatigue. The current study assessed cognitive fatigue on a lengthy attention task and examined its relationship with subjective reports of trait and state fatigue. Method: MS patients (20 relapsing, 20 secondary progressive) and healthy controls (n=40) completed the Fatigue Severity Scale (FSS), a visual analogue scale (VAS) of fatigue, and the Attention Network Test (ANT). The ANT is a 25-minute computerized test of attention requiring speeded motor responses to visual stimuli. The task consists of three blocks. The VAS was administered before and after the ANT, and changes in state fatigue were assessed using a 2 (group) X 2 (time) repeated measures ANOVA. Changes in objective performance across time were measured using 2 (group) X 3 (block) repeated measures ANOVAs applied to accuracy and mean reaction time (RT). Spearman correlations were used to assess relationships among the measures of subjective and cognitive fatigue. Results: MS patients reported significantly more trait-level fatigue as measured by the FSS than healthy controls (p < .001, η2 = .31). On the VAS, both groups reported significantly greater levels of state-level fatigue after the ANT (p < .001, η2 = .23), and MS patients reported higher levels of state fatigue at both time points (p = .02, η2 = .67). However, there was no interaction, indicating MS patients were not differentially affected by the task. Objective measures of performance showed no significant changes in RT or


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Poster Session I, 21(S11) accuracy across testing blocks. Spearman correlations revealed no significant relationship between self-report measures of trait and state fatigue, and neither measure correlated with changes in patients’ RT or accuracy. Conclusion: Trait and state fatigue appear to be separate constructs. Self-report measures of fatigue bear little relationship to MS patients’ objective performance on an extended test of attention. Disclosure Alexandra Roth: nothing to disclose. Douglas Denney: nothing to disclose. Sharon Lynch: nothing to disclose relevant to this study. P513 Level of stress and coping strategies in the multiple sclerosis patients with mild disability R. Kotas1, A. Pokryszko-Dragan2, M. Nowakowska-Kotas2 1Department of Psychiatry, Regional Specialistic Hospital, Legnica, 2Department of Neurology, Medical University, Wrocław, Poland Introduction: Stress is an important factor contributing to quality of life and presumably also the course of disease in the patients with multiple sclerosis (MS). The level of stress and ways to manage it should be therefore considered in multidimensional care of MS patients. The purpose of study: To evaluate perceived level of stress and the coping strategies in the MS patients with mild disability. Material and methods: The studied group comprised 66 patients (17 men, 49 women) with relapsing-remitting MS, treated with disease-modifying agents. Duration of the disease was 1-20 years (mean 7.3), degree of disability in Expanded Disability Status scale (EDSS) ranged from 1 to 3.5 (mean 2.0). The level of stress was assessed by means of Perceived Stress Scale (PSS) questionnaire and coping strategies were defined on the basis of Coping Orientations to Problems Experienced (COPE) inventory. The results were compared for both sexes. Results: PSS results showed low perceived level of stress in 21 patients (31.8%), moderate in 17 (25.8%) and high in 28 ones (42.4%). Comparing both sexes, 47% of male patients and 32% of females showed low level of stress, 18% and 28% - moderate and 35% and 40% - high level of stress, respectively. Task oriented coping strategy was the dominant one in 42 patients, emotion oriented strategy - in 21 and avoidance oriented strategy - in 3. Task oriented strategy was preferred by 70% of men and 57% of women, emotion oriented strategy - by 29% of men and 33% of women, avoidance oriented strategy - by 6% of women and none of the men. Conclusions: The majority of MS patients with mild disability experiences moderate or high level of stress. Variety of preferred coping strategies, including sex differences, shows the need for individual approach to the patients´ condition.

P514 Survey-based assessment of the relationship between cognitive impairment and mentally stimulating activity in multiple sclerosis B. Prager1, A. Nowacki2, D. Conway3 1Lerner College of Medicine, 2Quantitative Health Sciences, Cleveland Clinic Foundation, 3Mellen Center for MS, Cleveland Clinic, Neurological Institute, Cleveland, OH, United States Introduction: Cognitive impairment (CI) is a significant issue in patients with multiple sclerosis (MS). In Alzheimer disease, mentally stimulating activities have been shown to protect against cognitive decline. However, the role of cognitively stimulating activities such as reading or puzzles and their relationship to CI in MS has not been assessed. We performed a pilot study to assess the association of self-reported CI with engagement in mentally stimulating leisure activities. Methods: Surveys were sent to patients at Cleveland Clinic with a diagnosis of multiple sclerosis as identified by electronic medical record review. CI scores were averaged from 24 self-reported metrics (1=least severe; 100=most severe) derived from existing questionnaires to assess cognitive dysfunction in the elderly. Activity level was reported based on hours per day spent engaging in reading, puzzles, internet use, video games, music, and writing. Depression was also assessed. The relationship between pre-specified outcomes of CI and each activity was assessed by t-test comparing the 0-0.25 hour group vs. the 2+ hour group for each variable. Linear regression models were also constructed to adjust for patient age, length of diagnosis, use of an assistive device, and level of education. Total activity score was measured on a linear ordinal scale summing the level of daily engagement in individual activities. Results: Survey response rate was 33.2% for a total of 316 completed surveys. The average CI score was 48.8 (σ=16.5, range=12.791.6). In the unadjusted comparison, use of an assistive device (p< 0.05), lower education (p< 0.05), lack of employment (p< 0.0001), and higher internet use (p< 0.05) were significantly associated with higher CI score. Use of an assistive device (p< 0.01), lack of employment (p< 0.0001) and, within the employed subset, work that was not mentally stimulating (p< 0.05) were associated with a higher depression score. There was no significant association between CI score and cumulative activity score. In the adjusted analysis, lack of internet use (β=-7.1; p< 0.01) and unemployment (β=5.5; p=0.001) remained significant predictors of higher CI score. Conclusions: Our evidence did not indicate significant relationships between self-reported mentally stimulating activities and CI. However, given the burden of CI in MS patients, further assessment with more sensitive and validated metrics, such as neuropsychological testing, may be warranted. Disclosure Briana Prager: nothing to disclose. Amy Nowacki: nothing to disclose. Devon Conway has received research support paid to his institution by the National Multiple Sclerosis Society.

Disclosure Roman Kotas: nothing to disclose Anna Pokryszko-Dragan: nothing to disclose Marta Nowakowska-Kotas: nothing to disclose

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P515 Prospective memory in MS: impact of cue salience and contribution of executive functioning


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E. Dagenais1, A. Tremblay1, M. Demers1, C. Jobin2, É. Roger3, P. Duquette3, I. Rouleau1 1Psychology, Université du Québec à Montréal, 2Neurology, Hôpital Sacré-Coeur de Montréal, 3Neurology, CHUM NotreDame, Montréal, QC, Canada Objective: Prospective memory (PM), i.e. the ability to remember to carry out an intended action at the appropriate time in the future, is crucial in everyday life. One way to improve PM performance is to increase the salience of cue announcing that it is time to perform the action. Multiple sclerosis (MS) patients often report PM failures and there is growing evidence for PM deficits among this population. However, such deficits are poorly characterized and their relation with cognitive status remains unclear. In order to better understand PM deficits in MS patients, this study investigated the impact of cue salience on PM, and its relation to retrospective memory and executive deficits in MS. Methods: Thirty-nine (39) MS patients were compared to 18 healthy controls on a PM task, modulating the cue salience (10 target words capitalized or not) during an ongoing 60-question general knowledge test. Results: MS patients performed worse than controls (whose performance was near perfect) on the PM task (U = 184.50, Z = -2.94, p = .003), regardless of the cue salience. Logistic regression analyses revealed that, among MS patients only, executive functions contributed significantly to the variance in PM (p = .022), whereas age, education and retrospective memory did not. Interestingly, the performance of low-executive and high-executive patients differed when the cue was not salient (U = 112.5, z = -2.23, p = .028) but not when it was salient, suggesting that low-executive MS patients benefited more from cue salience. Conclusions: These findings add to the growing evidence for PM deficits in MS, and they highlight the contribution of executive functions to certain aspects of PM performance. In MS patients with low executive functioning, high cue salience improves PM performance by reducing detection threshold and the need for environmental monitoring. In addition to their theoretical significance these results offer interesting rehabilitation possibilities. Disclosure E. Dagenais has received a FRQS scholarship for this project. A. Tremblay, M. Demers, E. Roger and I. Rouleau: nothing to disclose. C. Jobin has served on editorial boards and presented conferences for Biogen Idec, Genzyme, Novartis, EMD Serono, Teva. She has been supported to attend meetings by Biogen Idec, Genzyme, Novartis. P. Duquette has served on editorial boards, has been supported to attend meetings by EMDSerono, Biogen-Idec, Novartis, Genzyme, and TEVANeuroscience and holds grants from the CIHR and the MS Society of Canada.

P516 Processing speed test vs. symbol digit modalities test: test-retest reliability, practice effects, sensitivity, and convergent validity S. Rao1, D. Schindler1, L. Mourany1, B. Mamone1, C. Reece1, G. Losinski1, D. Kemeny1, R. Rudick2, J. Alberts1

1Cleveland

Clinic, Cleveland, OH, 2Biogen, Cambridge, MA, United States Background: The Processing Speed Test (PST) is an iPad®based cognitive measure designed to resemble the paper-and-pencil Symbol Digit Modalities Test (SDMT). The SDMT has been shown to be a reliable and sensitive measure of information processing speed in patients with multiple sclerosis (MS). The SDMT is technician administered and requires manual scoring, whereas the PST is self-administered and computer scored. We now report the results of a recently completed, large-scale, psychometric validation study comparing the PST and SDMT. Goals: To compare PST and SDMT on: 1) test-retest reliability, 2) practice effects, and 3) sensitivity to MS-related cognitive impairment. Convergent validity of the PST and SDMT was also examined. Methods: Participants consisted of 165 MS patients (119 women; mean age = 45.3; mean education = 14.6) and 217 healthy controls (HC; 131 women; mean age 40.1; mean education 15.9). Participants were administered the PST (120 sec.) and the oral version of the SDMT (90 sec.) twice separated by 60 minutes. Administration order was counterbalanced; alternate forms of the PST and SDMT were employed. Results: Test-retest reliability (concordance correlation coefficient; CCC) for the PST was 0.882 (MS) and 0.848 (HC); reliability for the SDMT was 0.891 (MS) and 0.790 (HC). Relative sensitivity in discriminating MS from HC participants was high for the PST (Cohen’s d = 0.746) and SDMT (d = 0.643). Practice effects were slightly greater for the PST than SDMT: MS (PST = +1.7 correct items; SDMT = -2.4) and HC (PST = +3.9; SDMT = +0.9). Pearson correlation between PST and SDMT total scores (convergent validity) was 0.784 for all participants, 0.748 for MS patients, and 0.776 for HCs. Conclusions: The high level of convergent validity between the PST and SDMT indicates that the two tests are assessing similar cognitive abilities. Both the PST and SDMT exhibit high and comparable levels of test-retest reliability. The PST demonstrates slightly higher sensitivity than the SDMT in discriminating MS from HC participants. Practice effects were small but slightly higher for the PST than SDMT. These data suggest that the selfadministered and computer-scored PST can provide an efficient and accurate substitute for the technician-administered and -scored SDMT as a rapid and effective screening tool for assessing processing speed deficits in the MS clinic. Study supported by: National Multiple Sclerosis Society, Novartis and Biogen. Disclosure Dr. Rao has received honoraria, royalties or consulting fees from: Biogen, Genzyme, Novartis, American Psychological Association, International Neuropsychological Society and research funding from the National Institutes of Health, US Department of Defense, National Multiple Sclerosis Society, CHDI Foundation, Biogen, and Novartis. Dr. Alberts has received royalties or consulting fees from Biogen and Boston Scientific and research funding from the National Institutes of Health and Biogen. Dr. Rudick is an employee of Biogen.


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Poster Session I, 21(S11) D. Schindler has received royalties from Biogen. L. Mourany, B. Mamone, C. Reece, G. Losinski, D. Kemeny nothing to declare. P517 The self-administered, iPad®-based processing speed test: impact of technician presence on task performance S. Rao1, D. Schindler1, L. Mourany1, B. Mamone1, C. Reece1, G. Losinski1, D. Kemeny1, D. Miller1, J. Rhodes2, G. Phillips2, R. Rudick2, J. Alberts1 1Cleveland Clinic, Cleveland, OH, 2Biogen, Cambridge, MA, United States Background: Screening for cognitive impairment in the MS clinic is uncommon because of the time and effort associated with technician supervised test administration and scoring. The Processing Speed Test (PST), an iPad®-based measure of information processing speed which resembles the Symbol Digit Modalities Test, was designed specifically to overcome these limitations in routine screening for cognitive impairment as the test is self-administered and scored automatically. However, a fundamental question involving self-administration is whether test performance differs when a technician is no longer supervising the administration. Goals: To compare PST test performance with and without a technician present. Methods: Participants included 24 MS patients (12 females; mean age=42.9; mean education=15.1 years) and 25 healthy controls (HC; 12 females; mean age=43.5; mean education=15.5 years). Disease course consisted of 20 relapsing-remitting, 3 secondary progressive, and one primary progressive MS. Both groups were administered the PST twice separated by one hour, once with a technician present (TP) and other with the technician absent (TA) from the examination room. The TA and TP administration order was counterbalanced. Participants were told at the outset that feedback on test performance would be provided after the second administration. Results: The HC group obtained mean total scores (SD) of 58.6 (11.9) and 58.9 (11.5) for the TP and TA conditions, respectively (p = 0.77). The MS group obtained mean total scores (SD) of 49.6 (14.8) and 50.6 (14.0) for the TP and TA conditions, respectively (p = 0.27). Conclusions: Results indicate that test performance is stable across the testing environments. Similar performance with and without a technician present supports the validity of self-administration in the routine screening of information processing speed deficits in the MS clinic using the PST. It is critical to note that we informed participants at the outset that their performance would be reviewed at the end of the examination session. It is conceivable that had we not provided this instruction, performance during the TA condition would have differed due to motivational factors. Of course, in the clinical setting, patients would assume that their performance would be reviewed with a healthcare provider. These results support the application of the PST in the routine screening of processing speed deficits in the MS clinic. Study supported by Biogen. Disclosure Dr. Rao has received honoraria, royalties or consulting fees from: Biogen, Genzyme, Novartis, American Psychological Association,

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International Neuropsychological Society and research funding from the National Institutes of Health, US Department of Defense, National Multiple Sclerosis Society, CHDI Foundation, Biogen, and Novartis. Dr. Alberts has received royalties or consulting fees from Biogen and Boston Scientific and research funding from the National Institutes of Health and Biogen. Dr. Miller has received royalties from Biogen and research funding from the National Multiple Sclerosis Society, Biogen and Novartis. Drs. Rhodes, Phillips, and Rudick are employees of Biogen. D. Schindler has received royalties from Biogen. L. Mourany, B. Mamone, C. Reece, G. Losinski, D. Kemeny nothing to declare. P518 Immunosuppressive therapy improves cognitive function in secondary progressive multiple sclerosis patients M. Kinner, R. Hoepner, P. Klotz, C. Prehn, R. Schneider, S. Faissner, A. Salmen, R. Gold, A. Chan Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany Background: Multiple Sclerosis (MS) associated cognitive decline especially in the secondary progressive (SP) phase is an unsolved problem. Methods: We retrospectively investigated the efficacy of firsttime mitoxantrone iv (mitox) treatment (mean dosage: 48.1 mg/ m² (SD15.8)) on cognitive function of 19 SPMS patients. As controls served 11 SPMS patients treated with intrathecal triamcinolone acetonide (IT) (21.6mg/month (SD7.2), injections every 1-4 months). In the mitox group, 1st standardized neuropsychological examination (NPE) was performed directly before first and 2nd NPE during or up to 4 months after last infusion (mean interval 17.1 months (SD6.6)). IT patients were assessed twice during therapy (mean interval 17.3 months (SD14.2)). Response to treatment was defined by an improvement in ⩾50% of the subtests (Multiple-Choice Vocabulary Intelligence Test, German Achievement Measure System Subtests 3/7, Regensburg Word Fluency Test, Verbal Learn-/ Memory-Test, Wechsler Memory Scale-Revised Subtests (visual reproduction, digit span forward/backward) and Shulman Clock Drawing Test). Results: Baseline characteristics were equally distributed within groups (gender, age at diagnosis, disease duration, interval between tests, age and Expanded Disability Status Scale (EDSS) at first assessment; each p>0.1); only co-administration of methylprednisolone iv was more frequent in the mitox group at both time points (1st test 9/19 patients vs. 2nd test 8/19). At baseline, 21/30 SPMS patients exhibited cognitive deficits in ⩾1 test without differences in overall neuropsychological function between treatment groups (p⩾0.05). Whereas IT had no impact on cognitive function, mitox led to an improvement predominantly in concentration, cognitive flexibility and memory function. This effect was independent of age, gender and disease duration. Higher EDSS at initiation of mitox (mean 4.4 (non responders; NR) vs. 5.9 responders (R), p⩽0.01) and a leukocyte nadir after mitox infusion ⩽2000/µl (3/7 (NR) vs 0/10 (R), p=0.02) were associated with better cognitive response.


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Discussion: Our data demonstrate that mitox treatment improves neuropsychological function especially in SPMS patients with high grade physical disability or pronounced immunological response to mitox. Despite small patient number and the retrospective approach our study indicates that an immunosuppressive therapy targeting neuroinflammatory responses has the potential to modulate cognitive dysfunction. Disclosure This work was in part supported by the German Ministry for Education and Research (BMBF, “German Competence Network Multiple Sclerosis” (KKNMS), CONTROL MS, 01GI0914). M Kinner ([email protected]) reports no disclosures. R Hoepner ([email protected]) received research and travel grants from Biogen Idec and Novartis. P Klotz ([email protected]) reports no disclosures. C Prehn ([email protected]) reports no disclosures. R Schneider ([email protected]) reports no disclosures. Simon Faissner ([email protected]) received travel grants from Biogen Idec and Genzyme. Anke Salmen ([email protected]) received personal compensation for activities with Novartis, Sanofi and Almirall Hermal GmbH. Ralf Gold ([email protected]) serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis. Andrew Chan ([email protected]) received personal compensation as a speaker or consultant for Bayer Schering, Biogen Idec, Merck Serono, Sanofi-Aventis and Teva Neuroscience. A. Chan received research support from the German Ministry for Education and Research (BMBF, German Competence Network Multiple Sclerosis (KKNMS), CONTROL MS, 01GI0914), Bayer Schering, Biogen Idec, Merck Serono and Novartis. P519 Cognitive behavioural therapy in multiple sclerosis: effectiveness in reducing depressive symptoms and cognitive impairments M. Bermúdez1, T. Olivares2, B. Moisés2, M.Á. Hernández1, C. Villar van Weigaert1 1Hospital Universitario Ntra Sra. de Candelaria, Santa Cruz de Tenerife, 2University of La Laguna, La Laguna, Spain Background: Depression and anxiety symptoms appear to be undertreated in MS. Patients consider mental health to be a critical determinant of overall burden. Recent findings suggests that Cognitive Behavioural Therapy (CBT) can be an effective treatment for depression in MS, while the evidence-base is still relatively small. On the other hand, several studies suggest that some

methods of the third wave of CBT could improve cognitive performance in general population. Taking this into account, the aim of this study was to examine the effectiveness of a CBT program in reducing not only mood disorders but also cognitive impairments in MS. Method: 24 patients were randomly assigned to CBT group (n=12) or wait list control condition (n=12) Mean age: 36.8 (SD=10.6); Mean EDSS: 2.0 (SD=1.6). Inclusion criteria: scores ⩾ 8 on one or both of the subscales of Hospital Anxiety and Depression Scale (HADS) and two subscales ⩽2SD in the Brief Repeatable Battery (BRB). Other assessment measures: Beck Depression Inventory (BDI-II) Multiple Sclerosis Quality of Life54 (MSQOL-54). Treatment consisted of 13 weekly 1.5-hour group sessions in CBT. Post-intervention assessment was conducted a week after the end of the therapy. Results: Group x time interaction analyses revealed a significant outcome on BDI scores, with the CBT group showing a significant decrease between pre and post-treatment [F(1,19)=4,32; p< 0,05)], as well as an increase (improvement) in a global memory measure from pre to post-treatment [F(1,20)=5,36; p< 0,05)]. CBT group also showed a decline on HADS scores but only marginally significant differences were obtained related to control group. Conclusions: These results are preliminary but show that CBT can be an effective treatment for reducing emotional distress and cognitive impairments in MS. Also highlight the importance of studying mood disorders together with cognitive performance. Disclosure Bermúdez Moisés: nothing to disclose. Olivares Teresa: nothing to disclose. Betancort Moisés: nothing to disclose. Hernández Miguel Ángel: nothing to disclose. Villar van Weigaert Claudia: nothing to disclose. P520 Integrative group-based cognitive rehabilitation efficacy in multiple sclerosis O. Rilo1, J. Peña1, N. Ojeda1, A. Rodriguez Antigüedad2, M. Mendibe Bilbao3, A. Gómez Gastiasoro1, J. DeLuca4,5, N. Chiaravalloti4,5, N. Ibarretxe Bilbao1 1University of Deusto, 2Basurto University Hospital, Bilbao, 3Cruces University Hospital, Baracaldo, Spain, 4Kessler Foundation, West Orange, 5Rutgers University New Jersey Medical School, Newark, NJ, United States Background: Cognitive impairment is a common consequence of Multiple Sclerosis (MS). There is some evidence for the efficacy of individual cognitive rehabilitation, but very few studies have attempted to address simultaneously the wide range of cognitive domains affected in a group format. Therefore, this study aimed to determine the efficacy of an integrative group-based cognitive rehabilitation program (REHACOP) on improving cognitive functioning in MS. Methods: Thirty-two MS participants were randomly assigned to the experimental (n=16) or control (n=16) group. The experimental group received cognitive rehabilitation for three months (three one-hour sessions per week) focused on attention (sustained, selective, alternating and divided attention), learning and memory


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Poster Session I, 21(S11) (verbal and visual memory, as well as working memory), executive functioning (objectives planning and attainment, verbal reasoning, categorisation and conceptualisation), language (verbal fluency, syntax, grammar, vocabulary and comprehension) and social cognition (social reasoning, theory of mind and moral dilemmas). Participants underwent an extensive neuropsychological assessment at baseline and follow-up, which included measures of attention (The Brief test of attention), working memory (Backward Digit Span subtest of the Wechsler Adult Intelligence Scale III), processing speed (Symbol Digit Modalities Test, the three and six letter version of the Salthouse Perceptual Comparison Test and the Trail Making Test A), verbal memory (Hopkins Verbal Learning Test - Revised), verbal fluency (Calibrated Ideational Fluency Assessment) and executive functioning (Stroop Color-Word Test). Significant differences between groups were found in neurologic impairment and mental fatigue scores, so these variables were included as covariates in repeated measures MANCOVA. Results: Group x time interactions showed that participants completing the REHACOP exhibited significant improvements when compared to the control group on working memory (p=0.004, np2=0.26), processing speed (p=0.030, np2=0.16), verbal memory (p=0.035, np2=0.15) and executive functioning (p=0.035, np2=0.15). Conclusion: Participants receiving REHACOP showed large improvements in several cognitive domains. These results suggest that cognitive rehabilitation using an integrative approach and administered in a group format can significantly improve cognitive functioning in persons with MS. Disclosure Oiane Rilo: nothing to disclose. Javier Peña: co-author and copyright holder of the REHACOP cognitive rehabilitation program. Natalia Ojeda: co-author and copyright holder of the REHACOP cognitive rehabilitation program Alfredo Rodriguez Antigüedad: nothing to disclose. Mar Mendibe Bilbao: nothing to disclose. Ainara Gómez Gastiasoro: nothing to disclose. John DeLuca: nothing to disclose. Nancy Chiaravalloti: nothing to disclose. Naroa Ibarretxe Bilbao: nothing to disclose. This study was funded by the Ministry of Economy and Competitiveness [PSI2012-32441; P.I: Dr. Ibarretxe-Bilbao]. P521 Decision-making in multiple sclerosis: a neuroeconomics approach M. Sepúlveda1, B. Fernández1, E.H. Martínez-La Piscina1, A. Saiz1, D. Levy2, P. Glimcher3, P. Villoslada1,4 1Neurology, Hospital Clinic and Institut d Investigació August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain, 2Recanati Business School, Tel Aviv University, Tel Aviv, Israel, 3Center for Neural Sciences, New York University, New York, NY, 4Neurology, University of California, San Francisco, CA, United States Background: Patients with either early or advanced MS suffers for impairments in the decision-making process. Nevertheless, it

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is unclear the influence that this decision-making impairment may exert over the patients quality of life and how this impairment relates to disease features. Methods: We analyzed 84 MS patients and 21 matched healthy controls using a novel battery of 4 tests developed based in economic decision process: 1) risk aversion, 2) delayed gratification, 3) rational preference, 4) learning task (crab game). All participants underwent cognitive examination using the Brief Repeatable Battery-Neuropsychology and demographic, quality of life, clinical and radiological characteristics were recorded. Results: MS patients showed higher risk aversion (general propensity to choose lottery 0.51 vs 0.64, p=0.009), a trend to choose lesser times the delayed gratification options (p=0.108) and had longer reactions times (p=0.033). Rational preference and learning rate tasks did not show differences between groups. Patients affected by progressive MS showed slower decision-making responses than RRMS patients. Regarding the impact of this impairment in social life, impaired decision-making process correlated with annual wages (r=0.36, p=0.043). In relation with general cognitive impairment, we found correlation between impaired decision-making and impaired verbal memory (r=-0.25, p=0.022), visual memory r=-0.27, p=0.013) and with reduced processing speed (r=-0.26, p=0.021). Normalized grey matter volume correlated with deliberation time (r=-0.32, p=0.005) and risk aversion (r=-0.25, p=0.029). Conclusions: MS patients suffer decision-making impairment (e.g. higher risk aversion and slower reaction time). This decisionmaking impairment is associated with cognitive and MRI features and seems to have implications on patient’s social life, even in absence of evident cognitive deficits. Understanding the decisionmaking impairment in MS may help to design strategies to cope with such disability and preventing its effects in their social life. Disclosure M. Sepúlveda: nothing to disclose, B. Fernández: nothing to disclose, E. H. Martínez-Lapiscina: nothing to disclose, D. Levy: nothing to disclose, P. Glimcher: nothing to disclose A Saiz: had received compensation for consulting services and speaking from Bayern-Schering, Merck-Serono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceuticals Industries Ltd and Novartis. P. Villoslada: has received consultation fees from Roche, Novartis, Neurotech Pharma and is founder and hold stocks of Bionure Farma.

Immunomodulation/Immunosuppression P522 Switching from branded to generic glatiramer acetate: two-year MRI data from the GATE trial demonstrates continuous efficacy F. Barkhof1, A. Belova2, K. Selmaj3, C. Wolf4, E.R.W. van den Tweel5, J.J.L. Oberyé5, R. Mulder5, N.P. Koper5, J.A. Cohen6, on behalf of the GATE Study Group 1Radiology, VU Medical Centre, Amsterdam, The Netherlands, 2Functional Diagnostics, Research Institute of Traumatology and Orthopaedy, Nizhniy Novgorod, Russian Federation, 3Medical University of Lodz, Lodz, Poland, 4Lycalis sprl., Brussels, Belgium, 5Synthon BV, Nijmegen, The Netherlands, 6Mellen Center, Cleveland Clinic, Cleveland, OH, United States


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Background: GTR (Synthon BV) is a generic glatiramer acetate that was demonstrated to be clinically equivalent to brand glatiramer acetate (GA, Copaxone® Teva) in the 9-month double-blind (DB) part of the GATE trial in patients with active relapsingremitting multiple sclerosis (RRMS). Goals: The extension of GATE aimed to show that GTR maintained effectiveness over 2 years and that the established treatment effect on MRI was maintained when switching from GA to GTR. Methods: Ambulatory RRMS patients with ⩾1 relapse in the year prior to screening and 1-15 T1-gadolinium-enhanced (GdE) brain lesions were randomized to receive daily 20 mg GTR, 20 mg GA, or placebo (PLC) for 9 months. Patients completing the DB part could enter the 15-month open-label (OL) treatment part and received daily injections of 20 mg GTR. Patients were monitored by MRI scans at baseline and months 7, 8, 9 (DB) and 12, 18, and 24 (OL). MRI scans were read blinded to treatment by the IAC (Amsterdam). Results: Of the 794 patients treated in the DB part, 728 patients continued in the OL part: 324 (GTR/GTR), 323 (GA/GTR), or 81 (PLC/GTR). At baseline the mean number of T1-GdE lesions was 2.5 to 2.8. During months 7 to 9 this was reduced to an equivalent level in the GTR and GA groups (range: 0.8-1.2). The mean T1-GdE lesion counts remained similar in the GTR/GTR and GA/GTR groups during months 12 to 24 (range: 0.6-0.7). The mean number of new T2 lesions at month 9 was 9.2 (GTR) and 7.3 (GA) and increased similarly in the OL part with 6.2 new T2 lesions in both GTR/GTR and GA/GTR groups. The mean increase in T2 lesion volume during the 9-month DB part was 466 mm3 (GTR) and 449 mm3 (GA). During the 15 month OL part the mean increase was 601 mm3 (GTR/GTR) and 645 mm3 (GA/GTR). T1 hypointense lesion volume increased by 91 mm3 (GTR) and 64 mm3 (GA) during the DB part and by 97 mm3 (GTR/GTR) and 122 mm3 (GA/ GTR) during the OL part. Brain volume changes assessed at month 9 and 18 showed mean decreases of 0.5% and 0.6% in the GTR/ GTR group and 0.6% and 0.6% in the GA/GTR group, respectively. As expected, the effect of treatment on MRI parameters in the PLC/ GTR group was evident at month 18 and was comparable to the effect observed in the DB part for the GTR and GA groups. Conclusions: When switching from branded to generic glatiramer acetate or continuing generic treatment, the effect established on MRI parameters is maintained, further supporting the equivalence of this generic compound. Disclosure F. Barkhof: personal fees (Bayer Schering Pharma, Sanofi Aventis, Biogen Idec, Teva, Merck Serono, Novartis, Roche, Synthon BV, Jansen Research, Genzyme), Data-analysis center (Biogen-Idec, TEVA, Merck Serono, Novartis, Roche, Synthon BV, Jansen Research); A. Belova: personal fees (Synthon BV); K. Selmaj: grants and personal fees (Synthon BV, Roche, Biogen Idec, Novartis, TEVA, Merck, Genzyme, Neuron, Receptos); C. Wolf has received honoraria for serving as a consultant for toBBB, Desitin, Investitionsbank Berlin, Keyrus, Novartis, Synthon BV, and Teva; E. van den Tweel,J. Oberyé, N. Koper, and R. Mulder: employees of Synthon BV; J. Cohen: grants and personal fees (EMD Serono, Genentech, Genzyme, Innate Immunotherapeutics, Synthon BV, Vaccinex).

P523 Daclizumab high-yield process (DAC HYP) vs. intramuscular interferon beta-1a in subgroups predictive of active disease: results from the DECIDE study H. Wiendl1, E. Havrdova2, J. Rose3, G. Giovannoni4, L.C. Tsao5, J. Zhao5, Q. Pan5, J. Elkins6, S.J. Greenberg5 1University Hospital Münster, Münster, Germany, 2Charles University, Prague, Czech Republic, 3University of Utah Medical School, Salt Lake City, UT, United States, 4The London School of Medicine and Dentistry, London, United Kingdom, 5AbbVie Biotherapeutics Inc., Redwood City, CA, 6Biogen, Cambridge, MA, United States Background: The DECIDE relapsing-remitting multiple sclerosis phase 3 study demonstrated efficacy and safety of daclizumab high-yield process (DAC HYP) vs. intramuscular interferon beta1a (IM IFN beta-1a). Here the components of active disease were evaluated and the efficacy of DAC HYP vs. IM IFN beta-1a was assessed in subgroups with baseline (BL) characteristics defining active disease, including highly active disease (HAD). Method: Patients (age 18-55 years [Y]; Expanded Disability Status Scale [EDSS] 0.0-5.0) were randomized to subcutaneous DAC HYP 150 mg every 4 weeks (W)(N=919) or IM IFN beta-1a 30 mcg weekly (N=922) for 96-144W. BL predictors of active disease were relapses in prior Y, gadolinium-enhancing (Gd+) lesions, disability and T2 lesion volume burden. The HAD subgroup was defined by ⩾2 relapses in prior Y and ⩾1 Gd+ lesions at BL. Pre-specified and post-hoc subgroup analyses compared treatments by annualized relapse rates (ARR) and MRI parameters (new/enlarging T2 and T1 Gd+ lesions) at W96 using negative binomial or logistic regression models adjusting for BL covariates excluding the covariate defining the subgroup. Result: On-study experience affirmed the value of BL disease characteristics to predict more active disease in each treatment arm. For example, ARRs were numerically greater in subgroups of IFN beta-1a-treated patients defined by BL characteristics of ⩾2 relapses in prior Y (0.538, n=446), ⩾1 Gd+ lesion (0.509, n=414), EDSS ⩾ 3.5 (0.410, n=291), or T2 lesion volume ⩾median (0.418, n=469) than in their corresponding cohorts with ⩽1 relapse in prior Y (0.312, n=476), no Gd+ lesion (0.301, n=495), EDSS < 3.5 (0.381, n=631), and T2 lesion volume < median (0.361, n=439). In the 388 patients with HAD (21%), DAC HYP (n=184) vs. IFN beta-1a (n=204) resulted in lower ARR (0.282 vs. 0.677, nominal p< 0.001). DAC HYP resulted in a 48.5% (95%CI [34.3, 59.7]) reduction in mean number of new/enlarging T2 lesions (9.1, 95%CI [7.6, 11.0], n=178) vs. IFN beta-1a (17.7 [14.9, 21.0], n=185), nominal p< 0.001, and 54.0% reduction in mean number of Gd+ lesions (0.8, SD=2.3, n=184) vs. IFN beta-1a (1.7, SD=4.3, n=204), nominal p< 0.001. DAC HYP was similarly effective vs. IFN beta-1a in BL disability and T2 lesion volume subgroups as well as the non-HAD and predictably less active BL subgroups. Conclusion: DAC HYP was more efficacious than IM IFN beta1a in patients at risk for high disease activity as well as patients with less active disease. Disclosure Biogen and AbbVie Biotherapeutics participated in the study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication.


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Poster Session I, 21(S11) H.W. received compensation for serving on Scientific Advisory Boards/Steering Committees for Bayer Healthcare, Biogen Idec, Genzyme, Merck Serono, Novartis and Sanofi Aventis. He has received speaker honoraria and travel support from Bayer Vital GmbH, Bayer Schering AG, Biogen Idec, CSL Behring, EMD Serono, Fresenius Medical Care, Genzyme, Merck Serono, Omniamed, Novartis and Sanofi Aventis. He has received compensation as a consultant from Biogen Idec, Merck Serono, Novartis and Sanofi Aventis. Prof. Wiendl received research support from Bayer Vital, Biogen Idec, Genzyme Merck Serono, Novartis, Sanofi Aventis Germany, Sanofi US as well as grants and research support from grants/ research supports: Bayer Healthcare, Biogen Idec, German Ministry for Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, Merck Serono, Novartis, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, RE Children’s Foundation, Sanofi Aventis/Genzyme and TEVA Pharma. K.S. has received compensation for consulting services from Genzyme, Novartis, Ono, Roche, Synthon, and Teva; and compensation for speaking from Biogen Idec. E.H. has received compensation as a consultant for Biogen Idec, Genzyme, Merk Serono, Novartis; for serving on a scientific advisory board for Biogen Idec, Genzyme, Receptos and Actelion; and for speaking for Actelion, Biogen Idec, Genzyme, Merk Serono, Novartis, and has received research support from Biogen Idec. J.R. has received research support from Biogen Idec, AbbieVie Biotherapeutics, Teva, Cumming Foundation, National Multiple Sclerosis Society, Veterans Affairs and the National Institute of Health. G.G. has received fees for participation in advisory board for AbbVie Biotherapeutics Inc., Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, Sanofi-Genzyme, Synthon, Teva, and Vertex; speaker fees from AbbVie Biotherapeutics Inc., Biogen, Bayer HealthCare, Genzyme, Merck Serono, SanofiAventis, and Teva; coeditor in chief of Multiple Sclerosis and Related Disorders; research support unrelated to study from Biogen, Genzyme, Ironwood, Merck Serono, and Novartis. J.E. is a full-time employee of Biogen Idec and may hold stock or options. L.C.T., J.Z., Q.P., and S.G. are full-time employees of AbbVie Biotherapeutics and may hold stock or options. The authors would like to thank Katherine Riester for her contributions to the analysis. Jane Rodgers, PhD, of AbbVie, provided medical writing assistance in the development of this publication. P524 Effects of daclizumab HYP on accumulation of disability exclusive of acute relapse in moderate/severe relapsing-remitting multiple sclerosis patients: a composite disability outcome from the DECIDE study J.L. Bennett1, B.A.C. Cree2, T. Leist3, H. Moses4, G. Giovannoni5, L.C. Tsao6, J. Zhao6, Q. Pan6, Y. Lin6, J. Elkins7, L. Chiodo6, R.R. Robinson6, S.J. Greenberg6 1University of Colorado Denver School of Medicine, Aurora, CO, 2University of California, San Francisco, San Francisco, CA, 3Thomas Jefferson University, Philadelphia, PA, 4Vanderbilt University Medical Center, Nashville, TN, United States, 5The London School of Medicine and Dentistry, London, United

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Kingdom, 6AbbVie Biotherapeutics Inc., Redwood City, CA, 7Biogen, Cambridge, MA, United States Background: DECIDE was a randomized, double-blind, doubledummy, active-controlled, 96-144 week phase 3 study, which demonstrated efficacy and safety of daclizumab high-yield process (DAC HYP, 150mg subcutaneous, every 4 weeks) vs. interferon beta-1a (IFN beta-1a, 30mcg intramuscular [IM], once weekly) in relapsing-remitting multiple sclerosis (RRMS). The disability composite endpoint provides an objective, reliable and clinically relevant measure, which may address some limitations of the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) and provide sensitive detection of change in neurophysical status over a range of functions. Method: Efficacy was evaluated post-hoc in a moderate/severe disability cohort (baseline EDSS ⩾3.5) over the study period on the disability composite endpoint (24-week confirmed 20% increase in 9 Hole Peg Test score or Timed 25 Foot Walk or ⩾ 1.0 point increase in EDSS vs. baseline). Progression was confirmed 168 days after initial onset and at last visit. No onset of relapse could occur within 74 days prior to the tentative disability progression. Cox regression for time to confirmed progression was used to compare treatment arms adjusting for prior IFN beta use, age (< 35 vs ⩾ 35), baseline EDSS and/or MSFC domains as covariates. Primary analyses were based on observed data. Result: DAC HYP (n=260) treatment was more effective than IM IFN beta-1a (n=291) in moderately/severely impaired RRMS in prolonging the onset of disability progression, exclusive of acute relapse, based on the disability composite endpoint, hazard ratio [95% CI]: 0.65 [0.44, 0.98], nominal p=0.04. Forty DAC HYPtreated patients (15.4%) and 62 IM IFN beta-1a-treated patients (21.3%) had a 24-week confirmed event on the composite disability endpoint. MSFC component outcomes were similar. Disability composite events were mostly captured individually by MSFC domains or EDSS (DAC HYP=90.0% [36/40]; IM IFN beta1a=85.5% [53/62]), with fewer events captured in combination (approx. 13%). Full safety data from DECIDE were previously described (Selmaj K, et al. Neurology. 2015; 84(14):P7.230). Conclusion: These analyses provide additional support for DAC HYP being more effective than IM IFN beta-1a in slowing disability progression, independent of acute relapses, in a cohort of RRMS with moderate/severe baseline disability. Disclosure Biogen and AbbVie Biotherapeutics participated in the study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. J.L.B. is on the editorial board for Journal of Neuro-ophthalmology, Multiple Sclerosis, and Neurology: Neuroimmunology & Neuroinflammation; holds patents for compositions and methods for the treatment of neuromyeltis optica, novel blocking monoclonal therapy for neuromyelitis optica; consulted for EMD-Serono, Questcor Pharmaceuticals, Alnaylam Pharmaceuticals, Medimmune, Abbvie, Novartis Pharmaceuticals, Chugai Pharmaceuticals, Genzyme, Genentech; received research support from Questcor Pharmaceuticals, Novartis Pharmaceuticals, NIH, Guthy-Jackson Foundation; holds stock in Apsara Therapeutics; and receives license fees and royalty payments from Aquaporumab.


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B.A.C.C. has received compensation for consulting from Abbvie, Biogen Idec, EMD Serono, MedImmune, Novartis, Genzyme/ sanofi aventis, Teva and has received contracted research support (including clinical trials) from Acorda, Biogen Idec, EMD Serono, Hoffman La Roche, MedImmune, Novartis and Teva. T.L. has received compensation for consulting from Abbvie, EMDSerono, Novartis, Genentech, Teva, Biogen, Bayer, Genzyme and for speaking from Novartis, Teva, Biogen,Genzyme. H.M. has received compensation for consulting and speaking from Biogen, Bayer, Teva, Genzyme and Novartis. G.G. received fees for participation in advisory board for AbbVie Biotherapeutics Inc., Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, Sanofi-Genzyme, Synthon, Teva, and Vertex; speaker fees from AbbVie Biotherapeutics Inc., Biogen, Bayer HealthCare, Genzyme, Merck Serono, SanofiAventis, and Teva; coeditor in chief of Multiple Sclerosis and Related Disorders; research support unrelated to study from Biogen, Genzyme, Ironwood, Merck Serono, and Novartis. J.E. is a full-time employee of Biogen and may hold stock or options. L.C.T. Y.L., J.Z., Q.P., L.C., R.R. and S.G. are full-time employees of AbbVie Biotherapeutics and may hold stock or options. The authors would like to thank Katherine Riester for her contributions to the analysis. Jane Rodgers, PhD, of AbbVie, provided medical writing assistance in the development of this publication. P525 Blockade of CD127 exerts a variable clinical effect in the marmoset EAE model Y.S. Kap1, J. Dunham1,2, N. van Driel1, J.D. Laman2, J.C. Lin3, B.A. ‘t Hart1,2 1BPRC, Rijswijk, 2University Medical Center Groningen, Groningen, The Netherlands, 3Rinat-Pfizer, San Francisco, CA, United States Interleukin-7 (IL-7) has complex biology with numerous functions, including T cell survival and proliferation, growth promotion of B cell progenitors, and enhancement of macrophage migration. Antibody blockade or deletion of the IL-7 receptor a (CD127) subunit in mouse models for multiple sclerosis (MS), i.e. experimental autoimmune encephalomyelitis (EAE), ameliorates disease, demonstrating an important pathogenic function of IL-7. Data also suggests that the IL-7/CD127 pathway may play an important role in multiple sclerosis (MS). We investigated whether IL-7R blockade with a novel mAb against human CD127 modulates EAE in the common marmoset. EAE was induced in seven marmoset twins by immunization with a 23-mer peptide from recombinant human myelin oligodendrocyte glycoprotein (MOG34-56) emulsified in incomplete Freund’s adjuvant. The ensuing progressive MS-like disease is characterized by demyelination of white and grey matter and a central pathogenic role of autoreactive T-cells. Treatment with the antiCD127 mAb or PBS as control was started 21 days after immunization followed by weekly intravenous administration. The anti-CD127 mAb caused functional blockade as shown by reduced phosphorylation of STAT5 upon ex vivo stimulation with IL-7. Despite the ubiquitous biological effect, we observed a dichotomous clinical effect. In three fast EAE progressor twins, treatment delayed disease onset, whereas in three slow EAE

progressor twins, treatment had no benefit. No treatment-associated changes were observed in MOG peptide-induced proliferation or IL-17A production by mononuclear cells. However, blockade of CD127 did alter the composition of mononuclear cells in blood or lymphoid organs of fast EAE progressor twins, namely a reduction of the percentages of CD20+CD40+ B cells. In conclusion, blockade of CD127 had clinical benefit in a subgroup of fast EAE progressor twins, which was associated with profound changes in the B cell compartment. Disclosure Yolanda S. Kap, Jordon Dunham, Nikki van Driel, Jon D. Laman and Bert A, ´t Hart have nothing to disclose. John Lin was a full-time employee of Rinat-Pfizer when the study was performed. The other authors report no conflict of interest. Publication of the data, irrespective of outcome, was part of the contractual agreement between Rinat-Pfizer and the BPRC as an independent research center.

P526 Immune response to seasonal influenza vaccine in patients with relapsing-remitting multiple sclerosis on long-term daclizumab HYP treatment L. Mehta1, R. Priestley1, K. Umans1, G. Ozen1, R. Robinson2, M. Sweetser3, J. Elkins1 1Biogen, Cambridge, MA, 2AbbVie Biotherapeutics, Redwood City, CA, 3Former Employee of Biogen, Cambridge, MA, United States Background: As part of routine preventative care, patients with relapsing-remitting multiple sclerosis (RRMS) may need to receive common inactivated vaccines. It is important for physicians to have information on whether vaccinations can be performed safely and effectively during immunomodulatory treatment for MS. Objective: To describe the immune response to inactivated seasonal influenza vaccine during long-term daclizumab high-yield process (DAC HYP) treatment. Methods: An optional vaccine substudy was performed within the SELECTED study. Patients entering SELECTED had received DAC HYP for 1-2 years (median number of doses: 48) in prior studies. In SELECTED, patients with RRMS received DAC HYP 150 mg subcutaneous every 4 weeks and must have completed ⩾3 months of uninterrupted DAC HYP treatment before entering the substudy. The seasonal vaccine (INFLUVAC®/IMUVAC® [Abbott]) contained 3 inactivated influenza virus strains selected by the World Health Organization (WHO) for the 2013/2014 season: A/ California/7/2009 (H1N1), A/Texas/50/2012 (H3N2), and B/ Massachusetts/2/2012 (B). The vaccine was administered as a single intramuscular dose. Seroprotection was defined as a post-vaccination hemagglutination (HA) antibody titer of ⩾40. Seroconversion was defined as a change from negative to seroprotected post-vaccination or a ⩾4x increase in titer if ⩾10 at baseline. Endpoints included the geometric mean titer ratio (GMTR) post- to pre-vaccination, and proportion of patients achieving seroprotection, and proportion of patients who seroconverted. Results: 90 patients received the influenza vaccine (mean exposure to DAC HYP treatment prior to vaccination, 49.6 doses). The


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Poster Session I, 21(S11) HA GMTR was 7.7 for A/H1N1, 9.0 for A/H3N2, and 4.3 for B. HA titers ⩾40 (seroprotection) were detected in 92% (95% confidence interval [CI]: 85%-97%) of patients for A/H1N1, 91% (83%-96%) for A/H3N2, and 67% (56%-76%) for B. Seroconversion was observed in 69% (95% CI: 58%-78%) of patients for A/H1N1, 69% (58%-78%) for A/H3N2, and 44% (34%-55%) for B. Adverse events (AEs) during the 28-day substudy were reported by 14 (16%) patients; serious AEs were reported by 2 patients (MS relapse and allergic dermatitis; 1 patient each). Conclusions: These data provide evidence that patients on longterm DAC HYP treatment mounted an immune response to the seasonal influenza vaccine at levels considered to confer protection against influenza infection. No safety issues were identified. Disclosure Lahar Mehta is a full-time employee of Biogen. Rebecca Priestley is a full-time employee of Biogen. Kimberly Umans is a full-time employee of Biogen and has a family member who holds stock in Sinovac Biotech. Gulden Ozen is a full-time employee of Biogen. Randy Robinson is a full-time employee of AbbVie Biotherapeutics. Marianne Sweetser was a full-time employee of Biogen at the time of the analysis. Jacob Elkins is a full-time employee of Biogen. This study was funded by Biogen and AbbVie Biotherapeutics Inc. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this abstract. Karen Spach, PhD (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Biogen and AbbVie Biotherapeutics reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P527 Ceramide synthase6 / C16-ceramides mediate anti-inflammatory effects during the development of EAE and MS possibly by suppressing the migration and by deactivation of neutrophils: a new target for anti-inflammatory therapy in MS? C.A. Mayer1, A. Männer de Bazo2, C. Foerch2, M. Eberle3, P. Ebel4, J. Barthelmes5, N. Tafferner6, N. Ferreiros5, T. Ulshöfer6, M. Henke6, S. Grösch5, G. Geisslinger5, K. Willecke7, S. Schiffmann5 1Neurologie, Uniklinikum Frankfurt, 2Neurology, GoetheUniversity Frankfurt, 3Pharmazentrum Frankfurt/ZAFES, Goethe-Universitý Frankfurt, Frankfurt, 4Molecular Genetics, Life and Medical Sciences Institute, University of Bonn, Bonn, 5Pharmazentrum Frankfurt/ZAFES, Goethe University Frankfurt, 6Project Group Translational Medicine and Pharmacology (TMP), Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Frankfurt, Germany, 7Molecular Genetics, Life and Medical Sciences Institute, University of Bonn, Bonn, Greenland In experimental autoimmune encephalomyelitis (EAE) we observed a 15-fold upregulation of Ceramide Synthase 6 (CerS6) mRNA expression in peripheral blood leukocytes before onset of EAE symptoms. In peripheral blood leukocytes (PBL) from Multiple sclerosis (MS) patients, a 3.9-fold upregulation was

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found. Total genetic deletion of CerS6 and the selective deletion of CerS6 in PBL exacerbated the progression of clinical symptoms in EAE, associated with enhanced leukocyte, predominantly neutrophil (NC) infiltration and enhanced demyelination in the lumbar spinal cord. Interferon-gamma/ tumor necrosis factor alpha (IFN-γ/TNF-α) and granulocyte colony-stimulating factor (G-CSF) both drive EAE development and induce expression of the integrin CD11b and the chemokine receptor CXCR2 and we found they also induce CerS6 expression. In vivo, the genetic deletion of CerS6 enhanced the activation/migration of NC, as reflected by an enhanced upregulation of CD11b and CXCR2. In vitro, the genetic deletion of CerS6 enhanced the activation status of IFN-γ/TNF-α-stimulated neutrophils, as shown by increased expression of nitric oxide (NO) and CD11b and an increased adhesion capacity. In G-CSF18 stimulated NC, the migration status was enhanced, as reflected by an elevated level of CXCR2 and an increased migration capacity. These data suggest that CerS6 and C16-Ceramides (C16-Cer) mediates feedback regulation by inhibiting the formation of CD11b and CXCR2 which are induced either by IFN-γ/TNF-α or by G-CSF, respectively. We conclude that CerS6/C16-Cer mediates anti-inflammatory effects during the development of EAE and MS possibly by suppressing the migration and deactivation of NC. Disclosure Max Eberle: I have nothing to disclose. Philipp Ebel: I have nothing to disclose. Christoph Mayer received travel grants from genzyme, biogen and Merck serono and speakers honoraria from genzyme, Merck serono and biogen. Julia Barthelmes: I have nothing to disclose. Nadja Tafferner: I have nothing to disclose. Nerea Ferreiros: I have nothing to disclose. Thomas Ulshöfer: I have nothing to disclose. Marina Henke: I have nothing to disclose. Annika Männer de Bazo received travel grants from genzyme. Christian Foerch received travel grants from TEVA pharma, biogen and genzyme and speakers honoraria from genzyme and biogen. Andreas Weigert: I have nothing to disclose. Sabine Grösch: I have nothing to disclose. Gerd Geisslinger: I have nothing to disclose. Klaus Willecke: I have nothing to disclose. Susanne Schiffmann: I have nothing to disclose. P528 Safety and tolerability of MEDI-551 in patients with relapsing forms of multiple sclerosis: results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study M. Agius1, G. Klodowska-Duda2, M. Maciejowski3, A. Potemkowski4, S. Sweeny5, J. Li6, W. Yao5, K. Patra5, J.N. Ratchford5, E. Katz5, A. Flor5 1Department of Neurology, University of California at Davis, Sacramento, CA, United States, 2Neuro-Care, 3KMKClinical Sp. z o.o., NZOZ RAWA-MED, Katowice, 4Osrodek Badan Klinicznych Indywidualnej Specjalistycznej Praktyki Lekarskiej, Szczecin, Poland, 5MedImmune, Gaithersburg, MD, 6MedImmune, Mountain View, CA, United States


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Background: CD19+ B-cells play a role in the pathophysiology of multiple sclerosis (MS). MEDI-551, a humanised, afucosylated IgG1κ monoclonal antibody, binds to and depletes CD19+ B-cells. Objectives: Assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of ascending intravenous (IV) and subcutaneous (SC) doses of MEDI551 in adults with relapsing forms of MS. Methods: In this phase 1 trial (NCT01585766), patients in 5 cohorts were randomised 3:1 to receive MEDI-551, 2 doses (days 1 and 15) of 30, 100, or 600 mg IV, or a single dose (day 1) of 60 or 300 mg SC, or matching placebo (PBO). Only IV patients received premedication to reduce risk of possible infusion reactions. Adverse events (AEs) were monitored. Blood was collected for PK, PD, and antidrug antibodies (ADAs). MRI was performed periodically. Patients were followed until the CD19+ B-cell count returned to the lower limit of normal (80 cells/µL) or to the end of the treatment period (day 169), whichever was later. Results: In total, 28 patients were randomised; 27 (MEDI-551, 20; PBO, 7) completed treatment (day 169). Nine patients remain in follow-up for B-cell recovery as of 1 April 2015. A rapid decline in B-cell counts was observed for all MEDI-551 dose groups. The mean drug half-life was 16 days. Higher doses caused longer B-cell depletion. Most related AEs seen only with MEDI-551 were single events, except for pyrexia, nasopharyngitis, oral herpes, and increased blood pressure (n=2 each). Infusion/injection reactions occurred in 6/15 MEDI-551 IV (40%), 2/6 MEDI-551 SC (33%), and 2/7 PBO patients (29%). Most injection/infusion reactions were grade 1 or grade 2 severity. Three serious AEs occurred in 2 patients in the MEDI-551 group (pyrexia, accidental opioid overdose, and death). The death was due to a mixed-drug intoxication that was not MEDI551 related (n=1, MEDI-551 30-mg IV cohort). ADAs were not observed in any patients. The mean number of cumulative new gadolinium-enhancing lesions over 169 days was 0.1 in the MEDI-551 group vs 1.1 in the PBO group. The mean number of new or newly enlarging T2 lesions at day 169 was 0.4 in the MEDI-551 group vs 2.2 in the PBO group. Conclusions: MEDI-551 showed promising safety and tolerability in patients with relapsing MS. Two IV infusions with MEDI551(30, 100, or 600 mg) or a single SC dose (60 or 300 mg) led to rapid, sustained B-cell depletion. Disclosure M. Agius has served as a remunerated consultant and/or on advisory boards for Genzyme, Biogen Idec, and Novartis; served as a lecturer for Novartis, Genzyme, Biogen Idec, Bayer, and Teva; has received travel expenses from Novartis, Genzyme, and Biogen Idec; and has received research funding from Novartis, Genzyme, MedImmune, NIH, Roche, and Acorda. G. Klodowska-Duda has nothing to disclose. M. Maciejowski has nothing to disclose. A. Potemkowski has nothing to disclose. S. Sweeny has nothing to disclose. J. Li is an employee of MedImmune and holds stock and/or stock options in the company. W. Yao has nothing to disclose. K. Patra is an employee of MedImmune and holds stock and/or stock options in the company. J.N. Ratchford has served as a remunerated consultant and/or on advisory boards for Biogen Idec and Genzyme; has developed educational presentations for Prime Education; has received research

funding from Novartis, Biogen Idec, and Sun Pharmaceuticals; and is an employee of MedImmune and holds stock and/or stock options in the company. E. Katz is an employee of MedImmune. A. Flor is an employee of MedImmune and has stock and/or stock options in the company. P529 High persistence with fingolimod in Canadian routine clinical practice Y. Lapierre1, P. O’Connor2, V. Devonshire3, M.S. Freedman4, M. Kremenchutzky5, M. Yeung6, P. Haddad7, R. Schecter7 1McGill University Health Centre, Montreal, QC, 2St. Michael’s Hospital, Toronto, ON, 3University of British Columbia Hospital, Vancouver, QC, 4University of Ottawa and Ottawa Health Research Institute, Ottawa, 5London Health Sciences Centre, London, ON, 6Foothill Medical Centre, Calgary, AB, 7Novartis Pharmaceuticals Canada Inc., Montreal, QC, Canada Background: Fingolimod was launched in Canada as the first oral disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS). The Gilenya® Go PrograTM provides education and support to patients with RRMS during fingolimod treatment. Services include coordination of first-dose observation (FDO) at specialized centers and follow-up contact to reinforce monitoring recommendations and compliance. Objective: To analyse the continuation rate, reasons for treatment discontinuation and incidence of adverse events during treatment. Methods: Data have been collected and analyzed for patients enrolled in the Canadian Gilenya® Go ProgramTM which was launched in March 2011. Results: At data cut-off, 2492 individuals had completed FDO; with 2072 patients being actively treated. 75.2% were female; mean age 41.2 years. Prior therapies (n=2271) were glatiramer acetate (31.1%), subcutaneous interferonβ-1a (25.2%), intramuscular interferonβ-1a (14.9%), natalizumab (14.2%), subcutaneous interferonβ-1b (10.1%); and other (1.1%). Patient-reported reasons for switching to fingolimod (n=1848) included lack of efficacy (34.9%), side effects (34.6%), and dissatisfaction with injections/ infusion (30.5%). Overall continuation rate with fingolimod was 86.4% over the three year observation period (in treatment minus withdrawals). There were 327 treatment discontinuations (d/c) with the most common reasons being adverse effects (59.8%), physician request (13.3%), lack of efficacy (9.3%) and patient request (8.7%). There were 19 early withdrawals (0.79%), defined as < 7 days after FDO. There were 4 cases of first-degree atrioventricular (AV) block and three cases of second-degree AV block. The incidence of all cardiac-related events leading to early withdrawal was rare (0.5%). 94.4% completed the scheduled ophthalmic examination. Conclusions: The GILENYA® Go ProgramTM provides ongoing data collection and insights on the patient experience for almost all fingolimod-treated patients in Canada, enabling the evaluation of use in routine clinical practice. In particular, it permits a greater understanding of the tolerability and persistence rate of fingolimod. Oral fingolimod has demonstrated good tolerability in clinical practice with a two-year continuation rate (76.6%) higher than the cumulative persistence rate at two years (41.5%-47.4%) observed with injectable DMTs in real world practice in Canada. GILENYA® and Go ProgramTM are registered trademarks


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Poster Session I, 21(S11) Disclosure Paul O’Connor - Has done studies with and received consulting honoraria with the following companies: Teva, Biogen Idec, Bayer, Novartis, Genzyme, Actelion, Merck Serono, Bristol Myers, and Receptos. Yves Lapierre - Has participated in Advisory boards for BiogenIdec, Novartis and Genzyme in the last year. He also has given presentations at conferences sponsored by Teva, EMD-Serono, Novartis and Genzyme in the past and taken part in clinical trials sponsored by Novartis, Biogen-Idec, EMD-Serono and Opexa. Virginia Devonshire - Has received honoraria from the following companies for Advisory meetings and speaker honorarium: EMD Serono, Biogen Idec, Teva Neurosciences, Novartis, Allergan and Genzyme. UBC has received payments for clinical trials in which Dr. Devonshire was the Principal Investigator from Novartis, Serono, and Genzyme. Mark Freedman - Has received honoraria or consultation fees from BayerHealthcare, Biogen-Idec, Chugai, EMD Canada, Genzyme, Novartis, Sanofi-Aventis, Teva Canada Innovation. Dr. Freedman is a member of the following company advisory boards, board of directors or other similar group: BayerHealthcare, Biogen-Idec, Hoffman La-Roche, Merck Serono, Novartis, Opexa, and SanofiAventis. Dr. Freedman is a Participant in the following company sponsored speaker’s bureau: Genzyme Marcelo Kremenchutzky - None in reference to this abstract. Otherwise, the London MS clinic and/or MK have received operational funding from the MS Society of Canada, research grants from Canadian Institute for Health Research, and research grants and consulting/speaker’s fees from Biogen, Genzyme, Novartis, Sanofi, Teva. Michael Yeung - Has received consultation fees from EMD Serono, Genzyme and Novartis, and the Canadian Agency for Drugs and Technologies in Health (CADTH)/Health Canada, and research support from Biogen-Idec, Genzyme, Hoffmann-La Roche, Novartis, and Teva Canada Innovation. Paola Haddad - Employee of Novartis Pharmaceuticals Canada Inc. Robyn Schecter - Employee of Novartis Pharmaceuticals Canada Inc. P530 Comparison of efficacy and persistence of first line fingolimod vs interferon-beta/glatiramer in the presence of prior disease activity T. Spelman1, G. Izquierdo2, R. Alroughani3, R. Fernández Bolaños4, E. Havrdova5, D. Horaova6, C. Oreja-Guevara7, J. Lechner-Scott8, M. Slee9, M. Barnett10, C. Boz11, M. Terzi12, F. Grand’Maison13, A. Lugaresi14, M. Trojano15, H. Butzkueven1, MSBase Study Group 1Department of Neurology, Royal Melbourne Hospital, Parkville, VIC, Australia, 2Hospital Universitario Virgen Macarena, Sevilla, Spain, 3Amiri Hospital, Kuwait City, Kuwait, 4Hospital Universitario Virgen de Valme, Sevilla, Spain, 5Charles University in Prague, 3rd Faculty of Medicine, Hospital Kralovske Vinohrady, 6Charles University, Prague, Czech Republic, 7Hospital Clínico San Carlos, Madrid, Spain, 8John Hunter Hospital, Newcastle, NSW, 9Flinders University and Flinders Medical Centre, Adelaide, SA, 10Brain and Mind Research Institute, Sydney, NSW, Australia, 11Karadeniz Technical University, Trabzon, 12Mayis University,

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Medical Faculty, Samsun, Turkey, 13Neuro Rive-Sud, Hôpital Charles LeMoyne, Montreal, QC, Canada, 14Department of Neuroscience, Imaging and Clinical Sciences, MS Center, University ‘G. d’Annunzio’, Chieti, 15Department of Basic Medical Sciences, Neuroscience and Sense Organs, University ‘G. d’Annunzio’, Bari, Italy Objective: To compare annualized relapse rates (ARR), time to first relapse, treatment persistence, EDSS change and disability progression in a propensity-matched, treatment-naïve MS patients with prior disease activity on first-line fingolimod relative to firstline interferon-beta (IFNβ) or glatiramer acetate (GA). Methods: The MSBase study is a global, longitudinal, observational registry for Multiple Sclerosis. At time of data extraction, the registry contained 31,429 patients from 104 centres across 30 countries adhering to a unified observational plan. All patients included in the analysis had at least one relapse in the 12 months prior to baseline. First line fingolimod initiations were 1:1 propensity matched to first-line IFNβ/GA commencements using sex, age, country, disease duration, EDSS, cerebral MRI and pre-treatment relapse activity as baseline matching characteristics. Matching quality was assessed via signed-rank and McNemar Chi tests and analysis of standardized differences. Predictors of time to first relapse, treatment discontinuation and disability progression were investigated using a clustered marginal Cox model, with simultaneous censoring of the matched pair to adjust for differences in follow-up duration. Results: A total of 180 first-line fingolimod patients were successfully matched to 180 IFNβ/GA initiations. Mean on-treatment ARR on first-line fingolimod was decreased by 66% to 0.27 relapses per year from 0.64 on BRACE treatment. Fingolimod was associated with a 46% reduction in the rate of first on-treatment relapse compared with first-line IFNβ/GA (HR 0.54, 95% CI 0.35-0.83). Fingolimod was associated with a 42% reduction in treatment discontinuation compared with IFNβ/GA (HR 0.58, 95% CI 0.34, 0.96). The proportion of patients experiencing an on-treatment disability progression event was lower in the fingolimod arm (10.4% vs 21.7%, p=0.021) however there was no difference in the rate of progression (HR 0.79, 95% CI 0.39, 1.61). Interpretation: The efficacy of fingolimod initiation, as assessed by time to first relapse and time to treatment discontinuation, was superior to that of IFNβ/GA in a first-line setting in propensity-matched MS patients. There was no difference in disability progression. Disclosure Tim Spelman received honoraria for consultancy, funding for travel and compensation for serving on scientific advisory boards from Biogen Idec Inc; speaker honoraria from Novartis. Guillermo Izquierdo received consulting fees from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi, and Teva. Raed Alroughani received honororia from Biologix, Bayer, Merck Sorono, GSK and Novartis, and served on advisory board for Biologix, Novartis and Merck Sorono Ricardo Fernández Bolaños did not declare any competing interests Eva Havrdova received speaker honoraria and consultant fees from Biogen Idec, Merck Serono, Novartis, Genzyme and Teva, as well as support for research activities from Biogen Idec and Merck Serono.


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Dana Horakova received speaker honoraria and consultant fees from Biogen Idec, Merck Serono, Novartis, Genzyme and Teva, as well as support for research activities from Biogen Idec and Merck Serono. Celia Oreja-Guevara received honoraria as scientific advisory board consultant from Biogen-Idec, Bayer-Schering, MerckSerono, Teva and Novartis; has participated in research projects by Biogen-Idec, GSK, Teva and Novartis Jeannette Lechner-Scott has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment and also clinic support from Bayer Health Care, Biogen Idec, CSL, Genzyme Sanofi, Merck Serono and Novartis. Mark Slee did not declare any competing interests Michael Barnett has received honoraria for participation in advisory boards and travel sponsorship from Novartis, BioCSL, Genzyme and Biogen Idec Cavit Boz received conference travel support from Biogen Idec, Novartis, Bayer-Schering, Merck-Serono and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. Murat Terzi received travel grants from Merck Serono, Novartis, Bayer-Schering, Merck-Serono and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. Francois Grand-Maison received an honorarium for organizing a CME event for Biogen Idec in 2013 and received consultation fees from Biogen Idec as well as from Novartis and Genzyme in 2013 and 2014. Alessandra Lugaresi was a Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis Advisory Board Member. She received travel grants and honoraria from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi and Teva, research grants from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi and Teva, travel and research grants from the Associazione Italiana Sclerosi Multipla. Maria Trojano received honoraria for consultancy and/or speaking from Biogen Idec, Genzyme-Sanofi, Merck Serono, Novartis, and Roche; research grants from Biogen Idec, Merck Serono, Novartis, and Teva. Helmut Butzkueven received compensation for serving on scientific advisory boards and as a consultant for Biogen Idec and Novartis; speaker honoraria from Biogen Idec Australia, Merck Serono Australia, and Novartis Australia; travel support from Biogen Idec Australia and Merck Serono Australia; research support from CASS Foundation (Australia), Merck Serono Australia, the Royal Melbourne

P531 MRI results in patients with CIS treated with interferon beta-1b: 11-year follow up in BENEFIT (BENEFIT 11) F. Barkhof1, M.P. Wattjes1, G. Edan2, M.S. Freedman3, X. Montalbán4, H.-P. Hartung5, B. Hemmer6,7, E.J. Fox8, S. Schippling9, R. Koelbach10, D. Pleimes11, C. Pohl12,13, R. Sandbrink5,12, G. Suarez14, E.-M. Wicklein12, L. Kappos15, the BENEFIT Study Group 1VU University Medical Center, Amsterdam, The Netherlands, 2CHU-Hopital Pontchaillou, Rennes, France, 3University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada, 4Hospital Universitari Vall d’Hebron, Barcelona, Spain, 5Department of Neurology, Heinrich-Heine Universität,

Düsseldorf, 6Technische Universität München, 7Munich Cluster for Systems Neurology (SyNergy), Munich, Germany, 8University of Texas Medical Branch, Austin, TX, United States, 9University Hospital Zurich, Zurich, Switzerland, 10PAREXEL International, 11Myelo Therapeutics GmbH, 12Bayer Pharma AG, Berlin, 13University Hospital of Bonn, Bonn, Germany, 14Bayer HealthCare Pharmaceuticals, Whippany, NJ, United States, 15Neurology, University Hospital Basel, Basel, Switzerland Background: Patients with clinically isolated syndrome (CIS) who had early treatment with interferon beta-1b in the BENEFIT trial had significantly better clinical outcomes up to 8 years after randomization when compared with patients who had a short delay. Outcomes on MRI were also more favorable with earlier treatment at the end of the placebo-controlled phase after 2 years up to the 5-year analysis; MRI was not assessed at Year 8. Objective: To report MRI findings at 11 years post-randomization Methods: Patients with CIS who had ⩾2 clinically-silent brain lesions on MRI were randomized to interferon beta-1b (early treatment) or placebo (delayed treatment). Patients remained on placebo until conversion to clinically definite MS or for 2 years. At 11 years, all patients were approached to undergo cross-sectional MRI follow-up with blinded centralized reading. Results: 278 of the original 468 patients participated in the 11-year follow up, with MRI data collected from 191 (68.7%, 114 and 77 respectively from the original early and delayed treatment groups). Both groups had similar baseline characteristics when assessed at Year 11 except for a higher number of T1 and T2 lesions in the early treatment arm. Year 11 findings were generally similar across groups: Overall, 86.4% had no gadolinium-enhancing lesions; median (Q1, Q3) new T2 lesions since Year 5 MRI: 2.0 (0.0, 6.0), T2 volume: 1760.0 mm³ (775.0, 4738.0), FLAIR cortical lesions: 2.0 (0.0, 5.0), normalized brain volume (NBV): 1519.0 cm³ (1433.0, 1585.0), cortical thickness: 2.640 mm (2.420, 2.980), mean upper cervical cord area (MUCCA): 76.60 mm2 (72.00, 83.00). There was a slight difference in median (Q1, Q3) number of T1 lesions: 4.0 (1.0, 11.0) in the early and 2.0 (1.0, 6.0) in the delayed group, which was driven by the imbalance in T2 lesion number at screening (risk ratio [95% CI] 1.02 [1.02, 1.03], p< 0.0001). T1 and T2 lesion volume correlated positively with EDSS and ARR and negatively with MSFC. Median (Q1, Q3) grey matter MTR in the early and delayed groups was 34.6% (29.6, 36.9) and 32.4% (29.7, 36.8), respectively. White matter MTR was 38.2% (33.4, 40.9) and 36.3% (33.0, 41.4), respectively. Conclusions: Compared with cohorts with similar disease duration, patients in BENEFIT had a relatively low lesion volume with little evidence of brain atrophy, both supportive of early treatment with interferon beta-1b for patients with CIS. Disclosure ● F Barkhof has received compensation for consultancy from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis, Genzyme, Roche, and Teva, and has received research support from the Dutch Foundation for MS research (an NGO). ● M Wattjes has received compensation for consultancy from Biogen Idec and Roche. He has also received speaking fees from Biogen Idec.


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Poster Session I, 21(S11) ● G Edan has received honoraria for lectures or consulting from Biogen Idec, Merck Serono, and Sanofi-Aventis, and received personal compensation for serving on the BENEFIT scientific advisory board and for speaking from Bayer Pharma AG. He has also received research support from Serono, (a grant to University Hospital to support a research program on MRI in MS) and from Teva (a grant to support a research program on anti-IBF neutralizing antibodies). ● MS Freedman has received compensation from Bayer HealthCare, Biogen Idec, EMD Canada, Chugai, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, and Teva Canada Innovation for consulting services. He also participates in a Genzyme-sponsored speakers bureau. ● X Montalbán has received speaking honoraria and travel expenses for scientific meetings and has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer, Biogen Idec, EMD, Genentech, Genzyme, Merck Serono, Neurotec, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, and Almirall. ● H-P Hartung has received honoraria for consulting and speaking at symposia from Bayer Pharma AG, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva, and SanofiAventis, with approval by the rector of Heinrich-Heine University. B Hemmer has served on scientific advisory boards for ● Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GSK, Chugai Pharmaceuticals, Micromet, and Genzyme Corporation; is author on patents re: KIR4.1 antibody testing in MS and genetic determinant of neutralizing antibody development in interferon-beta-treated patients; has received speaker honoraria from Bayer Schering, Novartis, Biogen Idec, Merck Serono, Roche, and Teva Pharmaceutical Industries Ltd.; and has received research support from Biogen Idec, Bayer Schering, Merck Serono, Five Prime, Metanomics, and Novartis. ● EJ Fox has received consulting fees, honoraria, travel, or research support from Acorda, Bayer, Biogen Idec, Eli Lilly, EMD Serono, Genzyme, GlaxoSmithKline, Novartis, Ono, Opexa Therapeutics, Pfizer, Roche, Sanofi, and Teva. ● S Schippling has received research grants from Biogen Idec, Bayer Schering Pharma and Genzyme and consulting/speaker fees from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, TEVA and Sanofi-Aventis. ● R Koelbach is a salaried employee of PAREXEL International. ● D Pleimes is a salaried employee of Myelo Therapeutics GmbH. He was a salaried employee and is currently a paid consultant for Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. DP owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. ● C Pohl is a salaried employee of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. He owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. ● R Sandbrink is a salaried employee of Bayer Pharma AG/ Bayer HealthCare Pharmaceuticals. He owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. ● G Suarez is a salaried employee of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. ● E-M Wicklein is salaried employee of Bayer Pharma AG.

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● L Kappos’ institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof Kappos’ activities as principal investigator and member or chair of planning and steering committees or advisory boards in trials sponsored by Actelion, Addex, Bayer HealthCare Pharmaceuticals, Bayer Schering Pharma, Biogen Idec, CLC Behring, Genentech, GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Praxicon, Roche, Sanofi-Aventis, Santhera, Siemens and Teva and royalties from Neurostatus GmbH. Prof Kappos has received grants from the Swiss MS Society, Swiss National Research Foundation, the European Union, Gianni Rubatto Foundation, and the Novartis and Roche Research foundations. P532 Switching from other oral DMTs to fingolimod: Canadian real world experience F. Grand’Maison1, P. O’Connor2, Y. Lapierre3, V. Devonshire4, P. Haddad5, R. Schecter5 1Clinique Neuro Rive-Sud, Greenfield Park, QC, 2St. Michael’s Hospital, Toronto, ON, 3McGill University Health Centre, Montreal, 4University of British Columbia Hospital, Vancouver, 5Novartis Pharmaceuticals Canada Inc., Montreal, QC, Canada Background: There are a number of oral disease modifying treatments (DMTs) for relapsing remitting multiple sclerosis (RRMS). Switching from one DMT to another is common in routine clinical practice, with the goal to minimize the risk of disease progression. Objective: This analysis evaluated the persistence and tolerability of fingolimod in patients who switched from either dimethyl fumarate or teriflunomide to fingolimod. The objective was to understand reasons for switching and to assess the continuation rate on fingolimod. Methods: Data were collected and analyzed for patients enrolled in the Canadian Gilenya® Go ProgramTM with data cut-off, February 2015. Patients were enrolled from across Canada. Results: At data cut-off, 149/2769 fingolimod-treated patients reported dimethyl fumarate (N=116) or teriflunomide (N=33) as their most recent treatment before fingolimod. Duration of previous treatment with either dimethyl fumarate or teriflunomide was not obtained. 75% were female (average age 41.5 years). Patientreported reasons for discontinuing previous treatments (n=149) included: side effects (55.7%), lack of efficacy (26.2%), no reason given (16.1%) and allergic reaction (2.0%). Discontinuations due to side effects were more common with dimethyl fumarate and lack of efficacy was more common with teriflunomide. During the observation period, the continuation rate on fingolimod was 91.3%, (94/103). Seven patients have stopped treatment with fingolimod. Of those, five patients are currently discontinued due to Adverse Events (AEs) post first dose. These AEs include infections (n=2), non-specific (n=2) and palpitations (n=1). The remaining two patients were discontinued due to patient request (n=1) and no reason was provided for the other case (n=1). At the time of data cut-off, mean time on fingolimod was 190 days and median time was 128 days. Conclusions: Fingolimod is a good switch option for patients previously treated with dimethyl fumarate or teriflunomide.


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Fingolimod is associated with good tolerability and retention rates. Understanding the persistence and tolerability profiles of the various DMTs used to treat RRMS is important for treatment selection and may help to optimize disease management over the long term. Gilenya® Go ProgramTM are registered trademarks Disclosure Francois Grand’Maison - Research support: Novartis, Ono Pharmaceuticals, Mitsubishi, CHUGAI, Opexa, Genzyme, Biogen. Speaker fees: Genzyme, Biogen Idec. Ad Boards : Roche, Biogen. Director of the MSBase Board. Paul O’Connor - Has done studies with and received consulting honoraria with the following companies: Teva, Biogen Idec, Bayer, Novartis, Genzyme, Actelion, Merck Serono, Bristol Myers, and Receptos. Yves Lapierre - Has participated in Advisory boards for BiogenIdec, Novartis and Genzyme in the last year. He also has given presentations at conferences sponsored by Teva, EMD-Serono, Novartis and Genzyme in the past and taken part in clinical trials sponsored by Novartis, Biogen Idec, EMD-Serono and Opexa. Virginia Devonshire - Honoraria from the following companies for Advisory meetings and speaker honorarium: EMD Serono, Biogen Idec,Teva Neurosciences, Novartis, Allergan and Genzyme. UBC has received payments for clinical trials in which Dr. Devonshire was the Principal Investigator from Novartis, Serono, and Genzyme. Paola Haddad - Employee of Novartis Pharmaceuticals Canada Inc. Robyn Schecter - Employee of Novartis Pharmaceuticals Canada Inc. P533 Vitamin D enhances interferon-beta1b response in multiple sclerosis A.T. Reder1, Z. Wang2, S. Causevic1, J. Garcia-Vargas1, P. Green1, S. Whang1, X. Feng1 1University of Chicago Medical Center, Chicago, IL, United States, 2Neurology, 1st Affiliated Hospital of Dalian Medical University, Dalien, China Objective: Determine molecular effect of Vitamin D3 on interferon-beta response in mononuclear cells. Background: Oral vitamin D has additive effects on IFN-b therapy in reducing MRI lesions and clinical activity in MS. The mechanism is unknown, and may be confounded by IFN elevation of serum vitamin D levels, lifestyle, and the subnormal endogenous IFN signaling present in therapy-naïve MS patients. Design/methods: MNC from therapy-naïve patients with stable RRMS (N=36), active RRMS (10), progressive MS (21), plus MS patients receiving IFN-b (15) or glatiramer treatment (11), plus other neurologic diseases (OND) (23) and healthy controls (19) were incubated in vitro with 160 U/ml IFN-beta-1b for 30min to 48h ± 100-200 nM Vit D3 (calcitriol; 12-60h pre-incubation). IFN-responsive transcription factors, p-Y-STAT1, p-S-STAT1, and also MxA protein, were measured with flow cytometry and western blots. Results: Vitamin D enhanced IFN-b induction of p-Y-STAT1 and MxA in MNC from therapy-naïve stable RRMS (p=0.024; 2-fold

change), in IFN-b-treated stable RRMS (p=0.026; 1.6-fold change), and in healthy controls (p=0.029; 2-fold change) and in OND (p=0.015; 1.5-fold change). There was less effect of Vit D on IFN responses during exacerbations and progression. Vit D had no effect on IFN response in glatiramer-treated patients. IFN response increased more in T cells than in monocytes. Conclusions: Vitamin D enhances IFN-beta activation of STAT1 by 100% in untreated patients and by 60% in IFN-treated patients. This increase in interferon signaling may provide a mechanism for benefits of vitamin D in preventing and ameliorating MS, before and during IFN-b therapy. Vitamin D is an inexpensive and safe way to amplify IFN-b’s therapeutic benefit. Disclosure Anthony T Reder and Xuan Feng have unrestricted grant support from the US National MS Society, Bayer, Biogen, and Novartis Zhe Wang, Suad Causevic, Julia Garcia-Vargas; Patricia Green, and Sean Whang have no confltcts P534 Optical coherence tomography and ophthalmological findings in patients with CIS treated with interferon beta-1b: 11-year follow-up in BENEFIT (BENEFIT 11) S. Lukas1, J.V.M. Hanson1, G. Edan2, M.S. Freedman3, X. Montalbán4, H.-P. Hartung5, B. Hemmer6,7, E.J. Fox8, F. Barkhof9, R. Koelbach10, D. Pleimes11, C. Pohl12,13, R. Sandbrink5,12, G. Suarez14, E.-M. Wicklein12, L. Kappos15, S. Schippling1, The BENEFIT Study Group 1University Hospital Zurich, Zurich, Switzerland, 2CHU-Hopital Pontchaillou, Rennes, France, 3University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada, 4Hospital Universitari Vall d’Hebron, Barcelona, Spain, 5Department of Neurology, Heinrich-Heine Universität, Düsseldorf, 6Technische Universität München, 7Munich Cluster for Systems Neurology (SyNergy), Munich, Germany, 8University of Texas Medical Branch, Austin, TX, United States, 9VU University Medical Center, Amsterdam, The Netherlands, 10PAREXEL International, 11Myelo Therapeutics GmbH, 12Bayer Pharma AG, Berlin, 13University Hospital of Bonn, Bonn, Germany, 14Bayer HealthCare Pharmaceuticals, Whippany, NJ, United States, 15Neurology, University Hospital Basel, Basel, Switzerland Background: Early treatment with interferon beta-1b in BENEFIT led to significantly better clinical and MRI outcomes compared with patients whose treatment was delayed. Assessing optical coherence tomography (OCT) in this cohort at 11 years could provide novel insights into long-term effects of treatment at CIS on retinal morphology and visual function. Objective: To report ophthalmological and OCT findings at 11 years post-randomization. Methods: Patients with CIS suggestive of MS were randomized to interferon beta-1b (early treatment) or placebo (delayed treatment). Patients remained on placebo until conversion to clinically definite MS or for 2 years. 11 years after randomization, all patients were approached to undergo a comprehensive reassessment that included an ophthalmological examination and OCT. Results: 278 patients were assessed at 11 years, with OCT assessment completed in 84 (30.2%) (early: 52, delayed: 32). Baseline


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Poster Session I, 21(S11) demographic and clinical characteristics were generally similar between the 2 groups, but at Year 11 a slightly higher percentage of patients in the delayed treatment group had a history of optic neuritis (37.5% vs 25.0%). Ophthalmological examination indicated generally good visual acuity in both groups (median [Q1, Q3] overall visual acuity score: right eye, 88 [84, 90]; left eye, 88 [82, 90]). No differences in OCT parameters were seen between the early and delayed groups. In the overall cohort, median (Q1, Q3) right/left eye global retinal nerve fiber layer thickness (G-RNFL, 12°) was 93.0 µm (85.0, 100.0)/91.5 µm (83.0, 101.0), total macular volume (TMV) was 8.37 mm3 (8.10, 8.75)/8.47 mm3 (8.03, 8.82), and ganglion cell inner plexiform layer thickness was 79.5 µm (72.0, 85.0)/80.0 µm (71.0/85.0). G-RNFL and PMB-RNFL thickness correlated negatively with annualized relapse rate, T1 hypointense lesion volume, and T2 hyperintense lesion volume at Year 11. G-RNFL also correlated positively with PASAT score at Year 11. Baseline vitamin D level was the only parameter that correlated with Year 11 OCT parameters (TMV, p=0.0453). Conclusions: Given the estimated annual loss in RNFL of 1-2 µm in patients with relapsing MS in the absence of optic neuritis as suggested by recent publications, patients in the BENEFIT cohort (all of whom received treatment relatively early in the course of MS) showed generally favorable OCT parameters as mirrored by visual outcomes 11 years following initial treatment. Disclosure ● S Lukas has received speaker fees from Heidelberg Engineering, Genzyme, and Biogen Idec ● JVM Hanson has received speaker fees from Biogen Idec ● G Edan has received honoraria for lectures or consulting from Biogen Idec, Merck Serono, and Sanofi-Aventis, and received personal compensation for serving on the BENEFIT scientific advisory board and for speaking from Bayer Pharma AG. He has also received research support from Serono, (a grant to University Hospital to support a research program on MRI in MS) and from Teva (a grant to support a research program on anti-IBF neutralizing antibodies). ● MS Freedman has received compensation from Bayer HealthCare, Biogen Idec, EMD Canada, Chugai, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, and Teva Canada Innovation for consulting services. He also participates in a Genzyme-sponsored speakers bureau. ● X Montalbán has received speaking honoraria and travel expenses for scientific meetings and has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer, Biogen Idec, EMD, Genentech, Genzyme, Merck Serono, Neurotec, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, and Almirall. H-P Hartung has received honoraria for consulting and ● speaking at symposia from Bayer Pharma AG, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva, and SanofiAventis, with approval by the rector of Heinrich-Heine University. ● B Hemmer has served on scientific advisory boards for Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GSK, Chugai Pharmaceuticals, Micromet, and Genzyme Corporation; is author on patents re: KIR4.1 antibody testing in MS and genetic determinant of neutralizing antibody development in interferon-beta-treated patients; has received

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speaker honoraria from Bayer Schering, Novartis, Biogen Idec, Merck Serono, Roche, and Teva Pharmaceutical Industries Ltd.; and has received research support from Biogen Idec, Bayer Schering, Merck Serono, Five Prime, Metanomics, and Novartis. ● EJ Fox has received consulting fees, honoraria, travel, or research support from Acorda, Bayer, Biogen Idec, Eli Lilly, EMD Serono, Genzyme, GlaxoSmithKline, Novartis, Ono, Opexa Therapeutics, Pfizer, Roche, Sanofi, and Teva. ● F Barkhof has received compensation for consultancy from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis, Genzyme, Roche, and Teva, and has received research support from the Dutch Foundation for MS research (an NGO). ● R Koelbach is a salaried employee of PAREXEL International. ● D Pleimes is a salaried employee of Myelo Therapeutics GmbH. He was a salaried employee and is currently a paid consultant for Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. DP owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. ● C Pohl is a salaried employee of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. He owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. ● R Sandbrink is a salaried employee of Bayer Pharma AG/ Bayer HealthCare Pharmaceuticals. He owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. ● G Suarez is a salaried employee of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. ● E-M Wicklein is salaried employee of Bayer Pharma AG. ● L Kappos’ institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof Kappos’ activities as principal investigator and member or chair of planning and steering committees or advisory boards in trials sponsored by Actelion, Addex, Bayer HealthCare Pharmaceuticals, Bayer Schering Pharma, Biogen Idec, CLC Behring, Genentech, GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Praxicon, Roche, Sanofi-Aventis, Santhera, Siemens and Teva and royalties from Neurostatus GmbH. Prof Kappos has received grants from the Swiss MS Society, Swiss National Research Foundation, the European Union, Gianni Rubatto Foundation, and the Novartis and Roche Research foundations. ● S Schippling has received research grants from Biogen Idec, Bayer Schering Pharma and Genzyme and consulting/ speaker fees from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, TEVA and Sanofi-Aventis. P535 Daclizumab HYP provided clinically meaningful benefits on cognitive outcomes versus intramuscular interferon beta-1a over 2 years: results from the DECIDE study R.H.B. Benedict1, S. Cohan2, S. Lynch3, P. Wang4, W. Castro-Borrero, J. Elkins4 1State University of New York at Buffalo, University at Buffalo School of Medicine and School of Medicine and Biomedical Sciences, State University of New York (SUNY), Buffalo, NY, 2Providence Multiple Sclerosis Center, Providence Brain and


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Spine Institute, Portland, OR, 3Department of Neurology, University of Kansas Medical Center, Kansas City, KS, 4Biogen, Cambridge, MA, United States Background: In the Phase 3 DECIDE study, daclizumab highyield process (DAC HYP) 150 mg subcutaneous every 4 weeks showed superior efficacy versus interferon (IFN) beta-1a 30 mcg intramuscular (IM) once weekly across a range of clinical, MRI lesion, and patient-centered outcomes in patients with relapsingremitting multiple sclerosis (RRMS). Objective: To evaluate the effects of DAC HYP versus IM IFN beta-1a on cognitive processing speed in DECIDE. Methods: The Symbol Digit Modalities Test (SDMT; oral response format) was administered at baseline and Weeks 24, 48, 72, and 96. Changes from baseline in SDMT score were analysed post hoc for all post-baseline data using a mixed effects model that included treatment as the fixed effect, time and intercept as the random effects, interaction terms for treatment and time, and adjusted for baseline SDMT, history of prior IFN beta use, and baseline age (⩽35 y vs >35 y). Based on recent research on vocational status and cognitive relapse anchors, cut-offs of 3- and 4-point changes from baseline were used to evaluate worsening or improvement in SDMT score. Binary longitudinal outcomes were analysed post hoc using the Generalized Estimating Equations (GEE) approach with a logistic model that included treatment group, time, treatment by time interaction, and adjusted for baseline SDMT score and baseline age (⩽35 y vs >35 y). Results: Greater mean (SD) improvement from baseline was observed in the SDMT score in the DAC HYP group compared with the IM IFN beta-1a group (+4.08 [12.4] vs +2.89 [12.7]; P=0.0274) at Week 96. Higher percentages of patients had ⩾3-point (60.0% vs 54.1%; P=0.0159) or ⩾4-point (55.4% vs 50.1%; P=0.0366) improvements in SDMT score at Week 96 for DAC HYP versus IM IFN beta-1a. A ⩾3-point decline in SDMT was observed in a lower percentage of patients treated with DAC HYP compared with IM IFN beta-1a at Weeks 24 (24.6% vs 28.6%; P=0.0468), 72 (21.0% vs 25.0%; P=0.0384), and 96 (19.4% vs 24.8%; P=0.0086). A lower percentage of DAC HYPtreated patients versus IM IFN beta-1a−treated patients had ⩾4-point decline at week 24 (20.4% vs. 24.8%; P=0.0258) with trends to significance observed at Weeks 72 (18.2% vs 21.5%; P=0.0649) and 96 (17.5% vs 21.1%; P=0.0556). Conclusions: Over 2 years of treatment, DAC HYP improved cognitive processing speed and prevented clinically meaningful cognitive decline compared with IM IFN beta-1a. Disclosure Ralph Benedict has received fees as a consultant for Biogen, Novartis, Genentech, and Genzyme and as a consultant for continuing medical education (CME) from EMD Serono; and has received research support from Biogen, Novartis, Acorda Therapeutics, and Mallinckrodt. Stanley Cohan is a paid consultant and serves on advisory boards for Biogen, Novartis, Genzyme and Mallinckrodt; participates in speaker bureaus for Biogen, Novartis, Genzyme, and Acorda Therapeutics; and receives research support from Biogen, Novartis, Genzyme, Mallinckrodt, Opexa, and Roche. Sharon Lynch has participated in numerous multicenter clinical trials in multiple sclerosis sponsored by Biogen, Bayer, Novartis,

Actelion, Roche, Teva, Artielle ImmunoTherapeutics, Sun Pharma, Acorda Therapeutics, Genzyme, Genentech, Opexa, the National Institutes of Health (NIH), and the National Multiple Sclerosis Society (NMSS). Ping Wang is an employee of Biogen. Jacob Elkins is an employee of Biogen. Lou Barbato is an employee of Biogen. This study was funded by Biogen and AbbVie Biotherapeutics Inc. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this abstract. Alison Gagnon (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P536 Pregnancy experience: preclinical data and pregnancy outcomes in the daclizumab high-yield process clinical program R. Gold1, D. Stefoski2, K. Selmaj3, E. Havrdova4, C. Hurst5, J. Holman6, S. Akella7, M. Sweetser8, P. McCroskery5 1St. Josef-Hospital/Ruhr-University Bochum, Bochum, Germany, 2Rush University Medical Center, Chicago, IL, United States, 3Medical University of Lodz, Lodz, Poland, 4First School of Medicine, Charles University, Prague, Czech Republic, 5Biogen, Cambridge, MA, 6AbbVie Inc., North Chicago, IL, 7AbbVie Biotherapeutics Inc., Redwood City, CA, 8Former Employee of Biogen, Cambridge, MA, United States Background: No formal studies of daclizumab high-yield process (DAC HYP) have been conducted in pregnant women. This abstract reports outcomes of pregnancies occurring during the DAC HYP clinical program and related preclinical studies. Methods: Reproductive and developmental toxicology studies to evaluate the effect of DAC HYP on male/female fertility, embryofetal development and pre- and post-natal development were conducted in cynomolgous monkeys. Outcomes of pregnancies occurring during the DAC HYP clinical program as of August 8, 2014 are reported. In the event of pregnancy, patients were immediately discontinued from treatment. Results: DAC HYP repeat-dose studies did not indicate any treatment effect on fertility, embryofetal, pre- and postnatal (6 months) development or show immune-mediated toxicity in cynomolgous monkeys. There were 37 pregnancies in 35 patients who became pregnant while on or within 6 months of stopping DAC HYP treatment and 6 pregnancies in 5 patients who had been off DAC HYP treatment for more than 6 months. A total of 43 pregnancies in 38 patients were reported; 4 women became pregnant more than once, 2 of these while on treatment and again >6 mo postdose. Two pregnancies were lost to follow-up and information is pending for 7 in women who became pregnant while on or within 6 months of stopping DAC HYP treatment. Among pregnancies with known outcomes (n=34), there were 18 (52.9%) live births (n=15 ⩽6 mo post DAC HYP treatment, n=3 > 6 mo post-treatment); 6 (17.7%) spontaneous abortions (n=4, n=2); 1 (2.9%) induced abortion due to risk of perinatal complications (n=1, n=0); 7 (20.6%) elective terminations (n=6, n=1); and 2 (5.9%) ectopic pregnancies (n=2, n=0) in women who became pregnant while on or within 6 months of stopping DAC HYP treatment or


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Poster Session I, 21(S11) off DAC HYP treatment for >6 months, respectively. One congenital abnormality was observed in a live birth from a patient who had discontinued DAC HYP approximately 3 months before becoming pregnant and who had received interferon beta-1a for 1 month at the start of pregnancy. The incidence of spontaneous abortions was consistent with the expected early pregnancy loss rate (12-22%) in the general population. Conclusions: The current data do not indicate an increased risk of adverse pregnancy outcomes or risk of fetal abnormalities associated with gestational exposure to DAC HYP, but the numbers are small and do not allow for definitive conclusions. Disclosure Ralf Gold has received compensation for consulting services from Biogen; Teva; Sanofi; Novartis; Bayer; Merck Serono. Dusan Stefoski has received honoraria from Biogen, Acorda, Serono, and Teva Neuroscience for consulting services, and speaker bureau honoraria from Biogen, Teva Neuroscience, EMD Serono, Elan, and Acorda. Krzysztof Selmaj has received compensation for consulting services from Biogen, Genzyme, Novartis, Ono, Roche, Synthon, and Teva, and compensation for speaking from Biogen. Eva Havrdova has received personal compensation from Bayer, Biogen, Sanofi Genzyme, Novartis, Merck Serono, and Teva, for consulting fees, honoraria for speaking, and advisory board fees. Christopher Hurst is a full-time employee of Biogen. Joan Holman is a full-time employee of AbbVie Inc. Surekha Akella is a full-time employee of AbbVie Biotherapeutics Inc. Lou Barbato is a full-time employee of Biogen. Marianne Sweetser was a full-time employee of Biogen at the time of the analysis. Peter McCroskery is a full-time employee of Biogen. The daclizumab HYP clinical program was funded by Biogen and AbbVie Biotherapeutics. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this abstract. Alison Gagnon (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P537 Initial experience with teriflunomide in a real-world clinical setting P. Duquette1, E. Roger1, N. Nadeau1, S. Hum2, C. Bigras2, P. Despault1, Y. Lapierre3, F. Grand’Maison4, Montreal MS Study Group 1Neurosciences, CHUM Notre-Dame, 2Neurology, MUHC MNI, Montréal, 3Neurology, Montreal Neurological Institute and Hospital, McGill University, Montreal, 4Multiple Sclerosis, Neuro Rive-Sud, Ville Lemoyne, QC, Canada Background: Teriflunomide (TFLU) was approved in Canada as monotherapy for the treatment of relapsing-remitting multiple sclerosis in November 2013. Its efficacy and adverse events have been described in randomized controlled trials (TEMSO and TOWER).

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Objectives: To describe our initial experience with TFLU: reasons for prescription and tolerance. Methods: TFLU has been regularly prescribed in our clinical practice since December 2013. All patients from two MS Clinics in the greater Montreal area, Centre Hospitalier de l’Université de Montréal (CHUM) and Neuro Rive-Sud (NRS) who were prescribed TFLU were included. Data was extracted from each clinic›s iMed databases. Basic demographics, clinical data, previous treatments, reason for switching and adverse events (AE) are summarized. Results: We have data on 289 patients CHUM (n=224) and NRS (n=65). Our maximal observation period is 17 months. Most patients had used another DMT (CHUM= 81.7%; NRS=77%). The mean age at TFLU start was similar for both sites (45.84; SD=10.57; 46.7 SD=9.76), as well as the mean annualized relapse rate 2 years before TFLU (0.34 SD=0.50 (n=195); 0.36 SD=0.62 (n=46)). Of the 224 patients seen at the CHUM, 192 patients had a followup visit. 31% reported no AE. The most common AEs found were mild transient hair loss (43.2%) and diarrhoea (35.4%), followed by nausea (10%), abdominal pain (6.3%) and paraesthesia (6.3%). Percentages of AEs reported in TEMSO and TOWER trials were much lower for hair loss (13%) and diarrhoea (17.9% and 11%). Nausea was similar (13.7% and 10%). The most common AE in the TEMSO trial was nasopharyngitis (26%), which we did not find in our population. The TOWER trial reported an ALT increase (14%) based on results greater than one time the upper limit of normal. We did not obtain the same results (1.6%) since we only considered results that were two times the upper limit, as we would in a regular clinical setting. ALT increases were all transitory. Conclusion: Most patients (66%) switched from an injectable treatment. Of those, the most frequent reason was convenience (45%). We have found a much higher rate of reported hair loss (43.2%) and diarrhoea (35,4%) and a lower rate of ALT increase (1.6%) than in the clinical trials. Overall, TFLU is well tolerated. We have had one serious adverse event (breast cancer) and one pregnancy which, was terminated. If accepted, the data will be updated at the time of the meeting. Disclosure This investigator-initiated study has been supported by an unrestricted grant from Genzyme. Pierrre Duquette has served on editorial boards and has been supported to attend meetings by EMDSerono, Biogen-Idec, Novartis, Genzyme, and TEVANeuroscience. P Duquette holds grants from the CIHR and the MS Society of Canada. Biogen-Idec, Novartis, and Genzyme are supporting similar investigator-initiated trials. F Grand’Maison Research support: Chugai, Ono Pharmaceuticals, Genzyme, Roche, Sanofi, Novartis, Biogen. Advisory boards: Biogen Speaker fees: Biogen, Genzyme Élaine Roger, Nancy Nadeau, Pierre Despault, and Stanley Hum have nothing to disclose P538 Rituximab as first-line therapy in neuromyelitis optica: efficiency and tolerability H. Zéphir1, R. Bernard-Valnet2, C. Lebrun-Frenay3, O. Outteryck1, B. Audoin4, B. Bourre5, S. Pittion6, S. Wiertlewski7,


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J.-C. Ouallet8, J. Ciron9, J.-P. Neau9, P. Clavelou10, R. Marignier11, D. Brassat12, NOMADMUS, SFSEP 1University of Lille, Lille, 22Pole des Neurosciences, CHU Toulouse and UMR 1043, Toulouse, 3CHU de Nice, Nice, 4Hôpital Universitaire de la Timone, Marseille, 5CHU de Rouen, Rouen, 6CHU de Nancy, Nancy, 7CHU de Nantes, Nantes, 8CHU de Bordeaux, Bordeaux, 9CHU de Poitiers, Poitiers, 10CHU de Clermont Ferrand, Clermont Ferrand, 11Hospices Civils de Lyon, Lyon, 12CHU de BordeauxToulouse, Toulouse, France Background: Neuromyelitis optica (NMO) is a life-threatening disease without any validated treatment strategy. Recent retrospective studies have suggested the efficacy of B cell depletion without any distinction between first-line or rescue therapy. Objective: To assess whether rituximab as first-line therapy in NMO could efficiently control the occurrence of relapses. Methods: A retrospective analysis of NMO patients from the NOMADMUS network found 32 patients receiving rituximab as first-line therapy. The measures were the percentage of relapsefree patients, changes in the annualized relapse rate (ARR), and changes in the EDSS. Tolerance was reported. Results: At baseline, NMO patients were 45 ± 12.1 years old, with a sex ratio of 5.4, and 87.5% of them had AQP4 antibodies. The median disease duration was 6.5 months [1-410], the mean EDSS was 5.8 ± 2.4 and the mean ARR was 3.8 ± 4.3. After rituximab with a mean follow-up of 28.7 ± 21 months, twenty-seven patients (84.3%) were relapse-free. Patients presented a 97% decrease of ARR (p=0.00001). EDSS decreased to 3.9 ± 2.6 (p = 0.01). No relevant side effect was noted. Interpretation: New retrospective data are presented on RTX use in NMOSD. When used as first-line therapy RTX is highly effective and well tolerated. Disclosure All authors have nothing to disclose concerning this work P539 Anti-mu CD52 treatment induces CD39+ regulatory cells in the GALT and suppresses inflammatory cytokine expression within the CNS of EAE mice A.B. Pant, Y. Wang, D. Mielcarz, M. Mishra, J.Y. Channon, K.M. Telesford, E.J. Kasper, C. Kircher, J. Ochoa-Repáraz, A. Haque, L.H. Kasper, S. Begum-Haque Microbiology/Immunology, Dartmouth College, Hanover, NH, United States Background: The gut accounts for 80% of immune cells and serves as an important reservoir for both T and B regulatory (Treg and Breg) cell populations. The interaction between the gut associated lymphoid tissue (GALT) and the commensal microflora is of critical importance in a range of autoimmune conditions. Due to the inaccessibility of human samples, the functional properties of GALT (Peyer’s patches (PP) and mesenteric lymph node (MLN)) derived regulatory lymphocyte populations are not fully understood. Lemtrada, a humanized monoclonal antibody, targets the CD52 protein on the surface of immune cells. We hypothesized that following treatment with anti-mu CD52, a population of

Tregs may arise that mediates protection in Experimental Autoimmune Encephalomyelitis (EAE) mice. Objective: To assess the impact of anti-muCD52 on regulatory cells with an emphasis on GALT derived populations in EAE mice. Design and methods: C57BL/6 mice were immunized with MOG peptide to induce EAE and treated therapeutically with anti-muCD52. Flow cytometric analysis was performed to determine the impact of therapy on GALT-derived CD39+ regulatory populations. Other activation and anti-inflammatory molecules were determined by RT-PCR and ELISA. Immunohistochemistry was performed to determine patterns of inflammation and demyelination. Results: Administration of anti-muCD52 resulted in lymphocyte depletion followed by repopulation. Minimal inflammation was observed in spinal cords of treated EAE mice. Furthermore, anti-muCD52 treatment resulted in an increased frequency of CD39+Foxp3 regulatory cells in PP, MLN, and spleen tissues resulting in significantly suppressed EAE disease progression. We observed a significant decrease in the expression of proinflammatory molecules such as IL-17, TNFa, and nitric oxide (NO) coupled with a significant increase of anti-inflammatory cytokine levels such as IL-10 in plasma. The high frequency of CD39+Foxp3 cells was also observed in MS patients treated with Lemtrada. Conclusions: We demonstrate that anti-muCD52 treatment directs the immune system away from pro inflammatory responses towards a more beneficial response in EAE. We observed a significant increase in CD39+Foxp3 Tregs in GALT tissues of treated mice, which may play a role in constraining pathogenic TH17 cells. Similar effects may also contribute to the prolonged effects of Lemtrada in MS patients. Disclosure This work is supported by a grant from Genzyme Corporation, Cambridge, MA, USA. P540 An open-label add-on trial of cetirizine for neuromyelitis optica: baseline data and preliminary results I. Katz Sand1, M. Fabian1, L. Cook2, R. Telford2, M. Chehade3, M. Masilamani3, T. Kraus3, C. Farrell1, S. Phelps1, M.E. Riffle3, J. Rose2, T. Moran3, F. Lublin1 1Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 2University of Utah, Salt Lake City, UT, 3Icahn School of Medicine at Mount Sinai, New York, NY, United States Objective: To determine the efficacy and tolerability of cetirizine as an add-on to current therapy for neuromyelitis optica (NMO). Background: NMO is a severe inflammatory disease affecting the CNS with the potential to cause serious neurological disability and in some cases, death. Currently available treatments have significant failure rates, necessitating ongoing research regarding novel therapies. Granulocyte infiltration with subsequent neutrophil and eosinophil degranulation are critical to the ultimate destruction of astrocytes, demyelination, and neuronal/axonal loss. This trial will examine the efficacy and tolerability of cetirizine, an eosinophil-stabilizer approved for allergy treatment, as an add-on to currently-available therapies for NMO.


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Poster Session I, 21(S11) Methods: Eligible patients met Wingerchuk 2006 NMO criteria or had optic neuritis or longitudinally-extensive transverse myelitis with positive NMO IgG, and were stable on current NMO therapy for 3 months. Subjects are followed clinically and with serum/CSF analysis for cytokines/chemokines associated with eosinophil priming (IL-3, IL-5, Il-13, GM-CSF, TNF-alpha), chemotaxis (eotaxins, RANTES, IL-8), degranulation (ECP and EDN), and expression of markers of activation and degranulation (CXCR2, CXCR4, CD63,CD69, ICAM-1) by flow cytometry at multiple time points over 1 year. Endpoints include relapse rates and relapse severity before and after cetirizine, tolerability, and changes in immunological parameters. Results: 16 subjects were enrolled between April 2014 and February 2015, including 4 in the CSF sub-study. 15 are female. 7 are black or African American and 9 are white. 3 identify as Hispanic. At the time of enrollment mean age was 39.7 and mean disease duration was 7.2 years. 13 subjects were anti-AQP4 antibody positive. Median EDSS was 3. Eight patients were being treated with rituximab, 7 with mycophenolate, and 1 with azathioprine. As of May 2015 no patient has discontinued study participation due to adverse effects from cetirizine. Immunological data, generally collected through month 6, will be processed in the coming months. Conclusions: Eosinophil-stabilizing properties and favorable safety profile make cetirizine an attractive add-on therapy for NMO. Thus far it has been generally well-tolerated in our patient population, with incoming data about efficacy expected over the coming months. Disclosure I. Katz Sand: Nothing to disclose. M. Fabian: Nothing to disclose. L. Cook: Nothing to disclose. R. Telford: Nothing to disclose. M. Chehade: Nothing to disclose. M. Masilamani: Nothing to disclose. T. Kraus: Nothing to disclose. J. Rose: Nothing to disclose. C. Farrell: Nothing to disclose. S. Phelps: Nothing to disclose. M. Riffle: Nothing to disclose. J. Rose: Nothing to disclose. T. Moran: Nothing to disclose. F. Lublin: Has received compensation for service on steering committees, data monitoring boards or as a consultant for Bayer HealthCare Pharmaceuticals; Biogen Idec; EMD Serono, Inc.; Novartis; Teva Neuroscience; Actelion; Sanofi; Acorda; Questcor/ Malinckrodt; Roche, Genentech; Celgene; Genzyme, MedImmune; Osmotica; Xenoport, Receptos; Forward Pharma; BBB technologies; Akros and is Co-Chief Editor of Multiple Sclerosis and Related Diseases. P541 Efficacy and tolerability of teriflunomide in a real-world clinical setting P. Duquette1, E. Roger1, N. Nadeau1, S. Hum2, C. Bigras2, P. Despault1, Y. Lapierre3, F. Grand’Maison4, Montreal MS Study Group 1Neurosciences, CHUM Notre-Dame, 2Neurology, MUHC MNI, Montréal, 3Neurology, Montreal Neurological Institute

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and Hospital, McGill University, Montreal, 4Multiple Sclerosis, Neuro Rive-Sud, Ville Lemoyne, QC, Canada Background: Teriflunomide (TFLU) is an oral formulation which was approved as a first line option in Canada for the treatment of relapsing-remitting multiple sclerosis (RRMS) on November 2013. Its efficacy and adverse events have been described in randomized controlled trials (TEMSO and TOWER). Data from regular practice are needed. Objectives: We have been using TFLU in regular clinical practice since December 2013. Our objective is to describe our initial experience with TFLU in terms of tolerance and clinical efficacy. Since most patients have switched from a previous disease-modifying treatment (DMT), we wanted to rule out a rebound of disease activity. Methods: All patients from two MS Clinics in the greater Montreal area, Centre Hospitalier de l’Université de Montréal (CHUM) and Neuro Rive-Sud (NRS) who were prescribed TFLU were included, regardless of time on treatment. Basic demographics, clinical data, reasons for discontinuation and number of relapses under TFLU are reported. Results: We have data on 289 patients. Our maximal follow-up duration is 17 months. Most patients had used another DMT (CHUM= 81.7%; NRS=77%). Of the 289 patients, 33 (11%) stopped taking TFLU, mainly due to lack of tolerance (10, or 63%), lack of efficacy (22%), adverse events (AEs) (4, or 12%) and 1 for planned pregnancy (3%). Lack of tolerance consisted of diarrhoea (62%), hair thinning (33,3%), nausea (24%), and abdominal discomfort (19%). The mean treatment duration before cessation was 130 days (range 6 - 390). From the CHUM cohort (224 patients), 19 experienced 1 relapse and 3 reported 2 relapses. From the NRS cohort (65 patients) 6 had 1 relapse and 2 had 2 relapses. The combined number of patients with relapses was 30 (10%). No patient experienced more than 2 relapses. Compliance, judging from patient reporting, is excellent. Conclusion: During this brief observation period, a total of 33 patients (11%) stopped TFLU, mainly because of poor tolerance (usually after a brief exposure) and lack of efficacy. A total of 30 patients (10%) experienced 1 or 2 relapses. We have observed no evidence of a rebound of disease activity, or of a higher rate of relapses, when compared to the rate before TFLU. The frequency of relapses is stable over time. Overall, we can confirm that TFLU is a well tolerated and effective option for RRMS patients in early stages of the disease. If accepted, the data will be updated at the time of the meeting. Disclosure This investigator-initiated study has been supported by an unrestricted grant from Genzyme. Pierrre Duquette has served on editorial boards and has been supported to attend meetings by EMDSerono, Biogen-Idec, Novartis, Genzyme, and TEVANeuroscience. P Duquette holds grants from the CIHR and the MS Society of Canada. Biogen-Idec, Novartis, and Genzyme are supporting similar investigator-initiated trials. F Grand’Maison Research support: Chugai, Ono Pharmaceuticals, Genzyme, Roche, Sanofi, Novartis, Biogen.


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Advisory boards: Biogen Speaker fees: Biogen, Genzyme Élaine Roger, Nancy Nadeau, Pierre Despault, and Stanley Hum have nothing to disclose P542 Effects of laquinimod on microglia and monocytes following traumatic brain injury A. Katsumoto1, A.S. Miranda2, O. Butovsky3, Z. Fanek3, R.M. Ransohoff1, B.T. Lamb1 1Neurosciences, Cleveland Clinic, Cleveland, OH, United States, 2School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil, 3Center for Neurologic Diseases, Brigham and Women’s Hospital Harvard Medical School, Boston, MA, United States Background: Laquinimod is an orally administered neuroimmunomdulator in development for the treatment of multiple sclerosis (MS) and Huntington’s disease (HD). The current studies utilized a model of traumatic brain injury (TBI) to assess the effect laquinimod has on TBI induced neuroinflammation including microglial activation and monocyte infiltration along with persistent inflammation and neurodegeneration. Methods: To test the hypothesis that laquinimod differentially affects microglia and monocytes to alter inflammation following TBI, CX3CR1GFP/+ CCR2RFP/+ mice were utilized to isolate microglia and infiltrating monocytes following TBI and examined via nanostring analysis for the levels of immune gene mRNAs. Mice were administered laquinimod or vehicle by oral gavage before and after the TBI and sacrificed 3 days after the injury for gene expression analyses. Results: In monocytes, laquinimod up-regulated genes related to phagocytosis and down-regulated toll-like receptor (TLR) signaling and adhesion molecules. Notably, we also found a significant elevation of CD45+CCR2+Ly6Chigh inflammatory monocytes in the brain 3 days following TBI by flow cytometry, which was reduced by laquinimod treatment (p< 0.05). Furthermore, gene expression analyses demonstrated microglia up-regulate TLR-4 cascade and NFκB signaling and at the same time down-regulate inflammatory (IL-6 and IL-8) at 3 days following TBI. Laquinimod treatment promoted an anti-inflammatory gene expression profile within microglia and hierarchical clustering showed that laquinimod treatment attenuated TBI-induced microglial gene expression closer to the sham group. In addition, immunohistochemistry showed that axonal damage was lessened following laquinimod treatment. Finally, laquinimod restored inhibited neurogenesis and enlarged ventricles induced by TBI. Conclusions: The current results suggest that laquinimod acts on both monocytes and microglia following TBI to attenuate inflammation by both reducing the recruitment of inflammatory monocytes as well as promoting a more sham-like microglial phenotype that leads to an amelioration of neuronal-based alterations induced by TBI.

P543 Six-year follow-up of delayed-release dimethyl fumarate in RRMS: integrated clinical efficacy data from the DEFINE, CONFIRM, and ENDORSE studies M. Hutchinson1, R. Gold2, R.J. Fox3, J.T. Phillips4, A. Bar-Or5, L. Kappos6, R. Zhang7, M. Yang7, J. Marantz7 1St. Vincent’s University Hospital, Dublin, Ireland, 2St. Josef Hospital, Ruhr University, Bochum, Germany, 3Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, 4Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, United States, 5Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada, 6University Hospital, Basel Neurology, Basel, Switzerland, 7Biogen, Cambridge, MA, United States Background: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated broad efficacy and an acceptable safety profile in patients with relapsingremitting multiple sclerosis (RRMS) in the Phase 3 DEFINE and CONFIRM studies; ENDORSE is an 8-year extension of DEFINE/CONFIRM. Objectives: To report long-term (6-year follow-up) clinical efficacy outcomes with DMF in patients with RRMS. Methods: Patients randomised to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued the same dosage in ENDORSE. Patients randomised to placebo (PBO; DEFINE/CONFIRM) or glatiramer acetate (GA; CONFIRM) were re-randomised 1:1 to DMF 240 mg BID or TID. Data were analysed by treatment arm in parent/extension study: BID/BID, TID/TID, PBO/BID, PBO/TID, GA/BID, GA/TID. Results for DMF 240 mg BID are reported, as this represents the maintenance dose of DMF approved for treatment of patients with relapsing MS. At the time of the last annual data cut-off (May 14, 2014), the minimum treatment follow-up for patients continuing DMF was approximately 5 years. Results: Of 2079 patients completing DEFINE/CONFIRM, 1736 were dosed in ENDORSE (n=501 [BID/BID], 502 [TID/TID], 249 [PBO/BID], 248 [PBO/TID], 118 [GA/BID], 118 [GA/TID]). Adjusted annualised relapse rates (ARRs) (95% confidence interval [CI]) for BID/BID during Years 1 and 2 (DEFINE/CONFIRM) and Years 3, 4, and 5 (ENDORSE) were 0.202 (0.162-0.252), 0.163 (0.128-0.208), 0.139 (0.105-0.184), 0.143 (0.109-0.188), and 0.138 (0.104- 0.183), respectively. For patients switching treatment from PBO or GA, the ARRs (95% CI) during Years 3, 4, and 5 were 0.176 (0.121-0.255), 0.131 (0.086-0.198), and 0.107 (0.068- 0.171) for PBO/BID and 0.182 (0.109-0.302), 0.137 (0.077-0.245), and 0.118 (0.062-0.225) for GA/BID, respectively. Estimated probability of disability progression remained low among patients continuing DMF. Updated data (6-year follow-up) will be presented. Conclusions: Treatment with DMF was associated with low relapse rates and estimated probability of disability progression over 5 years; these results support its use as a long-term treatment option for patients with RRMS.

Disclosure This work was supported by a research grant from Teva Pharmaceutical Industries.

Disclosure Supported by: Biogen.


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Poster Session I, 21(S11) M. Hutchinson: honoraria from Bayer Schering, Biogen, MerckSerono, and Novartis; editorial fees from the Multiple Sclerosis Journal. R. Gold: Honoraria from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders. R.J. Fox: Consultant fees from Actelion, Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Actelion, Biogen, and Novartis; research grant funding from Novartis. J.T. Phillips: Consultant fees from Acorda, Biogen, Genzyme, Merck, Novartis, Sanofi, Teva, and XenoPort; research support from Roche. A. Bar-Or: Honoraria/research support from Biogen, DioGenix, Genentech, GlaxoSmithKline, Guthy-Jackson Charitable Foundation, Medimmune, Merck Serono, Novartis, Ono Pharmacia, Receptos, Roche, Sanofi-Aventis, and Teva Neuroscience. L. Kappos: Steering committee/advisory board/consultant fees for Actelion, Addex, Bayer Health Care, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, Xenoport; speaker fees for Bayer Health Care, Biogen, Merck, Novartis, Sanofi-Aventis, Teva; educational support from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva; royalties from Neurostatus Systems GmbH; grants from Bayer HealthCare, Biogen, Merck, Novartis, Roche, Swiss MS Society, Swiss National Research Foundation, European Union, Roche Research Foundations. R. Zhang, M. Yang, J. Marantz: Employees of and hold stock/ stock options in Biogen. P544 Long-term follow-up of the safety of delayedrelease dimethyl fumarate in RRMS: interim results from the ENDORSE extension study C. Pozzilli1, J.T. Phillips2, R.J. Fox3, K. Selmaj4, R. Zhang5, M. Novas5, J. Rana5, R. Gold6 1Faculty of Medicine, Sapienza University of Rome, Rome, Italy, 2Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, 3Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, United States, 4Medical University of Lodz, Lodz, Poland, 5Biogen, Cambridge, MA, United States, 6St. Josef Hospital, Ruhr University, Bochum, Germany Background: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated efficacy and safety in the Phase 3 DEFINE/CONFIRM studies. ENDORSE is an 8-year extension of DEFINE/CONFIRM. As of Dec 2014, >135,000 patients (pts) have been treated with DMF, representing 112,000 pt-years of exposure. Objectives: To report safety outcomes from ENDORSE, investigating long-term effects of DMF in pts with RRMS. Methods: Pts randomised to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued on the same dosage in ENDORSE. Pts randomised to placebo (PBO; DEFINE/ CONFIRM) or glatiramer acetate (GA; CONFIRM) were re-randomised 1:1 to DMF 240 mg BID or TID. Adverse events (AEs)

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were analysed according to treatment received in the parent/ extension study: BID/BID (n=501), TID/TID (n=501), PBO/BID (n=249), PBO/TID (n=248), GA/BID (n=118), and GA/TID (n=119). Results: As of the latest annual interim data cut-off (May 14, 2014), total follow-up in ENDORSE for all groups was 4981 ptyears. Overall incidence of AEs: BID/BID, 91%; TID/TID, 92%; PBO/BID, 95%; PBO/TID, 93%; GA/BID, 88%; and GA/TID, 85%. Incidence of serious AEs: BID/BID, 22%; TID/TID, 25%; PBO/BID, 24%; PBO/TID, 16%; GA/BID, 16%; and GA/TID, 19%. Incidence of AEs leading to discontinuation was 6-7% and 14-26% in pts continuing and new to DMF, respectively. Incidence of serious infections was ⩽4% in all groups*(see footnote below). There were no new findings in hematologic outcomes compared with DEFINE/CONFIRM. Hepatic AEs occurred in ⩽3% of pts in any group; there was no evidence of increased risk of renal or urinary events. The overall incidence of malignancies remained low (2% for pts continuing DMF); no evidence of an increased risk of malignancy was observed. There were 5 deaths, none of which was considered study-drug-related. Updated interim data with longer-term follow-up will be presented. Conclusions: The long-term safety analysis from ENDORSE continues to demonstrate an acceptable safety profile for DMF in pts with RRMS. The overall benefit:risk profile of DMF remains favourable. *Note: Subsequent to the May 14, 2014 data cut-off for this interim report, a case of PML in a pt treated with DMF TID was reported in the setting of severe, prolonged lymphopenia (absolute lymphocyte count approximately < 0.5x109/L of 3.5 years duration). Aside from this single case, there is no overall increased risk for serious infections, including other opportunistic infections. Disclosure Supported by: Biogen. C. Pozzilli: Consultant fees from Actelion, Biogen, Genzyme, Merck Serono, Novartis, and Teva Neuroscience; grant/research support from Biogen, Merck Serono, Novartis, and Teva Neuroscience. J.T. Phillips: Consultant fees from Acorda, Biogen, Genzyme, Merck, Novartis, Sanofi, Teva, and XenoPort; research support from Roche. R.J. Fox: Consultant fees from Actelion, Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Actelion, Biogen, and Novartis; research grant funding from Novartis. K. Selmaj: Consultant fees from Genzyme, Novartis, Ono, Roche, Synthon, and Teva; fees for non-CME services from Biogen. R. Zhang, M. Novas, J. Rana: Employees of and hold stock/stock options in Biogen. R. Gold: Honoraria from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders. P545 Long-term effect of delayed-release dimethyl fumarate on total disability burden in DEFINE, CONFIRM, and ENDORSE: area under the curve analysis of changes from baseline in expanded disability status scale scores


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J. Lechner-Scott1, A. Bar-Or2, R.J. Fox3, R. Gold4, J. Xiao5, M.R. Edwards5 1University of Newcastle, Callaghan, NSW, Australia, 2Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada, 3Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, United States, 4St. Josef Hospital, Ruhr University, Bochum, Germany, 5Biogen, Cambridge, MA, United States Background: In the ongoing ENDORSE study, an extension of the Phase 3 DEFINE/CONFIRM studies, delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) had a sustained beneficial effect on 24-week confirmed EDSS progression. In pts treated continuously with DMF 240 mg twice daily (BID) vs those switched from placebo (PBO) in DEFINE/ CONFIRM to DMF BID in ENDORSE, estimated proportions with disability progression at 5 years were 18.6% and 21.1%, respectively. Compared with traditional disability progression analyses, area under the EDSS-time curve (AUC) analysis contains more information about the cumulative extent of disability over time because it is reflective of all EDSS scores during the study. Objectives: To quantify the effect of DMF on total disability burden in ENDORSE using AUC analysis to integrate measured EDSS changes during the study. Methods: In ENDORSE, pts randomised to DMF 240 mg BID or thrice daily (TID) in DEFINE/CONFIRM continued the same dose. Pts randomised to PBO (DEFINE/CONFIRM) or glatiramer acetate (GA; CONFIRM) were re-randomised 1:1 to DMF 240 mg BID or TID. Interim data as of May 14, 2014 were analysed by treatment arm in parent/extension study. Results for the approved DMF dose (240 mg BID) are reported; GA data are excluded due to low pt numbers. EDSS changes were computed; AUC of EDSS change scores were calculated for all pts (imputation applied for missing scores). Mean AUC of EDSS change was compared between treatment arms using ANCOVA ranked data adjusted for covariates (baseline EDSS, age, region and relapses prior to parent study). Positive AUC change from baseline indicates net worsening; negative change indicates net improvement. Results: The analysis included 501 pts continuously treated with DMF BID over 5 years (BID/BID) and 248 pts who received PBO in DEFINE/CONFIRM and DMF BID in ENDORSE (PBO/BID). Relative to DEFINE/CONFIRM baseline, 2-year adjusted mean (standard error [SE]) AUC changes in EDSS were 0.17 (0.08) for DMF BID and -0.02 (0.08) for PBO (P=0.004, indicating statistically significant improvement with DMF vs PBO). During the next 3 years in ENDORSE, adjusted mean (SE) AUC changes in EDSS from ENDORSE baseline were -0.07 (0.32) for BID/BID and -0.06 (0.33) for PBO/BID (P=0.996, indicating mean AUC changes from ENDORSE baseline were similar once all pts were receiving DMF). Conclusions: AUC analysis suggests a positive long-term benefit of DMF on a measure of total disability burden. Disclosure Supported by: Biogen. J. Lechner-Scott: Travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment and also clinic support as well as

research grants from Bayer Health Care, Biogen Idec, CSL, Genzyme Sanofi, Merck Serono and Novartis. A. Bar-Or: Honoraria/research support from Biogen, DioGenix, Genentech, GlaxoSmithKline, Guthy-Jackson Charitable Foundation, Medimmune, Merck Serono, Novartis, Ono Pharmacia, Receptos, Roche, Sanofi-Aventis, and Teva Neuroscience R.J. Fox: Consultant fees from Actelion, Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Actelion, Biogen, and Novartis; research grant funding from Novartis. R. Gold: Honoraria from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders. J. Xiao, M. R. Edwards: Employees of and hold stock/stock options in Biogen. P546 Lesion characteristics differentiating asymptomatic natalizumab-associated PML from new MS lesions M.T. Wijburg1,2, A. Vennegoor1, B.I. Witte3, S.D. Roosendaal2,4, E. Sanchez2, Y. Liu2,5, C.O. Martins Jarnalo2,6, B.M. Uitdehaag1, F. Barkhof2, J. Killestein1, M.P. Wattjes2 1Department of Neurology, 2Department of Radiology and Nuclear Medicine, 3Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, 4Department of Radiology, Erasmus Medical Centre, Rotterdam, The Netherlands, 5Department of Radiology, Xuanwu Hospital,Capital Medical University, Beijing, China, 6Department of Radiology, Medical Center Haaglanden, The Hague, The Netherlands Background: Since progressive multifocal leukoencephalopathy (PML) diagnosis in an asymptomatic stage leads to a more favorable outcome, natalizumab-treated MS patients who are at risk for developing natalizumab-associated PML are screened using MRI. However, early identification of PML can be difficult as these lesions may resemble new MS lesions. Lesion characteristics that may help to differentiate symptomatic PML lesions from MS lesions have previously been proposed. However, data on asymptomatic PML lesions are missing so far. Objective: To determine MRI characteristics that differentiate asymptomatic PML from new MS pathology in natalizumab treated MS patients. Methods: Four readers, blinded for all clinical information, assessed reference and follow-up brain MRI scans of 48 natalizumab-treated MS patients with either new asymptomatic PML lesions (n=21), new MS lesions (n=20) or no new lesions (n=7). Readers were asked to detect new lesions on the follow-up scan and score the lesion characteristics according to a dedicated scoring scheme based on previously reported characteristics. By using generalized estimated equations (GEEs), we corrected for multiple ratings. Missed lesions were excluded from the analysis. We calculated the odds ratio (OR) of the association with PML pathology for each characteristic. Results: Presence of “Milky Way appearance” was strongly associated with PML pathology (OR 68.6, 95% CI:9.0-519.7, p< 0.001). Ill-defined and mixed borders compared to sharp borders


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Poster Session I, 21(S11) towards both the white and grey matter were associated with PML (OR 9.1, 95% CI:4.0-20.5, p< 0.001 and OR 6.2, 95% CI:1.920.5, p=0.003 respectively for white matter and OR 3.7, 95% CI:1.6-8.8, p=0.003 and OR 4.8, 95% CI:1.6-14.5, p=0.006 respectively for grey matter). Cortical grey matter and juxtacortical white matter involvement were also associated with PML (OR 14.8, 95% CI:3.6-61.1, p< 0.001; OR 3.6, 95% CI:1.2-11.1, p=.023). Periventricular localization was strongly negatively associated with PML (OR 0.03, 95% CI:0.004-0.223, p=0.001). Conclusion: Many of the lesion characteristics described in symptomatic natalizumab-associated PML lesions were also significantly associated with PML pathology in asymptomatic PML patients. Interestingly, ill-defined and mixed borders towards grey matter were also associated with PML, as opposed to what was previously reported. Disclosure M.T. Wijburg: Nothing to disclose. A. Vennegoor: Has received speaking fees from Teva. VU Medical Center has received financial support for research activities from Bayer Schering Pharma, Biogen-Idec, GlaxoSmithKline, Merck Serono, Novartis, and Teva. B.I. Witte: nothing to disclose. S.D. Roosendaal: Nothing to disclose. E. Sanchez: Served as a consultant for F. Hoffmann-La Roche. Y. Liu: Is supported by the ECTRIMS-MAGNIMS Fellowship from The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). C.O. Martins Jarnalo: Nothing to disclose. B.M.J. Uitdehaag: Received personal compensation for consulting from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche en TEVA. F. Barkhof: Serves on the editorial boards of Brain, Neurology, Neuroradiology, Multiple Sclerosis Journal and Radiology, and serves as a consultant for Bayer-Schering Pharma, Sanofi-Aventis, Genzyme, Biogen-Idec, Teva, Novartis, Roche, Synthon BV and Jansen Research. J. Killestein: Accepted speaker and consulting fees from MerckSerono, Biogen Idec, Teva, Genzyme and Novartis. M.P. Wattjes: Received consultancy fees from Biogen Idec and Roche.

P547 Therapeutic treatment with ATX-MS-1467 reduces T1-weighted gadolinium leakage volume in a preclinical model of multiple sclerosis S. Huang1, A. Souza1, J.-K. Choi2, B. Tomkinson1, J. Mandeville2, T. Dellovade1 1Immunology and Neurology, EMD Serono Research and Development Institute, Billerica, 2Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States Background: ATX-MS-1467 is a mixture of four antigen processing independent epitopes based on immunodominant sequences of myelin basic protein (MBP) in Multiple Sclerosis (MS) patients with human leukocyte antigen (HLA) haplotypes DRB1*1501 and DQB1*0602. In a Phase 1b trial, ATX-MS-1467

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significantly reduced MRI activity and a Phase IIa trial is ongoing in MS patients. Here magnetic resonance imaging (MRI) was combined with experimental autoimmune encephalomyelitis (EAE) induced in humanized mice engineered to express the above HLA haplotypes to allow for real-time assessment of ATX-MS-1467 treatment on blood-brain barrier leakage. Objective: Assess the efficacy of therapeutic dosing with ATX-MS-1467 using T1-weighted gadolinium (Gd) MRI in a longitudinal study in a preclinical MS model. Methods: EAE was induced in double-transgenic (human HLA-DR15/MBP-specific T-cell receptor) mice with clinical disabilities measured by a subjective 0-5 scale. Initial clinical signs of EAE occurred around 7 days post-induction (dpi) and baseline T1-weighted Gd-enhanced MRI was conducted on 9 or 10 dpi. Mice with Gd leakage (Gd+) in the cerebellum at the baseline scan were divided into two group and dosed subcutaneously (sc) with either vehicle (phosphate-buffered saline; n=8) or ATX-MS-1467 (100 ug; n=7) every other day starting the day after baseline imaging. On 15 or 16 dpi, T1-weighted Gd MRI was repeated in the same animals and then mice were euthanized for histological analysis. Results: Therapeutic ATX-MS-1467 treatment starting after disease onset, significantly reduced clinical scores as compared to vehicle treatment (p< 0.05). At the baseline MRI (9/10 dpi), Gd+ volume was equivalent in vehicle and ATX-MS-1467 treated mice (7.36 +/- 1.8 and 7.02 +/- 1.7 mm3, respectively). At the follow-up MRI (15/16 dpi), Gd+ volume was significantly reduced in ATX-MS-1467 as compared to vehicle dosed mice (p< 0.05). ATX-MS-1467 resulted in a significant 77.4% reduction in Gd+ volume (1.1 +/- 0.3 mm3) as compared to baseline (p< 0.01). In contrast, the vehicle group had a 39.7% reduction in Gd+ volume (4.48 +/- 1.4 mm3) at follow-up that was not significantly different from baseline MRI (p=0.23). The differences in lesion volume were confirmed by histological analysis. Conclusion: Consistent with data from the Phase Ib clinical trial, therapeutic dosing with ATX-MS-1467 significantly reduced Gd+ leakage volume in a preclinical model of MS. Disclosure Study supported by EMD Serono Research and Development Institute, Inc., a subsidiary of Merck KGaA, Darmstadt, Germany. P548 Impact of early treatment of MS with interferon beta-1b: cognitive outcomes at the 11-year follow-up of BENEFIT (BENEFIT 11) F. Foley1, I.-K. Penner2, G. Edan3, M.S. Freedman4, X. Montalbán5, H.-P. Hartung6, B. Hemmer7,8, E.J. Fox9, F. Barkhof10, S. Schippling11, R. Koelbach12, D. Pleimes13, C. Pohl14,15, R. Sandbrink6,14, G. Suarez16, E.-M. Wicklein14, L. Kappos17, the BENEFIT Study Group 1School of Psychology, Yeshiva University, New York, NY, United States, 2University of Basel and University Hospital Basel, Basel, Switzerland, 3CHU-Hopital Pontchaillou, Rennes, France, 4University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada, 5Hospital Universitari Vall d’Hebron, Barcelona, Spain, 6Department of Neurology, Heinrich-Heine Universität, Düsseldorf, 7Technische Universität München, 8Munich Cluster for Systems Neurology (SyNergy),


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Munich, Germany, 9University of Texas Medical Branch, Austin, TX, United States, 10VU University Medical Center, Amsterdam, The Netherlands, 11University Hospital Zurich, Zurich, Switzerland, 12PAREXEL International, 13Myelo Therapeutics GmbH, 14Bayer Pharma AG, Berlin, 15University Hospital of Bonn, Bonn, Germany, 16Bayer HealthCare Pharmaceuticals, Whippany, NJ, United States, 17Neurology, University Hospital Basel, Basel, Switzerland Introduction: The BENEFIT trial demonstrated improved clinical outcomes in patients with a clinically-isolated syndrome (CIS) and early treatment with interferon beta-1b up to 11 years after randomization. Cognitive outcomes and cognitive fatigue data at Year 11 are presented here. Methods: In BENEFIT, patients with CIS were randomized to receive interferon beta-1b 250 µg (early treatment) or placebo (delayed treatment). After 2 years or conversion to CDMS, patients on placebo were offered active treatment. Eleven years after initial randomization, all patients were approached to complete a comprehensive reassessment, including PASAT-3 (longitudinal assessment since baseline) and SDMT (cross-sectional). Cognitive fatigue was assessed by dividing the SDMT 90 seconds standard interval into 30 seconds intervals during standard test administration. Results: 278 patients (of the original 468) were enrolled (71.3% of patients from sites participating in BENEFIT 11), 223 patients completed the PASAT, 211 the SDMT at year 11. Mean PASAT score throughout 11 years was higher in the early versus the delayed treatment group (early M=52.9, delayed M=52.0, p=0.007). Parametric longitudinal linear mixed models demonstrated an effect for time (F [1,358]=5.27, p=0.022), where the following parameters were included as covariates into the models: PASAT-3 total score at BENEFIT baseline, sex, age at BENEFIT baseline, time, initial treatment group and time X initial treatment group interaction. There were no time X treatment interaction effects, as the differences between groups emerged early in the trial and remained stable over 11 years (F [1,358]=0.10, ns). There were no cross-sectional differences in SDMT performance between groups at Year 11 (F [1,204]=0.47, ns), mean score for both groups was 53.0 (early M=53, delayed M=52.5) and comparable with prior studies in healthy controls and slightly higher than in reported cohorts of patients with RRMS. No signs of cognitive fatigue were detected at any SDMT interval. Conclusion: Superior PASAT performance in the early treatment group occurred early and persisted over 11 years. SDMT results are comparable to data from other MS populations of similar disease duration and healthy volunteers. These findings add more objective evidence that confirms the beneficial impact of early treatment with interferon beta-1b on the clinical course of MS. Disclosure ● FW Foley has received compensation for consulting with Biogen Idec and Bayer HealthCare Pharmaceuticals ● I-K Penner has received honoraria for speaking at scientific meetings, serving at scientific advisory boards and consulting activities from Actelion, Bayer-Schering, Biogen Nordic, Merck Serono, Novartis, Roche and Teva Sanofi-Aventis. ● G Edan has received honoraria for lectures or consulting from Biogen Idec, Merck Serono, and Sanofi-Aventis, and

received personal compensation for serving on the BENEFIT scientific advisory board and for speaking from Bayer Pharma AG. He has also received research support from Serono, (a grant to University Hospital to support a research program on MRI in MS) and from Teva (a grant to support a research program on anti-IBF neutralizing antibodies). ● MS Freedman has received compensation from Actelion, Bayer Healthcare, Biogen Idec, EMD Canada, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, and Teva Canada Innovation for consulting services and has received research/ educational grants from Bayer HealthCare and Genzyme. He also participates in a Genzyme-sponsored speaker’s bureau. ● X Montalbán has received speaking honoraria and travel expenses for scientific meetings and has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer, Biogen Idec, EMD, Genentech, Genzyme, Merck Serono, Neurotec, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, and Almirall. ● H-P Hartung has received honoraria for consulting and speaking at symposia from Bayer Pharma AG, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva, and Sanofi-Aventis, with approval by the rector of HeinrichHeine University. ● B Hemmer has served on scientific advisory boards for Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GSK, Chugai Pharmaceuticals, Micromet, and Genzyme Corporation; is author on patents re: KIR4.1 antibody testing in MS and genetic determinant of neutralizing antibody development in interferon-beta-treated patients; has received speaker honoraria from Bayer Schering, Novartis, Biogen Idec, Merck Serono, Roche, and Teva Pharmaceutical Industries Ltd.; and has received research support from Biogen Idec, Bayer Schering, Merck Serono, Five Prime, Metanomics, and Novartis. ● EJ Fox has received consulting fees, honoraria, travel, or research support from Acorda, Bayer, Biogen Idec, Eli Lilly, EMD Serono, Genzyme, GlaxoSmithKline, Novartis, Ono, Opexa Therapeutics, Pfizer, Roche, Sanofi, and Teva. ● F Barkhof has received compensation for consultancy from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis, Genzyme, Roche, and Teva, and has received research support from the Dutch Foundation for MS research (an NGO). ● S Schippling has received research grants from Biogen Idec, Bayer Schering Pharma and Genzyme and consulting/ speaker fees from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, TEVA and Sanofi-Aventis. ● Ralf Koelbach is a salaried employee of PAREXEL International. ● D Pleimes is a salaried employee of Myelo Therapeutics GmbH. He was a salaried employee and is currently a paid consultant for Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. DP owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. ● C Pohl is a salaried employee of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. He owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. ● R Sandbrink is a salaried employee of Bayer Pharma AG/ Bayer HealthCare Pharmaceuticals. He owns stock in Bayer


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Poster Session I, 21(S11) AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. ● G Suarez is a salaried employee of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. ● E-M Wicklein is salaried employee of Bayer Pharma AG. ● L Kappos’ institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof Kappos’ activities as principal investigator and member or chair of planning and steering committees or advisory boards in trials sponsored by Actelion, Addex, Bayer HealthCare Pharmaceuticals, Bayer Schering Pharma, Biogen Idec, CLC Behring, Genentech, GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Praxicon, Roche, Sanofi-Aventis, Santhera, Siemens and Teva. Prof Kappos has received grants from the Swiss MS Society, Swiss National Research Foundation, the European Union, Gianni Rubatto Foundation, and the Novartis and Roche Research foundations. P549 Survival in multiple sclerosis: a prospective cohort study P. Duquette1, T. Ducruet2, P. Despault3, E. Desplats2 1Neurology, CHUM Notre-Dame, 2Statistics, CHUMère-Enfant, 3Neurosciences, CHUM Notre-Dame, Montréal, QC, Canada Background: Several studies have documented that multiple sclerosis (MS) patients experience a lower longevity compared to the general population. Objective: To examine factors associated to overall survival, survival since disease onset, and relative mortality in MS patients. Methods: The CHUM Notre-Dame MS Clinic, in operation since 1975, has prospectively collected data in a predominantly FrenchCanadian population. Absolute and relative survival from disease onset were evaluated, using Kaplan-Meier analysis. A Cox proportional hazard was applied to identify potential factors associated with mortality and excess mortality. Life-expectancy at disease onset was calculated for an age and sex-matched Quebec reference population and compared to the survival in the study cohort. The following comorbidities were assessed: hypertension, depression, dyslipidemia, diabetes, stroke, heart disease, cancer, and COPD. Relative Mortality Ratios (RMR) were calculated to assess relative excess mortality. Results: The data extends over 50 years. The total MS population is 3758, comprised of 2754 women (73.3%) and 1004 men (26.7%). The median age at onset is 30.7 years. The clinical course is RRMS in 87% and PPMS in 13% of patients. Eight patients committed suicide (two from assisted-suicide in Europe). As is the case in the reference population, survival increases over time, but MS patients still experience a reduced life expectancy. The median survival time from disease onset is 42.9 years, that is 6.4 years lower than the the time for the reference population (p< 0.001). Survival is higher in the RRMS group than in the PPMS group (p< 0.001). Pregnant women have a better survival. RRMS patients who transited to SPMS have a significantly lower survival. Among comorbidities, only hypertension is negatively associated with survival, as is smoking. The relative excess mortality is higher in women than in men. Despite a gain in overall survival in MS patients, no evidence was found of a reduction in the gap in life expectancy in the later decades.

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Conclusions: We confirm in our population that MS patients experience a lower survival after disease onset, more so in progressive patients, whether primary or secondary. Hypertension and smoking further reduce survival. Pregnancy affords an increased longevity., There is no evidence of a gain in survival in the more recent decades. Disclosure Thierry Ducruet, Pierre Despault and Ève Desplats: Nothing to disclose. Pierre Duquette sat on advisory boards, has received support to attend meetings, and organised CME activities for Genzyme, TEVA, Biogen-Idec, Novartis, and EMD Serono. He is funded by the MS Society of Canada and by the CIHR. He initiated studies funded by Biogen-Idec, Novartis, Genzyme, and Genzyme.

P550 Incidence, severity, duration, and treatment of cutaneous adverse events in the DECIDE study of daclizumab HYP versus intramuscular interferon beta-1a in patients with relapsing-remitting multiple sclerosis L. Kircik1, J. Krueger2, M. Lebwohl1, F. Hougeir3, A. Friedman4, X. You5, N. Lucas5, M. Sweetser6, W Castro-Borrero, P. McCroskery5, J. Elkins5 1Mount Sinai Hospital, 2The Rockefeller University, New York, NY, 3Douglas Dermatology and Skin Cancer Specialists, llc, Atlanta, GA, 4Albert Einstein College of Medicine, New York, NY, 5Biogen, 6Former Employee of Biogen, Cambridge, MA, United States Background: An increased risk of cutaneous adverse events (AEs) was observed in the previous placebo-controlled SELECT study of daclizumab high-yield process (DAC HYP) in patients with relapsing-remitting multiple sclerosis (RRMS). Objective: To describe the incidence, severity, duration, and steroid treatment of cutaneous AEs reported in the DECIDE study of DAC HYP versus intramuscular (IM) interferon (IFN) beta-1a. Methods: DECIDE was a randomised, double-blind, active-controlled study of DAC HYP 150mg subcutaneous every 4 weeks vs IFN beta-1a 30mcg IM once weekly in RRMS patients for up to 144 weeks. AE severity was based on investigator assessment and serious AEs on standard criteria. Duration of cutaneous AEs and steroid use were evaluated post hoc and categorised by worst cutaneous AE reported in the order of serious, severe, moderate, and mild. Results: 1841 patients (DAC HYP n=919; IFN beta-1a n=922) were enrolled in DECIDE. Over 144 weeks, 344 (37%) DAC HYP patients and 176 (19%) IFN beta-1a patients reported a cutaneous AE. Overall, 191 (21%) vs 122 (13%) patients experienced mild, 132 (14%) vs 51 (6%) moderate, and 21 (2%) vs 3 (< 1%) severe cutaneous AEs in the DAC HYP vs IFN beta-1a groups. Serious cutaneous AEs were reported in 14 (2%) DAC HYP patients and 1 (< 1%) IFN beta-1a patient. Among patients with a cutaneous AE categorised by worst cutaneous AE reported, 190 (55%) vs 122 (69%) had mild, 129 (38%) vs 50 (28%) had moderate, 11 (3%) vs 3 (2%) had severe, and 14 (4%) vs 1 (< 1%) had serious cutaneous AEs for DAC HYP vs IFN beta-1a. The median


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(mean) duration in days for a cutaneous AE was as follows: mild 22.0 (58.8) vs 19.5 (62.1), moderate 40.5 (72.9) vs 21.5 (52.1), severe 70.5 (127.5) vs 12.0 (12.0), and serious 54.0 (111.1) vs 6.0 (6.0) for DAC HYP vs IFN beta-1a. Most patients with mild (154/190 [81%] DAC HYP vs 106/122 [87%] IFN beta-1a) or moderate (94/129 [73%] vs 36/50 [72%]) cutaneous AEs received topical steroids or were not treated with steroids, whereas treatment with systemic corticosteroids was more common in patients with severe (8/11 [73%] DAC HYP vs 1/3 [33%] IFN beta-1a) or serious (10/14 [71%] vs 0/1) cutaneous AEs. Conclusions: Cutaneous AEs were more common with DAC HYP than IFN beta-1a. Most patients with mild or moderate events were not treated or were treated with topical corticosteroids. Severe or serious event rates were low and these events were generally managed with systemic corticosteroids. Disclosure Leon Kircik has received honoraria for participation in advisory boards from Biogen and for speaker bureaus from Abbott Inc. James Krueger has been a consultant for Biogen and reviews and adjudicates cutaneous adverse events in Biogen- and AbbViesponsored clinical trials. Mark Lebwohl is an employee of the Mount Sinai Medical Center which receives research funds from AbGenomics, AbbVie, Amgen, Anacor, Aqua, Canfite Biopharma, Celgene, Clinuvel, Coronado Biosciences, Ferndale, Lilly, Janssen Biotech, LEO Pharmaceuticals, Merz, Novartis, Pfizer, Sandoz, and Valeant. Firas Hougeir serves as a consultant for Biogen and AbbVie Inc. Adam Friedman serves as a consultant for Biogen, Amgen, Galderma, Loreal, Aveeno, Microcures, Nano Biomed, Salvona, PHD skincare, Intraderm, Oculus, Nerium Biotech, Pfizer, and Valeant. Xiaojun You is a full-time employee of Biogen. Nisha Lucas is a full-time employee of Biogen. Marianne Sweetser was a full-time employee of Biogen at the time of the analysis. Peter McCroskery is a full-time employee of Biogen. Jacob Elkins is a full-time employee of Biogen. Lou Barbato is a full-time employee of Biogen. This study was funded by Biogen and AbbVie Biotherapeutics Inc. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this abstract. Alison Gagnon (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P551 MT-1303, a novel sphingosine 1-phosphate (S1P) receptor modulator, has less potential for bradycardia than fingolimod K. Sugahara1, Y. Maeda1, K. Shimano1, K. Ogawa2, H. Kumagai2, T. Yamamoto3, A. Mogami1, H. Kataoka1, H. Higashi1, M. Kikuchi1 1Pharmacology Research Laboratories I, 2DMPK Research Laboratories, 3Safety Research Laboratories, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan Introduction: MT-1303 is a novel S1P receptor modulator that was discovered by the chemical modification of fingolimod with

the aim of avoiding its heart rate-reducing effect. Like fingolimod, MT-1303 was converted to an active metabolite MT-1303 phosphate (MT-1303-P) by sphingosine kinases and acts as a S1P1 functional antagonist. Fingolimod has been reported to cause a transient and mild reduction in heart rate, which is possibly associated with a GIRK channel activation on atrial myocytes via its agonist activities at S1P1 and/or S1P3. Methods: The selectivity of human S1P receptors was assessed in intracellular Ca2+ mobilization assay using human S1P receptor (S1P1-5)-expressing cells. MT-1303 or fingolimod (1 mg/kg) was orally administered to rats, and the concentration of active metabolites in the heart were measured by LC-MS/MS. GIRK channel activation in human atrial myocytes was evaluated by the patch clamp method, and the effect on heart rates in monkeys was analyzed in telemetered conscious monkeys. Results: MT-1303-P showed an agonist activity at human S1P1 (EC50: 0.075 nM) more potently than S1P4 (EC50: 122.3 nM) and S1P5 (EC50: 0.47 nM), and no agonist activity at S1P2 or S1P3 up to 10,000 nM. Oral administration of MT-1303 at 0.1 mg/kg or higher reduced lymphocyte counts in peripheral blood in mice, rats and monkeys, suggesting inhibition of lymphocyte egress from the secondary lymphoid tissues by down-regulation of lymphocytic S1P1. When MT-1303 or fingolimod was added to HEK293 cells or primary human cardiac myocytes, the concentration of MT-1303-P in supernatants increased more slowly compared to fingolimod-P. After a single oral administration of MT-1303 or fingolimod, the concentration of MT-1303-P in the heart is relatively lower than fingolimod-P in rats. Therefore, it is likely that MT-1303-P is generated slowly in human after MT-1303 administration and MT-1303-P is less distributed to the heart in human compared to fingolimod-P. In human atrial myocytes, MT-1303-P and fingolimod-P activated GIRK channels at EC50 of 41.6 and 8.5 nM, respectively, and the potential of MT-1303-P for GIRK activation was approximately 5-time weaker than fingolomod-P. Moreover, MT-1303 showed no obvious effects on heart rate and electocardiogram up to 30 mg/ kg in monkeys. Conclusion: These results suggest that MT-1303 possesses a therapeutic potential for RRMS, while its effect on heart rate is anticipated to be less than that of fingolimod. Disclosure K. Sugahara: Nothing to disclose, Y. Maeda: Nothing to disclose, K. Shimano: Nothing to disclose, K. Ogawa: Nothing to disclose, H. Kumagai: Nothing to disclose, T. Yamamoto: Nothing to disclose, A. Mogami: Nothing to disclose, H. Kataoka: Nothing to disclose, H. Higashi: Nothing to disclose, M. Kikuchi: Nothing to disclose P552 Efficacy of delayed-release dimethyl fumarate in early multiple sclerosis: post-hoc analysis of the phase 3 DEFINE and CONFIRM studies according to baseline cognitive function G. Giovannoni1, R. Gold2, J.T. Phillips3, R.J. Fox4, J.B. Lewin5, A. Zhang5, J.L. Marantz5


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Poster Session I, 21(S11) 1Queen

Mary University of London, Blizard Institute, London, United Kingdom, 2St. Josef Hospital, Ruhr University, Bochum, Germany, 3Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, 4Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, 5Biogen, Inc., Cambridge, MA, United States Background: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated efficacy and safety in relapsing-remitting multiple sclerosis (RRMS) in the Phase 3 DEFINE and CONFIRM studies. As described previously (Raghupathi, AAN 2015, P3.211), an integrated database comprising >6500 patients from six Phase 3 RRMS clinical studies of four different disease-modifying therapies was created, employing uniform methodology to define baseline and outcome variables. In an analysis of this database (reported separately), baseline cognitive reserve as assessed by the Paced Auditory Serial Addition Test (PASAT-3; >39 points vs ⩽39 points) was found to be one of the strongest prognostic factors on a clinical disability progression composite measure based on Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Visual Function Test (VFT). PASAT-3 is a measure of cognitive function that assesses auditory information processing speed, calculation ability, attention, and concentration. Objectives: Investigate the efficacy of DMF on clinical measures in RRMS patients early in their disease course according to extent of cognitive impairment, defined as baseline PASAT-3 score >39. Methods: Eligibility criteria included age 18-55 years and EDSS score 0-5.0. Patients were randomized to receive DMF 240 mg twice (BID) or thrice daily, placebo, or subcutaneous glatiramer acetate (reference comparator; CONFIRM only) for up to 2 years. The 3-second PASAT was administered at baseline; higher scores (range: 0−60) indicate higher cognitive reserve. Outcome measures included annualized relapse rate (ARR) and risk of 12-week sustained disability progression. Results are reported for placebo and DMF BID (approved dosing regimen in all regions). Results: The integrated intent-to-treat population included 771 and 769 patients receiving placebo or DMF BID, respectively; among them, 593 and 616 had baseline PASAT-3 score >39. At 2 years, in patients with baseline PASAT-3 score >39, significant reductions with DMF BID compared with placebo were observed for ARR (51% reduction; P< .0001) and risk of 12-week confirmed disability progression (44% reduction; P=.0078). Additional outcome measures will be reported. Conclusions: Compared with placebo, DMF BID demonstrated beneficial effects on clinical outcomes in RRMS patients early in their disease course according to extent of cognitive impairment. Disclosure This study is supported by Biogen, Inc. Ralf Gold: Honoraria from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders. Gavin Giovannoni: Honoraria from Abbvie, Bayer HealthCare, Biogen, Canbex, FivePrime, Genzyme, GlaxoSmithKline, GW Pharma, Merck Serono, Novartis, Protein Discovery Laboratories, Roche, Synthon, Teva Neuroscience, UCB, and Vertex; research

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grant support from Biogen, Ironwood, Merck Serono, Merz, and Novartis; compensation from Elsevier as co−chief editor of MS and Related Disorders. J. Theodore Phillips: Consulting fees from Acorda, Biogen, Genzyme, Merck Serono, and Sanofi; research support from Roche. Robert J. Fox: Consultant fees from Actelion, Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Actelion, Biogen, and Novartis; research grant funding from Novartis. James B. Lewin: Employee of and holds stock/stock options in Biogen, Inc. Annie Zhang: Employee of and holds stock/stock options in Biogen, Inc. Jing L. Marantz: Employee of and holds stock/stock options in Biogen, Inc.

P553 Long-term safety of alemtuzumab in relapsing-remitting multiple sclerosis: pregnancy and infection data from a cohort of patients on open label studies in Cambridge, UK C.L. McCarthy, J.W.L. Brown, O. Tuohy, L. Azzopardi, O. Kousin-Ezewu, J.L. Jones, A. Compston, A.J. Coles Dept. of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom Background: Alemtuzumab is a lymphocyte-depleting, antiCD52 monoclonal antibody, recently licensed for use in active RRMS in Europe and the USA. This observational cohort study investigated the long term safety of alemtuzumab in RRMS. Methods: Clinical data was collected from a cohort of 86 patients who participated in open label studies of alemtuzumab in Cambridge, UK from 1999 to April 2015. Pregnancy outcomes and the occurrence of moderate-to-severe infections were recorded. Results: Over a median 10-year follow-up (range 92-176 months), 6 patients required hospital admission for infections (1 pyelonephritis, 4 pneumonia and 1 upper respiratory tract infection). 17 patients experienced varicella zoster virus reactivation (VZV). In this cohort 18 babies were born to 13 women treated with alemtuzumab. The median interval from their most recent alemtuzumab treatment to birth was 33 months (range 13-122 months). All of the babies were healthy and delivered without complications. Two women experienced a miscarriage but both went on to have two successful pregnancies each. Conclusions: During prolonged follow-up of this cohort of patients treated with alemtuzumab there was a low rate of significant infections. No increased risk of miscarriage or foetal abnormality was seen in the small number of pregnancies studied. Disclosure McCarthy CL, nothing to disclose. Brown JWL, nothing to disclose. Tuohy O, nothing to disclose. Azzopardi L, nothing to disclose. Kousin-Ezewu O, reports receiving funding from the Wellcome Trust and GlaxoSmithKline. Jones JL reports receiving consulting fees and lecture fees from Genzyme Sanofi.


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Compston DA, has received consulting fees, lecture fees, and grant support from Genzyme (a Sanofi Company) on behalf of the University of Cambridge; and lecture fees from Genzyme on behalf of himself and is a paid scientific advisor to the Lundbeck Foundation, Denmark. Coles AJ reports receiving consulting fees and lecture fees from Genzyme Sanofi and Merk Serono.

deaths in the active control group, and in 2 cases (complication of psoas abscess, autoimmune hepatitis) the contributory role for DAC HYP could not be excluded. Conclusions: The safety profile of DAC HYP has been well characterized in clinical studies, providing information on long-term experience for periods up to 6 years. Based on clinical experience, DAC HYP has a potential to represent an effective treatment option for RRMS with a positive benefit/risk profile.

P554 Safety and tolerability of daclizumab HYP in patients with relapsing-remitting multiple sclerosis: an integrated analysis of six clinical studies G. Giovannoni1, L. Kappos2, R. Gold3, B. Khatri4, K. Selmaj5, K. Umans6, S. Greenberg7, M. Sweetser8, P. McCroskery6, J. Elkins6 1Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, United Kingdom, 2University Hospital Basel, Basel, Switzerland, 3Department of Neurology, St. Josef-Hospital/ Ruhr-University Bochum, Bochum, Germany, 4Center for Neurological Disorders and The Regional Multiple Sclerosis Center, Milwaukee, WI, United States, 5Medical University of Lodz, Lodz, Poland, 6Biogen, Cambridge, MA, 7AbbVie Biotherapeutics Inc, Redwood City, CA, 8Former Employee of Biogen, Cambridge, MA, United States

Disclosure

Background: The safety and efficacy of daclizumab high-yield process (DAC HYP) has been evaluated in clinical studies in patients with relapsing-remitting multiple sclerosis (RRMS). Objective: To report integrated safety and tolerability analysis of DAC HYP in patients with RRMS. Methods: Safety data from six placebo- or active-controlled or open-label studies (including extensions) were pooled for analysis. Patients who received at least 1 dose of DAC HYP 150mg or 300mg subcutaneous every 4 weeks were included. Three studies were ongoing at the time of the analysis; patients who recently enrolled and lacked follow-up data were excluded. Safety and tolerability assessments included adverse event (AE) and serious AE (SAE) monitoring and laboratory tests. Results: A total of 1,785 patients were included in the safety population (DAC HYP 150mg, n=1492; DAC HYP 300 mg, n=293). The median overall time of exposure to DAC HYP was 27.6 months, total number of patient-years exposed was 4098, and 573 patients were exposed for ⩾3 years. The incidence of AEs was 88% and SAEs 25% (16% excluding MS relapse). In 14% of patients, AEs led to treatment discontinuation. The most common AEs (incidence ⩾10%) were MS relapse, nasopharyngitis, upper respiratory infection, headache, and urinary tract infection. The overall incidence of infections was 62%, serious infections 4%, cutaneous events 35%, and serious cutaneous events 2%. Elevated liver transaminases (AST or ALT) occurred in 11% (⩾3×ULN) and 6% (>5×ULN) of patients. The incidence of serious, potentially inflammatory gastrointestinal events was < 1%. The incidence of infections, cutaneous events, nervous system disorders, GI events, hepatobiliary disorders, or investigations did not increase over time. Overall, AEs were manageable with standard medical care, including treatment with topical or systemic corticosteroids and antibiotics. Five deaths were reported in patients treated with DAC HYP compared with 5

Gavin Giovannoni has received research grant support from Bayer Schering Healthcare, Biogen, GW Pharma, Merck Serono, Merz, Novartis, Sanofi and Teva and personal compensation for participating on advisory boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from Abbvie, Bayer Schering Healthcare, Biogen, Canbex Therapeutics, Eisai, Elan, Five Prime Therapeutics, Genentech, Genzyme, GlaxoSmithKline, Ironwood Pharma, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals. Ludwig Kappos’ institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: steering committee, advisory board and consultancy fees from Actelion, Addex, Bayer Health Care, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, Xenoport; speaker fees from Bayer Health Care, Biogen, Merck, Novartis, SanofiAventis, Teva; support of educational activities from Bayer Health Care, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva; royalties from Neurostatus Systems GmbH; grants from Bayer Health Care, Biogen, Merck, Novartis, Roche, Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations. Ralf Gold has received speakers’ honoraria or research grant support from Bayer Schering Healthcare, Biogen, Merck Serono, Merz, Novartis, Sanofi and Teva and compensation for advisory board activities from Biogen, Merck Serono, Novartis and Teva. Bhupendra Khatri has received speakers’ honoraria and/or consulting compensation from Biogen, Novartis, Genzyme, Teva, Pfizer, Mallinckrodt, Avanir, Serono, and Bellevue. Krzysztof Selmaj has received compensation for consulting services from Genzyme, Novartis, Ono, Roche, Synthon, and Teva; compensation for speaking from Biogen. Kim Umans is a full time employee of Biogen; family member holds stock in Sinovac Biotech Ltd. Steven Greenberg is a full time employee of Abbvie Biotherapeutics Inc. Marianne Sweester was an employee of Biogen at the time of this analysis. Lou Barbato is a full time employee of Biogen. Peter McCroskery is a full time employee of Biogen. Jacob Elkins is a full time employee of Biogen. This study was funded by Biogen and AbbVie Biotherapeutics Inc. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this abstract. Maria Hovenden (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content.


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Poster Session I, 21(S11) P555 Reduced risk of disability progression in patients with MS treated with early vs delayed teriflunomide 14 mg P.W. O’Connor1, J.S. Wolinsky2, K. Thangavelu3, P. Truffinet4, P. Rufi4, L. Kappos5 1University of Toronto, Toronto, ON, Canada, 2University of Texas Health Science Center at Houston, Houston, TX, 3Genzyme, a Sanofi Company, Cambridge, MA, United States, 4Genzyme, a Sanofi Company, Chilly-Mazarin, France, 5University Hospital Basel, Basel, Switzerland Background: Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting MS. In TOWER (NCT00751881), the second pivotal, phase 3, randomized, placebo-controlled study in patients with relapsing forms of MS (RMS), teriflunomide 14 mg reduced risk of disability progression confirmed for ⩾12 weeks (CDP) vs placebo, with a hazard ratio reduction of 31.5% (P=0.0442). Patients completing the core TOWER study were eligible to enter an extension, in which those originally randomized to teriflunomide 14 mg continued treatment (early treatment) and those previously receiving placebo switched to teriflunomide 14 mg (delayed treatment). Objective: To investigate effects of early vs delayed treatment with teriflunomide 14 mg on disability progression, using data from TOWER and its extension. Methods: In the core TOWER study, patients with RMS were randomized 1:1:1 to receive teriflunomide 14 mg, 7 mg, or placebo. TOWER study duration was variable, ending 48 weeks after last patient randomized. In the extension (not powered a priori to compare early vs delayed treatment), all patients received teriflunomide 14 mg. This analysis compared risk of CDP in patients continuing with teriflunomide 14 mg vs patients switching from placebo to teriflunomide 14 mg, during TOWER and its extension, using a Cox proportional hazards model and log-rank test; probability of CDP was derived from Kaplan-Meier estimates. This analysis used a cut-off date of 31 July 2014 (up to 5.5 years of total study treatment). Results: Of 1169 patients randomized, 750 entered the extension (of whom 252 continued with teriflunomide 14 mg and 253 switched from placebo to teriflunomide 14 mg). Probability of CDP was consistently lower in the early treatment group vs the delayed treatment group. Probabilities of CDP for the early/ delayed treatment groups were 0.085/0.152 (end of Year 1), 0.159/0.206 (end of Year 2), 0.201/0.265 (end of Year 3), 0.242/0.302 (end of Year 4), and 0.267/0.302 (maximum followup at cut-off date), respectively. The 27.6% (95% CI: 0.1, 47.5) reduction in risk of CDP for early vs delayed treatment was statistically significant (P=0.0473). Further analyses of disability progression in TOWER will be presented. Conclusions: We observed a significant reduction in the risk of CDP in patients given early vs delayed treatment with teriflunomide 14 mg. This observation highlights the benefit of teriflunomide for mitigating disability progression in patients with MS. Disclosure Study supported by Genzyme, a Sanofi company. PWO: Consulting fees (Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, Sanofi, Teva, all related to MS clinical trials);

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contracted research (Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, Sanofi, Teva, for clinical trials work). JSW: Consulting fees (AbbVie, Actelion, Alkermes, Athersys, EMD Serono, Forward Pharma, Genentech, Genzyme, Novartis, Roche, Teva, Teva Neuroscience, to-BBB, XenoPort); contracted research (Genzyme, National Institutes of Health, National MS Society through the University of Texas Health Science Center at Houston, and Sanofi); royalties (University of Texas Health Science Center at Houston for monoclonal antibodies out-licensed to Chemicon International). KT and PR: Employees of Genzyme. PT: Employee of Genzyme, with ownership interest. LK: Author´s institution (University Hospital Basel) has received in the last 3 years and used exclusively for research support: steering committee, advisory board and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, Xenoport); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, Teva); support of educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva); royalties (Neurostatus Systems GmbH); grants (Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society, Swiss National Research Foundation). P556 Benefits on brain MRI lesion activity with daclizumab HYP compared with intramuscular interferon beta-1a are maintained through 144 weeks’ treatment: results from the DECIDE study D.L. Arnold1,2, L. Kappos3, H. Wiendl4, K. Selmaj5, E. Havrdova6, A. Boyko7, M. Kaufman8, J. Rose9, S. Greenberg10, L. Amaravadi11, K. Riester11, J. Elkins11 1NeuroRx Research, 2McGill University, Montreal, QC, Canada, 3University Hospital, Basel, Switzerland, 4University of Münster, Münster, Germany, 5Medical University of Lodz, Lodz, Poland, 6First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, 7Russian National Research Medical University named after N.I. Pirogov and the Moscow Multiple Sclerosis Center, Moscow, Russian Federation, 8Cole Neurological Institute, University of Tennessee, Knoxville, TN, 9Department of Neurology, University of Utah, and Neurovirology Research Laboratory VASLCHCS, Imaging and Neuroscience Center, Salt Lake City, UT, 10AbbVie Biotherapeutics Inc., Redwood City, CA, 11Biogen, Cambridge, MA, United States Background: Previous results from the DECIDE study showed that treatment with daclizumab high-yield process (DAC HYP) significantly reduced brain magnetic resonance imaging (MRI) measures of disease activity compared with intramuscular (IM) interferon (IFN) beta-1a in patients with relapsing-remitting multiple sclerosis (RRMS). These benefits were evident as early as Week 24, and maintained through Week 96. At Week 96, gadolinium-enhancing (Gd+), new/newly enlarging T2 hyperintense, and new T1 hypointense lesions were reduced by 65%, 54%, and 52% for DAC HYP vs IM IFN beta-1a (all P< 0.0001).


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Objective: To investigate the impact of DAC HYP vs IM IFN beta-1a on brain MRI outcomes following 144 weeks’ treatment in RRMS patients. Methods: DECIDE was a double-blind, randomised Phase 3 study of DAC HYP 150mg subcutaneous once every 4 weeks vs IFN beta-1a 30mcg IM once weekly for at least 96 weeks in RRMS patients. Treatment continued for up to 144 weeks until the last enrolled patient reached 96 weeks of treatment. Brain MRI was performed at Baseline and at Weeks 24, 96, and 144. No statistical analyses were performed for Week 144 endpoints. Results: The mean (SD) number of Gd+ lesions observed between Baseline and Week 144 was 66.6% lower in the DAC HYP group (n=201) vs the IM IFN beta-1a group (n=196) (0.26 [1.0] vs 0.78 [1.8]). There was a 56.3% reduction from Baseline in the mean number of new/newly enlarging T2 lesions in the DAC HYP group (n=202) vs the IM IFN beta-1a group (n=196) (5.72 [10.4] vs 13.08 [18.0]), and a 50.9% reduction in the mean number of new T1 hypointense lesions (n=201) vs the IM IFN beta-1a group (n=195) (2.87 [4.9] vs 5.85 [9.2]). The median percentage change from Baseline in T2 hyperintense lesion volumes were −1.7% and 3.9% for the DAC HYP (n=202) and IM IFN beta-1a groups (n=196), respectively (median Week 144 lesion volume: 5137.0 mm3 vs 5518.0 mm3), while median new/newly-enlarging T2 hyperintense lesion volumes at Week 144 were 0.0 mm3 (n=199) and 54.0 mm3 (n=193). Median percentage change from Baseline in T1 hypointense lesion volumes were 9.4% and 21.6% for the DAC HYP (n=201) and IM IFN beta-1a groups (n=191) (median Week 144 lesion volume: 1631.0 mm3 vs 1488.0 mm3). Conclusions: Available brain MRI data from the subgroup of patients who continued treatment through Week 144 indicate that brain MRI lesion burden remained numerically lower in patients treated with DAC HYP vs IM IFN beta-1a through 3 years of treatment.

Center for Clinical Studies in Münster, Germany, Merck Serono, Novartis, the NRW Ministry of Education and Research, the RE Children’s Foundation, Sanofi-Genzyme, and Teva Krzysztof Selmaj received consulting fees from Genzyme, Novartis, Ono, Roche, Synthon, and Teva; speakers fees from Biogen. Eva Havrdova received honoraria and research support from Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis, and Teva; advisory board for Biogen, Genzyme, Merck Serono, Novartis, and Teva. Alexey Boyko received consulting/speaker fees from and advisory board for Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis, Nycomed, Sanofi-Aventis, and Teva. Michael Kaufman received honoraria and research support from Biogen; financial support from Bayer HealthCare, EMD Serono, Novartis, and Teva; consultant for the Department of Defense and Dechert. John Rose received research support from AbbieVie Biotherapeutics Inc., Biogen, the Cumming Foundation, the National Institutes of Health, the National Multiple Sclerosis Society, Teva, and Veterans Affairs. Steven Greenberg is a full-time employee of AbbVie Biotherapeutics Inc. Lakshmi Amaravadi is a full-time employee of Biogen. Katherine Riester is a full-time employee of Biogen. Jacob Elkins is a full-time employee of Biogen. This study was funded by Biogen and AbbVie Biotherapeutics Inc. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this abstract. Paul Littlebury PhD (Excel Scientific Solutions, Horsham, UK) wrote the first draft of the abstract based on input from authors. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content.

Disclosure Douglas L Arnold received honoraria from Bayer HealthCare, Biogen, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, Merck Serono, Novartis, Roche, and Teva; employee of and stockholder in NeuroRx Research. Ludwig Kappos´s institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: steering committee/consulting fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, SanofiAventis, and Teva; royalties from Neurostatus Systems GmbH; grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis, Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society, and the Swiss National Research Foundation Heinz Wiendl received consulting fees and honoraria from Bayer HealthCare, Biogen, Fresenius Medical Care, GlaxoSmithKline, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi-Genzyme, and Teva; grants/contracts with Bayer HealthCare, Biogen, Deutsche Forschungsgesellschaft, the Else Kröner Fresenius Foundation, the Fresenius Foundation, the German Ministry for Education and Research, the Hertie Foundation, the Interdisciplinary

P557 Association between no evidence of disease activity (NEDA) and long-term clinical efficacy of delayed-release dimethyl fumarate (DMF) in patients with relapsing-remitting multiple sclerosis from the phase 3 study, ENDORSE E. Havrdova1, R. Gold2, R.J. Fox3, G. Giovannoni4, J. Xiao5, M.R. Edwards5 1Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, 2St. Josef Hospital, Ruhr University, Bochum, Germany, 3Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, United States, 4Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom, 5Biogen, Cambridge, MA, United States Background: In an integrated analysis of the Phase 3 DEFINE and CONFIRM studies, patients with relapsing-remitting multiple sclerosis treated with delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) were approximately twice as likely to have no evidence of disease activity (NEDA) than patients receiving placebo. Favourable NEDA outcomes were maintained throughout 5 years with continuous DMF treatment in the 8-year extension study, ENDORSE.


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Poster Session I, 21(S11) However, evidence that NEDA is correlated with long-term outcomes is still needed. Objective: To assess the association between NEDA and longterm clinical efficacy. Methods: Patients randomised to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued same dosage in ENDORSE; patients randomised to placebo or glatiramer acetate (CONFIRM only) were re-randomised 1:1 to DMF BID or TID. MRI cohort patients who fulfilled the following criteria (measured annually) were considered to have overall NEDA: no relapses, no 12-week Expanded Disability Status Scale (EDSS)confirmed progression, no gadolinium-enhanced lesions, and no new/enlarging T2 lesions. Clinical NEDA, assessed in the intentto-treat (ITT) population, was defined as no relapses and no EDSS progression. NEDA subgroups were determined based on NEDA status at Year 2 (end of DEFINE/CONFIRM; ENDORSE baseline). Year 3 of ENDORSE data, relative to ENDORSE baseline, are presented. Negative binomial model and a repeated-measures analysis were used to calculate the adjusted annualised relapse rate (ARR) and EDSS score, respectively; each adjusted for treatment, age, region, baseline EDSS score, and number of relapses before study. Results: Of 1736 ENDORSE ITT patients at study entry, 1118 had clinical NEDA and 618 did not have clinical NEDA. Of the MRI cohort, 799 patients had data on all 4 NEDA components: 171 had overall NEDA and 628 did not have overall NEDA. At Year 3 in ENDORSE, the ARR was significantly lower in patients with clinical and overall NEDA vs those without: 0.099 vs 0.268 (risk ratio: 0.371; P< 0.0001) and 0.081 vs 0.198 (risk ratio: 0.409; P< 0.0001), respectively. Throughout the 3 years in ENDORSE, clinical and overall NEDA patients maintained significantly lower EDSS scores than those without. Conclusions: Compared with patients who had evidence of disease activity, patients with NEDA at the end of DEFINE/ CONFIRM demonstrated strong and sustained effects across clinical endpoints over the next 3 years in ENDORSE. Disclosure Supported by: Biogen. E. Havrdova: honoraria from Bayer, Biogen, Merck Serono, Novartis, Genzyme, and Teva; research support from Biogen. R.Gold: honoraria from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders. R.J. Fox: consultant fees from Actelion, Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Actelion, Biogen, and Novartis; research grant funding from Novartis. G. Giovannoni: honoraria from Abbvie, Bayer HealthCare, Biogen, Canbex, FivePrime, Genzyme, GlaxoSmithKline, GW Pharma, Merck Serono, Novartis, Protein Discovery Laboratories, Roche, Synthon, Teva Neuroscience, UCB, and Vertex; research grant support from Biogen, Ironwood, Merck Serono, Merz, and Novartis; compensation from Elsevier as co−chief editor of MS and Related Disorders. J. Xiao: employee of and holds stock/stock options in Biogen. M.R. Edwards: employee of and holds stock/stock options in Biogen.

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P558 Reduction in brain volume loss in patients receiving daclizumab HYP versus intramuscular interferon beta-1a: results of the DECIDE study D.L. Arnold1,2, L. Kappos3, O. Khan4, S.A. Gauthier5, S. Greenberg6, W. Ma7, P. Wang7, J. Elkins7, G. Sabatella7 1NeuroRx Research, 2McGill University, Montreal, QC, Canada, 3University Hospital, Basel, Switzerland, 4Multiple Sclerosis Center, Wayne State University School of Medicine, Detroit, MI, 5Judith Jaffe MS Center, Weill Cornell Medical College, New York, NY, 6AbbVie Biotherapeutics Inc., Redwood City, CA, 7Biogen, Cambridge, MA, United States Background: Brain volume loss occurs more rapidly in patients with relapsing-remitting multiple sclerosis (RRMS) than in the general population, and may be associated with brain MRI disease activity and subsequent accumulation of disability. In the DECIDE study, daclizumab high-yield process (DAC HYP) significantly reduced the number of new/newly enlarging T2 hyperintense, new T1 hypointense, and total gadolinium-enhancing lesions compared with intramuscular (IM) interferon (IFN) beta-1a over 96 weeks of treatment. Objective: To assess the effect of treatment with DAC HYP versus IM IFN beta-1a on brain volume change occurring between baseline and Week 96 in patients with RRMS enrolled in the DECIDE study. Methods: DECIDE was a double-blind, randomised Phase 3 study of DAC HYP 150 mg subcutaneous once every 4 weeks versus IFN beta-1a 30 mcg IM once weekly for at least 96 weeks and for up to 144 weeks in patients with RRMS. Brain MRI was assessed at Weeks 0, 24, 96, and 144. The change in brain volume was analysed for the prespecified intervals of Weeks 0 to 24, Weeks 24 to 96, and Weeks 96 to 144, and was also analysed post hoc for Weeks 0 to 96. Whole brain volume change was evaluated as the percentage brain volume change (PBVC) using the Structural Image Evaluation using Normalisation of Atrophy method. Differences in PBVC were determined using an analysis of covariance model based on ranks, adjusting for normalised brain volume, history of prior IFN beta use and baseline age (⩽35 years vs >35 years). Results: Brain volume data were evaluable for 899 patients in the DAC HYP treatment group and 907 patients in the IM IFN beta1a group. Median annualised PBVC was significantly reduced in the DAC HYP treatment group between baseline and Week 96 compared with the IM IFN beta-1a group (-0.553 vs -0.580; P< 0.0001). Annualised PBVC also was reduced in the DAC HYP treatment group vs IM IFN beta-1a treatment group for each prespecified interval examined: Week 0 to Week 24 (-0.674 vs -0.745; P=0.0325) and Week 24 to Week 96 (-0.511 vs -0.549; P< 0.0001). The PBVC was lower in both groups (DAC HYP: -0.379 [n=161]; IM IFN beta-1a: -0.377 [n=149]) during Weeks 96 to 144. Further data on brain volume loss, analysed according to patient baseline and disease characteristics, will be presented. Conclusions: Over 3 years of treatment, DAC HYP was associated with less brain volume loss compared with IM IFN beta-1a in patients with RRMS. Disclosure Douglas L Arnold received honoraria from Bayer HealthCare, Biogen, EMD Serono, Genentech, Genzyme, GlaxoSmithKline,


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Merck Serono, Novartis, Roche, and Teva; employee of, and stockholder in, NeuroRx Research. Ludwig Kappos´s institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: steering committee/consulting fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; royalties from Neurostatus Systems GmbH; grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis, Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society, and the Swiss National Research Foundation. Omar Khan has nothing to disclose. Susan A Gauthier received honoraria from Teva Neuroscience and Genzyme; research support from NMSS, Biogen, Genzyme, Novartis Pharmaceuticals, EMD Serono, and Mallinkrodt. Steven Greenberg is a full-time employee of AbbVie Biotherapeutics Inc. Wei Ma is a full time employee of Biogen. Ping Wang is a full-time employee of Biogen. Jacob Elkins is a full-time employee of Biogen. Lou Barbato is a full-time employee of Biogen. This study was funded by Biogen and AbbVie Biotherapeutics Inc. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this abstract. Paul Littlebury, PhD (Excel Scientific Solutions, Horsham, UK) wrote the first draft of the abstract based on input from authors. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P559 Comparative efficacy of first-line natalizumab versus IFNb or glatiramer acetate in relapsing MS T. Spelman1, T. Kalincik1, V. Jokubaitis1, A. Zhang2, F. Pellegrini2, H. Wiendl3, S. Belachew2, R. Hyde2, F. Verheul4, A. Lugaresi5, E. Havrdova6, D. Horakova6, P. Grammond7, P. Duquette8, A. Prat8, G. Iuliano9, M. Terzi10, G. Izquierdo11, R. Hupperts12, C. Boz13, E. Pucci14, G. Giuliani14, P. Sola15, D. La Spitaleri16, J. Lechner-Scott17, R. Bergamaschi18, F. Grand’Maison19, F. Granella20, L. Kappos21, M. Trojano22, H. Butzkueven1, MSBase Study Group 1Department of Neurology, Royal Melbourne Hospital, Parkville, VIC, Australia, 2Biogen Idec, Cambridge, MA, United States, 3Department of Neurology, University of Münster, Münster, Germany, 4Groene Hart Ziekenhuis, Gouda, The Netherlands, 5Department of Neuroscience, Imaging and Clinical Sciences, MS Center, University ‘G. d’Annunzio’, Chieti, Italy, 6Charles University, Prague, Czech Republic, 7Center de Réadaptation Déficience Physique Chaudière-Appalache, Levis, 8Hôpital Notre Dame, Montreal, QC, Canada, 9Ospedali Riuniti di Salerno, Salerno, Italy, 1019 Mayis University, Samsun, Turkey, 11Hospital Universitario Virgen Macarena, Sevilla, Spain, 12Orbis Medical Centre, Sittard-Geleen, The Netherlands, 13KTU Medical Faculty Farabi Hospital, Trabzon, Turkey, 14Neurology Unit, ASUR Marche - AV3, Macerata, 15Nuovo Ospedale Civile S.Agostino/Estense, Modena, 16AORN San Giuseppe Moscati,

Avellino, Italy, 17John Hunter Hospital, Newcastle, NSW, Australia, 18Neurological Institute IRCCS Mondino, Pavia, Italy, 19Neuro Rive-Sud, Hôpital Charles LeMoyne, Montreal, QC, Canada, 20Neuro Rive-Sud, Hôpital Charles LeMoyne, Parma, Italy, 21Department of Neurology, University Hospital Basel, Basel, Switzerland, 22Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy Introduction: This is the first large-scale, head-to-head comparison of on-treatment relapse occurrence, therapy persistence, and disability outcomes in patients who either initiated natalizumab or a BRACE therapy as first-line treatment. Objective: To compare efficacy and treatment persistence in treatment naïve patients with relapsing-remitting multiple sclerosis (RRMS) initiating natalizumab compared with interferon-beta (IFNb)/glatiramer acetate (GA) therapies, using propensity scorematched cohorts from observational MS registries. Methods: The study population initiated IFNb/GA in the MSBase Registry or natalizumab in the TYSABRI Observational Program (TOP), had ⩾3 months of on-treatment follow-up, and active RRMS, defined as ⩾1 gadolinium-enhancing lesion on cerebral MRI at baseline and/or ⩾1 relapse within the 12 months prior to baseline. Baseline demographics and disease characteristics were balanced between propensity-matched groups. Annualized relapse rate (ARR), time to first relapse, treatment persistence, and disability outcomes were compared between matched treatment arms in the total population (n=366/group) and subgroups with higher baseline disease activity. Results: Three hundred and sixty-six (85.1%) first-line natalizumab commencements were successfully matched to a first-line BRACE initiation. First-line natalizumab was associated with a 68% relative reduction in ARR from a mean (SD) of 0.63 (0.92) on IFNb/GA to 0.20 (0.63) (p(signed-rank)< 0.0001), a 64% reduction in the rate of first relapse (hazard ratio [HR]= 0.36; 95% confidence interval [CI]=0.28-0.47; p< 0.001), and a 27% reduction in the rate of discontinuation (HR=0.73, 95%CI=0.58-0.93; p=0.01), compared with first-line IFNb/GA therapy. Confirmed disability progression and area under the EDSS-time curve analyses were not statistically significant. Similar relapse and treatment persistence results were observed in each of the higher disease activity subgroups. Conclusion: Initiating natalizumab as a first-line treatment for RRMS improves relapse and treatment persistence outcomes, compared to initiating first-line IFNb/GA therapy. This needs to be balanced against the risk of Progressive Multifocal Leukoencephalopathy (PML) in natalizumab treated patients. Disclosure T Spelman received honoraria for consultancy and funding for travel from Biogen Idec Inc. T Kalincik received compensation for conference travel and consultancy/speaker honoraria from Novartis, Biogen Idec, Genzyme, Sanofi Aventis, Teva, BioCSL and Merck Serono V Jokubaitis has received conference travel support from Novartis. A Zhang is an employee of Biogen Idec Inc. F Pelligrini is an employee of Biogen Idec Inc. H Wiendl received compensation for serving on scientific advisory boards for Bayer Healthcare, Biogen Idec, Genzyme, Merck


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Poster Session I, 21(S11) Serono, Novartis, and Sanofi; speaker honoraria and travel support from Bayer Schering AG, Bayer Vital GmbH, Biogen Idec, CSL Behring, Fresenius Medical Care, Genzyme, GlaxoSmithKline, GW, Merck Serono, Novartis, and Sanofi; compensation as a consultant from Biogen Idec, Merck Serono, Novartis, and Sanofi; research support from Bayer Vital GmbH, Biogen Idec, Merck Serono, Novartis, Sanofi Germany, and Sanofi US. S Belachew is an employee of Biogen Idec Inc. R Hyde is an employee of Biogen Idec Inc. F Verheul is an advisory board member for Teva Biogen Merck Serono and Novartis. A Lugaresi was a Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis Advisory Board Member. She received travel grants and honoraria from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi and Teva, research grants from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi and Teva, travel and research grants from the Associazione Italiana Sclerosi Multipla. E Havrdova received speaker honoraria and consultant fees from Biogen Idec, Merck Serono, Novartis, Genzyme and Teva, as well as support for research activities from Biogen Idec and Merck Serono. D Horakova received speaker honoraria and consulting fees from Biogen Idec, Merck Serono, Teva and Novartis, as well as support for research activities from Biogen Idec. P Grammond is a Novartis, Teva-neuroscience, Biogen Idec advisory board member, consultant for Merck Serono, received payments for lectures by Merck Serono, Teva-Neuroscience and Canadian Multiple sclerosis society, and received grants for travel from Teva-Neuroscience and Novartis. P Duquette has received honoraria for organising CME events and has obtained funding to attend meetings from Biogen Idec, EMD Serono, TEVA Neuroscience, Novartis, and Genzyme, has received funding for investigator-initiated trials with Biogen Idec, EMD Serono and Novartis, and has received peer-review funding from CIHR and from the MS Society of Canada. A Prat reports no conflicts of interest. G Iuliano had travel/accommodations/meeting expenses funded by Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis, and Teva M Terzi received travel grants from Merck Serono, Novartis, Bayer-Schering, Merck-Serono and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. G Izquierdo received consulting fees from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi, and Teva. R Hupperts received honoraria as consultant on scientific advisory boards from Merck-Serono, Biogen-Idec, Genzyme-Sanofi and Teva, research funding from Merck-Serono and Biogen-Idec, and speaker honoraria from Sanofi-Genzyme. C Boz received conference travel support from Biogen Idec, Novartis, Bayer-Schering, Merck-Serono and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. E Pucci did not declare any competing interests. G Giuliani did not declare any competing interests. P Sola did not declare any competing interests. D La Spitaleri received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen Idec, Sanofi Aventis, Teva and Merck-Serono. J Lechner-Scott has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria

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for talks and advisory board commitment and also clinic support from Bayer Health Care, Biogen Idec, CSL, Genzyme Sanofi, Merck Serono and Novartis. R Bergamaschi received speaker honoraria from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, Teva; research grants from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis, Teva; congress and travel/ accommodation expense compensations by Almirall, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, Teva. F Grand-Maison received an honorarium for organizing a CME event for Biogen Idec in 2013 and received consultation fees from Biogen Idec as well as from Novartis and Genzyme in 2013 and 2014. F Granella did not declare any competing interests. L Kappos received research support from Acorda, Actelion, Allozyne, BaroFold, Bayer HealthCare, Bayer Schering, Bayhill Therapeutics, Biogen Idec, Elan, European Union, Genmab, Gianni Rubatto Foundation, GlaxoSmithKline, Glenmark, MediciNova, Merck Serono, Novartis, Novartis Research Foundation, Roche, Roche Research Foundation, Sanofi-Aventis, Santhera, Swiss MS Society, Swiss National Research Foundation, Teva Neuroscience, UCB, and Wyeth. M Trojano received honoraria for consultancy and/or speaking from Biogen Idec, Genzyme-Sanofi, Merck Serono, Novartis, and Roche; research grants from Biogen Idec, Merck Serono, Novartis, and Teva. H Butzkueven received compensation for serving on scientific advisory boards and as a consultant for Biogen Idec and Novartis; speaker honoraria from Biogen Idec Australia, Merck Serono Australia, and Novartis Australia; travel support from Biogen Idec Australia and Merck Serono Australia; research support from CASS Foundation (Australia), Merck Serono Australia, the Royal Melbourne Hospital Friends of the Neurosciences Foundation, and the University of Melbourne. P560 Increased nuclear Nrf2 expression after fumarate treatment for multiple sclerosis and psoriasis I. Metz1, S. Traffehn1, K. Straßburger-Krogias2, K. Keyvani3, M. Bergmann4, K. Nolte5, M. Weber1, T. Bartsch6, R. Gold2, W. Brück1 1Department of Neuropathology, University Medical Center, Georg August University, Göttingen, 2Department of Neurology, St. Josef-Hospital/Ruhr-University Bochum, Bochum, 3Institute of Neuropathology, University of Duisburg-Essen, Essen, 4Institute of Clinical Neuropathology, Klinikum Bremen Mitte, Bremen, 5Department of Neuropathology, RheinischWestfälische Technische Hochschule Aachen, Aachen, 6Department of Neurology, Universitätsklinikum SchleswigHolstein, Kiel, Germany BG12 (Tecfidera®) is composed of dimethyl fumarate (DMF). It is an oral medication that is approved for the treatment of relapsing remitting multiple sclerosis (MS). DMF has next to antiinflammatory also putative neuroprotective mechanisms of action. Activation of the nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) antioxidant pathway is hypothesized to mediate neuroprotection.


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We analyzed a biopsy specimen from a 33 year old female MS patient with a relapsing remitting disease course and more than 1 year of DMF treatment at a dosage of 240 mg twice a day. Biopsy, performed 8 weeks after the last DMF dosage, showed an inactive demyelinated MS lesion. We compared the number of Nrf2positive nuclei in our DMF-treated patient with inactive demyelinated MS lesions from six patients not treated with DMF. 6fold higher numbers of Nrf2-positive nuclei were present in the DMFtreated patient compared to control MS patients. Next we performed double immunohistochemical stainings to identify Nrf2-positive cell populations. The strongest Nrf2 signal was found within astrocytes with nuclear and cytoplasmic Nrf2 expression, whereas most oligodendrocytes presented with a cytoplasmic Nrf2 signal only. Fumarates are also a common therapy for the skin disease psoriasis. Single cases of PML in patients treated with Fumaderm TM® have been reported. We enumerated Nrf2-positive nuclei in three PML lesions from patients with ongoing fumarate treatment. Our results showed that two patients had higher numbers of Nrf2positive nuclei (> 1400/mm²) and the last patient presented with similar numbers (104/mm²) compared to PML controls (mean: 122 Nrf2-positive nuclei/mm²). In conclusion, the present results suggest that Nrf2 is translocated into nuclei after fumarate treatment. This supports the idea that this neuroprotective pathway could be important for mediating therapeutic effects of fumarates. A note of caution is due when interpreting our findings since as a physiological response ‘natural inflammation’ in MS or PML may also cause an increase in Nrf2-expressing nuclei. Disclosure I.Metz received speakter honoraria and travel grants from Biogen Idec, Bayer Healthcare, TEVA, Serono, and Novartis and received research support from Biogen Idec and German Ministry for Education and Research. S. Traffehn received speaker honoraria from Biogen Idec. K. Straßburger-Krogias and K. Keyvani report no disclosures. M. Bergmann is on the advisory board for Clinical Neuropathology. K. Nolte reports no disclosures. M.S. Weber is an academic editor for PLoS One. T. Bartsch was a guest editor for Neuroscience and an assistant editor for BMC Neurology and received research support from DFG SFB. R. Gold is on the scientific advisory boards for TEVA, Bayer Schering, and Novartis and well an on the editorial board for The American Journal of Pathology, Journal of Neuroimmunology, and Experimental Neurology, is an editor for Therapeutic Advances in Neurological Diseases, has consulted for Biogen Idec, ELAN, TEVA, and Chugai Inc; and received research support from TEVA, Biogen Idec, Bayer Schering, Merck Serono, and Novartis. W. Brück is on the scientific advisory board for Genzyme, Novartis, Biogen Idec Germany, and TEVA; receiced speaker honoraria from TEVA, Sanofi, Genzyme, Novartis, Merck Serono, Biogen Idec, and Bayer; is on the editorial board for Acta Neuropathologica, Therapeutic Advances in Neurological Disorders, Multiple Sclerosis International, and Neuropathology and Applied Neurobiology; and received research support from the German Research Foundation, German Ministry for Science and Education.

P561 Efficacy of daclizumab HYP vs intramuscular interferon beta-1a on disability progression across patient demographic and disease activity subgroups in DECIDE S. Cohan1, L. Kappos2, H. Wiendl3, K. Selmaj4, E. Havrdova5, M. Kaufman6, J. Rose7, S. Greenberg8, L. Amaravadi9, W. Ma9, J. Elkins9 1Providence Multiple Sclerosis Center, Providence Brain and Spine Institute, Portland, OR, United States, 2University Hospital Basel, Basel, Switzerland, 3University of Münster, Münster, Germany, 4Medical University of Lodz, Lodz, Poland, 5First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, 6Cole Neurological Institute, University of Tennessee - Knoxville, Knoxville, TN, 7Department of Neurology University of Utah and Neurovirology Research Laboratory VASLCHCS, Imaging and Neuroscience Center, Salt Lake City, UT, 8AbbVie Biotherapeutics Inc., Redwood City, CA, 9Biogen, Cambridge, MA, United States Background: In DECIDE, the risk of 24-week confirmed disability progression was reduced by 27% (P=0.033) in patients with relapsing-remitting multiple sclerosis (RRMS) treated with daclizumab high-yield process (DAC HYP) 150 mg subcutaneous every 4 weeks vs patients treated with interferon (IFN) beta-1a 30 mcg intramuscular (IM) once weekly for 2-3 years. Objective: To examine the effect of DAC HYP vs IFN beta-1a on 24-week confirmed disability progression in patient subgroups based on baseline characteristics. Methods: Patients (age 18-55 y) were randomised to IFN beta-1a (n=922) or DAC HYP (n=919). Disability progression was defined as 24-week confirmed increase on the Expanded Disability Status Scale (EDSS) of ⩾1.0 point from baseline score of ⩾1.0 or ⩾1.5 points from baseline score of 0. For each subgroup, disability progression by EDSS was analysed by Cox Proportional Hazards model adjusted for baseline EDSS (continuous variable), history of prior IFN beta use, and baseline age (⩽35 or >35 years) (excluding covariates defining the subgroup). A multiple imputation method was used for missing data. Results: Risk of disability progression sustained for 24-weeks [Hazard Ratio (95% CI)] for DAC HYP vs IFN beta-1a yielded the following results across key patient subgroups and demographic groupings: Age, ⩽35 years, 0.46 (0.26, 0.84), >35 years, 0.86 (0.62, 1.20); male, 0.68 (0.41, 1.16), female, 0.76 (0.54, 1.06); EDSS, < 3.5, 0.64 (0.44, 0.95), ⩾3.5, 0.87 (0.56, 1.34); Presence of gadolinium-enhancing (Gd+) lesions, absent, 0.67 (0.46, 0.99), present, 0.77 (0.49, 1.21); T2 lesion volume, < median, 0.78 (0.50, 1.22), ⩾median, 0.66 (0.45, 0.96); Prior IFN beta use, yes, 0.64 (0.42, 0.98), no, 0.80 (0.54, 1.19); Disease duration, < 3 years, 0.76 (0.49, 1.18), ⩾3 to < 10 years, 0.72 (0.45, 1.17), ⩾10 years, 0.63 (0.34, 1.16); Relapses in previous 12 months, ⩽1, 0.79 (0.53, 1.17), ⩾2, 0.68 (0.45, 1.03); Prior MS treatment (excluding steroids), yes, 0.70 (0.48, 1.02), no, 0.75 (0.49, 1.16); Disease activity, low, 0.72 (0.52, 1.00), high (⩾2 relapses in the year prior to randomisation and ⩾1 Gd+ lesion at baseline MRI), 0.68 (0.36, 1.29). Conclusions: The overall effect of DAC HYP on risk of 24-week confirmed disability progression versus IFN beta-1a was supported by consistent results across all key subgroups. Trends were seen towards stronger effects in the subgroups of patients who were younger, previously received IFN beta, or had higher T2 lesion burden.


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Poster Session I, 21(S11) Disclosure Stanley Cohan is a paid consultant to serve on advisory boards for Biogen, Novartis, Genzyme & Mallinckrodt; is on the speaker bureaus of Biogen, Novartis, Genzyme and Acorda; and has received research support from Biogen, Novartis, Genzyme, Roche, Opexa and Mallinckrodt. Ludwig Kappos has received in the last 3 years and used exclusively for research support: steering committee, advisory board and consultancy fees from Actelion, Addex, Bayer Health Care, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, Xenoport; speaker fees from Bayer Health Care, Biogen, Merck, Novartis, Sanofi-Aventis, Teva; support of educational activities from Bayer Health Care, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva; royalties from Neurostatus Systems GmbH; grants from Bayer Health Care, Biogen, Merck, Novartis, Roche, Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations. Heinz Wiendl has received honoraria and consultation fees from: Bayer HealthCare, Biogen, Fresenius Medical Care, GlaxoSmithKline, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi-Genzyme BioVentures, and Teva Pharmaceutical Industries and has grants and contracts with Bayer HealthCare, Biogen, the German Ministry for Education and Research, Deutsche Forschungsgesellschaft, the Else Kröner Fresenius Foundation, the Fresenius Foundation, the Hertie Foundation, Merck Serono, Novartis, the NRW Ministry of Education and Research, the Interdisciplinary Center for Clinical Studies in Münster, Germany, the RE Children’s Foundation, sanofi-aventis/Genzyme, and Teva Pharmaceutical Industries. Krzysztof Selmaj has received compensation for consulting services from Genzyme, Novartis, Ono, Roche, Synthon, and Teva and compensation for speaking from Biogen. Eva Havrdova received speakers’ honoraria and research grant support from Bayer Schering Healthcare, Biogen, Genzyme, Merck Serono, Novartis, and Teva, and compensation for advisory board activities from Biogen, Genzyme, Merck Serono, Novartis, and Teva. Michael Kaufman has received honoraria and research support from Biogen; financial support from Bayer, EMD Serono, Novartis, and Teva; and is a consultant for Department of Defense and Dechert. John Rose has received research support from: Biogen, AbbieVie Biotherapeutics, Teva, Cumming Foundation, National Multiple Sclerosis Society, VA and NIH. Steven Greenberg is a full-time employee of AbbVie Biotherapeutics. Lakshmi Amaravadi is a full-time employee of Biogen. Wei Ma is a full-time employee of Biogen. Jacob Elkins is a full-time employee of Biogen. This study was funded by Biogen and AbbVie Biotherapeutics. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this abstract. Rebecca Jarvis (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content.

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P562 Improvements in patient-reported outcomes with teriflunomide: week 24 interim results from the US cohort of the Teri-PRO phase 4 study P.K. Coyle1, C. LaGanke2, B. Khatri3, K. Edwards4, S. Cavalier5, F. Baldinetti5, S. Brette6, R. Gold7 1Stony Brook University, Stony Brook, NY, 2North Central Neurology Associates, Cullman, AL, 3Regional MS Center, Center for Neurological Disorders at Wheaton Franciscan Healthcare, Milwaukee, WI, 4Multiple Sclerosis Center of Northeastern New York, Latham, NY, 5Genzyme, a Sanofi company, Cambridge, MA, United States, 6Lincoln, Boulogne-Billancourt, France, 7St Josef Hospital, Ruhr University Bochum, Bochum, Germany Background: Teriflunomide, a once-daily oral immunomodulator, is approved for relapsing-remitting MS, and has displayed consistent efficacy in placebo-controlled trials and a well-characterized safety profile. The ongoing phase 4 Teri-PRO (NCT01895335) study is investigating the efficacy, tolerability and satisfaction with teriflunomide in patients with relapsing forms of MS (RMS) in clinical practice. Objective: To describe interim treatment satisfaction and disability results using patient-reported outcomes (PROs) for patients enrolled in US centres in TeriPRO. Methods: Teri-PRO is a prospective, global, single-arm study primarily evaluating PROs in 1001 patients with RMS receiving once-daily teriflunomide for 48 weeks, according to local labelling. This interim analysis of the US patient subgroup reports global treatment satisfaction results, measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; version 1.4), at baseline (for patients switching from prior disease-modifying therapy [DMT]), and Week 4 (all patients). Patient-reported disability at baseline and Week 24, as measured by the MS Performance Scale (MSPS), is also reported. Results: US enrolment is complete (n=545); 473 (86.8%) and 72 (13.2%) patients received teriflunomide 14 mg and 7 mg, respectively. Mean age was 50.6 years (standard deviation [SD], 10.5 y), 76.0% were female, and baseline mean Expanded Disability Status Scale score was 3.74 (SD, 1.94). Use of ⩾1 other DMT within the past 2 years was reported by 385 patients (70.6%). After 24 weeks, 463 patients remained in the study. At Week 4, mean TSQM Global Satisfaction score for all patients was 72.2 (SD, 20.6). In patients switching from another DMT within 6 months of enrolment (n=316), mean TSQM Global Satisfaction score (n=305) was 74.9 (SD, 19.3), representing a 22.7 (SD, 29.4) point improvement vs baseline (n=268). At Week 24, mean MSPS total score (n=442) was 14.1 (SD, 7.3), representing an improvement of 0.7 (SD, 4.4) points vs baseline (n=439). A total of 384 (70.5%) patients experienced an adverse event, leading to treatment discontinuation for 49 (9.0%) patients. Conclusions: In this real-world clinical practice study, interim results illustrate that teriflunomide is associated with high levels of treatment satisfaction and a substantial increase in satisfaction in patients who switched to teriflunomide from other DMTs. Patient-reported disability remained stable after 6 months of teriflunomide treatment. Disclosure Study supported by Genzyme, a Sanofi company.


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PKC: Consulting fees (AbbVie, Accordant, Acorda, Bayer, Biogen Idec, Genentech/Roche, Genzyme/Sanofi, Novartis, Serono, Teva); research support (Actelion, Novartis, Opexa). CL: Consulting fees (Acorda, Bayer, Biogen Idec, EMD Serono, Genzyme/Sanofi, Novartis, Pfizer, Questcor, Teva Neurosciences, UCB); speaker bureaus (Acorda, Bayer, Biogen Idec, EMD Serono, Genzyme/Sanofi, Novartis, Pfizer, Questcor, Teva Neuroscience, UCB); fees from non-CME Services (Acorda, Bayer, Biogen Idec, EMD Serono, Genzyme/Sanofi, Novartis, Pfizer, Questcor, Teva Neuroscience, UCB); contracted research (Biogen Idec, Genzyme/ Sanofi, Novartis, Teva Neuroscience, Vaccinex). BK: Consulting fees (Bayer, Biogen Idec, Genzyme, Novartis, Pfizer, Questcor, Serono, Terumo, Teva); speaker bureaus (Bayer, Biogen Idec, Genzyme, Novartis, Pfizer, Questcor, Serono, Terumo, Teva). KE: Consulting services (Biogen, Genzyme); Speaker bureaus ( Biogen, Genzyme, Novartis); research support (Biogen, Eli Lilly, Easai Inc, Forum Pharmaceuticals, Genentech, Genzyme, Hoffman-La Roche, Novartis, Pfizer, Merz Pharmaceuticals, Vaccinex). SC: Employee of Genzyme, with ownership interest. FB: Employee of Genzyme. SB: Employee of Lincoln, mandated by Sanofi. RG: Consulting (Biogen, BayerSchering, Elan Genzyme, Roche, Teva); grant/research support (Biogen, BayerSchering, Genzyme, Teva).

procedures. A total of 530 patients at 46 US sites have been enrolled. Key inclusion criteria include age ⩾18 years, RRMS diagnosis (McDonald criteria), ⩾12 months continuous treatment with natalizumab monotherapy prior to initiation of DMF, and initiation of DMF ⩾12 months prior to enrolment. Patients are eligible to enrol regardless of current DMF use. Results: Preliminary results (16 January 2015 database lock) are shown; final results will be presented. The preliminary analysis comprised 227 evaluable patients (mean age: 47 years). Overall risk of relapse 1 year after initiation of DMF was 25%. Overall ARR during DMF treatment (0.295) increased compared with the natalizumab treatment period (0.114) but was lower than 1 year prior to initiation of natalizumab (0.480). Risk of relapse 1 year after initiation of DMF was similar in patients with pre-natalizumab disease activity (⩾1 relapse 1 year prior to natalizumab) compared with patients without pre-natalizumab disease activity (25.3% vs 24.8%). In patients with washout duration ⩽90 days compared with patients with washout duration >90 days, risk of relapse 1 year after initiation of DMF was lower (16% vs 33%) and ARR 1 year after initiation of DMF was lower (0.181 vs 0.423). Conclusions: Preliminary findings suggest that DMF may be a reasonable treatment option for patients who discontinue natalizumab in the real-world setting. Shorter natalizumab washout duration was associated with better clinical outcomes (lower risk of relapse and ARR) on DMF treatment. Final results will be presented.

P563 Real-world clinical outcomes in relapsing-remitting multiple sclerosis patients who switch from natalizumab to delayed-release dimethyl fumarate: a multicenter, retrospective, observational study (STRATEGY) S. Cohan1, H. Moses2, J. Calkwood3, C. Tornatore4, C. Laganke5, K.E. Smoot1, M. Mann6, V. Meka6, M. Okwuokenye6, C. Hotermans6, L. Meltzer6 1Providence Multiple Sclerosis Center, Portland, OR, 2Department of Neurology, Neuroimmunology Division, Vanderbilt University Medical Center, Nashville, TN, 3Schapiro Center for Multiple Sclerosis, Minneapolis Clinic of Neurology, Golden Valley, MN, 4Department of Neurology, Medstar Georgetown University Hospital, Washington, DC, 5North Central Neurology Associates, Cullman, AL, 6Biogen, Inc., Cambridge, MA, United States

Disclosure

Background: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) may be a therapeutic option for patients with relapsing-remitting multiple sclerosis (RRMS) who are treated with natalizumab and require a change in therapy. However, there is limited information regarding standardized practices for transitioning patients from natalizumab to DMF. Clinical practices and switch protocols vary, and predictors of favourable treatment outcomes on DMF following natalizumab are not well understood. Objectives: Present results of clinical practice outcomes (annualized relapse rate [ARR] and risk of relapse) in a Phase 4, retrospective, observational study of patients with RRMS who switched from natalizumab to DMF. Methods: STRATEGY is performed through a single time point medical chart abstraction without required study visits or

This study is supported by Biogen, Inc. Stanley Cohan: research support from Biogen, Novartis, Genzyme, Roche, and Mallinckgrodt; advisory boards and steering committees for Biogen, Novartis, Genzyme, and Mallinckrodt; honoraria from Biogen, Novartis, Genzyme, and Acorda. Jonathan Calkwood: advisory, consultancy, and speaker activities for Acorda, Bayer Healthcare, Biogen, EMD Serono, Genzyme, Mylan, Novartis, Questcor, and Teva; grant/research activities with Biogen, Genzyme, Novartis, Receptos, Roche, and Xenoport. Christopher LaGanke: advisory, consultancy, and speaker activities for Acorda, Bayer Healthcare, Biogen, EMD Serono, Genzyme, Novartis, Pfizer, Questcor, Teva Neuroscience; research support from Bayer Healthcare, Biogen, Genzyme, GSK, Novartis, Pfizer, Teva Neuroscience, and Vaccinex. Carlo Tornatore: consultant fees and research support from Biogen, Genzyme, and Novartis; Speaker Bureau for Biogen. Harold Moses: consulting, speaker fees, and research support from Biogen, Teva, Bayer, EMDSerono, Genzyme, Novartis, and Avanir. Kyle E. Smoot: advisory and speaker activities for Acorda, Biogen, EMD Serono, Genzyme, Novartis, and Teva. Monica Mann: employee of and holds stock/stock options in Biogen. Venkata Meka: employee of and holds stock/stock options in Biogen. Macaulay Okwuokenye: employee of and holds stock/stock options in Biogen. Christophe Hotermans: employee of and holds stock/stock options in Biogen. Leslie Meltzer: employee of and holds stock/stock options in Biogen.


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Poster Session I, 21(S11) P564 Longer-term follow-up of the efficacy of delayedrelease dimethyl fumarate in newly diagnosed patients with RRMS: an integrated analysis of DEFINE, CONFIRM, and ENDORSE J. Marantz1, R. Gold2, G. Giovannoni3, J.T. Phillips4, R.J. Fox5, A. Zhang1 1Biogen, Cambridge, MA, United States, 2St. Josef Hospital, Ruhr University, Bochum, Germany, 3Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom, 4Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, 5Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, United States Background: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated efficacy and safety in patients with relapsing-remitting multiple sclerosis (RRMS) in the Phase 3 DEFINE and CONFIRM studies. ENDORSE is an 8-year extension of DEFINE/CONFIRM. Objective: To report long-term outcomes with DMF in newly diagnosed patients with RRMS. Methods: In ENDORSE, patients randomised in DEFINE/ CONFIRM to DMF 240 mg twice (BID) or thrice daily (TID) continued on the same dosage. Patients randomised to placebo (PBO) or glatiramer acetate (GA; CONFIRM only) were re-randomised 1:1 to DMF BID or TID. Results for DMF 240 mg BID are reported, as this represents the approved dosage. The GA arm was excluded from the parent analysis of newly diagnosed patients in DEFINE/ CONFIRM. “Newly diagnosed” was defined as multiple sclerosis diagnosis within 1 year prior to parent study entry and either treatment-naïve or previously treated with corticosteroids alone. Minimum follow-up (data as of May 14, 2014) was approximately 5 years; BID/BID patients remaining on study received approximately ⩾5 years continuous DMF treatment; PBO/BID patients remaining on study received 2 years PBO (DEFINE/CONFIRM) followed by approximately ⩾3 years DMF (ENDORSE). Results: The newly diagnosed population included 144 BID/BID and 85 PBO/BID patients. At 5 years (ENDORSE Year 3), the annualised relapse rate (ARR) (95% confidence interval [CI]) in the newly diagnosed population was 0.137 (0.101, 0.186) in BID/ BID and 0.169 (0.113, 0.253) in PBO/BID. Although the ARR at 5 years was lower in BID/BID patients compared with those who received delayed treatment (PBO/BID), PBO/BID patients demonstrated improvements after switching to DMF in ENDORSE: ARR (95% CI) was 0.244 (0.163, 0.367) from Years 0-2 (DEFINE/ CONFIRM), and 0.102 (0.060, 0.174) from Years 3-5 (ENDORSE). The Kaplan-Meier estimated proportion (95% CI) of patients with 24-week confirmed disability progression at 5 years was 8.1% (4.6%, 14.3%) in BID/BID and 20.4% (13.0%, 31.4%) in PBO/ BID. Updated 6-year data (ENDORSE Year 4) will be presented. Conclusion: Long-term treatment with DMF demonstrated strong and sustained effects on relapses and disability progression across newly diagnosed patient subgroups (BID/BID and PBO/BID). Disclosure Supported by: Biogen. J. Marantz, A. Zhang: employees of and hold stock/stock options in Biogen.

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R. Gold: consultant fees from Bayer HealthCare, Biogen, Merck Serono, Novartis, Teva Neuroscience, and Genzyme; grant/ research support from Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage as editor of Therapeutic Advances in Neurological Disorders. G. Giovannoni: honoraria from Abbvie, Bayer HealthCare, Biogen, Canbex, FivePrime, Genzyme, GlaxoSmithKline, GW Pharma, Merck, Merck Serono, Novartis, Protein Discovery Laboratories, Roche, Synthon, Teva Neuroscience, UCB, and Vertex; research grant support from Biogen, Ironwood, Merck Serono, Merz, and Novartis; compensation from Elsevier as cochief editor of Multiple Sclerosis and Related Disorders. J.T. Phillips: consultant fees from Acorda, Biogen, Genzyme, Merck Serono, and Sanofi; research support from Roche. R.J. Fox: consultant fees from Actelion, Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Actelion, Biogen, and Novartis; research grant funding from Novartis. P565 Efficacy of delayed-release dimethyl fumarate in early multiple sclerosis: post-hoc analysis of the phase 3 DEFINE and CONFIRM studies according to baseline disability R. Gold1, G. Giovannoni2, J.T. Phillips3, R.J. Fox4, J.B. Lewin5, A. Zhang5, J.L. Marantz5 1St. Josef Hospital, Ruhr University, Bochum, Germany, 2Queen Mary University of London, Blizard Institute, London, United Kingdom, 3Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, 4Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, 5Biogen, Inc., Cambridge, MA, United States Background: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated efficacy and safety in relapsing-remitting multiple sclerosis (RRMS) in the Phase 3 DEFINE and CONFIRM studies. An analysis of data from the AFFIRM study of natalizumab in RRMS indicates that patients with lower levels of disability tend to demonstrate the greatest benefit on clinical outcomes (Havrdova et al, ECTRIMS 2013, P519). Hence, DMF treatment may be particularly effective in slowing disease progression and reducing overall disease burden in patients with early MS as indicated by lower levels of disability. Previous analyses of DEFINE/CONFIRM demonstrated that DMF efficacy was robust in patients newly diagnosed with MS (Gold et al. 2015) and in patients who were naïve to prior treatment with disease-modifying therapies (Hutchinson et al., ECTRIMS 2013, P563). Objectives: Investigate the efficacy of DMF on clinical measures in RRMS patients early in their disease course according to extent of disability, defined as baseline Expanded Disability Status Scale (EDSS) score ⩽2.0. Methods: Eligibility criteria included age 18-55 years and EDSS score 0-5.0. Patients were randomized to receive DMF 240 mg twice (BID) or thrice daily, placebo, or subcutaneous glatiramer acetate (reference comparator; CONFIRM only) for up to 2 years. EDSS was assessed at baseline and every 12 weeks thereafter. Outcome measures included annualized relapse rate (ARR) and risk of 12-week confirmed disability progression. Results are


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reported for placebo and DMF BID (approved dosing regimen in all regions). Results: The integrated intent-to-treat population included 771 and 769 patients receiving placebo or DMF BID, respectively; among them, 362 and 373 had baseline EDSS score ⩽2.0. At 2 years, in patients with baseline EDSS score ⩽2.0, reductions with DMF BID compared with placebo were observed for ARR (adjusted relapse rate [95% confidence interval, CI]: 0.132 [0.102, 0.170] vs 0.357 [0.291, 0.438]; 63% reduction; P< .0001) and risk of 12-week confirmed disability progression (0.14 vs 0.24; 40% reduction; P=.0066). Additional data will be reported. Conclusions: Compared with placebo, DMF BID demonstrated beneficial effects on clinical outcomes in RRMS patients early in their disease course according to extent of disability. Disclosure This study is supported by Biogen, Inc. Ralf Gold: honoraria from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders. Gavin Giovannoni: honoraria from Abbvie, Bayer HealthCare, Biogen, Canbex, FivePrime, Genzyme, GlaxoSmithKline, GW Pharma, Merck Serono, Novartis, Protein Discovery Laboratories, Roche, Synthon, Teva Neuroscience, UCB, and Vertex; research grant support from Biogen, Ironwood, Merck Serono, Merz, and Novartis; compensation from Elsevier as co−chief editor of MS and Related Disorders. J. Theodore Phillips: consulting fees from Acorda, Biogen, Genzyme, Merck Serono, and Sanofi; research support from Roche. Robert J. Fox: consultant fees from Actelion, Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Actelion, Biogen, and Novartis; research grant funding from Novartis. James B. Lewin: employee of and holds stock/stock options in Biogen, Inc. Annie Zhang: employee of and holds stock/stock options in Biogen, Inc. Jing L. Marantz: employee of and holds stock/stock options in Biogen, Inc. P566 Six-year follow-up of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: MRI outcomes from DEFINE, CONFIRM and ENDORSE D.L. Arnold1,2, R.J. Fox3, R. Gold4, E. Havrdova5, L. Kappos6, T. Yousry7, D. MacManus7, R. Zhang8, M. Yang8, J. Rana8 1NeuroRx Research, 2Montreal Neurological Institute, McGill University, Montreal, QC, Canada, 3Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, United States, 4St. Josef Hospital, Ruhr University, Bochum, Germany, 5Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, 6University Hospital, Basel Neurology, Basel, Switzerland, 7University College London Institute of Neurology, Queen Square Multiple Sclerosis Centre, NMR Research Unit, London, United Kingdom, 8Biogen, Cambridge, MA, United States

Background: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated efficacy and safety in patients with relapsing-remitting multiple sclerosis (RRMS) in the 2-year, Phase 3 DEFINE and CONFIRM studies. ENDORSE is an ongoing, 8-year extension study of DEFINE and CONFIRM. Objective: To report integrated magnetic resonance imaging (MRI) outcomes with DMF from DEFINE, CONFIRM, and ENDORSE. Methods: In ENDORSE, patients randomised in DEFINE/ CONFIRM to DMF 240 mg twice (BID) or thrice daily (TID) continued same dosage. Patients randomised to placebo (PBO) or glatiramer acetate (GA; CONFIRM only) were re-randomised 1:1 to DMF 240 mg BID or TID. Brain MRI scans were obtained yearly in ENDORSE from an MRI cohort. Although data were collected for both DMF regimens, only BID data are reported as this represents the approved dosage. Data (as of May 14, 2014) were analysed by parent/extension study arm: BID/BID, PBO/ BID, and GA/BID. Results: Of 982 MRI cohort patients completing DEFINE/ CONFIRM, 746 received treatment in ENDORSE; 363 received DMF BID (211 BID/BID, 104 PBO/BID, 48 GA/BID). Among the 152 BID/BID patients remaining after 5 years’ follow-up, 63% were free of new/enlarging T2 hyperintense lesions and 73% were free of new T1 hypointense lesions during Year 5 (Year 3 of ENDORSE), and 88% were free of gadolinium-enhanced lesions at the Year 5 scan (ENDORSE Year 3 scan). For PBO/BID, no new/enlarging T2 hyperintense lesions were observed in 34% (n=29/85) of patients during Year 2 in DEFINE/CONFIRM (treatment with PBO) and in 68% (n=38/56) during Year 5 (Year 3 of DMF treatment in ENDORSE). Updated 6-year data (ENDORSE Year 4) will be presented. Conclusion: Reduced frequency of new MRI lesions was maintained over 5 years with continued DMF therapy. After switching from PBO to DMF in ENDORSE, patients demonstrated MRI outcomes similar to those observed with DMF in DEFINE/ CONFIRM Disclosure Study supported by: Biogen. D.L. Arnold: honoraria/revenue/consultancy: Acorda Therapeutics, Biogen, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, MedImmune, Mitsubishi, Novartis, Opexa Therapeutics, Receptos, Roche, Sanofi-Aventis, Teva; employee and stockholder of NeuroRx; research support from Novartis and Biogen. R.J. Fox: consultant fees from Allozyne, Avanir, Biogen, Novartis, Questcor, and Teva; grant and research support from Novartis. R. Gold: honoraria and research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience. E. Havrdova: honoraria from Bayer, Biogen, Genzyme, GlaxoSmithKline, Merck Serono, Novartis, Sanofi, and Teva. L. Kappos: University Hospital Basel has received research support and payments that were used for research support of Prof. Kappos’s activities as principal investigator and member or chair of planning and steering committees or advisory boards in trials sponsored by Actelion, Addex Therapeutics, Bayer HealthCare Pharmaceuticals, Bayer Schering Pharma AG, Biogen, CSL Behring, Genentech, GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Praxicon, Roche, Sanofi-Aventis, Santhera, Siemens, and Teva. Prof. Kappos has


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Poster Session I, 21(S11) received grants from the Swiss Multiple Sclerosis Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis Research Foundation, and Roche Research Foundation. T. Yousry: research grants from Biogen, GlaxoSmithKline, Schering AG, and Novartis for analysis of data from trials in multiple sclerosis; honoraria and travel expenses for advisory committee work from Biogen, Bayer Schering, and Novartis. D. MacManus: research grants from Apitope, Biogen, GlaxoSmithKline, Novartis, Richmond Pharma, Schering. R. Zhang, M. Yang, J. Rana: employees of and hold stock/stock options in Biogen.

Conclusions: AHSCT should be considered as an alternative treatment option for aggressive MS if performed according to very restrictive qualification criteria in highly specialized hematological centers.

P567 Autologous haematopoietic stem cell transplantation with reduced-intensity conditioning for aggressive multiple sclerosis: the Polish experience L. Szczechowski1, M. Smilowski1, G. Helbig2, M. KrawczykKulis2, S. Kyrcz-Krzemien2 1Department of Hematology and Bone Marrow Transplantation, A.Mielecki Hospital of Medical University of Silesia, 2Department of Hematology and Bone Marrow Transplantation, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

P568 Long-term therapy with interleukin-6-receptor blockade in highly active neuromyelitis optica spectrum disorder M. Ringelstein1, I. Ayzenberg2, J. Harmel1, A.-S. Lauenstein3, E. Lensch3, F. Stögbauer4, K. Hellwig2, G. Ellrichmann2, M. Stettner1, A. Chan2, H.-P. Hartung1, B. Kieseier1, R. Gold2, O. Aktas1, I. Kleiter2 1Department of Neurology, Medical Faculty, HeinrichHeine-University Düsseldorf, Düsseldorf, 2Department of Neurology, St. Josef-Hospital, Ruhr University Bochum, Bochum, 3Department of Neurology, German Diagnostic Clinic, Wiesbaden, 4Department of Neurology, Klinikum Osnabrück, Osnabrück, Germany

Background: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that leads to an inflammatory processes resulting in demyelination and axonal degeneration. Current treatment of relapsing-remitting MS (RRMS) includes immunomodulatory and immunosuppressive agents, which are effective, but usually in earlier and more benign forms. The immunomodulatory treatment has limited efficacy in aggressive forms of RRMS, and relapses occur despite treatment continuation. Autologous haematopoietic stem cell transplantation (AHSCT) should be considered as a therapeutic approach for patients with aggressive MS who failed conventional therapy. Objectives: The aim of this study is to confirm the efficacy and safety of reduced-intensity immunosuppression followed by AHSCT among MS patients with aggressive forms of the disease. Methods: 39 RRMS and secondary progressive MS (SPMS) patients met the qualification criteria for autologous hematopoietic stem cell transplantation. The qualification criteria were established according to the guidelines of the European Group for Blood and Marrow Transplantation (EBMT) 2012, current literature as well as our own experience. The group consisted of 29 patients with RRMS and 10 patients with SPMS. The stem cells were mobilized with cyclophsosphamide (Cy) and granulocytecolony stimulating factor (G-CSF). After conditioning the stem cells were re-infused into the patient. The primary endpoint was the observation of relapse free survival (RFS) defined as relapse absence in the follow-up; progression free survival (PFS) - no progression in EDSS score and MRI-event free survival (MRI-EFS) - lack of new T2 changes. Those three parameters define the overall disease free survival (DFS) - lack of any signs of disease. Results: A 4 years RFS was 86%. MRI-EFS was 78% and PFS was 82%. The DFS was observed in 72% of patients. No mortality was observed. Short term side effects were limited to symptoms which are common due to AHSCT procedures. No long term side effects have been observed so far.

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Disclosure Lech Szczechowski: Nothing to disclose Marek Smilowski: Nothing to disclose Grzegorz Helbig: Nothing to disclose Malgorzata Krawczyk-Kulis: Nothing to disclose Slawomira Kyrcz-Krzemien: Nothing to disclose

Background: Neuromyelitis optica (NMO) is characterized by disabling relapses of optic neuritis and myelitis and the presence of aquaporin-4 antibodies (AQP4-ab). Interleukin-6 (IL-6), significantly elevated in serum and cerebrospinal fluid of NMO patients, induces AQP4-ab production by plasmablasts and represents a novel therapeutic target. Goals: Aim of the study was to evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized antibody targeting the IL-6 receptor, in NMO and NMO spectrum disorders (NMOSD). Methods: Eight Caucasian female patients with highly active AQP4-ab seropositive NMO (n=6) and NMOSD (n=2), resistant to previous medications including B-cell depletion, were switched to TCZ (6-8 mg/kg). Annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS), spinal cord and brain magnetic resonance imaging (MRI), AQP4-ab titers, pain levels (numerical rating scale), and adverse effects were retrospectively evaluated for 10-51 treatment months. Results: Patients were followed-up for 30.9 ± 15.9 (mean ± SD) months after switch to TCZ. 2/8 patients received add-on therapy with monthly steroid pulses (temporary) or azathioprine, respectively. During TCZ treatment the median ARR significantly decreased from 4.0 (interquartile range 3.0-5.0) in the last year prior to TCZ to 0.365 (0-0.785) (p=0.0078) and the median EDSS from 7.25 (5.375-8.375) to 5.5 (2.625-6.5) (p=0.0313). Active MRI lesions appeared in 6/8 patients at TCZ onset and in 1/8 at last MRI. Three patients remained relapse-free during TCZ treatment. In 5 patients a total of 8 relapses occurred, 4 within the first 2.5 months of therapy. Five attacks were associated with delayed TCZ administration (⩾40 days) and 6 with reduced TCZ dosage (6 mg/kg instead of 8 mg/kg). AQP4-ab titers (p=0.0156) and pain levels (p=0.0156) dropped significantly during TCZ treatment.


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Adverse effects included moderate cholesterol elevation in 6/8, infections in 4/8, and deep venous thrombosis and neutropenia in one patient each. Conclusions: This study suggests that prolonged TCZ therapy may be safe and effective from early treatment phases on for otherwise therapy-resistant highly active NMO and NMOSD. Relapse patterns indicate that adherence to a regular therapeutic regimen with monthly infusions of 8 mg/kg TCZ may increase efficacy. Disclosure Marius Ringelstein received speaker honoraria from Novartis and travel reimbursement from Bayer Schering, Biogen Idec and Genzyme with permission by the Rector of Düsseldorf University Hospital. Ilya Ayzenberg received travel reimbursement from the International Headache Society. Jens Harmel received travel reimbursement from Merck Serono with permission by the Rector of Düsseldorf University Hospital. Ann-Sophie Lauenstein received travel reimbursement from UCB, Eisai and Genzyme. Eckart Lensch received speaker honoraria and travel reimbursement from Bayer Health Care, Biogen Idec, Genzyme, Sanofi Aventis and Teva. Florian Stögbauer received honoraria for speaking and travel reimbursement from Biogen Idec, Novartis, Boehringer and Genzyme. Kerstin Hellwig received grants from the German Research Foundation. She received honoraria for speaking and research grants from Biogen Idec, Bayer, Teva, Merck, Novartis, and Genzyme. Gisa Ellrichmann received speakers or scientific grant support from Biogen Idec, TEVA Pharma, Almirall Pharma and Novartis Pharma. Mark Stettner received speaker honoraria and travel reimbursement from Biogen Idec, Novartis Pharmaceuticals and Teva Pharma GmbH with permission by the Rector of Düsseldorf University Hospital. Andrew Chan received personal compensation as a speaker or consultant for Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Teva Neuroscience. A. Chan received research support from the German Ministry for Education and Research (BMBF, German Competence Network Multiple Sclerosis (KKNMS, 01GI0914), Biogen Idec, Genzyme, and Novartis. Hans-Peter Hartung received grants by Walter-and-Ilse-RoseStiftung, Eugène Devic European Network (EU-FP7) and the German Ministry for Education and Research, received honoraria for consultancy and speaking from Bayer Health Care, Biogen Idec, GeNeuro, Genzyme, Novartis, Opexa, Teva, Sanofi Aventis, Roche and holds patents with permission by the Rector of Heinrich-Heine-University Düsseldorf. Bernd Kieseier received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Bayer Health Care, Biogen Idec, Genzyme/Sanofi Aventis, Grifols, Merck Serono, Mitsubishi Europe, Novartis, Roche, Talecris, TEVA, and UCB. Ralf Gold serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma,

and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of the American Journal of Pathology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Merck Serono and Novartis. Orhan Aktas received grants by the German Research Foundation (DFG), Eugène Devic European Network (EU-FP7), German Ministry for Education and Research, Schaufler Foundation, honoraria for lectures by Novartis, Bayer Schering, Teva, Biogen Idec, and he holds patents and received travel/accommodations/ meeting expenses by Novartis, Bayer Schering, and Merck Serono with permission by the Rector of Heinrich-Heine-University Düsseldorf. Ingo Kleiter received honoraria for consultancy/speaking and travel reimbursement from Bayer Health Care, Biogen Idec, Chugai, and Novartis Pharmaceuticals and research grants from the Mercator Foundation, Bayer Health Care, Biogen Idec, Novartis, and Teva Pharma GmbH. P569 Lymphocyte counts in patients receiving daclizumab HYP in DECIDE H. Wiendl1, G. Giovannoni2, S. Greenberg4, J. Sheridan4, L. Amaravadi3, P. McCroskery3, G Giannattasio3 1University of Münster, Münster, Germany, 2Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, United Kingdom, 3Biogen, Cambridge, MA, 4AbbVie Biotherapeutics Inc., Redwood City, CA, United States Background: Daclizumab high-yield process (DAC HYP) blocks high-affinity interleukin-2 receptor (IL-2R) signaling by binding to the α subunit (CD25) of the IL-2R. This action leads to targeted reduction of proinflammatory effector T cell activities and expansion of CD56bright natural killer (NK) cells. Objective: To assess changes in blood lymphocyte counts in patients treated with DAC HYP versus intramuscular (IM) interferon (IFN) beta-1a and determine a potential relationship between lymphocyte count and infection status in patients treated with DAC HYP. Methods: DECIDE was a randomised, double-blind, active-controlled study that compared DAC HYP 150 mg subcutaneous (SC) every 4 weeks with IFN beta-1a 30 mcg IM once weekly in patients with relapsing-remitting multiple sclerosis (RRMS). For DAC HYP (n=919) and IFN beta-1a (n=922) patients, whole blood samples were collected and analysed for lymphocyte count, CD4+ T-cell, CD8+ T-cell, and CD56bright NK cell counts. Further, these cell counts were examined in DAC HYP patients with and without infections. Results: Median changes from baseline in total lymphocyte count for the DAC HYP and IFN beta-1a groups were −5.6% and −4.1% at Week 48 and −10.4% and −5.6% at Week 96. Median changes from baseline in CD4+ T cell counts for the DAC HYP and IFN beta-1a groups were −13.4% and −4.4% at Week 48 and −15.4% and −0.8% at Week 96. Median changes from baseline in CD8+ T cell counts for the DAC HYP and IFN beta-1a groups were −14.3% and −11.4% at Week 48 and −17.8% and −4.7% at Week 96. Median changes from baseline in CD56bright NK cell counts for


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Poster Session I, 21(S11) the DAC HYP and IFN beta-1a groups were +394.5% and +31.7% at Week 48 and +630.8% and +28.2% at Week 96. Median values of lymphocyte counts in DAC HYP patients who experienced an infection were similar to those who did not at Week 96 (total lymphocytes [x109 cells/L], 1.68 vs 1.64; CD4+ T-cell [cells/mm3], 701.00 vs 579.00; CD8+ T-cell [cells/mm3], 302.00 vs 246.50; and CD56brightNK cell [cells/mm3], 71.63 vs 56.70). Conclusions: Modest decreases in total lymphocyte counts and CD4+ and CD8+ T cells were observed in both treatment groups, and were stable over 2 years of treatment. Over the treatment period, large (~400% to 600%) increases were observed in CD56bright NK cells in the DAC HYP group and small (~30%) increases were observed in the IFN beta-1a group. There was no apparent association between infection status and lymphocyte counts in DAC HYP-treated patients. Disclosure Heinz Wiendl received consulting fees and honoraria from Bayer HealthCare, Biogen, Fresenius Medical Care, GlaxoSmithKline, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi-Genzyme, and Teva; grants/contracts with Bayer HealthCare, Biogen, Deutsche Forschungsgesellschaft, the Else Kröner Fresenius Foundation, the Fresenius Foundation, the German Ministry for Education and Research, the Hertie Foundation, the Interdisciplinary Center for Clinical Studies in Münster, Germany, Merck Serono, Novartis, the NRW Ministry of Education and Research, the RE Children’s Foundation, Sanofi-Genzyme, and Teva Gavin Giovannoni received research grant support from Bayer Schering Healthcare, Biogen, GW Pharma, Merck Serono, Merz, Novartis, Sanofi and Teva and personal compensation for participating on advisory boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from Abbvie, Bayer Schering Healthcare, Biogen, Canbex Therapeutics, Eisai, Elan, Five Prime Therapeutics, Genentech, Genzyme, GlaxoSmithKline, GW Pharma, Ironwood Pharma, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals. Wanda Castro-Borrero is a full-time employee of Biogen. Steven Greenberg is a full-time employee of AbbVie Biotherapeutics Inc. James Sheridan is a full-time employee of AbbVie Biotherapeutics Inc. Lakshmi Amaravadi is a full-time employee of Biogen. Peter McCroskery is a full-time employee of Biogen. Lou Barbato is a full-time employee of Biogen. This study was funded by Biogen and AbbVie Biotherapeutics Inc. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this abstract. Rebecca Jarvis, PhD (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P570 Efficacy of natalizumab and fingolimod in relapsingremitting multiple sclerosis in real world clinical practice R. Totaro1, G. Costantino2, P. Bellantonio3, M. Danni4, C. Di Carmine1, R. Fantozzi3, R. Cerqua4, A. Fuiani2, C. Mundi2, S. Ruggieri3, C. Marini1, L. Provinciali4, A. Carolei1

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1Department

of Neurology, University of L’Aquila, L’Aquila, of Neurology, Ospedali Riuniti, Foggia, 3Department of Neurology, IRCCS Neuromed, Pozzilli, 4Department of Neurology, University of Ancona, Ancona, Italy 2Department

Objective: The aim of our study was to assess the efficacy at the 1-year follow-up in a cohort of patients treated with either fingolimod or natalizumab in the real world clinical practice. Methods: We enrolled 391 patients starting either natalizumab or fingolimod for RRMS, referred to four multiple sclerosis centers throughout Central and Southern Italy between March 2007 and July 2013. The main end point was the cumulative proportion of patients free from any disease activity, as defined by freedom from relapse, Expanded Disability Status Scale progression, new or newly enlarging T2 lesions and gadolinium enhancing lesions at magnetic resonance imaging (MRI) assessed at 12-month follow-up. As additional end-points, we also considered each single disease activity measure independently. Results: Out of 391 patients, 197 were treated with natalizumab and 194 with fingolimod. Out of 194 patients who started with fingolimod, 52 were previously treated with natalizumab. The cumulative proportion of patients free from any disease activity was 72.0% in the natalizumab and 59.1% in the fingolimod group (P=0.014). This proportion was lower in fingolimod patients with prior natalizumab exposure compared to those without (51.7% vs. 61.8%; P=0.008). Moreover, the cumulative proportion of patients free from new MRI lesions was 87.5% in the natalizumab vs. 70.0% in the fingolimod group (P< 0.001); the cumulative proportion of patients free from clinical relapse was 82.5% in the natalizumab vs. 81.3% in the fingolimod group (P=0.739); 93.5% of patients on natalizumab were free from Expanded Disability Status Scale progression compared to 89.6% of patients on fingolimod (P=0.186). Conclusions: Results from the present prospective observational study suggest greater efficacy of natalizumab over fingolimod in the real-world setting. In our study, a higher proportion of patients treated with natalizumab showed absence of combined clinical and radiological disease activity being largely driven by radiological outcome parameters. Since direct comparison coming from head-to-head studies is still lacking, long-term follow-up real world studies are warranted to attempt to fill this gap. Disclosure RT received funding for travel or speaker honoraria from Almirall, Bayer, Biogen, Merck Serono, Novartis, Sanofi-Aventis, and TEVA. GC received funding for travel or speaker honoraria from Biogen, Merck Serono, Novartis, Sanofi-Aventis, and TEVA. PB received funding for travel or speaker honoraria from Bayer, Biogen, Merck Serono, Novartis, Sanofi-Aventis, and TEVA. MD received funding for travel or speaker honoraria from Bayer, Biogen, Merck Serono, Novartis, Sanofi-Aventis, and TEVA. RF received funding for travel or speaker honoraria from Bayer, Biogen, Merck Serono, Novartis, Sanofi-Aventis, and TEVA. RC received funding for travel or speaker honoraria from Biogen, Merck Serono, Novartis, Sanofi-Aventis, and TEVA. AF received funding for travel or speaker honoraria from Bayer, Biogen, Merck Serono, Novartis, Sanofi-Aventis, and TEVA. LP received funding for travel or speaker honoraria from Bayer, Biogen, Merck Serono, Novartis, Sanofi-Aventis, and TEVA.


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P571 Hepatic disorders due to teriflunomide in multiple sclerosis treatment. Impact and management in clinical practice J. Meca-Lallana1,2, R. Hernández-Clares1,2, E. CarreónGuarnizo1,2, M. Cerdán-Sánchez1,2, R. Carrasco-Torres1,2, B. Palazón-Cabanes1,2, C. Sánchez-Vizcaíno Buendía1, G. SalgadoCecilia2,3, J. Jimenez-Veiga1,2, A. León-Hernández2,4, J.J. MartínFernández5 1Unidad de Esclerosis Múltiple. Servicio de Neurología, Hospital Clínico Universitario Virgen de la Arrixaca, 2Cátedra de Neuroinmunología Clínica y Esclerosis Múltiple, UCAM Universidad Católica San Antonio, 3Servicio de Inmunología, 4Servicio de Radiodiagnóstico. Unidad de Neurorradiología, 5Servicio de Neurología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain Background: Teriflunomide has been recently approved in Europe as a disease modifying drug for the treatment of relapsing-remitting multiple sclerosis (RRMS). Regulatory agencies recommend monitoring liver enzymes (LE) every 2 weeks during the first 6 months of treatment due to potential risk of liver failure. Objective: To find out which proportion of patients under treatment with teriflunomide present hepatic disorders in clinical practice as well as its clinical impact and management. Methods: Prospective study in which all patients with RRMS who have started a teriflunomide treatment in our center are analyzed. Blood test of LE (ALT, AST, GGT), bilirubin and alkaline phosphatase (ALP) was performed every 2 weeks during the first 6 months and every 8 weeks thereafter until one year of treatment was completed. The results of the LE test were stratified according to the World Health Organization toxicity grading scale (grade 0: less than 1.25-fold the upper limit of normal [ULN], grade 1: between 1.26 and 2.5 ULN, grade 2: between 2.6 and 5 ULN, grade 3: between 5.1 and 10 ULN, grade 4: over 10 ULN) as well as ALP and bilirubin levels. The percentage of patients taking 1, 2 and 3 or more drugs together with teriflunomide was also analyzed. Results: We included 42 patients (average age 36.2 [range: 21-50], 71.7% women). In the first 6 months 28.5% (n=12) showed asymptomatic elevation of ALT (grade 0: 16.6%, grade 1: 9.5%, grade 2: 2.3%, grades 3 and 4: 0%. Elevation between 1 and 3 ULN: 26.2%). Asymptomatic bilirubin elevation grade 1 (between 1.1 and 1.5 ULN) was observed in 9.5% (n=4). Treatment was not interrupted nor discontinued in any case by reasons of ALT or bilirubin elevation. Patients with toxicity grade 1 and 2 (ALT or bilirubin) were forbidden to consume fatty foods and alcoholic beverages, and levels normalized. Concomitant treatment was observed in 64.3% (n=27) (1 drug: 14.3%, 2 drugs: 16.6%, 3 or more drugs: 33.3%). No statistically significant relationship between ALT elevation and the number of concomitant drugs was found. Conclusion: In our clinical experience, LE elevation between 1 and 3 ULN because of teriflunomide (26.2%) is lower than the observed on the pooled safety data from the clinical trials Phase 2, TEMSO, TOWER and TOPIC (47.4%). If treatment with teriflunomide is effective, it should not be suspended or discontinued because of ALT elevation before taking dietary measures and also considering the concomitant treatments.

Disclosure J. Meca-Lallana has received honoraria as moderator and speaker at meetings and participated in clinical trials sponsored by BiogenIdec, Novartis, Merck-Serono, Almirall, Teva and Genzyme. R. Hernández-Clares has received honoraria as moderator and speaker at meetings and participated in clinical trials sponsored by Biogen-Idec, Novartis, Merck-Serono,Teva and Genzyme. E. Carreón-Guarnizo has received honoraria as moderator and speaker at meetings and participated in clinical trials sponsored by Biogen-Idec, Novartis and Merck-Serono. M. Cerdán-Sánchez: Nothing to disclose. R. Carrasco-Torres: Nothing to disclose. B. Palazón-Cabanes: Nothing to disclose. C. Sánchez-Vizcaíno Buendía: Nothing to disclose. G. Salgado-Cecilia: Nothing to disclose. J. Jimenez-Veiga: Nothing to disclose. A. Leon-Hernández: Nothing to disclose. J.J. Martín-Fernández: Nothing to disclose. P572 A myeloid directed immune modulator, MIS416, modulates homeostatic CNS leucocyte trafficking - implications for neuro-inflammation R. Girvan1, M. White2, V. Pearson1, A. La Flamme2, G. Webster1 1Innate Immunotherapeutics Ltd, Auckland, 2Victoria University, Wellington, New Zealand Background: MIS416 is a myeloid directed immune response modifier in a Phase 2B trial in patients with secondary progressive multiple sclerosis (SPMS). This progressive stage of disease is increasingly recognised to reflect CNS-compartmentalised innate inflammation. MIS416 enhances myeloid-derived negative regulators of inflammation in mouse and human studies. Of significance is the ability of MIS416 to enhance regulatory leucocytes in the periphery, as these have the potential to access the CNS by homeostatic trafficking. Objective: To determine evidence of MIS416 directed myeloid CNS trafficking Methods: For mouse CNS trafficking studies, fluorescent labelled MIS416 was administered weekly (4 weeks; 100 or 200 µg). Myeloid subsets in the peripheral blood, brain and spinal cord were analysed by flow cytometry at 24 hrs or 7 days post each dose. Immunohistochemistry on frozen brain sections was used for MIS416 and cell localisation studies and analysis of choroid plexus modifications. Patients (n=15) with SPMS were treated weekly (i.v; 500 µg) (NCT01191996). Peripheral blood mononuclear cells were collected at 24 hr post dose for weeks 1-4 of the trial. These cells were analysed for myeloid subsets using flow cytometry. Plasma samples were analysed for chemokines by ELISA methodology. Results: In non-diseased mice, MIS416 enhanced regulatory monocytic myeloid/DC subset trafficking into the brain and spinal cord in the absence of BBB modulation. The data supports our hypothesis, that MIS416 mobilised peripheral myeloid cells access the CNS via the choroid plexus/CSF barrier, which is a main route for CNS immune surveillance. Furthermore, MIS416 may have a direct effect within the CNS, as we also found


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Poster Session I, 21(S11) monocytic myeloid cells containing MIS416 within the CNS (“Trojan Horse” pathway). In MIS416 treated patient samples, modulation of the peripheral blood monocytes towards an anti-inflammatory “non-classical” phenotype was transiently detectable following each dose of MIS416. MIS416 therapy also induced chemokines involved in non-inflammatory myeloid trafficking such as CXCL3 and CXCL10. Conclusion: We propose that by stimulating the choroid plexus/ CSF barrier, MIS416 mobilised non-inflammatory myeloid cells can access the CNS and act locally to re-establish an environment permissive to endogenous repair mechanisms. Transcriptomics studies are underway on CNS tissue to further define how MIS416 therapy influences CNS homeostatic pathways. Disclosure Gill Webster, Rebecca Girvan and Victoria Pearson are employees of Innate Immunotherapeutics Ltd, Australia. Madelaine White and Anne La Flamme are employees of Victoria University, New Zealand and are collaborators of Innate Immunotherapeutics Ltd. The work was equally funded by Innate Immnotherapeutics Ltd and Victoria University.

P573 Costimulatory blockade with abatacept (CTLA4Ig) in relapsing-remitting multiple sclerosis: results from the ACCLAIM trial S.J. Khoury1,2, J. Rochon3, L. Ding4, M. Byron5, D.L. Arnold6, S. Cook1, W. Gao4, P. Tosta7, P.H. Sayre7, D. Smilek7, ACCLAIM Study Group 1Partners MS center, Brigham and Women’s Hospital, Boston, MA, United States, 2Abu Haidar Neuroscience Institue, AUBMC, Beirut, Lebanon, 3Rho Inc., Chapel Hill, NC, 4Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, Bethesda, MD, 5Rho, Inc., Chapel Hill, NC, United States, 6McGill University, Montreal, QC, Canada, 7Immune Tolerance Network, San Francisco, CA, United States Background: Abatacept (CTLA4-Ig) is a T cell costimulationblocking agent approved for rheumatoid arthritis. A phase I study of CTLA4-Ig previously showed feasibility of this approach in subjects with relapsing-remitting multiple sclerosis (RRMS). Objectives: ACCLAIM (A Cooperative Clinical Study of Abatacept in Multiple Sclerosis) was a phase II, randomized, double-blind, placebo-controlled, multi-center trial of safety and efficacy of abatacept in participants with RRMS. Methods: Sixty-five participants were enrolled in the study at 19 clinical sites, representing approximately half of the original enrollment target. Participants were randomized 2:1 in favor of abatacept, and received monthly intravenous infusions of either abatacept or placebo for 24 weeks in blinded fashion. The primary endpoint was the mean number of new inflammatory gadolinium-enhanced lesions obtained on MRI scans performed every 4 weeks, averaged over the interval from week 8 to week 24. A cross-over design was employed whereby subjects were switched to the opposite treatment arm at 28 weeks to determine the duration of treatment effect.

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Inclusion criteria required a diagnosis of definite RRMS according to the McDonald criteria, and active disease defined as either a documented clinical exacerbation or at least one gadoliniumenhanced lesion on MRI in the year prior to enrollment. Results: Low clinical and MRI disease activity were present in both the abatacept and the placebo groups at baseline and during the study. A greater range of gadolinium-enhanced MRI lesions was noted in the placebo group at baseline. The data were analyzed using a Wilcoxon rank sum test stratified on the presence or absence of gadolinium-enhanced lesions in the year prior to enrollment. The 24 week results are reported here. No statistically significant difference was observed in the adjusted mean number of new inflammatory MRI brain lesions averaged from week 8 to week 24 between the abatacept group (mean 0.43, SD 0.94, median 0.2, range 0-5) and the placebo group (mean 1.66, SD 3.63, median 0.3, range 0-16), p = 0.87. No statistically significant differences were observed in other MRI parameters of MS disease activity, or in clinical assessment of disease activity. Abatacept was well tolerated in this study population. Conclusions: This phase II study did not demonstrate efficacy of abatacept in reducing inflammatory lesions on MRI, nor clinical measures of disease activity in RRMS. Disclosure Samia Khoury, MD reports grant support from Novartis Pharmaceuticals. James Rochon, PhD has no disclosures. Linna Ding, MD has no disclosures. Margie Byron, MStat has no disclosures. Douglas L. Arnold, MD reports an ownership interest in NeuroRx, which performed the MRI analysis for the trial, and personal fees from Acorda, Biogen Idec, Genzyne, Hoffman-La Roche, Innate Immunotherapeutics, MedImmune, Mitsubishi Pharma, Novartis, Receptos, Sanofi Aventis and Teva outside the submitted work. Sandra Cook, BSN reports receiving salary support from Merck Serono, Inc. Wendy Gao, BSN, MS has no disclosures. Patti Tosta, RN, MS has no disclosures. Peter H. Sayre, MD, PhD has no financial or other conflicts of interest to disclose related to the ACCLAIM abstract. Dawn Smilek, MD, PhD has no disclosures. Support: National Institute of Allergy and Infectious Disease (N01 AI15416, UM1 AI109565, and HHSN272200800029C). Study medication and financial support also provided by BristolMyers Squibb. P574 The effect of disease modifying therapies on brain atrophy in patients with clinically isolated syndrome: a systematic review and meta-analysis G. Tsivgoulis1, A.H. Katsanos2, N. Grigoriadis3, G.M. Hadjigeorgiou4, I. Heliopoulos5, P. Papathanasopoulos6, A. Tsivgoulis1, C. Kilidireas7, K. Voumvourakis1, HELANI (Hellenic Academy of Neuroimmunology) 1Second Department of Neurology, “Attikon” Hospital, School of Medicine, University of Athens, Athens, 2Department of Neurology, School of Medicine, University of Ioannina, Ioannina, 3Second Department of Neurology, “AHEPA” University Hospital, Aristotelion University of Thessaloniki,


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Thessaloniki, 4Department of Neurology, University Hospital of Larissa, University of Thessaly, Larissa, 5Second Department of Neurology, Alexandroupolis University Hospital, Democritus University of Thrace, Alexandroupolis, 6Department of Neurology, University of Patras Medical School, Patras, 7First Department of Neurology, “Eginition” Hospital, School of Medicine, University of Athens, Athens, Greece Background: Brain atrophy is associated with cognitive deficits in patients with clinically isolated syndrome (CIS) and can predict conversion to clinical definite multiple sclerosis. The aim of the present meta-analysis was to evaluate the effect of disease-modifying drugs (DMD) on brain atrophy in patients with CIS. Methods: Eligible placebo-control RCTs of patients with CIS that reported changes in brain volume during the study period were identified by searching MEDLINE, SCOPUS and the CENTRAL Register of Controlled Trials. This meta-analysis has adopted PRISMA guidelines for systematic reviews and meta-analyses. Results: We found 3 eligible studies, comprising 1362 patients. The mean percentage change in brain volume was found to be significantly lower in DMD treated patients versus placebo treated subgroup (SMD= -0.13, 95%CI: -0.25 ─ -0.01; p=0.04). In the subgroup analysis of the two studies that provided data on brain volume changes for the first (0-12 months) and second (13-24 months) year of treatment, DMD attenuated brain volume loss in comparison to placebo during the second year (SMD= -0.25; 95%CI: -0.43, -0.07; p< 0.001), but not during the first year of the treatment (SMD= -0.01; 95%CI: -0.27, 0.24; p=0.93). No evidence of heterogeneity was found between estimates, while funnel plot inspection revealed no evidence of publication bias. Conclusions: DMD appear to attenuate brain atrophy over time in patients with CIS. The effect of DMD on brain volume loss is evident after the first year of treatment. Disclosure Dr. Georgios Tsivgoulis has been supported by European Regional Development Fund Project FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123). Dr Tsivgoulis has received research support (not related to this project) by Teva Pharmaceutical Hellas and Novartis Hellas. Dr Katsanos reports no sources of funding. Dr. Grigoriadis has received research support (not related to this project) by Biogen Idec, Novartis, TEVA, Merck Serono, Genesis Pharma Dr. Hadjigeorgiou reports no sources of funding Dr. Heliopoulos reports no sources of funding Dr. Papathanasopoulos has received research support (not related to this project) by Biogen Idec, Novartis, TEVA, Merck Serono, Genesis Pharma Dr. Athanasios Tsivgoulis reports no sources of funding Dr. Kilidireas reports no sources of funding Dr. Voumvourakis has received research support (not related to this project) by Teva Pharmaceutical Hellas, Merck Hellas, Genesis Pharma and Novartis Hellas. P575 Risk of early relapse following switch to oral agents for multiple sclerosis

T. Spelman1, L. Mekhael2, T. Burke2, H. Butzkueven1, S. Hodgkinson3, E. Havrdova4, D. Horakova4, P. Duquette5, G. Izquierdo6, F. Grand’Maison7, P. Grammond8, M. Barnett9, J. Lechner-Scott10, R. Alroughani11, M. Trojano12, A. Lugaresi13, F. Granella14, E. Pucci15, S. Vucic2, MSBase Study Group 1Department of Neurology, Royal Melbourne Hospital, Parkville, VIC, 2Westmead Hospital, 3Liverpool Hospital, Sydney, NSW, Australia, 4Charles University, Prague, Czech Republic, 5Hôpital Notre Dame, Montreal, QC, Canada, 6Hospital Universitario Virgen Macarena, Sevilla, Spain, 7Neuro Rive-Sud, Hôpital Charles LeMoyne, Montreal, 8Center de Réadaptation Déficience Physique Chaudière-Appalache, Levis, QC, Canada, 9Brain and Mind Research Institute, Sydney, 10John Hunter Hospital, Newcastle, NSW, Australia, 11Amiri Hospital, Kuwait City, Kuwait, 12Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, 13Department of Neuroscience, Imaging and Clinical Sciences, MS Center, University ‘G. d’Annunzio’, Chieti, 14University of Parma, Parma, 15Neurology Unit, ASUR Marche - AV3, Macerata, Italy Objective: Early relapse in long-term stable patients switching from IFNβ/GA or natalizumab to oral therapy are unknown. The objective of this study was to compare early relapse and progression in MS patients switching to oral therapy following a period of stable disease on interferon-beta, glatiramer acetate or natalizumab (IFNβ/GA/NAT), relative to a propensity-matched comparator of patients remaining on IFNβ/GA/NAT. Methods: The MSBase study is a global, longitudinal registry for Multiple Sclerosis. Time to first 6-month relapse in previously stable MS patients switching from platform injectables or natalizumab (“switchers”) to oral agents were compared with propensity matched patients remaining on IFNβ/GA/natalizumab (“stayers”) using a Cox Marginal Model. Results: Five-hundred and seventy-five switchers were successfully matched to 575 stayers on a 1:1 basis. There was no difference in the proportion of patients recording at least 1 relapse in the first 1-6 months by treatment arm (7.5% of switchers; 5.9% stayers, p=0.288). The mean Annualised Relapse Rate (p= 0.1234) and the rate of first 6-month relapse by treatment arm (HR 1.27, 95% CI 0.81, 2.01) were also comparable. There was no difference in the rate of disability progression by treatment arm (HR 2.40, 95% CI 0.84-6.81). Interpretation: This is the first study to compare early relapse probability in the period immediately following switch to oral treatment in a population previously stable on treatment. There was no evidence of rebound disease within the first 6 months of switching to oral therapy. Disclosure Tim Spelman received honoraria for consultancy, funding for travel and compensation for serving on scientific advisory boards from Biogen Idec Inc; speaker honoraria from Novartis. Linda Mekhael did not declare any competing interests. Therese Burke received compensation for serving on scientific advisory boards and as a consultant for Biogen Idec and Bayer; speaker honoraria from Merck Serono Australia, Genzyme and Biogen Idec and travel support from Biogen Idec Australia and Novartis Australia .


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Poster Session I, 21(S11) Helmut Butzkueven received compensation for serving on scientific advisory boards and as a consultant for Biogen Idec and Novartis; speaker honoraria from Biogen Idec Australia, Merck Serono Australia, and Novartis Australia; travel support from Biogen Idec Australia and Merck Serono Australia; research support from CASS Foundation (Australia), Merck Serono Australia, the Royal Melbourne Hospital Friends of the Neurosciences Foundation, and the University of Melbourne. Suzanne Hodgkinson did not declare any competing interests. Eva Havrdova received speaker honoraria and consultant fees from Biogen Idec, Merck Serono, Novartis, Genzyme and Teva, as well as support for research activities from Biogen Idec and Merck Serono. Dana Horakova received speaker honoraria and consultant fees from Biogen Idec, Merck Serono, Novartis, Genzyme and Teva, as well as support for research activities from Biogen Idec and Merck Serono. Pierre Duquette has received honoraria for organising CME events and has obtained funding to attend meetings from Biogen Idec, EMD Serono, TEVA Neuroscience, Novartis, and Genzyme, has received funding for investigator-initiated trials with Biogen Idec, EMD Serono and Novartis, and has received peer-review funding from CIHR and from the MS Society of Canada. Guillermo Izquierdo received consulting fees from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi, and Teva. Francois Grand´Maison received an honorarium for organizing a CME event for Biogen Idec in 2013 and received consultation fees from Biogen Idec as well as from Novartis and Genzyme in 2013 and 2014. Pierre Grammond is a Novartis, Teva-neuroscience, Biogen Idec advisory board member, consultant for Merck Serono, received payments for lectures by Merck Serono, Teva-Neuroscience and Canadian Multiple sclerosis society, and received grants for travel from Teva-Neuroscience and Novartis. Michael Barnett has received honoraria for participation in advisory boards and travel sponsorship from Novartis, BioCSL, Genzyme and Biogen Idec Jeannette Lechner-Scott has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment and also clinic support from Bayer Health Care, Biogen Idec, CSL, Genzyme Sanofi, Merck Serono and Novartis. Raed Alroughani received honororia from Biologix, Bayer, Merck Sorono, GSK and Novartis, and served on advisory board for Biologix, Novartis and Merck Sorono Maria Trojano received honoraria for consultancy and/or speaking from Biogen Idec, Genzyme-Sanofi, Merck Serono, Novartis, and Roche; research grants from Biogen Idec, Merck Serono, Novartis, and Teva. Alessandra Lugaresi is a Bayer Schering, Biogen Idec, Genzyme, Merck Serono Advisory Board Member. She received travel grants and honoraria from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi and Teva, research grants from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi and Teva, travel and research grants from the Associazione Italiana Sclerosi Multipla. Franco Granella has served on scientific advisory boards for Biogen Idec, Novartis and Sanofi Aventis and has received funding for travel and speaker honoraria from Biogen Idec, Merck Serono, and Almirall.

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Eugenio Pucci served on scientific advisory boards for Genzyme, Novartis and Biogen-Idec; he has received honoraria and travel grants from Sanofi Aventis, Novartis, Biogen Idec, Merck Serono, Genzyme and Teva; he has received travel grants from Associazione Marchigiana Sclerosi Multipla e altre malattie neurologiche. Steve Vucic did not declare any competing interests. P576 The concept of no evidence of disease activity in multiple sclerosis after autologous hematopoietic stem cell transplantation - assessing outcome parameters across trials A. Wundes1, L.M. Griffith2,3,4, G.E. Georges5, B.A. McLaughlin5, C.E. Kane5, G. Von Geldern1, K.R. Maravilla1, J.D. Bowen6, G.H. Kraft1, R.A. Nash7 1University of Washington, Seattle, WA, 2Division of Allergy, Immunology and Transplantation (DAIT), 3National Institute of Allergy and Infectious Diseases (NIAID), 4National Institute of Health (NIH), Bethesda, MD, 5Fred Hutchinson Cancer Research Center, 6Swedish Neuroscience Institute, Seattle, 7Colorado Blood Cancer Institute, Denver, WA, United States Background: High dose immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) has been studied in patients with severe multiple sclerosis (MS) for 20 years. Despite differences in study design, overall the field has moved to target patients with insufficient response to standard therapy earlier in their disease and towards relapsing rather than progressive MS. Interpretation and comparison of outcomes for different AHSCT trials is impeded by the heterogeneous disease patterns treated and by the lack of agreement on optimal endpoints. Objective: To illustrate how different outcome parameters used in AHSCT trials in MS can affect the perceived efficacy of this treatment. Results: Outcome measures (primary endpoint, where specified) from 16 reports of AHSCT trials involving a total of 1,047 subjects were extracted from the literature. Outcome was assessed by changes in EDSS disability (n=9), MS relapses (n=1), MRI activity (n=3), by progression-free survival (n=4) and/or MS-disease activity-free survival (n=2) using various definitions (allowing for double counting). Only HALT-MS and one other clinical trial prospectively defined a composite endpoint encompassing EDSS progression, relapse and MRI changes as in no evidence of disease activity (NEDA), and mortality as the primary endpoint. Such an endpoint seems a particularly sensitive indicator identifying any type of MS disease activity. In the HALT-MS trial, 21% (5/24 patients) met composite endpoint at 3-year interim analysis. In contrast progression-free survival, the endpoint used most commonly in historic AHSCT studies, was 90.9% (22/24) and relapsefree survival was 87% (21/24) for this same study. Unfortunately, with the exception of one single study, data available from the other reports did not allow NEDA to be applied to them. Conclusions: While multiple AHSCT trials report a favorable impact in otherwise poorly-controlled MS, the inability to compare treatment outcomes across trials hampers progress in this area of research. Selection of outcome parameters significantly alters the impression of efficacy. International consensus on relevant outcome parameters is needed. Collection of standardized outcome data in future trials according to NEDA would allow comparison across tri-


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als and thereby maximize the utility of data and the value of individual patient participation in clinical trials in AHCST for MS.

astrocytes. Collectively, our results suggest that exercise has beneficial effects on brain health and function in the marmoset EAE model.

Disclosure A Wundes, GE Georges, JD Bowen, GH Kraft, RA Nash are investigators, BA McLaughlin and CE Kane members of the study team and LM Griffith the NIAID Medical Officer and Medical Monitor for the HALT-MS clinical trial, which is sponsored by DAIT, NIAID, NIH and conducted by the ITN (ITN grant number: N01 AI015416). There are no other potential conflicts of those authors pertaining to this abstract. G Von Geldern and KR Maravilla: nothing to disclose.

Disclosure

Neuroprotection

Kimberley A Phillips: Southwest National Primate Research Center (NIH grant P51 OD011133); no conflict of interest is reported. Marjorie K Hambright: Nothing to disclose. Kelly Hewes: Nothing to disclose. Brian M Schilder: Nothing to disclose. Anwar Jagessar: Nothing to disclose. Bert ´t Hart: Biomedical Primate Research Centre; no conflict of interest is reported. Suzette D Tardif: Nothing to disclose.

P577 Effects of exercise on disease progression and cognition in the marmoset EAE model K.A. Phillips1,2, M.K. Hambright3, K. Hewes1, B.M. Schilder4, A. Jagessar5, B. ‘t Hart5, S.D. Tardif2 1Psychology, Trinity University, 2Southwest National Primate Research Center, San Antonio, TX, 3College of Coastal Georgia, Brunswick, GA, 4George Washington University, Washington, DC, United States, 5Biomedical Primate Research Centre, Rijswijk, The Netherlands

P578 Siponimod - direct CNS effects of an immunomodulatory drug? P. Ehling1,2, M. Cerina1, V. Narayanan1, A.M. Herrmann1, S. Pankratz1, S. Bock1, K. Göbel1, A. Schubart3, H. Wiendl1, S.G. Meuth1,2 1Neurology Clinic, 2Institute of Physiology I, Neuropathophysiology, University Hospital Muenster, Muenster, Germany, 3Novartis Pharma AG, Basel, Switzerland

A growing body of evidence indicates physical activity is beneficial for brain health and function. Aerobic exercise promotes adult neurogenesis and neurotrophic factor expressions, has a neuroprotective effect against volumetric loss of the hippocampus, and may buffer cognitive impairment associated with aging and disease. We investigated the effects of regular, moderate exercise on disease onset, spatial memory and brain health in the experimental autoimmune encephalomyelitis (EAE) marmoset model of multiple sclerosis. Twelve adult male marmosets were randomly assigned to one of four experimental conditions: a) EAE induced by myelin oligodendrocyte glycoprotein residues 34 - 56 (pMOG) and exercise (n = 4); b) EAE induced by pMOG and no exercise (n = 4); placebo and exercise (n = 2); or placebo and no exercise (n = 2). We assessed cognitive dysfunction using the radial arm maze (RAM) spatial memory task and tested for associations with brain health, which we assessed through the quantification of glial fibrillary acidic protein (GFAP) in serum and prefrontal cortex samples. Baseline measures included blood draws, training on RAM, and initial exercise protocol training. Over the course of 10 weeks, subjects were tested weekly on RAM. Assessment of clinical symptoms occurred daily. End of project measures included a blood draw and extraction of the brain. EAE marmosets that exercised showed a delayed onset of clinical symptoms (M = 53.5 ± 6.4 days versus M = 37.5 ± 9.1 days) and a reduction in errors in the spatial memory task (M = 4.75 errors versus M = 12.38 errors) compared to EAE marmosets that did not exercise. Serum GFAP concentrations were reduced and GFAP concentration in the prefrontal cortex was increased in EAE subjects who exercised. As the release of GFAP from brain tissue into the blood stream is an indicator of the loss of astrocytic structural integrity, the GFAP results indicate improved brain health via less degradation of

Background: Siponimod (BAF312) is a selective sphingosine 1-phosphate receptor 1, 5 (S1P1/5) modulator currently under clinical development for the treatment of secondary progressive multiple sclerosis. In the immune system siponimod has shown to inhibit lymphocyte egress thereby reducing pathological immune cell invasion into the brain. Objective: To test the hypothesis that besides its immunomodulatory effect siponimod exerts a non-immunological, direct effect in the central nervous system. Methods: We stereotactically induced lesions targeted to either white or grey matter regions by injection of proinflammatory cytokines in mice that were immunized with myelin oligodendrocyte glycoprotein 10 days earlier (focal experimental autoimmune encephalomyelitis, EAE). To allow distinction between peripheral and central drug effects, siponimod was administered either systemically (3 mg/kg p.o. per day) or directly to the brain lesion site via implantable osmotic pumps and brain infusion cannulae (1 µg/ day). Behavioural, histological and flow cytometric analyses were performed on both 2 and 5 days after focal EAE induction. Results: Siponimod induced reduction of absolute lymphocyte counts and less severe EAE symptoms in systemically treated mice. Flow cytometry revealed reduced immune cell infiltrates at both grey and white matter lesions compared to sham-treated controls. After systemic siponimod treatment locomotor activity was slightly increased in the open field arena 2 days and 5 days after focal EAE induction compared to vehicle-treated controls. In the rotarod setup, treated mice with white matter lesions revealed less locomotor deficits 5 days after focal EAE induction. In preliminary experiments with direct drug application to the brain lesion via osmotic pumps, lymphocyte counts in peripheral blood and lymph nodes were similar between treated and untreated mice.


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Poster Session I, 21(S11) Conclusion: Systemic siponimod ameliorates the EAE disease course by inhibiting lymphocyte egress from lymphoid organs. Drug application directly to the brain lesion site does not affect peripheral immune cell counts. This opens up the opportunity for investigations concerning central drug effects. Disclosure This work is supported by Novartis Pharma AG (Basel, Switzerland). PE has received further honoraria for lecturing, travel expenses for attending meetings and financial research support from Merck Serono and Novartis. MC has received financial research support from Novartis and Biogen Idec. VN declares no conflict of interest. AMH declares no conflict of interest. SP declares no conflict of interest. SB declares no conflict of interest. KG has received honoraria for lecturing and travel expenses for attending meetings and has received financial research support from Biogen Idec, Merck Serono, Novartis and Teva. HW received honoraria for serving on Scientific Advisory Boards, for lecturing and travel expenses from Bayer Healthcare, Biogen Idec, CSL Behring, EMD Serono, Fresenius Medical Care, Sanofi- Genzyme, Omniamed, Merck Serono and Novartis. AS is an employee of Novartis Institutes of BioMedical Research, Novartis Pharma AG SGM has received honoraria for lecturing and travel expenses for attending meetings and has received financial research support from Bayer Health Care, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, MSD, Novartis, Novo Nordisk, Roche, SanofiAventis and Teva.

P579 Melanocortin 4 receptors on oligodendrocytes and oligodendrocyte precursors signal ACTH protection from in vitro death induced by mechanisms involved in cell damage in multiple sclerosis R.P. Lisak, L. Nedelkoska, J.A. Benjamins Neurology, Wayne State University, Detroit, MI, United States Objective: Determine if melanocortin 4 receptors (MC4R) signal ACTH protection of oligodendrocytes (OL) and OL precursors (OPC) in vitro from apoptosis (staurosporine), or cell death induced by excitotoxicity (glutamate), reactive oxygen species (ROS from H2O2) and an inflammatory mediator (quinolinic acid, QA, from indoleamine metabolism). Background: ACTH, a melanocortin (MC) peptide used to treat multiple sclerosis (MS) relapses, is believed to act by stimulating corticosteroid (CS) production by the adrenals via MC2R. ACTH may exert a therapeutic effect independent of CS by stimulating other MCR, including MC4R. MCR are distributed throughout the organism including in the brain. We reported that ACTH 1-39 protects OL in vitro from cell death induced by mechanisms likely involved in OL damage in MS. Protection appeared to involve direct protection of OL, which we reported for the first time, along with OL expression of MC4R; ACTH also protected OPC (Benjamins et al. 2013, 2014). We investigated whether signaling

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through MC4R is involved in protection from different toxic stimuli. Methods: Glial cultures enriched for OL (88%) or OPC (75%) were prepared from neonatal rat brains, and incubated with: 1) THIQ (specific MC4R agonist); 2) HS104 (MC4R antagonist) + ACTH; 3) THIQ + inducer of OL/OPC death; 4) THIQ + ACTH + inducer of OL/OPC death; 5) HS104 + inducer of OL/OPC death; 6) HS104 + ACTH + inducer of OL /OPC death; 7) medium alone. Cell death was assessed by uptake of trypan blue. Results: As previously reported, ACTH inhibited OL and OPC death induced by staurosporine, glutamate, ROS and QA. THIQ, the MC4R agonist, mimicked ACTH protection for each toxic agent, and the MC4R antagonist HS104 blocked the ability of ACTH to protect OL and OPC from each of the agents tested. Conclusion: Current experiments confirm that ACTH protects OL and OPC from cell death in vitro induced by apoptosis, excitotoxicity, ROS and a mediator of inflammation. Blocking of ACTH protection by a MC4R antagonist and mimicking of ACTH protection by a MC4R agonist demonstrate that the MC4R on OL and OPC are functional and activate signaling pathways that protect against mechanisms involved in cell damage in MS, suggesting potential beneficial effects in neurologic diseases. Support: Investigator Initiated Research Award (RPL), Mallinckrodt Pharmaceuticals Autoimmune and Rare Diseases Division and the Parker Webber Chair in Neurology (DMC Foundation). Disclosure RP Lisak has received funding for research from Mallinckrodt Pharmaceuticals, Teva Pharmaceuticals, Novartis, Avanir, Acorda. He has been a consultant for Mallinckrodt and Syntimmune. He is a member of a speakers list (non-treatment talks only) for Teva and has served as an expert witness in patent cases for Teva and Acorda. Ms Nedelkoska has nothing to disclose. JA Benjamins has received funding for research from Mallinckrodt, Teva and Avanir. P580 Sodium channel blockade with phenytoin has a neuroprotective effect on the ganglion cell complex after acute optic neuritis R. Raftopoulos1, A. Rangarajan2, C.-L. Chen3, S. Hickman4, A. Toosy5, C.A. Wheeler-Kingshott5, D. Altmann5, S. Malik5, D. Paling5, M. Yiannakas5, K. Schmierer6, B. Sharrack4, R. Sheridan5, G. Giovannoni7, L. Balcer8, D. Miller5, H. Ishikawa9, R. Kapoor5 1Institute of Neurology, University College London, London, United Kingdom, 2Pittsburgh Schools of Medicine and Engineering Directorate, Ocular Imaging Center, UPMC Eye Center (PA), 3University of Pittsburgh, Pittsburgh, PA, United States, 4Sheffields Teaching Hospital NHS Foundation Trust, Sheffield, 5Institute of Neurology. University College London, 6Blizard Institute, Centre for Neuroscience and Trauma, Barts and the London School of Medicine and Dentistry and The Institute of, 7Blizard Institute, Centre for Neuroscience and Trauma, Barts and the London School of Medicine and Dentistry, London, United Kingdom, 8Department of Neurology, NYU Langone Medical Center, New York, NY, 9University of


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Pittsburgh Schools of Medicine and Engineering Director, Ocular Imaging Center, Pittsburgh, PA, United States Background: We reported recently in a phase 2 trial that sodium channel blockade with phenytoin is neuroprotective in acute optic neuritis (AON). The primary outcome measurements were the thickness of the peripapillary retinal nerve fibre layer (RNFL) and macular volume (MV), measured using optical coherence tomography (OCT). Objective: We now seek to determine whether this neuroprotective effect is selective for particular anatomical layers of the retina. Methods: Patients with AON were randomized within 2 weeks of symptom onset to receive phenytoin or placebo for 3 months. Spectral domain fast macular and papillomacular bundle (PMB) OCT scans were performed at baseline and after 6 months. Masked automated retinal layer segmentation was performed to obtain average thickness measures of RNFL, ganglion cell and inner plexiform layer (GC/IPL), and the composite ganglion cell complex (GCC = RNFL + GC/IPL). Active - placebo differences in mean 6 month affected eye RNFL, GC/IPL and GCC were calculated from macular (n=60) and PMB (n=48) scans, adjusted for the corresponding baseline measurements in the unaffected eye. Results: At baseline, the mean thicknesses of the RNFL, GC/IPL and GCC were similar in the active and placebo groups in the macula and PMB. In the intention to treat comparison mean adjusted affected eye macular RNFL thickness at 6 months was 4.67 um greater in the active group (p= 0.01, a 42 % treatment effect). Mean adjusted macular GCC thickness was 5.63 um greater in the active group (p=0.02, a 28 % treatment effect). Treatment had no significant effect on macular GC/IPL when measured alone. In the PMB, mean adjusted RNFL thickness was 2.49 um greater in the active group at 6 months, mean GC/IPL thickness 2.79 um greater, and mean GCC thickness 5.41 um greater. However, these differences did not reach statistical significance. Conclusion: In addition to its neuroprotective effect on the peripapillary RNFL, these findings suggest that sodium channel blockade with phenytoin also appears to prevent degeneration of the macular ganglion cell complex after AON. Disclosure This trial was spnsored by grants from the National MS Society and the MS Society of Great Britain and Northern Ireland, UCL, UCLH Biomedical research centre and Novartis RE Raftopoulos has nothing to disclose A Rangarjan has nothing to disclose CL Chen has nothing to disclose S Hickman has nothing to disclose A Toosy has nothing to disclose CA Wheeler-Kingshott receives research funding from EPSRC, UK MS Society, Horizon2020, Biogen Idec, Novartis, Wings for Life. D Altmann partially funded by the Multiple Sclerosis Society of Great Britain and Northern Ireland S Malik has nothing to disclose D Paling has nothing to disclose M Yiannakas has nothing to disclose

K Schmierer is PI on trials sponsored by Novartis and Roche. He has received speaking honoraria from, and served on advisory boards for, Novartis and Merck-Serono. KS is in receipt of a HEFCE Clinical Senior Lectureship and grant support from Barts and The London Charity, the US National MS Society and Novartis. B Sharrack receives research funding from UK MS Society, Biogen Idec, Merck Serono and Novartis. R Sheridan has nothing to disclose G Giovannoni honoraria from Abbvie, Bayer HealthCare, Biogen, Canbex, FivePrime, Genzyme, GlaxoSmithKline, GW Pharma, Merck Serono, Novartis, Protein Discovery Laboratories, Roche, Synthon, Teva Neuroscience, UCB, and Vertex; research grant support from Biogen, Ironwood, Merck Serono, Merz, and Novartis; compensation from Elsevier as co−chief editor of MS and Related Disorders. L Balcer consulting for Biogen and Genzyme; clinical trial advisory board for Biogen. David Miller received honoraria through payments to my employer, UCL Institute of Neurology, for Advisory Committee and/or Consultancy advice in multiple sclerosis studies from Biogen Idec, GlaxoSmithKline, Novartis, Merck, Chugai, Mitsubishi Pharma Europe and Bayer Schering Pharma. I have also received compensation through payments to my employer for performing central MRI analysis of multiple sclerosis trials from GlaxoSmithKline, Biogen Idec, Novartis, Apitope and Merck. The Queen Square MS Centre at UCL Institute of Neurology is supported by the UK MS Society and UCL-UCLH Biomedical Research Centre. H Ishikawa has nothing to disclose Raju Kapoor has received compensation for consultancies, lectures, participation in advisory boards and support for travel to medical meetings from Biogen, Genzyme, Karo Bio, Novartis, Teva and Roche P581 Fingolimod reduces deep grey matter and regional volume loss in the brain of RRMS patients: a post-hoc analysis of FREEDOMS and FREEDOMS II data T. Sprenger1,2,3, L. Gaetano2,3, E.-W. Radue2, N. Mueller-Lenke2, D.A. Häring4, D. Tomic4, L. Kappos5 1Departments of Medicine, Clinical Research, and Biomedical Engineering, 2Medical Image Analysis Center, 3Department of Neurology, University Hospital Basel, 4Novartis Pharma AG, 5Neurology, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, Basel, Switzerland Background: Brain volume loss (BVL) and specifically grey matter (GM) involvement have been found to be strongly associated with MS-related disability and cognitive decline. While fingolimod has been shown to significantly reduce whole BVL vs. placebo and interferon beta-1a i.m. in relapsing-remitting MS (RRMS) patients, no data on specific effects on grey matter and various brain regions were available thus far.


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Poster Session I, 21(S11) Objective: To assess the effect of fingolimod vs. placebo on thalamus alone (THAL), cortical grey matter (cGM), deep grey matter (dGM = THAL + putamen + caudate nucleus + globus pallidus), white matter (WM), and ventricular volume (VV). Methods: This explorative post-hoc analysis used pooled data from FREEDOMS and FREEDOMS II trials (N=2355). Patients received either oral fingolimod (F0.5mg; N=783/F1.25mg; N=799) or placebo (N=773). Whole BV, cGM and WM were assessed by SIENAX, dGM and THAL by FIRST. Bilateral volumes of dGM, THAL, cGM, WM and VV were measured at BL, month 12 and 24. Percentage change from BL was summarised based on the respective normalized volume (to skull size) at each visit and analysed in a repeated measures model treating T2 volume at BL and number of Gd-T1 lesions at BL as continuous covariates, and treatment, study and visit as factors. Results: The sum of cGM, dGM and WM was in good agreement with the previously reported whole BV (r=93.8%, p< 0.001). Mean % changes from BL to Month 24 in placebo arm were: cGM=−1.77%, dGM=−2.14%, THAL =−1.53%, WM=−0.25%. Over the study period, smaller reductions were seen in fingolimod arms in dGM (F0.5mg=−1.83%; F1.25mg=−1.57%; both p< 0.05 vs. placebo) and THAL (F0.5mg=−1.13%; F1.25mg=−0.77%; p< 0.01 vs placebo), reductions of cGM were numerically smaller vs. placebo, but not significant. A small increase in WM was noted in fingolimod treated patients (p< 0.001, both doses vs. placebo). VV enlarged significantly less in fingolimod arms (F0.5mg: 4.13%; F1.25mg: 3.67%; placebo: 6.97%; p< 0.001 both doses). High T2 lesion volume at BL predicted cGM, dGM and THAL volume loss (all, p< 0.0001), but not WM loss, while BL Gd+ lesions were a weaker but more general predictor of all aspects of BVL. Conclusions: These results confirm GM loss as a main driver of BVL in RRMS. A history of focal damage, as indicated by a high BL T2 lesion volume was predictive of on-study GM volume loss. Fingolimod treatment significantly reduced volume loss in dGM (including THAL) as well as WM vs. placebo. Disclosure Funding source: This study is supported by Novartis Pharma AG, Basel, Switzerland. Till Sprengers’ institution (University Hospital Basel) received research support and payments that were used exclusively for research support for Prof. Sprenger´s consultation and speaking activities for Mitsubishi Pharma, Eli Lilly, Genzyme, Novartis, ATI, Actelion, Electrocore, Biogen Idec and Allergan. T Sprenger has received grants from the Swiss MS Society, Swiss National Research Foundation, EFIC-Grünenthal and Novartis Pharmaceuticals Switzerland. Ernst-Wilhelm Radue has received research support from: Biogen Idec, Merck-Serono, Novartis and Actelion. Ludwig Kappos’ institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: steering committee/consulting fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; royalties from Neurostatus Systems GmbH; grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis,

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Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society, and the Swiss National Research Foundation. Dieter A. Häring and Davorka Tomic are employees of Novartis Pharma AG Basel, Switzerland. Laura Gaetano and Nicole Mueller-Lenke have nothing to disclose.

Neurorepair P582 ABT-555, a human anti-RGMa monoclonal antibody promotes axon regeneration and neuroprotection in multiple sclerosis models B.K. Mueller1, Y. Cui1, L. Huang2, S. Greenberg3, H. Schoemaker1 1AbbVie Inc., Ludwigshafen, Germany, 2AbbVie Biotherapeutics, Worcester, MA, 3AbbVie Biotherapeutics, Redwood City, CA, United States Summary: Repulsive Guidance Molecule a (RGMa) is a potent inhibitor of axon regeneration and remyelination and is involved in neuronal cell death. In addition RGMa plays an important role in neuroinflammation. Targeting RGMa by the selective antibody ABT-555 promotes axon regeneration, enhances neuroprotection, stimulates remyelination and decreases microglial inflammation. Objective: To present the preclinical data of ABT-555 in several different MS-related animal models. Methods: Anti-RGMa antibodies, including ABT-555, were evaluated in a rat spinal cord targeted experimental autoimmune encephalitis (tEAE) model induced by myelin oligodendrocyte glycoprotein (MOG)-sensitization followed by local injection of tumor necrosis factor-beta (TNF)-b and gamma interferon (IFN)-g; in an optic neuritis model using the same protocol of MOG sensitization; and in a mouse MOG disseminated EAE model (dEAE) immunized with MOG in complete Freund´s adjuvant and boosted with pertussis toxin. Results: Administration of ABT-555 accelerated functional recovery in both EAE models, enhanced axonal regeneration within inflammatory lesions, and stimulated remyelination. Treatment with RGMa antibodies also decreased the inflammatory signal by CD68+ cells within the spinal cord. ABT-555 stimulated regenerative axon growth within the inflammatory optic nerve lesion in a dose dependent manner on immunohistochemistry (IHC) and reduced degeneration of the retinal nerve fiber layer measured using optical coherence tomography (OCT), proving its potent neuroprotective efficacy . Conclusions: The specific targeting of RGMa by ABT-555 in several animal models of autoimmune inflammatory disease of the CNS resulted in immune modulation and neuroprotection and neuroregeneration and this new therapeutic strategy may provide novel benefit in patients with MS and warrants further study. The early clinical evaluation of ABT-555 in healthy volunteers and MS patients is currently underway. Disclosure All authors are employees of AbbVie. The design, study conduct, and financial support for this research was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.


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P583 A thyromimetic drug accelerates remyelination in vivo: a small molecule approach to promoting repair in multiple sclerosis D. Bourdette, M. Hartley, P. Chaudhary, G. Marracci, T. Scanlan Oregon Health & Science University, Portland, OR, United States Background and goal: Chronic demyelination contributes to permanent disability (MS) and progressive axonal degeneration in multiple sclerosis (MS). The thyroid hormone, triiodothyronine (T3), accelerates differentiation of oligodendrocyte precursor cells (OPC) into mature oligodendrocytes (OL). T3 stimulates remyelination in the cuprizone model and experimental autoimmune encephalomyelitis. However, chronic T3 therapy is not a practical treatment for MS because of the adverse effects on heart, bone, and skeletal muscle of hyperthyroidism. Sobetirome is a thyromimetic drug devoid of cardiac effects that has been studied in phase 1 trials for lowering cholesterol. We determined whether sobetirome could accelerate remyelination in the lysolecithin model to assess the potential of thyromimetics for the treatment of MS. Methods and results: We stereotactically injected lysolecithin (2%) into the corpus callosum of C57BL/6 mice. Five days later we randomized mice for histology or daily injections of vehicle, T3 (0.4 mg/kg) or sobetirome (5 mg/kg). Treated mice were processed for histology 10, 12 and 15 days after lysolecithin injection. Serial sections through the lesion were stained for myelin with Black Gold. Sections were evaluated blinded to treatment. Area of demyelination in each section was determined and a volume of demyelination determined. At day 5 mean volume of the demyelination at the injection site was 0.062mm^3. In mice receiving vehicle mean of volume of demyelination rose on day 10 and 12 to 0.067 and 0.082 and fell to 0.022 on day 15. In mice receiving T3, volume of demyelination at days 10, 12 and 15 were 0.070, 0.019 and 0.016, respectively. In mice receiving sobetirome, the volume of demyelination on days 10, 12 and 15 were 0.074, 0.055 and 0.028, respectively. The volumes of demyelination on day 12 for mice receiving T3 and sobetirome versus vehicle were significantly lower (p=0.0214). The effect of treatment on the cell populations in the lesion (OPCs, OLs, and microglia) analyzed by immunofluorescence and the presence of thinly remyelinated axons measured by electron microscopy will be presented. Conclusion: This is the first demonstration of the ability of a thyromimetic drug to accelerate remyelination in vivo. Thyromimetics represent a class of small molecule drugs that might stimulate remyelination in MS with a better safety profile than thyroid hormone. Disclosure Dr. Bourdette is a co-inventor of a licensed pending patent application claiming the use of sobetirome for the treatment of multiple sclerosis and received research funding from the Laura Fund for Innovation in MS Research. Dr. Hartley is a co-inventor of a licensed pending patent application claiming the use of sobetirome for the treatment of multiple sclerosis. Dr. Chaudhary is a co-inventor of a licensed pending patent application claiming the use of sobetirome for the treatment of multiple sclerosis.

Dr. Marracci is a co-inventor of a licensed pending patent application claiming the use of sobetirome for the treatment of multiple sclerosis. Dr. Scanlan is a co-inventor of a licensed pending patent application claiming the use of sobetirome for the treatment of multiple sclerosis and received research funding from the Laura Fund for Innovation in MS Research. P584 Overexpression of Olig2 promotes differentiation of neural stem cells into oligodendrocytes only in non-inflammatory conditions A.M. Malvandi, L. Ottoboni, A. Merlini, E. Butti, G. Martino San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Neuroimmunology Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, Milan, Italy Stem cell-based regenerative therapies represent a promising alternative strategy for multiple sclerosis (MS) patients and in particular for those experiencing the progressive phase of the disease. However, the complexity of central nervous system microenvironment in MS renders this strategy not easy to approach. As a matter of fact, the inflammatory reaction occurring in MS halts transplanted neural stem/precursor cells (NPCs) to differentiate as they remain in an undifferentiated status where they are still therapeutically efficacious but just because are capable to buffer the ongoing inflammation via the release of neuroprotective molecules, the so called “bystander effect”. In this study we aimed at examining whether forced expression of pro-myelinating genes into NPCs could have effects on their differentiation capacity towards oligodendrocytes in both physiological and inflammatory conditions. Our preliminary results showed that, in physiological condition, over expression of Olig2 gene in a primary adult subventricular zone (SVZ) derived murine NPC line (NPC-Olig2) could significantly promote the differentiation into O4+ oligodendrocytes (> 60%) in comparison to non-transfected ones (11.1%), which differentiated mainly in GFAP+ cells (> 50%), while the frequency of GFAP+ cells in NPC-Olig2 was < 25%. Moreover, in presence of epigenetic inducers of oligodendrocyte differentiation such as triiodothyronine (T3), and ErbB inhibitor, NPC-Olig2 cells significantly differentiated into O4+ cells and lowered GFAP+ as well, when compared to NPCs. To mimic the inflammatory condition, we evaluated NPC differentiation in presence of TNFa (5 ng/ml)/ IFNg (5 ng/ml) cocktail in culture media. The results showed that in both NPC-Olig2 and NPC wild type cells most of the them maintain a bipolar-elongated shape and expressed the GFAP+ astrocytic marker (>85%). This occurred with T3 and ErbB inhibitors as well. In conclusion, our study clearly showed that over/forced expression of Olig2 in SVZ-derived NPCs is enough to commit them towards oligodendrogenesis but not in inflammatory condition when such cells tend to differentiate an astrocytic phenotype. Further in vivo studies will be necessary to confirm in vitro findings. Disclosure AMM supported by McDonald Fellowship from Multiple Sclerosis International Federation (MSIF.org). The authors has any potential conflict of interest to disclose.


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Poster Session I, 21(S11) P585 Diffusion tensor imaging effects of mesenchymal stem cell transplantation in multiple sclerosis D. Ontaneda, E. Offerman, M. Karafa, E. Fisher, J. Lin, K. Sakaie, P. Imrey, M. Phillips, M. Lowe, J. Cohen Cleveland Clinc, Cleveland, OH, United States Objective: To determine the effect of mesenchymal stem cell (MSC) transplantation on diffusion tensor imaging (DTI) measures from cortico-spinal tracts (CST), normal appearing white matter (NAWM), and lesional tissue in subjects with multiple sclerosis (MS). Background: MSCs have potent immunomodulatory, tissue-protective, and repair-promoting properties in vitro and in animal models. The effect of MSCs on brain tissue integrity in MS measured by DTI is unknown. Design and methods: 24 subjects with relapsing-remitting or secondary progressive MS, Expanded Disability Status Scale (EDSS) 3.0-6.5, clinical or radiographic disease activity in the prior 2 years, and optic nerve involvement were enrolled into a phase I study of autologous bone marrow-derived culture expanded MSCs. Seven MRI studies with DTI sequences were obtained, six at roughly monthly intervals from 3 months prior to 3 months post-MSC transplantation, and again at 6 months post-transplant. Probabilistic tractography was conducted in the CST using the ipsilateral cerebral peduncle and hand knob region as target and seed. Average values within the CST tract masks on the right and left were derived for fractional anisotropy (FA), mean diffusivity (MD), longitudinal diffusivity (LD) and transverse diffusivity (TD). Lesional tissue was identified using automated techniques from fluid attenuated inversion recovery sequences. Images were co-registered with DTI and metrics were derived. Linear mixed effect statistical models were used to compare CST and lesional tissue evolution prior to and after MSC transplantation. Results: Significant increases in slopes between the pre-transplant period and the initial 3 month post-transplant period were observed for MD (12.8 mm2/sec/30 days p=0.001), LD (18.3 x10-6 mm2/sec/30 days p=0.007) and TD (10.0 x10-6mm2/sec/30 days p=0.004) from lesional tissue. No significant difference was observed for lesional FA. Significant increases in the slopes of FA from the CST were observed on both right (3.9 x10-6mm2/sec/30 days p=0.04) and left (4.25 x10-6mm2/sec/30 days p=0.01) sides. No consistent (left and right) significant effects were observed for LD, TD, or MD in the CST. Changes from post-infusion month 3 to 6 will also be presented for all DTI metrics. Conclusions: MSC transplantation alters trends of tissue integrity measures in the brains of subjects with MS. Lesional tissue may be differentially affected over NAWM by MSC and may indicate possible restorative effects. Disclosure Funded (in part) by the NIH Cleveland CTSC KL2TR000440 to DO and Dept of Defense PRRP W81XWH-10-1-0271 to JC. Daniel Ontaneda: is supported by NIH KL2 award and has recieved consulting fees from Alkeremes, Acorda Therapeutics, Biogen Idec, Genzyme, Teva Neuroscience. Erik Offerman: has nothing to disclose Mathew Karafa: has nothing to disclose Elizabeth Fisher: is an employee of Biogen Idec

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Jian Lin: has nothing to disclose Peter Imrey: has nothing to disclose Ken Sakaie: has nothing to disclose Michael Phillips: has nothing to disclose Mark Lowe: has nothing to disclose Jeffrey Cohen: has received personal compensation for serving as a consultant from Novartis and research support through his institution from Genzyme, Novartis, Receptos, Synthon, and Teva.

Long-term treatment monitoring P586 Should brain atrophy be incorporated to patterns of response to therapy in MS? G.M.A. Figueira, R.C. Silveira, M.F. Xavier, F.F.A. Figueira Neurology, Hospital São Francisco, Rio de Janeiro, Brazil Background: Multiple sclerosis (MS) is an autoimmune disorder with expression over the central nervous system (CNS), leading to inflammation and degeneration. Markers of response to therapy in MS rely on inflammation. Although subtle and difficult to access on conventional imaging, axonal loss seems to be cornerstone for disability. Significant brain atrophy can be found in more than 50% of apparently stable treated patients, so it`s conceivable that an optimal response to therapy might target both inflammatory as well as degenerative component of disease. Corpus callosum (CC) is a major interhemispheric white matter bundle, easily accessible by imaging. Its atrophy, measured by corpus callosum index (CCI), proved to be valid and simple and showed good correlation to axonal loss in MS. So CCI proved potential for screening therapy response in MS. Design/method: A cohort of 217 RRMS patients diagnosed according McDonald 2001, on regular DMD treatment was prospectively followed for 5 years. They were stratified based on clinical and MRI data, as optimal, partial and non responders. MRI studies were performed at baseline and yearly, focus on callosal atrophy, measured by CCI using an orthogonal semi-automated linear system applied on a conventional mid-sagital T1W imaging. A control group was composed by data from 23 patients with non-inflammatory non-progressive neurologic disorders. Results: On follow up 136 patients (62.6%) had no relapses, 148 (68.2%) no EDSS progression, 93 (42.8%) no new/enlarging T2W lesions and 189 (87.1%) no Gd enhancing lesion on T1W sequences. On combination, 89 patients (41.0%) were classified as optimal responders to therapy while 77 (35.4%) were non responders. After the first year, CCI was able to distinguish these patients (p = 0.036; R2=0.73). Other 51 cases (23.5%) were considered as partial responders, with no EDSS progression. In this intermediate group CCI varied largely, from an almost stable pattern to significant atrophy. Conclusion: Corpus callosum atrophy seems to be a feasible and reliable marker for cell loss in MS. Our findings suggest that brain atrophy can be detected early in the course of disease and be added as a valuable marker to determine the response to therapy, a finding with a potential strategic impact. CCI proved to be a practical tool, able to detect morphologic changes shortly in the course of RRMS patients. Disclosure Gustavo Figueira: Nothing to disclose Raquel Silveira: Nothing to disclose


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Mariana Xavier: Nothing to disclose Fernando Figueira received personal compensation for lectures and scientific consulting from Biogen Idec, Genzyme, Merck Serono, Novartis and MedScape. P587 US patient perspectives on the multiple sclerosis treatment experience: results of a US web-based survey P. Wicks1, N.P. Thomas2, N. Kotowsky2, E. Cochin1, D. Hurley2, B. Musch2, L. Julian2 1PatientsLikeMe, Cambridge, MA, 2Genentech Inc., a Member of the Roche Group, South San Francisco, CA, United States Background: Patients with multiple sclerosis (MS) initiate, maintain and discontinue therapy for a variety of reasons. Objective: This study aimed to understand patient perspectives around factors that may influence these treatment decisions. Methods: Individuals with MS who were aged 18 and older and active participants in the “PatientsLikeMe” online health community completed a survey assessing factors for initiating and discontinuing available disease-modifying therapy (DMT, defined by FDA-approved MS DMTs in the US). Satisfaction with current DMT was evaluated using the Treatment Satisfaction Questionnaire for Medication (TSQM). Responses were reported for non-initiators, previous users and current users of DMT and by self-reported diagnosis of relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS). Results: A total of 943 patients (91%) completed the survey, 803 of whom self-reported a diagnosis of RRMS (n = 626) or SPMS (n = 177). Most respondents were female (78%), white (92%) and educated (96%, high school or higher). Among patients with either MS subtype, 65 (8%), 184 (23%) and 554 (69%) reported never initiating, previously using or currently using a DMT, respectively. Among those who have never used a DMT, a third of patients cited perceived side-effect burden and a preference for alternative therapies as primary reasons for not initiating treatment. Compared with SPMS patients, more RRMS patients cited mild disease (15% vs 4%), mode of administration (14% vs 6%), and not wanting to take medication (14% vs 8%) as reasons for not using DMTs. Previous users reported discontinuation of DMT due to side effects (57%) and perceived lack of efficacy (RRMS 16% vs SPMS 35%). Treatment satisfaction was mid to high among those on DMT, ranging from a TSQM mean score of 58.7 to 83.8, where general treatment satisfaction and perceived treatment effectiveness was higher in RRMS vs SPMS patients (83.8 vs 68.4). Conclusions: Patient treatment decisions are influenced by a variety of factors, including disease severity, side effects and treatment efficacy. Understanding patient perceptions and assumptions about treatment benefits and risks provides value by increasing the potential for improved patient engagement and movement towards patient-centered MS care. Disclosure Paul Wicks is an employee of PatientsLikeMe. Nina Parikh Thomas is an employee of Genentech Inc., a member of the Roche Group. Nirali Kotowsky is an employee of Genentech Inc., a member of the Roche Group.

Elisenda Cochin is an employee of PatientsLikeMe. Dana Hurley is an employee of Genentech Inc., a member of the Roche Group. Bruno Musch is an employee of Genentech Inc., a member of the Roche Group. Laura Julian is an employee of Genentech Inc., a member of the Roche Group. P588 Long-term use of glatiramer acetate in MS: possible predictors of the differences in treatment effect after 10-15 years of therapy A. Boyko, on behalf of Neurologists of MS Center Neurosurgery and Medical of the Pirogov’s Russian National Research Medical University, Moscow, Russian Federation The long-term prospective observations in DMT of MS are highly needed. In 2000, 205 active RRMS patients started DMT with glatiramer acetate (GA). At baseline all patients had active disease with 2.15 (0.06) annual relapse rate (ARR) and EDSS 1.5-5.0. 74 patients (74.3% female) received GA for at 10 years with positive results - mean ARR 0.14 (0.02) for 10 years and EDSS 2.53 (0.16) at 10th year of the observation. EDSS scores remained stable or showed minimal worsening (< 1.0) in 71.6%. These effects were independent on MS severity at the baseline. Later 5 patients were lost because of different reasons. 69 patients were observed at regular every 6-month visits for following 5 years (15 years total). Results: A significant increase in ARR and EDSS in 37 primary responders to GA was seen at 11-14 years of GA therapy with ARR 0.24-0.49 per year and EDSS progression up to 4.12 (0.23) at the 15-years time point (Limited Resporders - LR). The significant increase in EDSS in these patients was seen at 13-14 years of GA therapy. In 8 of these patients MS course changed to SPMS and GA was stopped. At the same time, in 32 patients (62.5% female) the MS course still remained stabile with mean ARR 0.07 (0.02) per year and EDSS 2.27 (0,14) at 15th year of GA therapy (Long-term Positive Responders - LTPR). The possible prognostic factors of LTPR are discussed. The only difference in demographic characteristics was slightly younger age of MS onset. At the same time, LR had significantly more frequent relapses during first 4-7 years of GA (mean 0.19-0.27 per year), than LTPR (0.090.13 per year). Thus, even a present of very few relapses during first 4-7 years of GA therapy (even in those proposed to be responders) could predict negative changes after 11-13 years of GA with increase in ARR, EDSS and SPMS. The total absence of relapses during first 4-7 years of DMT might predict positive outcome after 15 years of therapy. Disclosure Disclosure of conflict of interest and source of funding is mandatory. Alexey Boyko: received consulting/speaker fees from and advisory board for Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis, Nycomed, Sanofi-Aventis, and Teva. No grant or support for this study. P589 Long-term effect of disease-modifying drugs on disability progression in multiple sclerosis: a meta-analysis


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Poster Session I, 21(S11) A. Signori, M.P. Sormani University of Genova, Genova, Italy Background: In recent years the impact of disease-modifying drugs on long-term progression was assessed both in several observational studies and in randomized controlled trial (RCT) extensions. Objectives: To summarize the long-term impact of immunomodulatory drugs (Interferon-Beta (IFN-β) or Glatiramer Acetate (GA)) in relapsing-remitting (RR) multiple sclerosis (MS) patients. Methods: We systematically collected all published studies reporting the long-term efficacy of IFN-β or GA in RRMS patients. Treatment effect was assessed on two endpoints: the time to progression to a confirmed and sustained EDSS score of 6 and the time to progression to Secondary Progressive (SP) phase. A random effect model was used to pooling the effects of treatment on endpoints in terms of hazard-ratios (HR) with their 95% confidence interval (CI). Results: Nine studies, 8 observational and 1 RCT extension, with a total of 11261 RRMS patients, reported quantitative data on treatment effect for time to EDSS 6. The main treatment was IFN-β and only two studies had a small portion of patients treated with GA. A significant treatment effect in reducing progression to EDSS 6 resulted from the pooled estimate: HRpooled = 0.49 (95% CI: 0.34-0.69; p< 0.001). Five observational studies, involving a total of 3723 patients, reported quantitative information on time to SP. All studies reported a significant treatment effect on this outcome with an estimated pooled HR of 0.36 (95% CI: 0.29 - 0.44; p< 0.001). Conclusions: Treatment with immunomodulatory drugs seems to reduce long-term probability of disability progression. Additional well-designed observational studies could help to confirm these findings. Disclosure Alessio Signori: Nothing to disclose Maria Pia Sormani: Reports personal fees from Merck Serono, Biogen Idec, Teva, Actelion, Synthon, Allozyne, outside the submitted work. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

P590 Detection and management of immune thrombocytopenia in alemtuzumab-treated patients in the multiple sclerosis clinical development program A. Cuker1, D.L. Arnold2,3, J.A. Cohen4, A.J. Coles5, E.J. Fox6, H.-P. Hartung7, E. Havrdova8, K.W. Selmaj9, D.H. Margolin10, L. Kasten11, M.A. Panzara10, D.A.S. Compston5, on behalf of the CAMMS223, CARE-MS I and II Investigators 1University of Pennsylvania, Philadelphia, PA, United States, 2NeuroRx Research, 3Montréal Neurological Institute, McGill University, Montréal, QC, Canada, 4Cleveland Clinic, Cleveland, OH, United States, 5University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom, 6Central Texas Neurology Consultants, Round Rock, TX, United States, 7Heinrich-Heine University, Düsseldorf, Germany, 8First Medical Faculty, Charles University in Prague, Prague, Czech

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Republic, 9Medical University of Łódź, Łódź, Poland, 10Genzyme, a Sanofi company, 11PROMETRIKA, LLC, Cambridge, MA, United States Background: Alemtuzumab, approved in >40 countries for relapsing multiple sclerosis (MS), had superior efficacy compared with subcutaneous interferon beta-1a and a manageable, consistent safety profile across trials. Immune thrombocytopenia (ITP) was observed in approximately 2% of patients treated with alemtuzumab 12 or 24 mg in MS clinical trials in up to 12 years of follow-up. Goals: To summarise the ITP experience in alemtuzumab phase 2/3 studies and their extension. Methods: In phase 2 CAMMS223 (NCT00050778) and phase 3 CARE-MS (NCT00530348; NCT00548405) studies, patients with active relapsing-remitting MS who were either treatmentnaive or had an inadequate response (⩾1 relapse) to prior therapy received alemtuzumab at baseline and Month 12. Patients could enter an extension (NCT00930553) for ongoing follow-up and asneeded retreatment with alemtuzumab 12 mg after relapse or magnetic resonance imaging activity. Platelet counts were assessed monthly from treatment initiation to 48 months after the last alemtuzumab dose, and patients and physicians were educated about ITP signs and symptoms. Potential ITP cases were identified by reported adverse events and platelet-based criteria defined per the study protocol. Results: As of December 2014, 34 of 1486 (2.3%) alemtuzumabtreated patients developed ITP with no alternative plausible aetiology. All events occurred within 48 months of the last dose of alemtuzumab (range, 1-44). Apart from the fatal index case and 2 patients with ongoing ITP at last follow-up, all other patients had durable response to treatment for ITP, including 2 patients with sustained spontaneous resolution without treatment. Most patients recovered with first-line therapy (n=22; intravenous immunoglobulin, corticosteroids, and/or platelet transfusion), and 7 received second-line therapy (rituximab or splenectomy). All post-index cases were detected through the monitoring program prior to the development of serious haemorrhage. Compliance with monthly complete blood count monitoring was >96%. Relapse and disability outcomes were not impacted by ITP. Conclusion: In clinical trials, ITP occurred in 2.3% of alemtuzumab-treated patients. Onset of ITP fell within the recommended monitoring period from the first dose to 48 months after the last dose in all cases. Most patients recovered with first-line therapy. Monitoring and education programs continue to be effective in early detection and successful management of ITP. Disclosure Study supported by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. AC: Personal compensation for consulting, serving on a scientific advisory board, and/or speaking (Baxter, Bayer, Daiichi-Sankyo, and Genzyme), and research support (Stago). DLA: Compensation for serving as a speaker, consultant, and advisory board participant, and receiving research support (Acorda, Bayer, Biogen Idec, Canadian Institutes of Health Research, Eli Lilly, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, MedImmune, Merck Serono, MS Society of Canada, NeuroRxResearch, Novartis, OpexaTherapeutics, Receptos, Roche, Sanofi, and Teva); holds stock in NeuroRxResearch.


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JAC: Personal compensation for serving as a consultant or speaker (EMD Serono, Genentech, Innate Immunotherapeutics, and Vaccinex). AJC: Consulting fees, lecture fees, and institutional grant support (Genzyme). EJF: Consultancy fees, honoraria, travel, and research support (Bayer Healthcare, BiogenIdec, Eli Lilly, EMD Serono, Genzyme, Novartis, Ono, OpexaTherapeutics, Pfizer, Sanofi, and Teva). H-PH: Honoraria for consulting and speaking at symposia (Bayer Healthcare, BiogenIdec, CSL Behring, Genzyme, Merck Serono, Novartis, Octapharma, Roche, Teva, and Sanofi, with approval by the Rector of Heinrich Heine-University). EH: Honoraria and consulting fees (Bayer, GlaxoSmithKline, Genzyme, Biogen Idec, Sanofi-Aventis, Merck Serono, Roche, Teva, and Novartis); consulting services, speaking and serving on scientific advisory boards and research support (Czech Ministry of Education). KWS: Consulting fees (Biogen Idec, Genzyme, Novartis, and Roche); lecture fees (Bayer Healthcare Pharmaceuticals, Biogen Idec, Merck Serono, and Novartis), and financial compensation for scientific presentations (Genzyme). DHM: Employee of Genzyme. LK: Provides statistical support as a consultant for Genzyme. MAP: Employee of Genzyme. DASC: Consulting fees and grant support (Genzyme) and lecture fees (Bayer Schering Pharma) on behalf of the University of Cambridge; and personal remuneration for lecture fees (Genzyme) from July 2014. P591 Long-term safety and effectiveness of fingolimod: 7 year data from the LONGTERMS study J. Cohen1, L. Kappos2, K. Selmaj3, R. Gottschalk4, A. Pradhan4, Y. Chen4, N. Putzki5 1Cleveland Clinic, Neurological Institute, Cleveland, OH, United States, 2Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital, Basel, Switzerland, 3Department of Neurology, Medical University of Lodz, Lodz, Poland, 4Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States, 5Novartis Pharma AG, Basel, Switzerland Background: LONGTERMS is an open-label, single-arm, long-term extension study of phase 2/3/3b fingolimod trials in relapsing MS, studying long-term safety and effectiveness of fingolimod. Objective: Evaluate long-term safety and effectiveness in subpopulations of patients (pts) treated with fingolimod in phase 3/3b core/extension studies transitioning to LONGTERMS and estimate occurrence rate (OR) of serious infections in pts from LONGTERMS with sustained low absolute lymphocyte count (ALC). Methods: Safety analysis was based on LONGTERMS cohort on continuous fingolimod 0.5mg (LC; n=1655, median exposure: 3.9y) previously enrolled in three phase 3 trials plus their extensions, and core cohort (CC; n=1212, exposure: 1.6y) pooled from core phase 3 trials. Incidence rate ratios (IRRs; IR for LC/CC) were reported for any AEs, SAEs and AEs of special interest. In a separate analysis, infections of pts from LONGTERMS cohort

(N=3154) on continuous fingolimod 0.5mg and with sustained low ALC (< 0.4x109L for ⩾60% records; [N=1084]) were summarized by fingolimod exposure (>/⩽2y). OR ratio (OccRR; OccR for >2/⩽2y) of serious infections was calculated. Effectiveness analysis included evaluation of relapse and disability outcomes in 980 pts from FREEDOMS/FREEDOMS II (pooled FREEDOMS; median exposure: 6.4y) and 732 from TRANSFORMS (exposure: 6.9y) who received ⩾1 fingolimod dose in LONGTERMS. ARR (LS mean) and % of relapse free pts were assessed by treatment interval from fingolimod initiation up to data cut off. Kaplan-Meier (KM) estimates for pts not reaching EDSS score 4, 6, or 7 were evaluated. Data cut-off: Oct 2014. Results: IRRs (95% CI) for AEs and SAEs were 0.74 (0.69-0.80) and 0.72 (0.58-0.89), respectively. IRRs for AEs of special interest were < 1 except for reports of lymphopenia presumably due to blinding of lymphocyte counts >0.2x109L in CC. OccRR (>2/⩽2y; CI) of serious infections for pts with sustained low ALC was: 1.47 (0.75- 3.01). No increase of lymphopenia was reported in these pts. ARR remained low: M0-12 (pooled FREEDOMS, 0.16 and TRANSFORMS, 0.19) to M0-84 (0.10 and 0.12). Most pts remained relapse free (63% and 60%), and did not reach EDSS (KM estimates at Month (M) 60) ⩾4 (76% and 78%), ⩾6 (90% and 93%) and ⩾7 (98% and 99%). Conclusion: Long-term exposure of pts in this cohort did not raise new safety concerns and the overall low rate of serious infections was confirmed in pts with sustained low ALC. Clinical disease activity remained low for up for to 7y. Disclosure Funding source: This study is supported by Novartis Pharma AG, Basel, Switzerland. Jeffrey Cohen has received personal compensation for serving as a consultant from Novartis and research support through his institution from Genzyme, Novartis, Receptos, Synthon, and Teva. Ludwig Kappos’ institution (University Hospital Basel) has received in the last 3 years and used exclusively for research support: steering committee, advisory board, and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, Xenoport); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, Teva); support of educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva); royalties (Neurostatus Systems GmbH); grants (Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society, Swiss National Research Foundation). Krzysztof Selmaj has received compensation for serving as consultant or speaker or he or institution he works for has received research support from Novartis, Biogen Idec, Merck Serono, Roche, ONO Pharmaceuticals, Genzyme. Rebecca Gottschalk is an employee of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Ashish Pradhan is an employee of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Yu Chen is an employee of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Norman Putzki is an employee of Novartis Pharma AG


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Poster Session I, 21(S11) P592 Update - real life use of natalizumab and fingolimod in Austria: benefit-risk data from the Austrian multiple sclerosis treatment registry M. Guger1, C. Enzinger2, F. Leutmezer3, J. Kraus4,5, T. Berger6 1Department of Neurology and Psychiatry, General Hospital Linz, Linz, 2Department of Neurology, Medical University of Graz, Graz, 3Department of Neurology, Medical University of Vienna, Vienna, 4Research Institute of Neurointervention/ Department of Neurology, Paracelsus Medical University, Salzburg, 5Department of Neurology, Public Hospital Zell am See, Zell am See, 6Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria Background: High efficacy of Natalizumab and Fingolimod in the treatment of relapsing-remitting multiple sclerosis (MS) has been proven in randomized trials. However, such trials do not necessarily reflect real-life situations faced in everyday practice. The Austrian MS Treatment Registry (AMSTR), established in 2006 and extended in 2011 to maintain quality control and comply with reimbursement regulations of the Austrian sick funds, allows to obtain such data, to assess indications, the clinical profiles of the treated populations and to monitor safety in a real life setting. Methods: The baseline documentation within the AMSTR includes duration of disease, relapses within the last 12 months, EDSS, MRI activity and previous disease modifying therapies. Entry of follow up data (relapses, EDSS, adverse events) is required at 3 months intervals. In addition, changes in treatment are documented. The statistical values below indicate means (range), unless otherwise indicated. Results: As of May 11th 2015, the registry comprised 1309 patients treated with Natalizumab (70.3% female) and 495 patients started with Fingolimod (69.1% female). At baseline, their mean age was 35.4 (14-67) years in the Natalizumab and 38.8 (16-72) years in the Fingolimod group, with disease durations of 7.6 (0-40) years and 9.1 (0-37) years, respectively. The relapse rate in the year before start of respective drugs was 2.2 with Natalizumab and 1.7 with Fingolimod. For those treated for at least one year, the subsequent annualized relapse rates decreased to 0.35 (Natalizumab) and 0.34 (Fingolimod). At baseline, the EDSS was 3.1 (1-7) in the Natalizumab and 2.6 (1-6) in the Fingolimod treated group. EDSS stabilization or improvement was observed in 85% (Natalizumab) and 78% (Fingolimod). Conclusion: For more than 9 years, the AMSTR has proved valuable to measure quality of care and monitor treatment, providing neurologists with highly relevant information for clinical practice. Continuous optimization and extension of this registry represents an unanimous goal and necessity. Therefore, new treatment modules are currently being implemented and data monitoring and communication will be further improved. Disclosure The Austrian MS Treatment Registry is supported by unrestricted grants of Biogen-Idec Austria, Novartis Austria and Genzyme Austria. Michael Guger received support and honoraria for research, consultation, lectures and education from Allmirall, Bayer, Biogen Idec, Genzyme, Merck, Novartis, Octapharma, Sanofi Aventis and TEVA ratiopharm.

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Dr. Christian Enzinger has received funding for travel and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis Genzyme, and Teva Pharmaceutical Industries Ltd./sanofi-aventis; research support from Merck Serono, Biogen Idec., and Teva Pharmaceutical Industries Ltd./sanofi-aventis; serving on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Genzyme, Merck Serono, Novartis, and Teva Pharmaceutical Industries Ltd./sanofi-aventis; academic editor for PLOSOne. Fritz Leutmezer: Nothing additional to disclose Dr. Kraus received support for research, consultation, and education from Allmirall, Bayer, Biogen-Idec, Biotest, Genzyme, Medtronic, Merck-Serono, Novartis, Octapharma, SanofiAventis, TEVA ratiopharm. Thomas Berger has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for multiple sclerosis: Almirall, Bayer, Biogen Idec, Genzyme, Merck, Novartis, Octapharma, ratiopharm, Sanofi Aventis, TEVA. His institution has received financial support by unrestricted research grants (Biogen Idec, Bayer, Merck, Novartis, ratiopharm, Sanofi Aventis) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen Idec, Merck, Novartis, Octapharma, Sanofi Aventis, TEVA. P593 36 months PANGAEA: a 5-year non-interventional study of safety, efficacy and pharmacoeconomic data for fingolimod patients in daily clinical practice T. Ziemssen1, H. Albrecht2, J. Haas3, L. Klotz4, M. Lang5, C. Lassek6, S. Schmidt7, B. Tackenberg8, C. Cornelissen9 1Zentrum für klinische Neurowissenschaften, Universitätsklinikum Carl Gustav Carus, Dresden, 2Praxis für Neurologie, Munich, 3Zentrum für Multiple Sklerose, Jüdisches Krankenhaus Berlin, Berlin, 4Klinik für allgemeine Neurologie, Universitätsklinikum Münster, Münster, 5Nervenärztliche Gemeinschaftspraxis, Ulm, 6Neurologische Gemeinschaftspraxis Kassel und Vellmar, Kassel, 7Neurologische Gemeinschaftspraxis Schmidt, Neudecker & Viebahn GbR, Bonn, 8Klinik für Neurologie, Universitätsklinikum Gießen und Marburg, Marburg, 9Novartis Pharma GmbH, Nuremberg, Germany Background: Once daily oral fingolimod (FTY720; Gilenya®, Novartis Pharma AG), a sphingosine 1-phosphate receptor (S1PR) modulator, is approved for the treatment of relapsing remitting multiple sclerosis (RRMS) in over 80 countries and approximately 114,000[WB1] patients have been treated with fingolimod in both the clinical trial and post-marketing settings. Total patient exposure exceeds 195,000 patient years (Jan 2015). Objective: PANGAEA (Post-Authorization Non-interventional German sAfety study of GilEnyA in RRMS patients) is a non-interventional study, conducted in Germany, to investigate long-term safety, tolerability and effectiveness of fingolimod in daily clinical practice. Here we present data of the fourth interim-analysis. Methods: Recruitment into PANGAEA finished in December 2013. 4229 patients were enrolled. In this interim-analysis we present data from patients that are treated with fingolimod for up to 36 months.


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Results: The proportion of female patients was 71.6% and the mean age was 39.4 ± 10.0 years. The annualized relapse rate of all PANGAEA patients improved from 1.5 (baseline) to 0.43 (month 12), 0.41 (month 24) and 0.37 (month 36). Of all PANGAEA patients 67.9% in the first, 68.3% in the second and 70.1% in the third year were relapse free. The average EDSS of all PANGAEA patients was stable over 36 months at 3.0. In year 3 of PANGAEA 70.5% of the patients had no clinical disease activity measured by relapse activity and sustained EDSS progression. 10.8% of the patients discontinued the Fingolimod therapy in the first year (9.1% second year), 4,3% (2.3% second year) because of adverse events. 45.4% of the patients experienced no adverse events so far. Patients treatment satisfaction measured by the TSQM (Treatment Satisfaction Questionnaire for Medication)-9 Score, improved by 3 points over 24 months. Conclusions: The results of the 4th yearly interim analysis of PANGAEA support the positive safety and efficacy profile demonstrated in phase III clinical trials. PANGAEA is a valuable source of fingolimod data in daily clinical routine. Disclosure T. Ziemssen has received personal compensation for participating on advisory boards, trial steering committees and data and safety monitoring committees, as well as for scientific talks and project support from: Bayer HealthCare, Biogen Idec, Elan, Genzyme, Merck Serono, Novartis, Roche, Sanofi-Aventis, Synthon and Teva. H. Albrecht has received compensation from Biogen, Bayer, Genzyme, Merck Serono, Novartis, Sanofi Aventis, Teva. J. Haas has received compensation from Allergan, Biogen, Bayer,Novartis, Genzyme, Sanofi Aventis, Octapharma L. Klotz received compensation for serving on scientific advisory boards for Genzyme and Novartis. She received speaker honoraria and travel support from Novartis, Merck Serono and CSL Behring. She receives research support from Novartis and Biogen Idec. M. Lang has received travel grants, speaker’s honoraria, financial research support, consultancy fees from Teva, Merck Serono, Genzyme -Sanofi, Novartis, Bayer, Biogen Idec. C. Lassek has received travel grants, speaker’s honoraria, financial research support, consultancy fees from Teva, Merck Serono, Genzyme -Sanofi, Novartis, Bayer, Biogen Idec. S. Schmidt has received speaking honoraria, travel compensations and has served on advisory boards for BayerVital, Biogen, MerckSerono, Novartis and Teva. B. Tackenberg has received travel reimbursements, speaker and consulting honoraria from Bayer Healthcare, Biogen Idec, Genzyme, Merck Serono, Novartis Pharma, Sanofi-Aventis and Teva Pharma as well as research support from Bayer Healthcare, Biogen-Idec and Novartis Pharma. C. Cornelissen is an employee of the Novartis Pharma GmbH, Nuremberg, Germany P594 Treatment satisfaction with injectable disease-modifying therapy in patients with isolated demyelinating syndrome or relapsing-remitting multiple sclerosis O. Fernández1, M. Forner2, on behalf of the STICK Study Investigators

1Institute

of Clinical Neuroscience, Hospital Regional Universitario Carlos Haya, Malaga, 2Genzyme, a Sanofi company, Barcelona, Spain Background: There are now several disease-modifying therapy (DMT) options available to patients with relapsing-remitting MS in Spain. Patient-reported outcomes, such as treatment satisfaction, are of increasing importance to both healthcare professionals and patients when making decisions about therapy. Objective(s): To evaluate treatment satisfaction of patients with isolated demyelinating syndrome or relapsing-remitting MS (RRMS) treated with injectable DMTs. The STICK study will determine the factors that influence treatment satisfaction, and the impact of satisfaction on adherence, disease activity and associated costs. Methods: In this multicentre, observational study, treatment satisfaction and quality of life data were collected at a single visit at enrolment, and medical charts were reviewed retrospectively for clinical history. Treatment satisfaction and quality of life were assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM), the Multiple Sclerosis Quality of Life Questionnaire (MSQoL-54) and supplementary questions. Results: Patients (N=445) were treated with injectable DMTs for a mean of 4.8 years (standard deviation [SD], 3.9); mean Expanded Disability Status Scale score was 1.6 (SD, 1.5) and mean number of relapses in the past year was 0.3 (SD, 0.6). A total of 253 (56.9%) patients reported at least 1 adverse event (AE): 26.6% reported injection-site reactions and 21.1% reported flu-like symptoms. Mean TSQM domain scores were: 66.8/100 (SD, 18.7) for Effectiveness; 72.5/100 (SD, 23.9) for AEs; 62.2/100 (SD, 19.2) for Convenience; and 68.8/100 (SD, 18.6) for Satisfaction. Mean MSQoL-54 scores were 67.8/100 (SD, 16.8) for physical health and 69.0/100 (SD 13.7) for mental health. In total, 364 patients (81.8%) reported at least 1 drawback with their treatment, 243 (54.6%) for injection-site problems and 193 (43.4%) for AEs. Regarding the method of administration, 82.7% of patients who responded (n=381) would prefer a once-daily oral treatment. Conclusions: Despite low disease activity, most patients treated with injectable DMTs for isolated demyelinating syndrome or RRMS reported drawbacks with their therapy, due mostly to route of administration and AEs. The majority of the patients in this analysis would prefer an oral over an injectable treatment. Disclosure Study supported by Genzyme, a Sanofi company. OF: Honoraria as consultant in advisory boards, and as chairman or lecturer in meetings, and has also participated or participates at present in clinical trials and other research projects promoted by Actelion, Allergan, Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche and Teva. MF: Employee of Genzyme.

P595 Lessons from clinical practice: lymphocyte and leukocyte count on innovative MS treatments K. Thomas, M. Kaufmann, J. Eisele, T. Ziemssen Center of Neurological Science. University Hospital Carl Gustav Carus, Dresden, Germany


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Poster Session I, 21(S11) Background: With more emerging treatment options for patients with relapsing-remitting multiple sclerosis (MS), which have significant impact on peripheral immune function, the evaluation of lymphocyte subsets plays a more important role in initial treatment decision and management. In daily clinical routine the proportions and functions of peripheral blood lymphocytes are frequently analyzed. Design: We evaluated MS patients on different disease modifying therapies during treatment. We included each 90 patients on natalizumab (NAT), fingolimod (FTY), dimethyl fumarate (DMF) and 30 patients on teriflunomide (TER). For a treatment period up to 2 years proportions and functions of peripheral blood lymphocytes compared with clinical parameters including EDSS, disease activity and adverse events were analyzed. Results: Treatment with NAT showed a significant increase of cell populations. Leukocytes rose from 6,87 GPT/l to 8,45 GPT/l after 6 months (M) and up to 8,88 GPT/L after 12 M of treatment. Lymphocytes increased significantly from 1,84 GPT/L to 3,24 GPT/L after 6 M and to 3,31 GPT/L after 12 M. During FTY treatment, leukocyte count decreased significantly after 6 M from 7,31 GPT/L to 4,33 GPT/L and after 12 M to 4,30 GPT/L. Lymphocytes decreased on average from 2,07 GPT/L to 0,59 GPT/L in M 6 and to 0,50 after 12 M below a lower range of 1,5 GPT/L. Likewise a significant decrease of leucocytes and lymphocytes could be noticed during DMF treatment. After 6 M leukocyte count reduced from 6,52 GPT/L to 4,85 GPT/L and lymphocyte count from 1,86 GPT/L to 1,20 GPT/L. At M 12 of treatment, the leucocytes decreased to 4,73 GPT/L and lymphocytes to 0,96 GPT/L. In case of treatment with TER the number of leucocytes declined from 6,62 GPT/L to 5,64 GPT/L after 6 M and continuing to 5,18 GPT/L after 12 M. The number of lymphocytes decreased as well after 6 M from1,99 GPT/L to 1,64 GPT/L and to 1,52 GPT/L after 12 M. Though, leukocytes and lymphocytes significantly decreased on average within normal values. Further comparison of proportions of lymphocyte subsets and correlation with clinical data including EDSS, MRI activity or infectious adverse events will be presented. Conclusion: Here we present first data on long-term follow up analysis of peripheral cell subtypes during innovative MS therapies in clinical practice. Whereas FTY and DMF treated patients presented significant lymphopenia, leukocytes and lymphocytes are in normal range during NAT and TER treatment. Disclosure K. Thomas has received speaker honorarium from Novartis, Bayer and Biogen idec. T. Ziemssen is on the scientific advisory board for Bayer Healthcare, Biogen Idec, Novartis, Merck Serono, Teva, Genzyme, Synthon; has received speaker honorarium from Bayer Healthcare, Biogen Idec, Genzyme, MSD, GSK, Novartis, Teva, Sanofi, Almirall, research support from Bayer Halthcare, Biogen Idec, Genzyme, Novartis, Teva and Sanofi. J. Eisele and M. Kaufmann have nothing to disclose. P596 Baseline characteristics and interim analysis results of TRANSITION: a 2-year observational study evaluating the safety profile of patients with multiple sclerosis who switched from natalizumab to fingolimod

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H. Butzkueven1,2, B. Weller3, P.S. Giacomini4,5, S. Cohan6, T. Ziemssen7, D. Tomic8, E. Verdun Di Cantogno8, T. Faivre8, T. Sett9, M. Trojano10 1Department of Medicine, University of Melbourne, 2Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia, 3Department of Clinical Neurosciences, NHS Lothian, Edinburgh, United Kingdom, 4Department of Neurology and Neurosurgery, McGill University, 5Multiple Sclerosis Clinic, Montreal Neurological Institute and Hospital, Montreal, QC, Canada, 6Providence Multiple Sclerosis Center, Portland, OR, United States, 7Center of Clinical Neurosciences, University Hospital Carl Gustav Carus, Dresden, Germany, 8Novartis Pharma AG, Basel, Switzerland, 9Novartis Healthcare Pvt Ltd., Hyderabad, India, 10Dipartimento di Scienze Mediche di Base, Neuroscienze e Organi di Senso (SMBNOS), Università degli Studi di Bari Aldo Moro, Bari, Italy Background: Approximately 15-20% of patients (pts) currently being treated with fingolimod were switched from previous natalizumab treatment, main reason for switch being risk of progressive multifocal leukoencephalopathy (PML). Natalizumab has a long half-life and overlapping immune effects when starting a new disease modifying therapy (DMT) is a concern. Objective: To present results of an interim analysis when 50% of the pts completed 1-year follow-up. Methods: TRANSITION, a multicentre, 2 year, prospective, observational, single-cohort study included relapsing MS pts who received the last natalizumab infusion within 12 months of enrolment and either started fingolimod at study entry or within the past 12 months. Exposure-adjusted Incidence rate (IR) per 100 patient-year (PY) of adverse events (AEs) of special interest was calculated with 95% confidence interval (CI) assuming a Poisson distribution. MS disease activity was described using EDSS score. Treatment preference and reason for switch were recorded. Results: As of Dec 31 2014, 639 pts (mean age 41.9 years) were enrolled; majority were females (70.9%); 83.5% were JCV+. Mean previous natalizumab exposure was 153.2 weeks, mean washout period was 15.0 weeks (range 0-112), major reasons for treatment-switch were JCV+ serology (68.5%) and >2 years of natalizumab treatment (29.1%). Mean fingolimod exposure at time of analysis was 55.6 weeks. In safety set (n=605), AEs and serious AEs (SAEs) were reported for 48% and 8% pts, respectively. Exposure-adjusted IRs (95% CI) per 100 PY for AEs of special interest were hypertension 2.8 (1.66; 4.42), lymphopenia 1.85 (0.96; 3.23), leukopenia 0.92 (0.34; 1.99), liver transaminase elevation 0.46 (0.09; 1.34), 2nd degree atrioventricular block 0.3 (0.04; 1.1), macular oedema 0.3 (0.04; 1.1), basal cell carcinoma 0.3 (0.04; 1.1), infections 15.2 (12.2; 18.7). For those infections that were reported as SAEs, IR was 1.38 (0.63; 2.62). No PML cases occurred. Mean EDSS score was 3.3 at 1 year vs 3.4 at baseline. 57% of pts preferred fingolimod vs 42% who opted for natalizumab. Conclusions: In this interim analysis, baseline characteristics of TRANSITION cohort are consistent with MS patients on secondor third-line DMT in clinical practice. Long-term exposure and JCV positivity were most frequent reasons for switching from natalizumab to fingolimod. The well-characterized safety profile of fingolimod was confirmed in MS pts switching from natalizumab and EDSS remained stable.


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Disclosure Funding source: This study is supported by Novartis Pharma AG, Basel, Switzerland. Helmut Butzkueven has received compensation for serving as consultant or speaker or he or institution he works for has received research support from Biogen Idec, Novartis, Merck Serono and Sanofi-Genzyme; on the editorial board of Multiple Sclerosis International and Multiple Sclerosis and Related Disorders; received project grants from National Health and Medical Research Council (NHMRC), Australian Research Council Linkage Grant RG and National MS Society (USA). Belinda Weller has received compensation for consulting, speaking and travel fees from: Novartis, Genzyme, Biogen, Merck and Teva. Paul Steven Giacomini has received honoraria for speaking, consulting, and advisory board participation from Allergan, Bayer HealthCare, Biogen Idec, EMD Serono, Genzyme, Novartis, Roche and Teva Neuroscience. He has received research support from Biogen Idec and Teva Neuroscience; has been a consultant for NeuroRx Research, an imaging Contract Research Organization; and has acted as a principal investigator or subinvestigator for clinical trials for Alexion, Bayer HealthCare, Biogen Idec, Elan, EMD Serono, GlaxoSmithKline, Novartis, Ono, Roche-Genentech, Sanofi-Aventis and Teva Neuroscience. Stanley Cohan has received speaking honoraria, served on steering committees or advisory boards and has received research support from Biogen, Novartis, Sanofi-Genzyme, Roche, Acorda, Opexa, and Mallinckrodt. Tjalf Ziemssen has received personal compensation for participating on advisory boards, trial steering committees and data and safety monitoring committees, as well as for scientific talks and project support from: Bayer HealthCare, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Sanofi-Aventis, Synthon and Teva. Davorka Tomic is an employee of Novartis Pharma AG, Basel, Switzerland. Elisabetta Verdun Di Cantogno is an employee of Novartis Pharma AG, Basel, Switzerland. Thea Faivre is an employee of Novartis Pharma AG, Basel, Switzerland. Torsha Sett is an employee of Novartis Healthcare Pvt Ltd., Hyderabad, India. Maria Trojano has served on scientific Advisory Boards for Biogen Idec, Novartis, Genzyme and Merck Serono; has received speaker honoraria from Biogen-Idec, Bayer-Schering, Sanofi Aventis, Merck-Serono, Teva and Novartis; has received research grants from Biogen-Idec, Merck-Serono, and Novartis. P597 Erythroblastaemia in natalizumab-treated patients with multiple sclerosis S. La Gioia1, V. Barcella1, M. Seghezzi2, S. Buoro2, B. Frigeni1, M. Vedovello1, M.Z. Conti1, M. Rottoli1 1Scienze Neurologiche, 2Medicina di Laboratorio, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy Background: Early papers on the clinical use of natalizumab in relapse remitting multiple sclerosis (RRMS) patients reported erythroblastemia as occasional and transient. A previous report on 14 RRMS patients treated with natalizumab observed on blood

smears a high prevalence of nucleated red blood cells (NRBCs) (93%) versus a negative value in 14 interferon treated patients. Aims: To determine the prevalence and absolute count of NRBCs in peripheral blood of natalizumab, fingolimod, interferon, glatiramer acetate patients and healthy controls of the same geographic area using the same equipment for lab analysis. Materials and methods: Peripheral blood samples were consecutively selected from RRMS patients of our Multiple Sclerosis center on November and December 2014. The samples of 162 consecutive patients with RRMS were analysed in the study, including 26 subjects on natalizumab treatment, 76 subjects on interferon, 44 subjects on glatiramer acetate, 16 subjects receiving fingolimod and 240 healthy controls of the same geographic area. Blood samples were all processed using XN-9000-Hematology Analyzer. NRBC presence was subsequently verified by microscopic analysis. Results: The rate of samples with NRBCs positivity was significantly higher in natalizumab-treated patients (88.5%) compared with all the other treatment groups (0.0% for fingolimod, 6.3% for interferon, 6.8% for glatiramer acetate) and healthy controls (0.0%) (p< 0.0001). The median absolute count of NRBCs resulted significantly higher in natalizumab-treated patients (median 0.020/mcl, p value< 0.0001) as opposed to fingolimodtreated, interferon-treated, glatiramer acetate-treated patients and control population. Haemoglobin levels were comparable and no morphologic alterations were evident at a subsequent revision of red blood cells. Conclusions: We confirm erythroblastaemia as a common finding of natalizumab treatment in RRMS patients. A more extended knowledge and an adequate long-term observation of this phenomenon is essential to better understand any pathological long term implication. Disclosure All authors: Nothing to disclose, no sources of funding. P598 The IMSE 2 study: a Swedish nationwide pharmaco-epidemiological and genetic study focused on long-term safety and efficacy of fingolimod S. Johansson1, L. Forsberg1, N. Nordin1, J. Hillert1, A. Svenningsson2, J. Lycke3, J. Burman4, A.-M. Landtblom4, F. Walentin5, C. Martin6, P. Nilsson7, C. Dahle8, F. Piehl1, T. Olsson1 1Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, 2Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, 3Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, 4Department of Neuroscience, Uppsala University, Uppsala, 5Örebro University Hospital, Örebro, 6Department of Clinical Science, Danderyd Hospital, Stockholm, 7Department of Neurology, Lund University, Lund, 8Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden Background: Fingolimod (FGL) is an oral disease modulatory drug (DMD) for patients with relapsing-remitting multiple sclerosis (RRMS).


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Poster Session I, 21(S11) Objective: To follow up the efficacy and long-term safety of FGL in a real-world setting. Methods: Swedish MS patients are registered in the nationwide web-based Swedish MS registry (SMSreg). Before FGL initiation patients are asked to participate in the “Immunomodulation and Multiple Sclerosis Epidemiology” study (IMSE 2). Adverse events (AEs) and clinical measures are obtained from SMSreg and blood samples are collected. Results: From September 2011 until March 2015, 1270 patients (69% female; 88% RRMS) were included. Mean disease duration before FGL was 80.9 months. Most frequent DMDs before FGL were natalizumab (NTZ) (32%) and interferons (30%). During follow-up, 387 patients discontinued FGL, mainly due to AEs (38%) or lack of effect (38%). 40% came from the prior NTZ group. In patients with baseline and 12 month data, significant improvements were found in MS Severity Scale (MSSS) (-8.2%), Symbol Digit Modalities Test (SDMT) (+5.4%), MS Impact Scale (MSIS29) psychological (-6.6%) and European Quality of life-5 Dimension test (EQ-5D) (+2.1%). Non-significant changes were seen in Extended Disability Status Scale (EDSS), MSIS-29 physical and Visual Analogue Scale (VAS). When stratifying the patients into those treated with NTZ (switched mainly due to John Cunningham virus positivity) or not during < 6 months prior to FGL initiation; EDSS scores worsened significantly (+6.4%) in the prior NTZ group, but were stable in the non NTZ group. The difference between the groups was significant, even after controlling for age, sex and EDSS score at baseline. SDMT and MSIS-29 psychological scores improved significantly in both groups (+1.6%, +7.9% and -4.3%, -7.9%). MSSS, MSIS-29 physical, EQ-5D and VAS scores improved significantly only in the non NTZ group (-14.2%, -4.6%, +3.7%, +5.5%). The differences between the groups were significant, even after controlling for age, sex and baseline values for each test respectively. Conclusions: The real-world experience of FGL is largely consistent with data from published phase III clinical trials. However our data also indicates a worse outcome in patients with prior NTZ therapy, likely due to higher disease activity from onset and/ or delays in wash-out time before switching drug. Continued follow up is of importance in the post-marketing setting to optimize treatment choice. Disclosure Susanne Johansson, Linda Forsberg and Nina Nordin: Nothing to disclose. Jan Hillert, Fredrik Piehl, Charlotte Dahle and Tomas Olsson have received unrestricted research grants or honoraria for lectures or advisory boards from Biogen, Novartis, Merck Serono, Teva and Sanofi. Claes Martin has received honoraria for lectures and advisory boards from Biogen, Novartis, Merck Serono, Teva and Genzyme a Sanofi Company. Jan Lycke has received travel support and/or lecture honoraria from Bayer Schering Pharma, Biogen, Novartis, Teva and Genzyme a Sanofi Company; has served on scientific advisory boards for Almirall, Teva, Biogen, Novartis and Genzyme a Sanofi Company; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, Novartis and Teva.

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Anders Svenningsson has received travel support and/or lecture honoraria from Biogen, Merck Serono, Genzyme s Sanofi Company, Novartis and Baxter; has received unconditional research grants from Bayer Schering Pharma and Biogen. Petra Nilsson has received honoraria for lectures and advisory boards from Merck Serono and Genzyme a Sanofi Company, advisory boards for Novartis, lectures for Biogen and has received unrestricted grants from Biogen. Joachim Burman has received travel support and/or lecture honoraria from Almirall, Biogen, Genzyme a Sanofi Company, Hospira and Merck Serono; has received unconditional research grants from Biogen and Merck Serono. Anne-Marie Landtblom has received honoraria from Merck Serono, Teva, Biogen, Genzyme a Sanofi Company. The IMSE studies have received unrestricted grants from Biogen and Novartis. P599 A Swedish nationwide pharmaco-epidemiological and genetic study of the long-term safety and efficacy of natalizumab S. Johansson1, L. Forsberg1, J. Hillert1, P. Nilsson2, C. Dahle3, A. Svenningsson4, J. Lycke5, A.-M. Landtblom6, J. Burman6, F. Walentin7, C. Martin8, F. Piehl1, T. Olsson1 1Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, 2Department of Neurology, Lund University, Lund, 3Department of Clinical and Experimental Medicine, Linköping University, Linköping, 4Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, 5Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, 6Department of Neuroscience, Uppsala University, Uppsala, 7Örebro University Hospital, Örebro, 8Department of Clinical Science, Danderyd Hospital, Stockholm, Sweden Background: Natalizumab (NTZ) is a disease modulatory treatment for relapsing-remitting multiple sclerosis (RRMS) with high efficacy. Post-marketing surveillance is important for the determination of long-term safety and efficacy outcome measures in a real-world setting. Upon NTZ launch in Sweden (August 2006) the “Immunomodulation and Multiple Sclerosis Epidemiology” study (IMSE 1) was initiated. Objective: To follow-up the long-term safety and efficacy of NTZ in a real-world setting. Methods: MS patients in Sweden are registered in the nationwide web-based Swedish MS registry (SMSreg), descriptive data of adverse events (AEs), Extended Disability Status Scale (EDSS), MS Severity Scale (MSSS), Symbol Digit ModalitiesTest (SDMT), MS Impact Scale (MSIS-29) and relapses are registered. The IMSE 1 study includes data collected from SMSreg and blood sampling at baseline, 6, 12, and 24 months. The Wilcoxon Signed-Rank Test was used to assess changes in efficacy scores. Results: From August 2006 until April 2015, 2643 patients (72.0% female; 86.2% RRMS) have been included in IMSE 1. Of these, 1430 patients are currently treated with NTZ. Mean treatment duration is 32.5 months and mean age at treatment start is 36.5 years. 1355 patients (51.3%) discontinued NTZ treatment at some point, 268 of them restarted later. The main reasons for discontinuation


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were; anti-John Cunningham virus antibody positivity (JCV+) (41.4%) and pregnancy/planned pregnancy (15.2%). In patients on continuous NTZ treatment for ⩾5 years (n=496), long lasting, significant, stabilization of disease activity is evident. EDSS scores decreased with 12.1%, MSSS scores with 37.5%, MSIS-29 physical and psychological scores with 13.9% and 17.1%, and SDMT scores increased with 24.0% (mean score at 5 years compared to baseline). Serious AEs were rare (2.4%, 64 events), but included 8 cases (1 fatal) of progressive multifocal leukoencephalopathy (PML, 0.3%), the latest case reported in December 2012. Currently 21.8% of patients with ongoing NTZ treatment are JCV+, compared to 58% when testing started. A total of 25 deaths have been recorded, four patients died during NTZ treatment but the death reasons have not been associated with NTZ. Conclusions: SMSreg proves to function well as a post-marketing drug surveillance platform, providing long-term data regarding drug effects and AEs. NTZ is generally well tolerated with sustained efficacy, though the risk of PML is an important concern. Disclosure Susanne Johansson, Linda Forsberg and Nina Nordin: Nothing to disclose. Jan Hillert, Fredrik Piehl, Charlotte Dahle and Tomas Olsson have received unrestricted research grants or honoraria for lectures or advisory boards from Biogen, Novartis, Merck Serono, Teva and Sanofi. Claes Martin has received honoraria for lectures and advisory boards from Biogen, Novartis, Merck Serono, Teva and Genzyme a Sanofi Company. Jan Lycke has received travel support and/or lecture honoraria from Bayer Schering Pharma, Biogen, Novartis, Teva and Genzyme a Sanofi Company; has served on scientific advisory boards for Almirall, Teva, Biogen, Novartis and Genzyme a Sanofi Company; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, Novartis and Teva. Anders Svenningsson has received travel support and/or lecture honoraria from Biogen, Merck Serono, Genzyme s Sanofi Company, Novartis and Baxter; has received unconditional research grants from Bayer Schering Pharma and Biogen. Petra Nilsson has received honoraria for lectures and advisory boards from Merck Serono and Genzyme a Sanofi Company, advisory boards for Novartis, lectures for Biogen and has received unrestricted grants from Biogen. Joachim Burman has received travel support and/or lecture honoraria from Almirall, Biogen, Genzyme a Sanofi Company, Hospira and Merck Serono; has received unconditional research grants from Biogen and Merck Serono. Anne-Marie Landtblom has received honoraria from Merck Serono, Teva, Biogen, Genzyme a Sanofi Company. The IMSE study has received unrestricted grants from Biogen. P600 A Swedish nationwide pharmaco-epidemiological and genetic study (IMSE) of the long-term safety and efficacy of dimethyl fumarate

L. Forsberg1, S. Johansson1, N. Nordin1, J. Hillert1, A. Svenningsson2, J. Lycke3, J. Burman4, A.-M. Landtblom4, F. Walentin5, C. Martin6, P. Nilsson7, C. Dahle8, F. Piehl1, T. Olsson1 1Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, 2Pharmacology and Clinical Neuroscience, Umeå University, Umeå, 3Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, 4Department of Neuroscience, Uppsala University, Uppsala, 5Örebro University Hospital, Örebro, 6Department of Clinical Science, Danderyd Hospital, Stockholm, 7Department of Neurology, Lund University, Lund, 8Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden Background: Dimethyl fumarate (DMF) is an oral therapy for relapsing-remitting multiple sclerosis (RRMS), the efficacy of which has been shown in phase II and III studies. However; postmarketing surveillance is important to determine the long-term safety and efficacy outcome measures in a real-world setting. DMF has therefore been included into the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE). Objectives: To follow-up the long-term safety and efficacy of DMF in a real-world setting. Methods: MS patients in Sweden are registered into the nationwide web-based Swedish MS registry (SMSreg). The IMSE study includes descriptive data of adverse events (AEs), extended disability status scale (EDSS), MS severity scale (MSSS), symbol digit modalities test (SDMT), MS impact scale (MSIS-29) and relapses obtained from SMSreg. Blood samples are collected at baseline and after 12 months of treatment. Results: 1,077 patients have been included in the IMSE 5 study until April 30th, 2015 most of which have switched from interferons or glatiramer acetat treatments (50%), 197 patients (18%) were treatment naïve. 87% of the patients have RRMS (9% missing data on MS phenotype). The mean treatment duration is 5.7 months, the mean age at treatment start is 41.0 years and 75% are female. 127 patients (12%) terminated their treatment at some point, of which 6 patients later restarted. 956 patients are currently treated with DMF. The most common reason for discontinuation was AEs (77%); mainly gastrointestinal disorders (32%) and flushing/ rashes (11%). 443 patients have been treated for at least 6 months and 16 patients have been treated with DMF for at least 12 months. In patients treated with DMF continuously for ⩾6 months (n=443), improvements in mean values at 6 months of treatment compared to mean baseline values have been noted for EDSS scores by 19%; MSSS by 17%; and SDMT by 2%. EQ5D and VAS scores did not improve during this time period. MSIS-29 scores are collected yearly and are therefore not presented at this time. Two patients (0.2%) have died due to reasons unrelated to DMF treatment. Conclusions: SMSreg proves to function well as a post-marketing drug surveillance platform, providing data regarding drug efficacy and AEs. DMF is generally well tolerated; however a longer follow-up period is needed to assess the real-world efficacy and safety of DMF.


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Poster Session I, 21(S11) Disclosure The IMSE study has received unrestricted grants from Biogen. Linda Forsberg: nothing to disclose. Susanne Johansson: nothing to disclose. Nina Nordin: nothing to disclose. Jan Hillert, Fredrik Piehl, Charlotte Dahle and Tomas Olsson have received unrestricted research grants or honoraria for lectures or advisory boards from Biogen, Novartis, Merck Serono, Teva and Genzyme a Sanofi Company. Claes Martin has received honoraria for lectures and advisory boards from Biogen, Novartis, Merck Serono, Teva and Genzyme a Sanofi Company. Jan Lycke has received travel support and/or lecture honoraria from Bayer Schering Pharma, Biogen, Novartis, Teva and Genzyme a Sanofi Company, Aventis; has served on scientific advisory boards for Almirall, Teva, Biogen, Novartis and Genzyme a Sanofi Company; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, Novartis and Teva. Anders Svenningsson has received travel support and/or lecture honoraria from Biogen, Merck Serono, Genzyme a Sanofi Company, Novartis and Baxter; has received unconditional research grants from Bayer Schering Pharma and Biogen. Petra Nilsson has received honoraria for lectures and advisory boards from Merck Serono and Genzyme a Sanofi Company, advisory boards for Novartis, lectures for Biogen and has received unrestricted grants from Biogen. Joachim Burman has received travel support and/or lecture honoraria from Almirall, Biogen, Genzyme a Sanofi Company, Hospira and Merck Serono; has received unconditional research grants from Biogen and MerckSerono. Anne-Marie Landtblom has received honoraria from Merck Serono, Teva, Biogen and Genzyme a Sanofi Company. P601 Real life experience with interruption of natalizumab treatment C.S. Simonsen1,2, E.G. Celius2, S.M. Moen2 1Department of Neurology, Vestre Viken Hospital, Drammen, 2Department of Neurology, Oslo University Hospital, Oslo, Norway Background: Patients on Natalizumab (NTZ) stop treatment due to risk of progressive multifocal leukoencephalopathy (PML), lack of efficacy, development of secondary progressive disease (SPMS) or wish for pregnancy. We did a real-life post-NTZ study to see which patients stopped NTZ and status 1 year on. Method: We did a retrospective journal search of all patients stopping NTZ at the neurological departments in two hospitals in south-east Norway. We noted cause of drug-cessation, choice of new disease modifying drug, Expanded Disability Status Scale (EDSS) and MRI findings at start of NTZ treatment, at time of cessation and after 1 year. Results: Of 230 patients on NTZ, 84 patients have stopped (73% women). Main reasons for stopping were JC-virus positivity and risk of PML (37%), suspicion of SPMS (13%), lack of efficacy (12%) and wish for pregnancy (12%). The most used drugs after NTZ was Fingolimod (45%), Alemtuzemab (13%), 1st line therapy

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(injectables, teriflunomide or dimethyl-fumarate) (13%), Mitoxantrone/Rituximab (6%) and stem cell transplantation (2,4%). 14% were not started on new drug. Of the 11 patients thought to have SPMS, 4 patients had significant attacks within the first year and were started on either Alemtuzemab or Fingolimod. 65 patients had at least 1 year follow-up, and of these 49 (75%) were on a new medication (Group I), 14 patients were on no medication (Group II) and 2 patients were dead (suicide and brain tumour). Group I was on average 36,6 years old with a disease duration of 8,3 years (median 8) when starting NTZ, while Group II was 41,1 years old and a disease duration of 7,3 years (median 4,5). EDSS changed in Group I from 3.2 at start of NTZ-treatment to 4,3 one year after cessation and in Group II from 3,9 to 4,9 one year after cessation. Average time spent on NTZ was the same. Conclusion: Risk of PML is the main reason for stopping NTZtreatment. Patients not on treatment after one year were older, had shorter disease duration and a higher EDSS both before treatment and 1 year after stopping than those switched to a new drug. Further real-life observation studies of patients stopping treatment are needed. Disclosure Cecilia Smith Simonsen: nothing to disclose Stine Marit Moen: nothing to disclose Elisabeth G. Celius: nothing to disclose P602 Impact of fingolimod on headache course in a multicenter MS population E. Binello1, A. Mattioda1, C. Chiavazza1, C. Chisari2, C. Leone2, M. Vercellino1, C. Solaro3, L. Pinessi1, P. Cavalla1, F. Patti2 1MS Centre, Department of Neuroscience, University Hospital City of Health and Science of Turin, Turin, 2Department DANA, ‘GF Ingrassia’, Neuroscience Section (Multiple Sclerosis Centre), University of Catania, Catania, 3Neurology Unit, Head and Neck Department, ASL 3 ‘Genovese’, Genova, Italy Background: Multiple sclerosis (MS) and headache coexist in many patients. Disease-modifying drugs (DMDs) for MS may play a role in causing or exacerbating headache.An association between fingolimod (FTY) and headache has been described in randomized trials; an observational study reported headache as the most frequent adverse event leading to discontinuation of FTY during the first three months of therapy. Conclusive data regarding the impact of this drug on co-morbid primary headache in MS are still lacking. Objectives: To investigate the effect of FTY on headache in a multicenter Relapsing-Remitting (RR) MS patients population. Methods: The prevalence of primary headache, according to the International Classification of Headache Disorders Society, was assessed in a series of consecutive FTY treated MS patients at baseline and after 3, 6 and 12 months. The occurrence of de novo headache and of status migrainosus was recorded. Results: 289 RR-MS patients were evaluated. At baseline, 176 patients showed a co-morbid headache (tension-type in 108 cases). During the first 12 months of treatment, 90 patients (51%) reported an improvement in intensity and frequency of headache (most cases were therapeutic shifts from beta-interferon); 57 cases had a


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stable headache, while 29 patients (16%) reported a worsening headache (mainly migraine). Moreover a status migrainosus was reported by 11 patients (not experienced in the last 2 years); in one case, it represented the onset of a de novo migraine.A change of pre-existing headache subtype was observed in 5 cases. De novo headache occurred in 12 patients: 11 developed a tension-type headache, 1 a migraine without aura. Moreover, 2 patients (0,7%) discontinued FTY because of headache worsening. Conclusion: Impact of FTY on headache frequency and characteristics represents an open question. In our population, FTY was associated with the development of a de novo headache in 4% of patients; an abnormal prevalence of status migrainosus (3.8%) was also recorded, in one case leading to treatment discontinuation. A significant proportion of patients, previously treated with beta-interferon, reported an improvement of their pre-existing headache, mainly tension-type. Most patients with pre-existing headache tolerate well FTY; however clinicians should pay attention to migraine patients who may experience an exacerbation of their headache, with a possible impact on treatment adherence. Disclosure C. Solaro received honoraria from Bayer Schering, Biogen Idec, Merck Serono, Teva, Almirall, and Sanofi Genzyme. He received research grants and support by the FISM (Fondazione Italiana Sclerosi Multipla). F. Patti received honoraria from Almirall, Bayer, Biogen, Merck Serono, Novartis, Sanofi Genzyme, and TEVA; he also received research grants from FISM and MIUR. E. Binello: nothing to disclose. A. Mattioda: nothing to disclose. C. Chiavazza: nothing to disclose. P. Cavalla: nothing to disclose. C. Chisari: nothing to disclose. C. Leone: nothing to disclose. M. Vercellino: nothing to disclose. L. Pinessi: nothing to disclose. P603 Long-term effectiveness and safety of natalizumab in a Portuguese cohort I. Correia, S. Batista, I. Marques, C. Nunes, G. Gonçalves, C. Macário, L. Sousa Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal Introduction: Natalizumab long-term efficacy in RelapseRemitting Multiple Sclerosis (RRMS) has been shown in randomized clinical trials, but real world long-term data is missing. Objective: Report the long-term effectiveness and safety of natalizumab in a Portuguese Cohort of RRMS patients. Methods: Prospective study of RRMS patients treated with natalizumab over at least two years collected in our IMED database. Annualized relapse rate, EDSS, MRI, JC virus antibody status, previous treatments and adverse events were analysed. Results: 71 patients included: 71,8% female, with mean age of 29,7 years at RRMS diagnosis, 36,8 years at natalizumab start and with mean treatment duration of 44,8 months (24-91). Natalizumab treatment was associated with a nine-fold decrease in annualized relapse

rate (1,7 vs. 0,2, p< 0,001), which progressively decreased over treatment time, as well as 1 point reduction of the median EDSS (3,5 vs. 2,5, p< 0,001). Of the 64 patients with MRI comparative studies, 92.2% did not have lesion load increase. There was no clinical evidence of disease activity in 71,8% of the patients during the first year (n=71), 67,6% in the second year (n=71), 78,5% in the third year (n=65), 84,2% in the fourth year (n=38), 83,3% in the fifth year (n=24), 83,3% in the sixth year (n=12). There was no evidence of disease activity (NEDA) in 43,6% of the patients (n=39) after three years of treatment, decreasing to 26,9% (n=26) after four years and 18,8% (n=16) after five years of treatment. Natalizumab was suspended in 40 patients mostly due to positive JC virus antibodies (85%). One year after natalizumab suspension, there was a three-fold increase in annualized relapse rate (0,2 vs. 0,6, p=0,01) and an increase of 0,5 points in EDSS (2,5 vs. 3,0, p=0,03), however these results were better than before natalizumab treatment, with rebound activity occurring in only two patients. There were 3 cases of progressive multifocal leukoencephalopathy (PML) diagnosed before risk stratification with JC virus index. The patients were 35, 36 and 50 years old, all female, PML occurred after 25, 66 and 29 infusions respectively and all except the first patient had previous immunosuppressant therapy Although these patients survived, they became highly disabled with EDSS above 6,5. Conclusion: Natalizumab showed effectiveness in our Cohort, being associated with reduction of relapse rate and EDSS and with MRI lesion load stabilization. PML was the main complication. Disclosure Inês Correia: nothing to disclose. Dr. Sónia Batista has received grant support from Biogen and speakers´ bureau fees from Biogen, Novartis and Merck. Inês Marques: nothing to disclose. Dr. Carla Nunes has received speakers´ bureau fees and have been advisory board member for Biogen, Novartis, Teva, Bayer, Genzyme and Merck. Dr. Grilo Gonçalves has received speakers´ bureau fees and have been advisory board member for Biogen, Novartis, Teva, Bayer, Genzyme and Merck. Dr. Carmo Macário has received speakers´ bureau fees and have been advisory board member for Biogen, Novartis, Teva, Bayer, Genzyme and Merck. Dr. Lívia Sousa has received speakers´ bureau fees and have been advisory board member for Biogen, Novartis, Teva, Bayer, Genzyme and Merck.

Risk management for disease modifying treatments P604 Interferon-β therapy and risk of thrombocytopenia in multiple sclerosis patients T. Koudriavtseva1, D. Plantone1, R. Renna1, C. Mandoj2, C. Mainero3,4 1Neurology Unit, 2Clinical Pathology, Regina Elena National Cancer Institute, Rome, Italy, 3Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, 4Harvard Medical School, Boston, MA, United States Background/aims: Thrombocytopenia is a well-described adverse event of several disease-modifying therapies (DMT) in


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Poster Session I, 21(S11) multiple sclerosis (MS). On the other hand, an increased prevalence of MS has been reported in patients with immune thrombocytopenia. In this retrospective, cross-sectional, case-control study we evaluated in a heterogeneous MS cohort: 1) the prevalence of thrombocytopenia in comparison with sex- and agematched controls; 2) the relationship between thrombocytopenia and patients’ demographic, clinical characteristics; 3) the risk for thrombocytopenia in relation to DMT. Methods: 187 consecutive MS patients [51 males, mean age (±SD) 44.5±10.7 years] and 200 controls (56 males, mean age 45.5±12 years) were included. Thrombocytopenia was defined as platelet count lower than normal laboratory values (130-400x109/L). Results: The prevalence of thrombocytopenia was significantly higher in MS patients than in controls (7% vs 2.5%, p=0.04). Thrombocytopenia was present only in relapsing-remitting MS cases, and significantly associated with lower EDSS (p=0.002) and with a trend for shorter disease duration (p=0.06). It was more frequent in patients on high-dose interferon-β therapy compared with those on low-dose interferon-β therapy, other therapies or untreated patients (p=0.02). High-dose interferon-β therapy was associated with more than 8-fold increase in the risk for thrombocytopenia (Odds ratio 8.60, 95% Confidence Interval: 1.01-74.48 adjusted for EDSS, disease duration and type of disease). Conclusion: The prevalence of thrombocytopenia was increased in MS patients treated with DMT. High-dose interferon-β therapy is the variable most strongly associated with thrombocytopenia likely through the activation of innate immunity.

Methods: Patients must have received 12 or more consecutive NTZ treatments, be anti-JCV-ab positive, not have received prior immunosuppressive therapy, and been free of clinical relapses during prior 12 months of NTZ treatment. Patients began teriflunomide 14 mg daily, within 4 weeks after their last dose of NTZ. Monthly 3T brain MRI, EDSS, laboratory tests, interim history and complete neurological and physical examinations were performed for 6 months. Results: To date, 28 patients have had at least 6 months of teriflunomide after NTZ withdrawal. Mean age was 47 (SD=8.55). 79 percent were female. The mean number of NTZ treatments prior to starting teriflunomide was 47. The mean EDSS at baseline was 3.23 (SD=1.45); and after 6 months of teriflunomide treatment mean EDSS was 3.09 (SD=1.37). Results showed 21 of the 28 patients stable in all MRI parameters from baseline to month 6. Five patients had new T2 hyper-intensities. Contrast enhancing lesions occurred in four of these 5 patients. Of these patients there were 2 patients who had mild deficits resolving after IV steroids. Teriflunomide was discontinued in one patient at month 5. There was no emergence of PML. There were 10 patients with hair thinning, and 3 patients experienced transient mild elevation of LFTs, twice normal or less with spontaneous resolution without discontinuation of terifluomide, although in one patient, teriflunomide was held for 5 days. Discussion: There is a need for a DMT that can reduce the high risk of breakthrough MS disease activity commonly seen in patients, particularly in the first 6 months, after discontinuing NTZ due to PML risk. Our results demonstrate that teriflunomide may be a safe and effective therapy for the transition from NTZ.

Disclosure No conflict of interest or financial interest is reported. T. Koudriavtseva reports consulting fees from Bayer Schering, and Institutional grant from Merck Serono, Biogen Idec, Novartis, Bayer Schering outside the submitted work. C. Mainero reports consulting fees from Biogen outside the submitted work. D. Plantone: Nothing to disclose. R. Renna: Nothing to disclose. C. Mandoj: Nothing to disclose. P605 An interim analysis of monthly surveillance 3T MRI in MS patients switching from long term natalizumab to teriflunomide in a prospective study K.R. Edwards1, S. Cohan2, J. Thomas3, J.T. O’Connor1, T. Gervasi2 1MS Center of Northeastern New York, Latham, NY, 2Providence Multiple Sclerosis Center, Providence Brain and Spine Institute, Portland, OR, 3Albany Medical College, Albany, NY, United States Background: Natalizumab (NTZ) has the risk of causing progressive multifocal leukoencephalopathy (PML) after extended use by patients testing positive for serum anti-JCV-antibody. There is a need to have an alternative disease modifying treatment (DMT) that would be safe and effective to prevent recurrence of MS exacerbations upon discontinuation of NTZ. Objectives: To determine if teriflunomide will be safe and effective in reducing breakthrough MS disease activity in patients switching from NTZ.

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Disclosure KRE: Consulting services (Biogen, Genzyme); Speakers Bereau (Biogen, Genzyme, Novartis); research support ( Biogen, Eli Lilly, Easai Inc, Forum Pharmaceuticals, Genentech, Genzyme, Hoffman-La Roche, Novartis, Pfizer, Merz Pharmaceuticals, Vaccinex). SC: Serves on steering committees and advisory boards for Biogen, Novartis, Sanofi-Genzyme and Mallinckrodt, receives research support from Biogen, Novartis, Sanofi-Genzyme, Roche, Opexa, and Mallinckrodt, receives speaking honoraria from Biogen, Novartis, Sanofi-Genzyme and Acorda. JT: Nothing to disclose. JTO: Nothing to disclose TG: Nothing to disclose P606 Characterization of absolute lymphocyte count profiles in MS patients treated with delayed-release dimethyl fumarate: considerations for patient management R.J. Fox1, A. Chan2, R. Gold2, J.T. Phillips3, K. Selmaj4, R. Zhang5, I. Chang5, M. Novas5, J. Rana5, J.L. Marantz5 1Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, United States, 2St. Josef Hospital, Ruhr University, Bochum, Germany, 3Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, United States, 4Medical University of Lodz, Lodz, Poland, 5Biogen, Inc., Cambridge, MA, United States Background: Delayed-release dimethyl fumarate (DMF) demonstrated robust efficacy and an acceptable safety profile in


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relapsing-remitting multiple sclerosis (RRMS) in clinical studies. Recent labelling changes include a recommendation to consider interruption of DMF treatment in pts with absolute lymphocyte counts (ALCs) < 500/mm3 persisting ⩾6 mos to minimize the risk of subsequently developing severe, prolonged lymphopenia and its potential complications with continued treatment. Objectives: Provide practical considerations for management of DMF-treated MS pts by characterizing ALC profiles and examining efficacy in pts with and without lymphopenia enrolled in clinical trials. Methods: An integrated analysis of the Phase 2b and 3 (DEFINE, CONFIRM, and ENDORSE) DMF studies was conducted; the analysis population comprised 2470 MS pts with any post-baseline ALC (median [range] follow-up: 39.0 [0.0-90.5] mos). ALCs were assessed at weeks 4, 8, 12, and every 12 weeks thereafter. The data cut-off was 14 May 2014. Results: Mean ALCs decreased by approximately 30% during the first yr of treatment, then plateaued, remaining above lower limit of normal (LLN; 910/mm3) throughout the observation period. Among pts treated for ⩾6 mos (N=2,099), 47 (2.2%) experienced ALCs < 500/mm3 persisting ⩾6 mos. ALCs remained ⩾LLN in 84% of pts during the first 6 mos and in 76% of pts during the first yr; of these pts, 0.1% and 0%, respectively, developed ALCs < 500/mm3 persisting ⩾6 mos at any time. Of the 47 pts with ALCs < 500/mm3 persisting ⩾6 mos, 9 discontinued or completed the study (8 had ALCs ⩾1 mo post-treatment). All of these pts showed increases in ALCs after their final DMF dose. Reduction in annualized relapse rate with DMF 240 mg BID v placebo was not substantially different in pts with lymphopenia (at least 1 ALC < LLN) v pts without lymphopenia (all ALCs ⩾LLN): 58% v 49% in DEFINE; 48% v 40% in CONFIRM. Aside from a single case of progressive multifocal leukoencephalopathy in the setting of severe, prolonged lymphopenia, there is no overall increased risk for serious infections, including other opportunistic infections. Conclusions: ALC profiles are well characterized and generally stable over time. Although data are limited, there is evidence of ALC improvement after DMF discontinuation. Therapeutic efficacy in pts with or without lymphopenia suggests that lymphopenia is not a primary mechanism of action of DMF. The overall benefit-risk of DMF remains favourable. Disclosure This study was funded by Biogen, Inc. Robert J. Fox: Consultant fees from Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Biogen, and Novartis; research grant funding from Novartis. Andrew Chan: Personal compensation for activities with Allmirall Hermal, Bayer Schering, Biogen, Genzyme, Merck Serono, Novartis, Sanofi Aventis, and Teva Neuroscience; research support from Biogen, Genzyme, and Novartis. Ralf Gold: Honoraria from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders. J. Theodore Phillips: Consulting fees from Acorda, Biogen, Genzyme, Merck Serono, and Sanofi; research support from Roche.

Krzysztof Selmaj: Compensation for consulting services from Genzyme, Novartis, Ono, Roche, Synthon, and Teva; compensation for speaking from Biogen. Ray Zhang: Employee of and holds stock/stock options in Biogen, Inc. Ih Chang: Employee of and holds stock/stock options in Biogen, Inc. Mark Novas: Employee of and holds stock/stock options in Biogen, Inc. Jitesh Rana: Employee of and holds stock/stock options in Biogen, Inc. Jing Marantz: Employee of and holds stock/stock options in Biogen, Inc. P607 Quantitative comparison of MS patient-reported injection site reactions and flu-like symptoms with non-pegylated and pegylated subcutaneous interferon beta drugs in NARCOMS G. Wang1, T. Tyry2, S.S. Cofield1, R.A. Marrie3, A. Salter1, R.J. Fox4, F. Dangond5, H. Zhang5, G.R. Cutter1, the CombiRx Investigator Group 1Biostatistics, University of Alabama at Birmingham, BIRMINGHAM, AL, 2Dignity Health, St Joseph’s Hospital and Medical Center, Phoenix, AZ, United States, 3MS Clinic, University of Manitoba, Winnipeg, MB, Canada, 4Mellen Center for MS, Cleveland Clinic, Cleveland, OH, 5EMD Serono, Rockland, MA, United States Background: Injection site reactions (ISR) are side effects of using injectable disease-modifying therapies (DMTs) in MS. Drug substance, route of administration, and patient characteristics influence the risk and severity of ISR. Since ISR and other drug-related manifestations, such as flu-like symptoms (FLS), may impact adherence, it is important to assess patient perception of the size and duration of post-injection ISR and their experience with FLS. Objectives: To demonstrate the use of a calibrated visual scale of ISR and to report FLS in new and established users of two injectable DMTs: non-pegylated interferon beta-1a (IFN) given subcutaneously (SC) three times a week and pegylated interferon beta-1a (PIFN) given SC every two weeks. Methods: In this ongoing pilot study participants self-reported their experience after the first full dose of their DMT in a supplemental NARCOMS survey. A 5-point Likert scale (1-5) with color pictures of erythema with increasing ordinal levels of size and severity was used to report the injection site redness. A 10-point Likert scale (1-10) was used for other ISRs including pain, swelling, bruising, lumps, and necrosis. For both scales, higher values indicate worse ISR. FLS were measured as None, Mild, Moderate, Severe. Comparisons were made across 3 groups: currently taking PIFN (PIFN), currently taking IFN (C-IFN), and formerly took IFN (F-IFN). Results: As of May 2015, 25 respondents were mostly white (80 %), female (96 %), with mean (SD) disease duration for the 5 (20%) PIFN users, the 9 (36%) C-IFN users, and the 11 (44%) F-IFN users: 13.8 (11.3), 22.6 (11.3), and 22.0 (10.1) years, respectively. The mean duration of PIFN use was about 6 months. All 5 PIFN users, 6 (75%) C-IFN users, and 9 (90%) F-IFN users reported redness with a median (IQR) 3 (1, 3.5), 2.5 (1, 3), and 2


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Poster Session I, 21(S11) (1, 3.5), respectively. PIFN reported more incidences of lumps (2/5 vs 2/9) and FLS (4 vs 3) than C-IFN, but less of pain (0 vs 7), swelling (1 vs 5), bruising (1 vs 6), and necrosis (0 vs 3). F-IFN reported more incidences of most ISRs and FLS than C-IFN (data not shown). Conclusions: ISRs occurred in more than 50% of participants, but more severe ISR such as lumps, swelling, and necrosis happened less often. PIFN users reported more flu-like symptoms, lumps, and redness in this pilot study. If these preliminary data are confirmed by our ongoing larger surveys, this visual scale may be suitable as a patient-reported outcome in other studies. Disclosure Dr. Wang has nothing to disclose. Dr. Tyry has nothing to disclose. Dr. Cofield has received support for consulting services, DSMB service, and/or grant support; no direct conflicts. Dr. Marrie has conducted clinical trials for sanofi aventis. Dr. Salter has received support for consulting services and grant support; no direct conflicts. Dr. Fox has received personal consulting fees from Biogen Idec, MedDay, Novartis, Questcor, Teva, and XenoPort. Dr. Dangond is an employee of EMD Serono, Inc. Dr. Zhang is an employee of EMD Serono, Inc. Dr. has consulting and/or DSMB commitments in Past 12 months. Participation of Data and Safety Monitoring Committees: All of the below organizations are focused on medical research: Apotek, Biogen-Idec, Cleveland Clinic(Vivus), Glaxo Smith Klein Pharmaceuticals, Gilead Pharmaceuticals, Horizon Pharmaceuticals, Modigenetech/Prolor, Merck/Ono Pharmaceuticals, Merck, Merck/ Pfizer, Neuren, Sanofi-Aventis, Teva, NHLBI (Protocol Review Committee), NINDS, NICHD (OPRU oversight committee). Consulting, Speaking fees & Advisory Boards:Consortium of MS Centers (grant), D3 (Drug Discovery and Development), Genzyme, Genentech, Jannsen Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, Novartis, Opexa Therapeutics, Receptos, Roche, EMD Serono, Spiniflex Pharmaceuticals, Somahlution, Teva pharmaceuticals, Transparency Life Sciences. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL.

Background: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated efficacy and an acceptable safety profile in relapsing-remitting multiple sclerosis (RRMS) in clinical studies. As women of childbearing age comprise a large proportion of the MS population, it is important to evaluate effects of DMF exposure on pregnancy. Objectives: We report preclinical data from animal reproductive toxicology studies and the outcomes of pregnancies occurring during the DMF clinical development program, as well as postmarketing experience. Methods: Reproductive and developmental toxicology was evaluated in rats and rabbits. As of 26 March 2014, clinical studies included 2,898 MS patients, 320 psoriasis patients, 101 rheumatoid arthritis patients, and 813 healthy volunteers; subjects were required to use reliable contraception and immediately discontinue drug in the event of pregnancy. Outcomes as of June 30, 2014 are reported for pregnancies in clinical trials and postmarketing experience. Results: There was no evidence of impaired fertility in rats or teratogenicity in rats and rabbits given DMF. As of 30 June 2014, a total of 63 pregnancies were reported in clinical studies, including 45 in subjects exposed to DMF, 13 in subjects exposed to placebo, and four in subjects exposed to glatiramer acetate. Pregnancy outcomes are known for 40 of 45 pregnancies in subjects receiving DMF: 27 live births (60%), 3 spontaneous abortions (7%), and 10 elective terminations (22%). Information is pending for 4 subjects and 1 was lost to follow-up. The incidence of spontaneous abortion was consistent with the expected rate of early pregnancy loss in the general population (12-22%). A total of 135 pregnancies were reported in the postmarketing setting (104 spontaneous reports and 31 solicited reports); pregnancy is ongoing in 103 cases. There were 10 live births, 13 spontaneous abortions, and 5 elective terminations; 2 patients were lost to follow-up. There was one reported foetal abnormality (not considered associated with DMF). Outcomes continue to be monitored through spontaneous reports in the postmarketing setting and a pregnancy registry; updated data will be presented. Conclusions: Based on available evidence with known gestational exposure limited to the first trimester, DMF was not associated with increased risk of foetal abnormalities or adverse pregnancy outcomes. The overall benefit-risk of DMF remains favourable. Disclosure

P608 Delayed-release dimethyl fumarate and pregnancy: preclinical studies and pregnancy outcomes from clinical trials and postmarketing experience J. Li1, R.J. Fox2, J.T. Phillips3, E. Havrdova4, A. Bar-Or5, L. Kappos6, N. Kim1, P. Valencia1, L. Oliva1, M. Novas1, R. Gold7, J. Rana1 1Biogen, Inc., Cambridge, MA, 2Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, 3Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, United States, 4First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, 5Montreal Neurological Institute, McGill University, Montreal, QC, Canada, 6University Hospital Basel, Basel, Switzerland, 7St. Josef Hospital, Ruhr University, Bochum, Germany

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This study was funded by Biogen, Inc. Jie Li: Employee of and holds stock/stock options in Biogen. Robert J. Fox: Consultant fees from Actelion, Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Actelion, Biogen, and Novartis; research grant funding from Novartis. J. Theodore Phillips: Consulting fees from Acorda, Biogen, Genzyme, Merck Serono, and Sanofi; research support from Roche. Eva Havrdova: Honoraria from Bayer, Biogen, Genzyme, GlaxoSmithKline, Merck Serono, Novartis, Sanofi, and Teva; research support from Biogen; supported by PRVOUK-P26/ LF1/4, program of Ministry of Education, Czech Republic. Amit Bar-Or: Honoraria and/or research support from Amplimmune, Aventis, Bayhill Therapeutics, Berlex, Biogen, Diogenix, Eli-Lilly, EMD Serono, Genentech, GlaxoSmithKline,


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Medimmune, Novartis, Ono Pharma, Receptos, Roche, Sanofi Genzyme, and Teva Neuroscience. Ludwig Kappos: Institution (University Hospital Basel) received and used exclusively for research support: steering committee, advisory board and consultancy fees from Actelion, Addex, Bayer Health Care, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, Xenoport; speaker fees from Bayer Health Care, Biogen, Merck, Novartis, Sanofi-Aventis, Teva; support of educational activities from Bayer Health Care, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva; royalties from Neurostatus Systems GmbH; grants from Bayer Health Care, Biogen, Merck, Novartis, Roche, Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations. Norman Kim: Employee of and holds stock/stock options in Biogen. Patricia Valencia: Employee of and holds stock/stock options in Biogen. Lauren Oliva: Employee of and holds stock/stock options in Biogen. Mark Novas: Employee of and holds stock/stock options in Biogen. Ralf Gold: Honoraria from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders. Jitesh Rana: Employee of and holds stock/stock options in Biogen. P609 Modeling probability of cases of dimethyl fumarateassociated PML  with normal lymphocytes R. Carruthers1, B.C. Healy2 1Neurology, University of British Columbia, Vancouver, BC, Canada, 2Neurology, Brigham and Women’s Hospital Harvard Medical School, Boston, MA, United States Background: A case of progressive multifocal leukoencephalopathy (PML) in a patient treated with dimethyl fumarate (DMF) without lymphocytopenia has concerning implications for Multiple Sclerosis (MS) patients taking delayed-release dimethyl-fumarate. Objective: Explore whether a model of PML risk in DMF-treated patients with normal lymphocytes built using the number of DMF-treated patients worldwide (presently 100,000) and incidence of lymphocytopenia (< 500 cells per cubic millimeter) sustained over 6 months (2%) can predict rates of PML occurring with normal lymphocytes. Methods: We apply a range of negative predictive values (NPV) (0.9995, 0.999,0.995, 0.99) in order to calculate the number of patients at risk for PML despite normal lymphocyte counts (false negatives). We then apply a range of rates of developing PML (0.0001, 0.001, 0.01) in that group in order to calculate the expected number of PML cases. By using the binomial function, we calculate the probability of a given number of DMF-associated PML cases in patients with normal lymphocyte counts. Results: Given the large numbers of patients with normal lymphocyte counts, one can predict cases of DMF-associated PML

cases even with superb negative predictive value (eg. 86% chance of 3 or more cases with a NPV of 0.995 and a risk of PML of 1/100). More than one case of PML case in DMF-treated patients with normal lymphocytes would suggest that the risk of PML must be higher than 1/1000, unless the NPV was 0.99 or less. Conclusion: With this model, one has a means to establish a threshold rate of DMF-associated PML cases normal lymphocytes at which it is improbable that our understanding of PML risk is adequate. More than three cases of PML with normal lymphocytes in 100,000 DMF-treated patients would be troubling especially for patients with milder forms of MS. Disclosure RC is participating in clinical trials in both MS and NMO as site PI with MedImmune and Teva, in addition to other involvement in trials sponsored by Roche, Genzyme, Biogen, Novartis. RC has received honoraria for speaking from Genzyme, Biogen and Teva.

P610 Lymphopenia in patients on dimethyl fumarate (DMF): data from the providence multiple sclerosis center K.E. Smoot, C. Chen, E. Baraban, L. Grote, K. Kresa-Reahl, S. Cohan Providence Multiple Sclerosis Center, Providence Brain and Spine Institute, Portland, OR, United States Objective: To evaluate the prevalence of lymphopenia in patients treated with DMF. Background: Two phase III pivotal trials showed that DMF reduces circulating lymphocyte count by approximately 30%, and sustained grade III lymphopenia (absolute lymphocyte count; ALC < 0.5) has been observed in approximately 2% of patients. In addition, progressive multifocal leukoencephalophy was recently reported in a lymphopenic patient with ALC ranging from 0.29 to 0.58 for more than 3 years. Given this case, the long-term safety of DMF has been questioned in the setting of prolonged lymphopenia. Therefore, close observation of patient’s lymphocyte count potentially may be important. Methods: This was a retrospective study of patients who were prescribed DMF 240 mg twice day for relapsing MS between March 2013 and May 2015 at Providence MS Center. Review of medical record was performed at the time of starting DMF and every 6 months thereafter until discontinuation. For patients who stopped DMF because of lymphopenia, ALC was monitored until it returned to the normal range. Results: 323 patients were included: mean duration on DMF was 17.57 (±6.3) months and mean age was 49 (±12.1) years. 8.67% (28/323) of the patients had their ALC dropped below 0.5 at some point during DMF treatment. These patients were found to be older than those without lymphopenia (58.7 vs 48.1 years, p < 0.001). A trend of ALC decline was observed in this cohort- from 2.037± 0.89 (n = 323) at baseline, to 1.67 ± 0.66 (n = 74) at 0-2.99 months, to 1.44 ± 0.71 (n = 183) at 3-5.99 months, to 1.32 ± 0.67 (n = 208) at 6-11.99 months, and to 1.15 ± 0.83 (n = 138) at 12 months or longer after starting DMF treatment. Conclusions: Our data suggest that grade III lymphopenia is more prevalent in older patients, about 4 times more common in a community-based cohort than previously reported from clinical


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Poster Session I, 21(S11) trials, and might not spontaneously resolve for several months. The prevalence of lymphopenia could have been underestimated in the clinical trials because patients older than 55 were excluded to participate. The study results emphasize the importance of ongoing ALC monitoring in this population. Disclosure Kyle Smoot - Honorarium and/or Consulting Fees from Acorda, Biogen, EMD Serono, Pfizer, Novaritis, and Teva. Chiayi Chen - No disclosures. Lois Grote - No disclosures. Elizabeth Baraban - No disclosures. Kiren Kresa-Reahl - Honorarium and/or Consulting Fees from Acorda, Biogen, EMD Serono, Pfizer, Novaritis, and Teva. Stanley Cohan - Research support from Biogen, Novartis, SanofiGenzyme, Opexa, Mallinckrodt and Roche-Genentech. Served as a paid consultant on advisory boards or steering committees for Biogen, Novartis, Sanofi-Genzyme and Mallinkrodt. Received speaker honoraria from Biogen, Novartis, Sanofi-Genzyme and Acorda. P611 Pregnancy outcomes after exposure to fingolimod and in the general population Y. Geissbühler1, G. Koren2, H. Wang3, H. Butzkueven4,5, H. Tilson6, T.M. Macdonald7, J. Vile8, K. Hellwig9 1Novartis Pharma AG, Basel, Switzerland, 2The Hospital for Sick Children, Toronto, ON, Canada, 3Quintiles, Cambridge, MA, United States, 4Department of Neurology, Royal Melbourne Hospital, Parkvile, VIC, Australia, 5Department of Medicine, University of Melbourne, Parkville, VIC, Australia, 6University of North Carolina School of Public Health, Chapel Hill, NC, United States, 7Ninewells Hospital and Medical School, Dundee, United Kingdom, 8Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States, 9Department of Neurology, St. Josef Hospital, Ruhr University, Bochum, Germany Background: The incidence of multiple sclerosis (MS) is higher among women and peaks at approximately 30 years of age. Thus, the potential impact of MS treatment on pregnancy outcomes is of utmost importance for this patient population. Limited data are available on fingolimod effects on pregnancy outcomes. Objective: To present updated information on pregnancy outcomes from different data sources in women exposed to fingolimod. Methods: Data on pregnancy outcomes (prospective cases) from the Multinational Gilenya® Pregnancy Exposure Registry and the Novartis safety database are reported here. In the Gilenya Pregnancy Registry prospective cases are those where condition of the foetus was NOT assessed through prenatal testing and outcome of the pregnancy was NOT known at the time of enrolment. For the Novartis safety database, prospective cases include any pregnancies with unrecognized foetal abnormalities or unknown fetal outcome, which is a broader definition. Results: As of end of February 2015, a total of 879 cases related to fingolimod exposure (maternal) were reported in the Novartis safety database including the 83 cases from the Gilenya Pregnancy Registry. Among the prospective cases with known outcomes (n=33), the prevalence (95% confidence interval [CI]) of congenital/major congenital malformations in live births in the

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pregnancy registry was 3.8% (95% CI: 0.1, 19.6)/ categorization into major malformations by adjudicators is ongoing. The corresponding prevalence in the Novartis safety database (prospective cases with known outcome=349 including 56 registry cases (see methods section)) was 5.4% (95% CI: 2.9, 9.0)/2.1% (95% CI: 0.7, 4.7) and all of the above are comparable with published reports from general population (3.2% to 3.6%/2.1% to 4.1%). Data from fingolimod unexposed MS patients will be presented upon availability as well as data of pregnancy outcomes other than malformations. Conclusion: Although firm conclusion can’t be drawn based on the limited available information, the results so far suggest that the prevalence of congenital malformations following exposure to fingolimod is in line/similar to that observed in the general population. Disclosure Funding source: This study is supported by Novartis Pharma AG, Basel, Switzerland. Gideon Koren has nothing to disclose Helmut Butzkueven has received compensation for serving as consultant or speaker or he or institution he works for has received research support from Biogen Idec, Novartis, Merck Serono and Sanofi-Genzyme; on the editorial board of Multiple Sclerosis International and Multiple Sclerosis and Related Disorders; received project grants from National Health and Medical Research Council (NHMRC), Australian Research Council Linkage Grant RG and National MS Society (USA) Hugh Tilson is widely associated with the multinational pharmaceutical industry, including services rendered on several global pregnancy and disease registries; advisor to the FDA, HRSA and the WHO Collaborating Centers on Drug Safety matters T M MacDonald has received compensation for serving as consultant or speaker or he or institution he works for has received research support from Novartis, Pfizer, Ipsen & Menarini, Kaiser Permanante, Takeda, Recordati, Servier, Menarini, NiCox and AstraZeneca Kerstin Hellwig has received compensation for serving as consultant or speaker or he or institution he works for has received research support from Bayer, Schering Healthcare, Teva, Sanofi Aventis, Biogen Idec, Merck Serono and Novartis Hong Wang is an employee of Quintiles, Cambridge, MA, USA Yvonne Geissbühler and Jere Vile are employees of Novartis Pharma AG, Basel, Switzerland P612 Acute humoral and cellular effects during the first alemtuzumab infusion week in active multiple sclerosis (MS) patients K. Thomas, J. Eisele, M. Marggraf, N. Kretschmann, L. Neubeck, T. Ziemssen Center of Neurological Science. University Hospital Carl Gustav Carus, Dresden, Germany Background: The approved anti-CD52 antibody alemtuzumab (ATZ) exerts its clinical efficacy by its specific pattern of depletion and repopulation of different immune cells. Although longterm effects on different immune cell subsets in blood are well described, little is known about acute effects taking place directly


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during the 1st ATZ infusion week, which have not been analysed in both phase 3 studies. Methods: 14 patients with active MS have been included before ATZ infusion: Besides typical clinical parameters (body temperature, blood pressure, heart rate) blood samples were collected at different time intervals (before, after application of prednisolone, after ATZ infusion) every day of infusion. Complete blood cell count, acute phase proteins (APP), serum cytokine profile, complement activation, distribution of peripheral immune cells and their potential of cytokine release were investigated. Results: Leukocyte respectively granulocyte count markedly increased up to 25 Gpt/l already after 1st ATZ infusion and lined up to normal values in the following days. Lymphocytes (LYM) decreased from mean 1.9 GpT/l down to 0.2 Gpt/l after 1st and < 0.05 GPT/l after 2nd infusion. Absolute CD4+, CD8+, CD19+ LYM count demonstrated a slight recovery before ATZ and dropped dramatically to nearly 0 after each infusion. Monocytes decreased from 0.48 Gpt/l to 0.14 Gpt/l after 1st ATZ application and kept stable at about 0.1 Gpt/l. Cytokine-release of IFNg, IL4, IL10, IL12, IL17 after in vitro stimulation of LYM and antigen presenting cells was already impaired after 1st and completely suppressed after 2nd ATZ infusion. After 1st ATZ, cytokine serum level increased on average up to 150pg/ml IFN-g, 100pg/ml IL-1b, 300pg/ml IL-6 and 180pg/ml TNF-a. Whereas IFN-g and IL-1b could not be detected any more after 1st infusion, IL-6 and TNF-a were increased during all infusions. After ATZ infusion, C-reactive protein peaked up to 110 mg/ml on day one and day three. Procalcitonine increased up to 55 ng/ml on day one and declined constantly by following days. Clinical parameters did not demonstrate any abnormalities during the infusion. Conclusion: Dramatic effects could be demonstrated during ATZ infusion. So regular blood analysis during the infusion could not be recommended as significant. ATZ related artefacts would be shown which could not help regarding clinical decision-making (eg. APP, LYM). Notable, targeted blood LYM, are only a minor population of the overall LYM pool. Disclosure K. Thomas has received speaker honorarium from Novartis, Bayer and Biogen idec. T. Ziemssen is on the scientific advisory board for Bayer Healthcare, Biogen Idec, Novartis, Merck Serono, Teva, Genzyme, Synthon; has received speaker honorarium from Bayer Healthcare, Biogen Idec, Genzyme, MSD, GSK, Novartis, Teva, Sanofi, Almirall, research support from Bayer Halthcare, Biogen Idec, Genzyme, Novartis, Teva and Sanofi. J. Eisele, M. Marggraf, N. Kretschmann and L. Neubeck have nothing to disclose. P613 Diagnostically challenging PML: case of a small unifocal lesion with mild radiological progression and CSF negative for JCV DNA and antibodies M.H. Hyland, G.A. Yeaney, A.D. Goodman University of Rochester Medical Center, Rochester, NY, United States Objective: To describe an atypical and diagnostically challenging case of progressive multifocal leukoencephalopathy (PML).

Background: PML in the setting of natalizumab therapy for MS has been reported very rarely with repeatedly negative PCR for JC polyomavirus (JCV) DNA in CSF. Methods: A 38 year-old woman with relapsing multiple sclerosis (MS) treated with natalizumab for 44 months with known JCV antibody seropositivity had a new left thalamic non-enhancing T2 hyperintensity seen on brain MRI within days of development of new right upper extremity tremor. This prompted discontinuation of natalizumab because of suspicion of PML. Results: CSF was negative for JCV DNA within a week of symptom onset and on 4 additional tests, even after natalizumab was re-dosed once after 3 months to try to prevent MS flare in the setting of diagnostic uncertainty. JCV antibody in CSF was negative initially and 2 months post-symptom onset. The MRI lesion showed mild monthly progression from 7 x 6 mm at onset to 12 x 8 mm at 5 months. The patient´s tremor gradually progressed in severity but did not extend beyond her right arm, and no new symptoms developed. Stereotactic biopsy at 5 months demonstrated viral cytopathic effects, bizarre astrocytes, and positive immunohistochemistry for SV-40, consistent with PML. Conclusions: This PML case demonstrates that JCV DNA may be negative in CSF even when tested early and often. PML lesions on MRI may be unifocal with mild progression, and any degree of persistent clinical or radiological progression should further raise suspicion for PML in natalizumab treated MS patients. Brain biopsy may be critical to the diagnosis of PML and should be strongly considered even with modest progression when other testing has been inconclusive but clinical suspicion for PML remains high. Disclosure Megan Hyland: Nothing to disclose Gabrielle Yeaney: Nothing to disclose Andrew Goodman received compensation for consulting from Abbvie, Acorda Therapeutics, Biogen Idec, EMD-Serono, Genzyme-sanofi, Novartis, Teva, and his employer, the University of Rochester, received research support from Acorda Therapeutics, Avanir, Biogen-Idec, EMD-Serono, Genzyme-sanofi, Novartis, Ono, Roche, Sun Pharma, and Teva. P614 Risk of cancer in multiple sclerosis patients who developed high concentrations of neutralizing antibodies against interferon-beta N. Koch-Henriksen1,2, M. Magyari2,3, C. Johansen4,5, P.S. Sørensen3 1Dept. of Clinical Epidemiology, University of Aarhus, Aarhus, 2The Danish Multiple Sclerosis Registry, 3The Danish Multiple Sclerosis Center, 4Onchology Clinic, Copenhagen University Hospital, Rigshospitalet, 5The Danish Cancer Society Research Centre, Copenhagen, Denmark Background: A considerable fraction of MS patients treated with interferon-beta (INFb) develop neutralizing antibodies (NAbs). High titre antibodies tend to be long-lasting even after cessation of treatment, and they may also neutralize endogenous IFNb, which is thought to exert a natural protection against cancer. If so, patients who have developed high-titre NAbs may be at a higher risk of developing cancer later in life.


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Poster Session I, 21(S11) Objectives: To estimate the risk of cancer later in life in Danish IFNb-treated MS patients, who werehigh-titre NAb positive, compared with NAb negative. Methods: A central laboratory determined the NAb titres of all Danish IFNb-treated MS-patients, who had their first NAb-test between 1996 and 2008. Results of these tests were filed in the Danish MS Treatment Register. A NAb test was high-titre positive if the neutralization capacity exceeded 79%. Patients were regarded as NAb high-titre positive, if they had at least two positive and no subsequent negative test, and as NAb negative, if they had at least two negative and no positive tests. Information on cancers was obtained by linkage to the Danish Cancer Registry with end of follow-up 30 November 2010. Patients were excluded if they had a cancer diagnosis prior to one year after the first NAb test. High-titre NAb positive and NAb negative patients were propensity score matched (PSM) by logistic regression matching for age and year of first NAb-test, using ‘nearest neighbour’ 1:3 match with a ‘caliper’ of 0.1 standard deviations of propensity scores and exact matching for sex. Patients were followed to the date of cancer diagnosis, death, emigration, or end of follow-up, whichever came first. The hazard ratio (HR) for cancer was estimated by Cox regression modelling. Results: Following PSM 1,776 patients divided in 447 high-titre NAb positive and 1,329 NAb negative patients were included. The total number of patients who developed cancer was 82 distributed as 24 NAb high-titre positive and 58 NAB negative, respectively. The Hazard ratio for developing cancer for NAb positive versus NAb negative was 1.2 (95% CI, 0.75 - 1.93; p = 0.45). Distribution of types of cancer was equal when comparing the two groups. Treatment with mitoxantrone had no effect on the risk for cancer (p = 0.65). Conclusion: With an observation period up to fourteen years, high titres of NAbs against IFNb in MS patients do not carry an increased risk for developing cancer later in life. Disclosure N. Koch-Henriksen has received honoraria for lecturing and participation in advisory councils, travel expenses for attending congresses and meetings, and financial support for monitoring the Danish MS Treatment Register from Bayer-Schering, MerckSerono, BiogenIdec, TEVA, Sanofi-Avensis, and Novartis. M. Magyari has served on scientific advisory board for BiogenIdec and TEVA and has received honoraria for lecturing from BiogenIdec, MerckSerono, Sanofi-Aventis, and Teva. She has received support for congress participation from BiogenIdec, MerckSerono, Novartis, and Genzyme. P. Soelberg Sørensen has served on scientific advisory boards for Merck Serono, Teva, Novartis, Sanofi -Aventis, and Biogen Idec and has received research support from BiogenIdec, Novartis, and Sanofi -Aventis and received speaker honoraria fromMerck Serono, Novartis, Teva, Sanofi -Aventis, Biogen Idec, and Genzyme. P615 Comparative analysis of oral disease-modifying therapies after natalizumab withdrawal in patients with multiple sclerosis N. Hadhoum1, O. Outteryck1, J. Labreuche2, M. Cambron1, A. Chouraki1, E. Duhin1, D. Ferriby1, A. Kwiatkowski3, A. Lacour1, A. Verier4, P. Hautecoeur3, P. Vermersch1

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1Department

of Neurology, 2Department of Biostatistics,CERIM, Lille University, CHU Lille, 3Department of Neurology, Hospital Group of Catholic Institute of Lille (GHICL), Lille, 4Department of Neurology, Valenciennes Hospital, Valenciennes, France Background: Managing the natalizumab (NTZ) withdrawal is crucial. Until now, no strategy has shown superior efficacy in preventing multiple sclerosis (MS) activity reactivation after NTZ cessation. Current data do not allow to specify the role of new oral treatments. Objective: To evaluate the efficacy and tolerability of dimethyl fumarate (DMF) and fingolimod (FG) in preventing post-NTZ disease activity recurrence. Methods: Patients with MS followed-up for 6 months after NTZ withdrawal (due to JCV index>1.5 and NTZ treatment duration>24months) from four centers in northern France were prospectively followed-up and treated either with FG or DMF after a short washout-period (1 month). Clinical examinations and MRI scans were performed at baseline and after 3 (M3) and 6 (M6) months. Results: A total of 108 patients stopped NTZ treatment in May 2014 (FG=50; DMF=58). There was no significant difference in baseline characteristics between the 2 sub-groups. At M3, in our overall cohort, 88.2% (n=90) of patients showed no new enhanced lesion and 89.8% (n=97) experienced no clinical activity. The mean EDSS was 3.05 (2.8 at baseline) and disability progression was noted in 12 patients. At M6, 65.6% (n=63) of patients showed no new active lesions and 71.3% (n=77) were clinically stable. The annualized relapse rate (ARR) was higher at M6 (1.133) compared with the NTZ period (0.208) (p< 0.0001). The mean EDSS was 3.18, 13 patients experienced disability progression. We observed in our overall cohort less enhanced lesions and a lower ARR after the switch than before NTZ initiation (p=0.0005 and p=0.005 respectively). The sub-group analysis did not showed significant differences for the cumulative number of enhanced lesions at M3 and M6 between DMF (0.78 ±1.61) and FG (1.44 ±2.5). There were no difference between DMF and FG comparing ARR, EDSS at M6. We report 1 confirmed case of progressive multifocal leukoencephalopathy (JCV-PCR+). Three additional patients experienced serious adverse effects, the evolution was favourable after treatment interruption. Conclusion: The switch to FG or DMF after a short washout period was well tolerated and globally led to favourable outcome since we did not observed rebound activity. However an increase of the EDSS was noted in a significant number of patients. Emergent therapies should be part of the strategy when stopping NTZ. It seems wise to remain cautious considering the lack of long-term data. A longer follow-up is warranted. Disclosure Hadhoum N. reports funding for travel from Teva Phamaceutical Industries, outside the submitted work. Outteryck O. reports grant for research from Novartis; grants and personal fees from Biogen-Idec, funding for travel from BiogenIdec, Genzyme-Sanofi, Merck-Serono, Novartis and Teva Pharmaceutical Industries Labreuche J.: Nothing to disclose Cambron M.: Congress fees and travel expenses from Biogen Idec, Novartis, Genzyme,Merck-Serono, Bayer, consulting fees from Novartis


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Chouraki A.: Travel grants and registration fees from Biogen and Genzyme-Sanofi Duhin E.: Nothing to disclose Ferriby D.:Biogen, Schéring, genzyme, Teva, Serono, Novartis Kwiatkowski A.: Nothing to disclose Lacour A.: Grants and consulting fee from LFB, Pfizer, Merz, research supports from: Biogen-Idhec, Serono, TEVA, Novartis, Pharnext, LFB, Octapharma, Alexion, Alnylam Verier A.: Biogen, Novartis, Teva, Merck Serono, Bayer, Genzyme Hautecoeur P.: Nothing to disclose Vermersch P.: Honoraria and consulting fees from Biogen, Genzyme-Sanofi, Bayer, Novartis, Teva, Merck-Serono, GSK and Almirall, research supports from Biogen, Bayer, Novartis and Merck-Serono P616 Variability of John Cunningham virus (JCV) index in multiple sclerosis patients treated with natalizumab in routine clinical practice N. Arndt, A.T. Reder, A. Javed Neurology, University of Chicago Medicine, Chicago, IL, United States Background and goals: Natalizumab is an effective therapy for MS. However, its use is guarded due to risk of progressive multifocal leukoencephalopathy (PML). Anti-JCV antibody (antiJCVAb) index is used to estimate risk for PML, values < 1.5 predicting lower risk. Fluctuations of the anti-JCVAb index over time may alter the risk for PML. However, minor changes in its value may be from assay variability and biological phenomena but not related to JCV viremia. This study determined test-retest variability in the anti-JCVAb index and whether its value varies among different MS subgroups. Design/methods: This was a retrospective analysis of the antiJCVAb index at the University of Chicago. For assessing testretest variability, Pearson’s correlation coefficient (r) and Bland-Altman (B-A) plot analyses were done. Multiple regression analysis examined whether age, race, and gender influenced the variability in anti-JCVAb index. 42 samples were available from two-time point (range 19 days-24 months) assessments and 87 for regression analysis. There were 31 males, 56 females, 28 African Americans, and 59 non African Americans. Results: The mean anti-JCVAb index values for times 1 and 2 were 1.73 (SD 1.40) and 1.63 (SD 1.21). The correlation coefficient for test-retest was 0.93. The B-A plot of the difference in time1-time 2 against the mean of time1+time 2 showed that the majority of time points (40/42) were within the 95% confidence interval of -0.97 and +1.15. However, for anti-JCVAb index values of > 1.5, there was less agreement on the B-A plot. The difference in variance between time 1 and time 2 (Pitman’s Test) had a correlation r-value of 0.374, p=0.015. Multiple regression did not show any effect of age, race, or gender on the anti-JCVAb index, although there was a trend seen in the regression model (Prob > F 0.08). In univariate analysis, female gender showed a trend towards lower JCV-Ab index (coef -0.67, t -.25, p>t 0.03). Also, of the 3 tested variables, gender had the highest input (beta coefficient -0.24). Conclusions: The test-retest anti-JCVAb index values have a high correlation and agreement appears higher for index values < 1.5.

Although there is significant variance in testing, the majority of the repeated index values fall within a narrow 95% confidence interval in our cohort. Disclosure N. Arndt has worked as a consultant for Biogen, Malinkrodt, Bayer, Novartis, Genentech and Genzyme. A. T. Reder has worked as a consultant for Bayer, Teva, Serono, Malinkrodt, Biogen, Genetech, Novartis, and Genzyme. A. Javed has worked as a consultant for Bayer, Teva, Serono, Malinkrodt, Biogen, Genentech, Novartis, and Genzyme. P617 Longitudinal anti-JCV antibody titres increase with natalizumab treatment J. Raffel, A. Gafson, O. Malik, R. Nicholas Imperial College London, London, United Kingdom Objectives: Anti-JC virus antibody (Ab) status is a risk factor for progressive multifocal leukoencephalopathy after natalizumab treatment in multiple sclerosis. Previous studies have used a cross-sectional approach to conclude that the presence and duration of natalizumab treatment does not influence anti-JCV Ab seropositivity. This study used a longitudinal approach to investigate whether anti-JCV Ab results change with natalizumab treatment. Methods: Anti-JCV Ab results (n= 1154) from the second-generation STRATIFY JCV™ DxSelect™ test were analysed from an observational cohort of MS patients on natalizumab (n = 485; n= 340 with repeat testing; n = 669 repeat tests). Results: At baseline, 59% (287/485) of patients were anti-JCV Ab seropositive; 33% (162/485) had a high anti-JCV Ab titre (> 1.5). Baseline titres and rates of seropositivity increased slightly with baseline patient age. With multiple tests repeated over time, 22.3% of seronegative patients seroconverted to seropositive, while 4.9% of seropositive patients seroreverted to seronegative. When comparing pairs of longitudinal tests, seroconversion rate remained greater than seroreversion rate (40/373 (10.7%) vs 18/296 (6.1%); p < 0.05). Moreover, anti-JCV Ab titres increased across longitudinal paired tests (mA-B 0.095; paired t(668) = 4.6; p< 0.0001). This magnitude of antibody level increase far exceeds that expected due to age alone. The mean increase in longitudinal anti-JCV Ab titre occurred in all baseline titre groups, other than tests with baseline titre >3.0 which had a mean decrease in longitudinal titre. Conclusion: Our data suggest that natalizumab therapy is associated with an increase in anti-JCV Ab titres over time. This conflicts with results from cross-sectional studies, which likely suffer from selection bias. Further work should focus on the underlying mechanisms, and the clinical relevance to risk stratification, of this phenomenon. Disclosure Biogen Idec provided the STRATIFY Gen2 assay free-of-charge, as per normal clinical practice. Joel Raffel: Nothing to disclose Arie Gafson: Nothing to disclose Omar Malik has received travel grants to educational meetings from Biogen Idec and honoraria from Biogen Idec, which have


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Poster Session I, 21(S11) been used exclusively for clinical research, outside the submitted work. Richard Nicholas has received grants, personal fees and nonfinancial support from Novartis, grants, personal fees and nonfinancial support from Biogen Idec, personal fees from Genzyme, personal fees from Roche, outside the submitted work. P618 Severe relapses and rebound activity after natalizumab discontinuation in MS patients with more than five years of treatment with stable disease course J. Fagius1, J. Burman1, A. Feresiadou1, E.-M. Larsson2 1Neuroscience/Neurology, 2Surgical Sciences/Radiology, Uppsala University, Uppsala, Sweden Background: Several reports have described rebound activity after cessation of therapy following 1-2 years of natalizumab (NTZ) treatment. It is unknown whether NTZ can be safely discontinued after prolonged treatment with a stable disease course. Aim: To evaluate if NTZ can be safely discontinued after ⩾5 years of freedom from documented inflammatory disease activity. Methods: Prospective clinical and MRI evaluation was performed at 0, 3, 6, and 10 months after cessation of therapy. Patients were instructed to contact the study neurologist if new symptoms appeared and then a semi-acute clinical examination and MRI was added. Fifteen patients (10 women) were included. Mean age was 48 years, mean MS duration 17 years, mean duration of NTZ therapy 68 months, mean number of relapses the year before starting NTZ 2.3. Mean EDSS was 3.5 at the inception of NTZ treatment and 2.9 at withdrawal. A high JC-virus index (>1.5) was present in 7 patients. Results: Disease activity with new relapses developed in 7/15 patients during the follow-up period; 6/15 patients developed new gadolinium enhancing lesions; 6/15 had both. Patients with new relapses increased their mean EDSS 1.4. The number of gadolinium enhancing lesions was 1-25. Disease activity appeared 3-6 months after NTZ cessation. Four patients developed rebound disease activity with severe relapses and/or gadolinium enhancing lesions at a magnitude not seen before. Discussion: NTZ is one of the most widely used and most effective drugs for MS. At present it is unknown how long such treatment should continue. In the natural course of MS inflammatory disease activity usually abates after 50 years of age. Thus it was justified to investigate if NTZ could be safely discontinued in a cohort of predominantly older MS patients with a stable disease course. Our results clearly demonstrate that this is not the case, and a significant proportion of patients experienced a pronounced return of disease activity. This suggests that NTZ arrests the aging of the immune system, interrupting the process leading to decrease of inflammatory activity seen in untreated patients. Conclusion: NTZ therapy cannot be safely withdrawn without starting alternative therapy, even in older patients with stable disease. Patients and neurologists are well advised to be aware of this dilemma, which should be taken into account when NTZ therapy is considered. Disclosure Jan Fagius has received travel support and/or lecture honoraria from Biogenidec, Genzyme/SanofiAventis, Schering/Bayer, TEVA, and

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Merckserono; has received an unconditional research grant from Biogenidec. Joachim Burman has received travel support and/or lecture honoraria from Almirall, Biogenidec, Genzyme/SanofiAventis, Hospira, and Merckserono; has received unconditional research grants from Merckserono, and Biogen. Amalia Feresiadou has nothing to declare. Elna-Marie Larsson has nothing to declare in relation to this study. P619 Fatal rebound MS activity following natalizumab withdrawal: ante and post-mortem immunological characterization of CNS-infiltrating cells C. Larochelle1,2, I. Metz3, M.-A. Lécuyer1, S. Terouz1, N. Arbour1, W. Brück3, A. Prat1,2 1Department of Neuroscience, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), 2Multiple Sclerosis Clinic, Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada, 3Department of Neuropathology, Universitätsmedizin Göttingen, Göttingen, Germany Background: Severe central nervous system (CNS) inflammatory activity resistant to high-dose steroids is an infrequent but potentially lethal complication of natalizumab (NTZ) withdrawal. As NTZ reinstatement can lead to acute worsening, therapeutic management of this condition is still unclear. Here we report the case of a 32-year-old woman who displayed fatal rebound MS activity, without progressive multifocal leukoencephalopathy, after NTZ discontinuation. We performed ante and post-mortem analysis of the peripheral and the CNS immune cell populations to help identify the most promising therapies to control this type of life-threatening CNS inflammation. Methods: Peripheral blood and cerebrospinal fluid were analyzed by flow cytometry during hospitalization. Post-mortem pathological analysis of the CNS was performed using immunohistochemistry and immunofluorescence. We successfully isolated cells from fresh post-mortem CNS parenchyma samples using Percoll gradient for subsequent flow cytometry characterization of immune cell populations. The profile of activation markers and adhesion molecules expressed by CNS-derived immune cells was compared to cytological and pathological findings. Results: Analysis of blood and cerebrospinal fluid (CSF) demonstrated an enrichment of highly activated CD4>CD8 T lymphocytes expressing high levels of adhesion molecules in the CSF. Post-mortem pathological analysis of the brain confirmed the absence of JCV infection and the presence of numerous active inflammatory demyelinating lesions in the white and grey matter, typical of immunological pattern II (IgG- and complement-mediated). Lymphocytes were the most abundant immune cells in CNS infiltrates, with predominance of CD8 T cells in the parenchyma. Numerous plasma cells were also present. Pathological findings were supported by flow cytometry analysis of isolated CNS-infiltrating cells, underlining the differences in T cell populations between the CSF and the parenchyma. Finally, analysis of the cytokine profile of CNS-infiltrating lymphocytes revealed high levels of pro-inflammatory cytokines interferon-gamma (CD4>CD8), interleukin-17 (CD8>CD4), and granzyme B (CD8>CD4).


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Conclusions: Our results suggest that using an approach targeting both T and B lymphocytes would be needed to successfully control the tremendous CNS inflammation associated with rebound MS activity after NTZ.

suggests that assessment of the Th17/IL-17 axis might prove to be an applicable predictive marker of rebound MS activity in patients switching immunotherapies. Disclosure

Disclosure Catherine Larochelle: Nothing to disclose Imke Metz: Nothing to disclose Marc-Andre Lecuyer: Nothing to disclose Simone Terouz: Nothing to disclose Nathalie Arbour: Nothing to disclose Wolfgang Brück: Nothing to disclose Alexandre Prat: Nothing to disclose P620 Dynamics of Th17 cells during and after cessation of natalizumab therapy B. Wildemann, A. Schwarz, M. Korporal-Kuhnke, J. Haas Department of Neurology, University Hospital of Heidelberg, Heidelberg, Germany Background: MS patients switching immunotherapy from natalizumab (NAT) are at risk to develop recurrence or even rebound disease activity. Mechanisms that govern breakthrough disease are not well understood and, so far, suitable biomarkers that help to identify those patients at risk to develop relapses and worsening of MS-related disability are not available. Possible immunological scenarios that might contribute to MS reactivation after withdrawal of highly effective immunotherapies include the facilitated entrance of potentially harmful immune cells such as proinflammatory effector T helper 17 (Th17) cells which have been acknowledged as crucial mediators of autoimmune tissue damage with a suggested pathogenic role in MS. Objective: We monitored prevalences of circulating Th17 cells before, during and following discontinuation of NAT to test for their eligibility as biomarker allowing identifying patients at risk to develop MS reactivation after cessation of NAT. Methods: The study was enrolled with 403 blood samples obtained from 57 patients exposed to NAT due to highly active MS. Samples were serially taken during NAT therapy, during wash-out, and after resuming immunotherapy with fingolimod (FTY) or dimethyl fumarate (DMF). We used multi-colour flow cytometry of isolated PBMCs to monitor a panel of T- and B-cell subsets - including Th17 cells - and ELISA to monitor IL-17 levels in serum and - when available - in cerebrospinal fluid (CSF). Results: As compared with untreated patients both, relative numbers of Th17 cells and IL-17 levels were increased in peripheral blood of patients undergoing NAT treatment. After cessation of NAT Th17- and IL-17 plasma levels dropped back to baseline. Of note, concentrations of Th17 cells and IL-17 were further decreased and almost undetectable in most blood samples obtained from those individuals who experienced a relapse during the washout phase, whereas high levels of IL-17 were detectable in (two) parallel CSF samples available from those patients. Conclusion: Our finding that disease reactivation following NAT withdrawal coincides with disappearance of Th17 cells from blood and, in parallel, high IL-17 levels in CSF might point to a facilitated re-entry of Th17 cells into the CNS prompted by the interrupted VLA4 blockade on trafficking lymphocytes. This

Supported by grants from Biogen Idec and the German Ministry for Education and Research (BMBF, “German Competence Network Multiple Sclerosis” (KKNMS), Research Alliance “Understand MS”, AII (FKZ 01GI0909) and B1 Alliance. Funding sources had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the abstract for publication. B. Wildemann has received honoraria for speaking/consulting and travel grants from Bayer Healthcare, Biogen Idec, Merck Serono, Genzyme, a Sanofi Company Novartis Pharmaceuticals, Teva Pharma GmbH, and research grants from Biogen Idec, Biotest, Merck-Serono, Novartis Pharmaceuticals, Teva Pharma GmbH, the German Ministry of Education and Research, and the Dietmar Hopp Foundation. J. Haas, A. Schwarz, and M. Korporal-Kuhnke have nothing to disclose.

P621 Disease activity after natalizumab discontinuation: a retrospective study from two Italian MS centers M. Lo Re1, P. Ragonese1, M. Capobianco2, S. Malucchi2, S. Realmuto1, M. Matta2, G. Salemi1, A. Bertolotto2 1University of Palermo, Palermo, 2Regional MS Centre AOU S.Luigi Gonzaga, Orbassano, Italy Background: Natalizumab (NTZ) discontinuation can be followed by the reactivation of Multiple Sclerosis (MS) disease activity: currently no Disease Modifying Drugs (DMDs) has been found able to abolish disease reactivation. Objective: 1) to determine the frequency of reactivation of MS after NTZ discontinuation, 2) to evaluate predictors of reactivation´ risk after NTZ discontinuation, and 3) to compare the effect of different treatment in reducing this risk. Patients and methods: Data from 132 patients with MS followed-up for 2 years before NTZ treatment and 1-year after interruption were collected from two Italian MS centers and retrospectively evaluated. The correlation between variables and MS reactivation was analysed by using unpaired t test for continuous variables and chi2 test for categorical variables. The relapse risk was estimated through a Cox regression model adjusted for: number of infusions, relapses in the two years before NTZ, washout period between NTZ and new therapy, therapeutic strategies after NTZ (no therapy, first-line therapies, Fingolimod, NTZ). Results: Overall, 72 patients had relapses after NTZ discontinuation and 60 patients had radiological reactivation. Rebound was observed in 28 patients. A higher number of relapses in the 2 year before NTZ treatment, a long wash-out period and a lower number of infusions of NTZ correlated with MS reactivation and rebound.


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Poster Session I, 21(S11) Ninety-five patients received DMDs after a mean wash-out of 5 months. Patients untreated had higher clinical and radiological activity and rebound in comparison to patients receiving DMDs. A lower risk of relapses was found in patients treated with secondline therapies (NTZ or Fingolimod) than in those treated with first-line therapies. Interestingly we observed no disease reactivation in a few patients treated with Rituximab (7 patients) and AHSCT (2 patients). One patient out of 4 treated with immunosuppressive therapy developed rebound. Conclusion: Our results confirm the risk of MS reactivation and rebound after NTZ suspension and indicate that an alternative treatment should be prompt resumed mainly in patients with a previous very active course and with a shorter NTZ therapy. Secondline therapies demonstrate a superiority in preventing relapses after NTZ discontinuation. Disclosure Marianna Lo Re, received travel expenses from Biogen, Novartis and Teva. Paolo Ragonese, received travel expenses or honoraria for consultancy from Merck Serono, Biogen, Novartis and Sanofy Genzyme and Teva Pharma. Marco Capobianco received speaking honoraria and/or consultant fees from Biogen, Merck-Serono, Novartis, Teva, Genzyme and Almirall Simona Malucchi received speaking honoraria and/or consultant fees from Biogen, Merck-Serono, Novartis, Teva, Genzyme. Sabrina Realmuto, received travel expenses from Biogen and Sanofy Manuela Matta received travel expenses from Novartis, Biogen, Teva Pharma and Almirall Giuseppe Salemi, received travel expenses or honoraria for consultancy from Merck Serono, Biogen, Novartis and Sanofy. Dr. Antonio Bertolotto received honoraria for serving in the scientific advisory boards of Almirall, Bayer, Biogen, Genzyme, with approval by the Director of AOU San Luigi University Hospital and received speaker honoraria from Biogen, Genzyme, Novartis, TEVA; his institution has received grant support from Bayer, Biogen, Merck, Novartis, TEVA from the Italian Multiple Sclerosis Society, Fondazione Ricerca Biomedica ONLUS and San Luigi ONLUS P622 Natalizumab treatment is associated with increased anti-JCV antibody seroconversion T. Schneider-Hohendorf1, N. Schwab1, B. Pignolet2, J. Breuer1, D. Brassat2, H. Wiendl1 1Neurology, University of Muenster, Muenster, Germany, 2Neurology, University of Toulouse, Toulouse, France Natalizumab treatment is associated with PML development. Seropositivity for anti-JCV antibodies is a risk factor for natalizumab-associated PML development. Recently, an anti-JCV antibody titer index value (JCV index) was published to further improve natalizumab-associated PML risk stratification. For patients with no prior immunosuppressant use, JCV index values were significantly higher in PML than in non-PML patients indicating that seropositive patients with low index values between

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0,4 and 0,9 have a lower PML risk compared to patients with titers above 0,9. That study, consisting of AFFIRM and STRATIFY-1 data, also revealed a seroconversion rate of up to 13% in 1.5 years consistent with a very recent interims analysis of the STRATIFY-2 study, which prompted a re-evaluation of the current natalizumab risk stratification algorithm by the EMA. We therefore analyzed JCV index and seroconversion rates in a German as well as in a second French cohort of 1912 and 1259 natalizumab-treated RRMS patients, respectively. Analysis of the JCV index showed no difference between seropositive patients of various disease entities (HD, RRMS, HIV, SLE), nor a correlation between JCV index and age in seropositive RRMS patients. However, JCV index values of seropositive patients rose by an average of 15.9% during one year of natalizumab treatment. Overall and cross-sectionally, anti-JCV antibody seropositivity rate was 55% and comparable to previously published cohorts with a change of the seropositivity rate by aging of about 0.5% per year. A cross-sectional analysis according to natalizumab treatment duration showed that the rate of JCV seropositivity rose from 40.0% at the beginning of the treatment to 54.6% after two years of treatment. High JCV seroconversion rates were further supported by longitudinal assessments of the patient cohorts: Germany-wide, 6.4% and in France, 9.2% of natalizumab-treated RRMS patients seroconverted each year significantly differing from the seroconversion by age of about 1% per year. This study clearly shows that natalizumab treatment facilitates JCV seroconversion demanding continuous monitoring of antiJCV antibody serostatus and JCV index. It further highlights the need for re-evaluation of the currently used risk stratification algorithm and additional PML-risk biomarkers. Finally, this data set is consistent with the hypothesis that the immune modulation by long term natalizumab treatment facilitates JCV activity or reactivation. Disclosure Disclosure of potential conflict of interest: TS-H received travel expenses compensation from Biogen. NS received honoraria for advisory boards and travel expenses from Biogen. BP and JB report no conflicts of interest. DB has received honoraria for lecturing and travel expenses for attending meetings and boards from Bayer-Schering, Biogen, Merck-Serono, Novartis, Sanofi-Aventis, and TEVA. HW received honoraria and consultation fees from Bayer Healthcare, Biogen, Fresenius Medical Care, GlaxoSmithKline, GW Pharmaceuticals, Merck Serono, Novartis Pharma, Sanofi Genzyme, and TEVA Pharma. Funding: This study was funded by the Deutsche Forschungsgesellschaft (DFG) Grant CRC128, Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), the PML Consortium to NS and HW, the Kompetenznetz Multiple Sklerose (Competence Network for Multiple Sclerosis) funded by the Federal Ministry of Education and Research (FKZ 01GI1308B 01GI0907) to HW, French Ministery of Health (PHRC 2008-005906-38, ARSEP (French MS society grant 2009 and 2011) to DB, and the EU (BEST-MS, FP7, 305477) to DB and HW.


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P623 The long-term impact of natalizumab on multiple sclerosis: to continue or to stop? F. Sangalli, L. Moiola, M. Radaelli, F. Esposito, B. Colombo, M. Rodegher, F. Martinelli-Boneschi, V. Martinelli, G. Comi San Raffaele Hospital, Milano, Italy Objective: To evaluate the probability of a 6-month-confirmed EDSS increase in patients discontinuing natalizumab (NAT) for risk stratification, compared to patients on long-term treatment. Methods: We collected data of 302 patients, subdivided into 2 groups as follows: patients who stopped NAT after at least 12 cycles and were followed for a minimum of 12 months (discontinuers); patients who received NAT for at least 24 months and were still on NAT at last follow-up. We analyzed clinical and neuroradiological data. Results: A total of 184 patients stopping NAT after 25 cycles on average, with a mean follow-up of 5 yearsv, were compared to 118 patients continuing NAT for a mean of 50 administration (continuers). At 6-years follow-up, discontinuers showed a significantly higher probability of EDSS sustained-worsening if compared to continuers (25% versus 10%, p=0,006), mainly due to disease reactivation after NAT stop. Moreover 43% of discontinuers lost the reduction of disability obtained during NAT. Risk factors for disability increase were higher baseline EDSS and older age at NAT start. Finally, NAT confirmed the well-known efficacy, showing a probability of “No Evidence of Disease Activity” of 63% after 6 years. Conclusion: Our data show that NAT discontinuation carries a 3-fold increased risk of disability if compared to drug continuation, especially for patients with higher EDSS. This finding need to be considered, together with information on PML risk stratification, in order to carefully evaluate a personalized benefit-risk profile of treatment with NAT. Disclosure Prof Comi received personal compensation for activities such as advisory board and consultant with the following companies: Novartis, Teva, Sanofi-Aventis, Merck Serono and Bayer Schering and for speaking with the following companies: Novartis, Teva, Sanofi-Aventis, Merck Serono, Biogen-Dompè and Bayer Schering. Dr Martinelli received travel supports and speaker fees for activities with Biogen Dompe, Merck-Serono, Bayer Schering, TEVA and Sanofi Aventis as a speaker. Dr. L. Moiola received personal compensation for speaking activity from Biogen Dompè and Sanofi-Aventis. Dr. F. Sangalli and Dr. M. Radaelli have nothing to disclose.

P624 Persistent lymphopenia after routine clinical use of dimethyl fumarate for relapsing remitting multiple sclerosis N.J. MacDougall1,2, P. Gallagher2, S. Murdoch2, L. Murray2, S. Webb2, J.R. Overell2 1Institute of Neuroscience and Psychology, University of Glasgow, 2Department of Neurology, MS Reseach Group,

Institute of Neurological Sciences, South Glasgow University Hospitals, Glasgow, United Kingdom Background: In Scotland dimethyl fumarate (DMF) has been used in routine clinical practice as a disease modifying agent in relapsing remitting multiple sclerosis since April 2014. Lymphopenia is reported during treatment with DMF. Progressive Multifocal Leukoencephalopathy (PML) has been reported in association with DMF-related lymphopenia. Methods: We audited the records of patients treated with DMF extracting data on treatment duration, lowest lymphocyte count (LCC), most recent LCC and LCC monitoring frequency. For patients with a LCC of 0.5 x 109/L or less we collected information on JC virus (JCV) status and clinical decision making. Results: From 20th April 2014-14 January 2015 228 patients resident in the Greater Glasgow and Clyde area were prescribed DMF. 199 patients were thought to be using DMF while 17 had stopped and 12 had not started treatment. 103 had used DMF for at least 6 months. Six patients prescribed DMF for >6 month had no evidence of LCC monitoring. Overall, 174 patients had their LCC checked at least once since starting DMF. There were 11/174 patients with LCC of 0.5 x 109/L or less (6.3%). Five were JCV positive and stopped treatment; 3 were JC V negative and 3 had not been tested. A LCC of 0.2 x 109/L was seen in 3 patients. One JCV negative patient stopped DMF due to a low LCC, 2 more stopped due to GI side effects and one stopped in preparation for pregnancy. A patient who stopped due to GI side effects still had a low LCC on fingolimod. Five months after stopping DMF 2 patients still had low LCC (0.5x109/L and 0.9x109/L). These patients had no other cause for persistent low LCC. The LCC nadir was 0.2x109/L for the first patient and 0.5x109/L for the second. Both patients had normal LCC in the past and no predictive factor for the current low LCC could be identified. Conclusions: In routine clinical use of DMF a lymphocyte count of 0.5x109/L or less was seen in 6.3% of patients. Low lymphocyte counts can persist after stopping DMF, and further long term follow up will characterise the duration of this. Given concerns about the risk of PML strict blood monitoring procedures to identify low lymphocyte counts are required. JCV testing may be a useful adjunct in determining PML risk in those with low lymphocyte counts. Disclosure NM has been funded to attend educational events by Biogen and Novartis PG has received funding for research and travel from Genzyme and travel funding for educational activities from Biogen Idec and UCB Pharma SM has been funded to attend educational events by Biogen LM has received honoraria from Novartis for participation in advisory boards and I have attended conferences funded by Biogen Idec SW has been sponsored by Biogen to attend conferences JO has received honoraria for speaking engagements and attendance at advisory boards from Teva, Novartis, Merck-Serono, Genzyme and Biogen. Additionally his department has received educational grants and funds to provide nursing and administrative staff from these companies.


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Tools for detecting therapeutic response P625 EAE in the marmoset as a preclinical model for B-cell targeting therapies Y.S. Kap1, S.A. Jagessar1, N. van Driel1, J.D. Laman2, B.A. ‘t Hart1,2 1BPRC, Rijswijk, 2University Medical Center Groningen, Groningen, The Netherlands Targeting B cells has proven to be an effective therapeutic approach for multiple sclerosis (MS). While new B cell targeting therapies continue to be developed, the exact role of B cells in MS remains unclear. A valid preclinical model to test new B cell targeting therapies and to investigate the pathogenic role of B cells is the marmoset model for MS, i.e. experimental autoimmune encephalomyelitis (EAE). Advantages of the marmoset EAE model are the development of myelin-specific immunoglobulins and the crucial role of B cells as antigen presenting cells leading to T cell activation. In addition, marmosets are naturally infected with the Epstein Barr virus (EBV)-like γ-herpesvirus CalHV3. We have investigated whether CD20+ B cell depletion in an antibody (Ab)-dependent and Ab-independent EAE model can halt the development of clinical symptoms and pathology and in which pathogenic processes the B cells play a crucial role. Marmosets were immunized with recombinant human myelin oligodendrocyte glycoprotein (rhMOG) in complete Freund’s adjuvant (Ab-dependent model) or with MOG34-56 in incomplete Freund’s adjuvant (Ab-independent model). Treatment with an anti-CD20 mAb was started 21 days after immunization. In both models, the development of clinical symptoms was prevented by depletion of CD20+ B cells. In the Ab-dependent model, the production of myelin-specific immunoglobulins was halted immediately after the start of the weekly treatment. Since secondary lymphoid organs (SLO) were available, a more detailed analysis could be performed demonstrating that B cells are involved in the egress of T cells from the SLO. This was shown by the increased number of T cells and the elevated percentage of CCR7+ T cells in SLO of B cell depleted animals. In addition, depletion of CD20+ B cells created a less immunostimulatory environment in the SLO reflected by reduced expression of MHC class II, CD40, CD83, and CD80/CD86 on CD3- cells. In marmosets treated with anti-CD20 mAb, the DNA load of CalHV3 was substantially reduced, while this was not observed in marmosets treated with anti-BLyS or anti-APRIL mAb, where B-cell depletion via withdrawal of essential survival and differentiation cytokines was not associated with a marked clinical effect. In conclusion, the marmoset EAE model is a very suitable model to investigate the effect of new B cell targeting therapies and the underlying pathological process. Disclosure Y.S. Kap, S.A. Jagessar, N. van Driel, J.D. Laman and B.A. ´t Hart have nothing to disclose

M.S. Freedman1, L. Kappos2, B.A.C. Cree3, E.-W. Radue4, G. Giovannoni5, S. Ritter6, D. Piani Meier7, D. Tomic7 1The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada, 2Neurology, Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital Basel, Basel, Switzerland, 3University of California San Francisco, San Francisco, CA, United States, 4Medical Image Analysis Center (MIAC), University Hospital, Basel, Basel, Switzerland, 5Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom, 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States, 7Novartis Pharma AG, Basel, Switzerland Background: No evidence of disease activity (NEDA) concepts are increasingly considered to assess efficacy of disease-modifying therapies (DMTs). NEDA-4 incorporates a measure of brain volume loss into NEDA and is defined as: (1) no MRI lesion activity, (2) no confirmed relapses, (3) no 6-month confirmed disability progression, and (4) less than 0.4% mean annual brain volume loss. Previously, pooled analyses of FREEDOMS and FREEDOMS II found odds ratios (ORs) of 4.41 in favour of fingolimod vs. placebo (PBO) for achieving NEDA-4 at 24 months in the overall population (p< 0.0001), and 6.37 for achieving NEDA-4 in young adults ⩽30 years of age (p< 0.001). Objective: To assess the likelihood of achieving a NEDA-4 status at 24 months in pooled FREEDOMS and FREEDOMS II trials, based on subgroups of gender, disease duration, number of relapses prior to study, baseline EDSS, MRI lesion activity and T2 lesion volume, and number of prior DMT treatments. Methods: In this post-hoc analysis, logistic regression of NEDA-4 on treatment was used to derive ORs and p-values. Results: The analysis included 783 and 773 patients treated with fingolimod and PBO, respectively. In all subgroups evaluated, patients treated with fingolimod had better odds for achieving NEDA-4. In females and males, ORs were 4.25 and 4.80, respectively, and 4.01 and 4.79 in patients with MS duration ⩽ or >3.5 years (p< 0.001). In patients with 1, 2, or >2 relapses in the prior 2 years, ORs were 4.32 4.24, and 5.48; with baseline EDSS ⩽ or >3.5, ORs were 3.97 and 8.20 (p< 0.001 for all). With T1 Gd-enhancement status (− or +), ORs were 4.40 and 6.65, and with T2 lesion volume ⩽ or >3300 mm3 at baseline, ORs were 4.36 and 4.75 (p< 0.001). In patients who had been previously treated with 0, 1, 2, or ⩾3 DMTs, ORs were 3.63 (p< 0.0001), 6.94 (p< 0.0001), 4.90 (p=0.0147) and 3.62 (p=0.0821) respectively. Conclusion: Across all subgroups fingolimod showed consistent efficacy and patients were approximately 4-5 times more likely to achieve NEDA-4 on fingolimod than placebo. Treatment benefit seemed more pronounced in patients with ongoing disease activity or higher burden at baseline, and patients who had been previously treated with one other DMT prior to fingolimod. Disclosure

P626 Efficacy of fingolimod on NEDA-4 in pooled FREEDOMS and FREEDOMS II studies by subgroups of baseline characteristics

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Funding source: This study is supported by Novartis Pharma AG, Basel, Switzerland. M. S. Freedman has received honoraria or consultation fees from BayerHealthcare, Biogen-Idec, Chugai, EMD Canada, Genzyme,


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Novartis, Sanofi-Aventis, Teva Canada Innovation. Dr. Freedman is a member of the following company advisory boards, board of directors or other similar group: BayerHealthcare, Biogen-Idec, Hoffman La-Roche, Merck Serono, Novartis, Opexa, and SanofiAventis. Dr. Freedman is a Participant in the following company sponsored speaker’s bureau: Genzyme. L. Kappos´s institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: steering committee/consulting fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; royalties from Neurostatus Systems GmbH; grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis, Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society, and the Swiss National Research Foundation. B.A.C. Cree has received personal compensation for consulting from Abbvie, Biogen Idec, EMD Serono, MedImmune, Novartis, Genzyme/sanofi aventis, Teva and has received contracted research support (including clinical trials) from Acorda, Biogen Idec, EMD Serono, Hoffman La Roche, MedImmune, Novartis and Teva. E.W. Radue has received research support from Biogen Idec, Merck-Serono, Novartis and Actelion. G. Giovannoni has received compensation for serving as a consultant or speaker for, or has received research support from: AbbVie, Bayer Schering Healthcare, Biogen Idec, Canbex, Eisai, Elan, Five Prime Therapeutics, Genzyme, Genentech, GlaxoSmithKline, Ironwood Pharmaceuticals, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva Pharmaceutical Industries, UCB and Vertex Pharmaceuticals. S. Ritter, D. Piani Meier, and D. Tomic are employees of Novartis. P627 Long-term effects of fingolimod on NEDA by year of treatment B.A.C. Cree1, L. Kappos2, M.S. Freedman3, J.A. Cohen4, T. Sprenger5,6, S. Ritter7, D. Tomic8, D. Piani Meier8 1University of California San Francisco, San Francisco, CA, United States, 2Neurology, Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital Basel, Basel, Switzerland, 3The Ottawa Hospital Research Institute, University of Ottawa and Ottawa Health Research Institute, Ottawa, ON, Canada, 4Cleveland Clinic, Neurological Institute, Cleveland, OH, United States, 5Medical Image Analysis Center, University Hospital Basel, 6Departments of Neurology, Clinical Research, and Biomedical Engineering, University Hospital Basel, Basel, Switzerland, 7Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States, 8Novartis Pharma AG, Basel, Switzerland Background: Previous studies in patients with RRMS have shown that fingolimod has sustained efficacy on clinical (relapses and disability progression) and MRI measures (lesion activity and brain volume loss, BVL) of disease activity and worsening. However, combined assessment applying no evidence of disease

activity (NEDA) concepts are increasingly used to better capture disease evolution and assess overall impact of disease-modifying therapies in patients with MS. Objective: To evaluate long-term efficacy of fingolimod in achieving NEDA-3 and NEDA-4 annually over 7 years. Methods: Post-hoc analysis was performed on data pooled from FREEDOMS and FREEDOMS II core studies and their extensions. Separate analyses were performed on patients randomized to fingolimod 0.5 mg from the start and patients randomized first to placebo (PBO) and then to fingolimod 0.5 mg in the extension. NEDA-3 was defined as: (1) no active (new/enlarging) T2 MRI lesions, (2) no relapses, and (3) no confirmed progression of disability (CDP) while NEDA-4 includes (4) mean annual BVL < 0.4% as an additional requirement. Odds ratios (ORs) and p-values were derived from logistic regression of NEDA-3 and NEDA-4 on treatment and study. Results: The analysis included 1398 patients who completed Year 1, and 1228, 797, 657, 620, 544, and 246 in years 2-7, respectively. In the fingolimod treatment arm, 44.6% and 62.1% of patients achieved NEDA-3 in Years 1 and 2 versus 18.5% and 27.5% on PBO (ORs vs. PBO, 3.56 and 4.33; p< 0.0001), and 27.1% and 32.5% achieved NEDA-4 in Years 1 and 2 versus 9.1% and 12.7% on PBO (ORs vs. PBO, 3.74 and 3.33; p< 0.0001). In Years 3-7, 54.0-70.9% of patients in the continuous fingolimod arm fulfilled criteria for NEDA-3 and 31.2-44.8% NEDA-4. Patients in the PBO arm benefitted from switching to fingolimod in Year 3, with 43.1-70.5% fulfilling NEDA-3 criteria in Years 3-7 and 16.8-44.4% NEDA-4, respectively. ORs through Year 5 significantly (all p< 0.05) favoured patients who started on fingolimod over patients who switched from PBO to fingolimod (1.47-1.75 for NEDA-3 in Years 3-5, 1.43-2.26 for NEDA-4). Conclusion: Fingolimod showed sustained efficacy in achieving NEDA-3 and NEDA-4 over 7 years. Patients who were on placebo for the first 2 years demonstrated substantial improvements in NEDA-3 and NEDA-4 outcomes after switching to fingolimod. However, patients who received fingolimod from the start appeared to derive more benefit throughout the first 5 years. Disclosure Funding source: This study is supported by Novartis Pharma AG, Basel, Switzerland. B.A.C. Cree has received personal compensation for consulting from Abbvie, Biogen Idec, EMD Serono, MedImmune, Novartis, Genzyme/sanofi aventis, Teva Neurosciences and has received contracted research support (including clinical trials) from Acorda, Avanir, Biogen Idec, EMD Serono, Hoffman La Roche, MedImmune and Teva Neurosciences. L. Kappos´s institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: steering committee/consulting fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; royalties from Neurostatus Systems GmbH; grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis,


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Poster Session I, 21(S11) Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society, and the Swiss National Research Foundation. M. S. Freedman has received honoraria or consultation fees from BayerHealthcare, Biogen-Idec, Chugai, EMD Canada, Genzyme, Novartis, Sanofi-Aventis, Teva Canada Innovation. Dr. Freedman is a member of the following company advisory boards, board of directors or other similar group: BayerHealthcare, Biogen-Idec, Hoffman La-Roche, Merck Serono, Novartis, Opexa, and SanofiAventis. Dr. Freedman is a Participant in the following company sponsored speaker’s bureau: Genzyme. Jeffrey A. Cohen has received personal compensation for serving as a consultant or speaker from Biogen Idec, Lilly, Novartis, and Vaccinex and received research support through his institution from Biogen Idec, BioMS, Genzyme, Novartis, Synthon, and Teva. T. Sprenger´s institution, the University Hospital Basel, has received payments for consultation and speaking activities for Mitsubishi Pharma, Eli Lilly, Genzyme, Novartis, ATI, Actelion, Electrocore, Biogen Idec and Allergan. These payments were used exclusively for research support. T Sprenger has received research grants from the Swiss MS Society, Swiss National Research Foundation, EFIC-Grünenthal and Novartis Pharmaceuticals Switzerland. S. Ritter, D. Tomic, and D. Piani Meier are employees of Novartis. P628 Efficacy of delayed-release dimethyl fumarate for relapsing-remitting multiple sclerosis using a composite measure of disability: integrated analysis of the phase 3 DEFINE and CONFIRM studies A. Bar-Or1, R. Gold2, R.J. Fox3, J.T. Phillips4, G. Giovannoni5, L. Kappos6, E. Havrdova7, M. Hutchinson8, J. Potts9, J.L. Marantz9 1Montreal Neurological Institute, McGill University, Montreal, QC, Canada, 2St. Josef Hospital, Ruhr University, Bochum, Germany, 3Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, 4Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, United States, 5Queen Mary University of London, Blizard Institute, London, United Kingdom, 6University Hospital Basel, Basel, Switzerland, 7First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, 8St. Vincent’s Hospital, Dublin, Ireland, 9Biogen, Inc., Cambridge, MA, United States Background: Compared with placebo, delayed-release dimethyl fumarate (DMF) significantly reduced the risk of sustained disability progression as assessed by the Expanded Disability Status Scale (EDSS) in an integrated analysis of the Phase 3 DEFINE and CONFIRM studies of relapsing-remitting multiple sclerosis. However, EDSS progression alone may not capture all aspects of disability. A composite functional outcome measure can be used to capture potentially clinically meaningful sustained worsening across multiple neuroperformance components. Objectives: In an integrated analysis of DEFINE/CONFIRM, we assessed the effect of DMF on the time to first of five possible events, including sustained EDSS progression or sustained worsening on Multiple Sclerosis Functional Composite (MSFC) components (timed 25-foot walk [T25FW], 9-hole peg test [9HPT], and Paced Auditory Serial Addition Test [PASAT-3]) or Visual Function Test (VFT; 2.5% Low Contrast Acuity Test).

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Methods: Eligibility criteria included age 18-55 years and EDSS score 0-5.0. Patients were randomized to receive DMF 240 mg twice (BID) or thrice daily, placebo, or subcutaneous glatiramer acetate (reference comparator; CONFIRM only) for up to 2 years. EDSS, MSFC components, and VFT were administered at baseline and 12-week intervals thereafter. A composite measure of time to 12-week and 24-week evidence of sustained clinical disability progression was used, defined as the first occurrence of any of the following: ⩾1.0-point increase from baseline EDSS score >0 or ⩾1.5-point increase from baseline EDSS score of 0; ⩾20% worsening from baseline on any MSFC component; and ⩾10-letter worsening from baseline on VFT. Statistical comparisons were based on a Cox proportional hazards model adjusted for baseline covariates. Results are reported for placebo and DMF BID (approved dosing regimen in all regions). Results: The integrated intent-to-treat population included 771 and 769 patients receiving placebo or DMF BID, respectively; among them, 768 and 766 had available time to event data for all outcome parameters and baseline covariates. At 2 years, time to the first single sustained event was reduced significantly with DMF compared with placebo (12-week sustained outcomes: 15% reduction, P =.0419; 24-week sustained outcomes: 23% reduction, P =.0048). Conclusions: Compared with placebo, DMF BID demonstrated significant slowing in disability progression as measured by a composite measure of disability. Disclosure This study is supported by Biogen, Inc. Amit Bar-Or: honoraria and/or research support from Amplimmune, Aventis, Bayhill Therapeutics, Berlex, Biogen, Diogenix, Eli-Lilly, EMD Serono, Genentech, GlaxoSmithKline, Medimmune, Novartis, Ono Pharma, Receptos, Roche, Sanofi Genzyme, and Teva Neuroscience. Ralf Gold: honoraria from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders. Robert J. Fox: consultant fees from Actelion, Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Actelion, Biogen, and Novartis; research grant funding from Novartis. J. Theodore Phillips: consulting fees from Acorda, Biogen, Genzyme, Merck Serono, and Sanofi; research support from Roche. Gavin Giovannoni: honoraria from Abbvie, Bayer HealthCare, Biogen, Canbex, FivePrime, Genzyme, GlaxoSmithKline, GW Pharma, Merck Serono, Novartis, Protein Discovery Laboratories, Roche, Synthon, Teva Neuroscience, UCB, and Vertex; research grant support from Biogen, Ironwood, Merck Serono, Merz, and Novartis; compensation from Elsevier as co−chief editor of MS and Related Disorders. Ludwig Kappos: Institution (University Hospital Basel) received and used exclusively for research support: steering committee, advisory board and consultancy fees from Actelion, Addex, Bayer Health Care, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, Xenoport; speaker fees from Bayer Health Care, Biogen, Merck, Novartis, Sanofi-Aventis, Teva; support of educational activities from Bayer Health Care,


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Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva; royalties from Neurostatus Systems GmbH; grants from Bayer Health Care, Biogen, Merck, Novartis, Roche, Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations. Eva Havrdova: honoraria from Bayer, Biogen, Genzyme, GlaxoSmithKline, Merck Serono, Novartis, Sanofi, and Teva; research support from Biogen; supported by PRVOUK-P26/ LF1/4, program of Ministry of Education, Czech Republic. Michael Hutchinson: honoraria from Bayer Schering, Biogen, Merck-Serono, and Novartis; editorial fees from the Multiple Sclerosis Journal; research grants from the Health Research Board, Ireland and Dystonia Ireland. James Potts: employee of and holds stock/stock options in Biogen, Inc. Jing L. Marantz: employee of and holds stock/stock options in Biogen, Inc. P629 Correlation of brain volume and physical measures with cognitive function using baseline data from the anti-LINGO-1 SYNERGY trial in multiple sclerosis D. Cadavid1, R. Hupperts2, J. Drulović3, K. Selmaj4, X. Montalban5, S. Kostić6, M. Vališ7, E. Evdoshenko8, Y. Zhang1, L. Xu1, M. Mellion1 1Biogen, Cambridge, MA, United States, 2Maastricht University Medical Center, Sittard, The Netherlands, 3University of Belgrade, Belgrade, Serbia, 4Medical University of Lodz, Lodz, Poland, 5Vall d’Hebron University Hospital, Barcelona, Spain, 6Military Medical Academy, Neurology Clinic, Belgrade, Serbia, 7Faculty of Medicine in Hradec Kralové, Charles University in Prague, Hradec Králové, Czech Republic, 8St. Petersburg’s Center of MS and Autoimmune Diseases, Saint Petersburg, Russian Federation Background: Cognitive impairment associated with MS (CIAMS) is a progressive, debilitating and frequent complication. Measuring CIAMS and treatment response in clinical trials has been difficult due to lack of standardized, feasible assessments. MS-COG is a composite cognitive assessment used in the phase 2 SYNERGY trial. Goals: To investigate the correlation of baseline cognitive function with MRI and physical/disability tests in patients in SYNERGY with relapsing-remitting (RR) or secondary progressive (SP) MS. Methods: 396 patients (312 RRMS; 84 SPMS) completed the 7 individual MS-COG components: brief visuospatial memory test (sum/delayed recall scores) and selective reminding test (immediate/delayed recall scores) for learning/memory; 2- and 3-second paced auditory serial addition test and symbol digit modality test (oral version) for information processing. Aggregate scores for memory/learning and information processing speed plus total composite score were calculated. MRI measures included normalized whole brain and cerebral cortical volumes, whole brain and normal appearing white matter median magnetization transfer ratio (MTR), whole brain fractional anisotropy and radial diffusivity (RD). Physical function/disability measures were: EDSS, individual functional system (FS) and total scores; 9-hole peg test (9NHP) dominant/non-dominant hand; timed 25 foot walk; 6

minute walk test. Correlations between mean baseline values were assessed by Pearson’s correlation coefficient. Results: MS-COG testing showed CIAMS was more frequent and severe in SPMS than RRMS. In RRMS and SPMS information processing was impaired, but in SPMS memory/learning was also severely impaired. In RRMS moderate MS-COG correlations ranging from 0.3-0.4 were seen with EDSS total, pyramidal FS, 9NHP and walking; in SPMS only cerebral FS (not including fatigue) moderately correlated with MS-COG. In RRMS and SPMS moderate correlations (range 0.3-0.5) were observed between MS-COG and whole and cortical brain volumes and whole brain RD, but not with MTR. Conclusions: CIAMS measured by MS-COG at baseline in SYNERGY was found in RRMS and SPMS. MS-COG components and aggregate scores correlated with MRI measures of tissue loss and whole brain RD in RRMS and SPMS; no correlations of MS-COG with any physical tests were found in SPMS. These results indicate that MS-COG measures important pathological consequences of MS to the brain not captured by traditional physical/disability measures. Disclosure This study was supported by Biogen (Cambridge, MA, USA). DC, YZ, LX, MM and NK: employees of and stockholders in Biogen. RH: advisor/speaker and received research support from Biogen, Merck Serono, Sanofi Aventis, Novartis JD: advisor/speaker for Merck, Novartis, TEVA, Medis, Bayer Schering Pharma and received research support from Ministry of Education and Science, Republic of Serbia (project no. 175031) KS: consultant/speaker for Biogen, Genzyme, Novartis, Ono, Roche, Synthon, Teva XM: speaker fees/travel expense reimbursement from and steering committee/advisory board for Actelion, Almirall, Bayer, Biogen, Genzyme, Merck, Neurotec, Novartis, Octapharma, Receptos, Roche, Sanofi-Aventis, Teva, and Trophos SK: none MV: personal fees from Biogen, Krka and Merck EE: fees for board membership, consultancy, speaking or grants which have been dedicated to research support from Biogen, Generium, Genfa Medica, Genzyme, Johnson & Johnson, Pharmstandart, Pharmsyntez, Roche, R-Pharm, Sanofi-Aventis and Takeda. Biogen provided funding for medical writing support in the development of this abstract. Becky Gardner (Excel Scientific Solutions, Horsham, UK) wrote the first draft of the abstract based on input from authors. Biogen reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P630 Post-natalizumab relapses and MRI activity do not predict long-term disability outcomes J. Raffel, A. Gafson, S. Dahdaleh, O. Malik, R. Nicholas Imperial College London, London, United Kingdom Introduction: In people with multiple sclerosis treated with interferon-beta or glatiramer acetate, new MRI lesions and relapses during the first year of treatment predict poor prognosis.


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Poster Session I, 21(S11) However, this association has not been studied in those receiving natalizumab. Methodology: Data were collected on early relapses and new MRI activity in the first year after initiation of natalizumab in an observational cohort of 161 patients. These were correlated with two long-term outcome measures. The first - ‘Clinical Activity Years 1-3’ - defined non-responders as those with EDSS progression OR relapses at years 1-3 post-treatment, versus baseline. The second - ‘Disability Progression Years 3+’ - defined non-responders as those with EDSS progression at 3-7 years post-treatment, versus baseline. Results: ‘Clinical Activity Years 1-3’ was predicted by early relapses (Odds Ratio (OR) 8.4; 95% Confidence Interval (CI) 3.321.3; p< 0.0001), and by a combined score of early relapses and MRI activity (Modified Rio Score 1: OR 4.7, CI 1.9-11.7; p < 0.001. Modified Rio Score 2: OR 18.2, CI 2.3-142.8; p < 0.001). In contrast, ‘Disability Progression Years 3+’ was not predicted by early relapses or MRI activity. Non-responders did not differ from responders in baseline age or baseline EDSS. Conclusions: Relapses and MRI activity in the first year of natalizumab treatment are predictive of medium-term conjugate outcome measures involving both relapses and EDSS progression, but do not predict long term disability outcomes as measured by EDSS progression alone. The clinical implications of these data are discussed.

with MS and those with high Sema4A do not respond well to IFN-β therapy. We also reported Sema4A inhibited the therapeutic effect of IFN-β in experimental autoimmune encephalomyelitis (EAE). However, it remains unknown whether other DMDs are effective for patients with high Sema4A or not. Objective: The purpose of this study is to establish clinical significance of Sema4A as a biomarker to choose therapeutic approach. Methods: The subjects for this investigation were 129 patients (our facility: 58 and other 45 facilities in Japan: 71) with MS who meet the Macdonald criteria 2010. We examined the serum Sema4A levels with a sandwich ELISA. We analyzed the association between Sema4A and clinical characteristics. Correlation between Sema4A levels and efficacy of IFN-β or Fingolimod was also analyzed. Results: The serum Sema4A titer was 3508 ± 6867 U/mL. About 30 % of patients with MS had high levels of Sema4A. Low Sema4A group tended to be good-responders compared to high sema4A group. The levels of Sema4A are not changed by Fingolimod treatment. Although sample size is small, Fingolimod attenuated the relapse rates for patients both with low and high Sema4A. Conclusions: The levels of Sema4A correlate with IFN-β resistance. Although sample size is not enough, Fingolimod seems to be effective for patients with high Sema4A. Sema4A can be a biomarker for treatment selection of MS.

Disclosure Joel Raffel: Nothing to disclose. Arie Gafson: Nothing to disclose. Sam Dahdaleh: Nothing to disclose. Omar Malik has received travel grants to educational meetings from Biogen Idec and honoraria from Biogen Idec, which have been used exclusively for clinical research, outside the submitted work. Richard Nicholas has received grants, personal fees and nonfinancial support from Novartis, grants, personal fees and nonfinancial support from Biogen Idec, personal fees from Genzyme, personal fees from Roche, outside the submitted work. P631 Sema4A as a biomarker for personalized therapy of multiple sclerosis T. Koda1, T. Okuno1, Y. Nakatsuji1, K. Takata1, A. Namba1, K. Yamashita1, J.A. Honorat1, S. Tada2, M. Kinoshita2, S. Sakoda3, A. Kumanogoh4, H. Mochizuki1 1Neurology, Osaka University Graduate School of Medicine, 2Neurology, Osaka General Medical Center, 3Neurology, National Hospital Organization Toneyama National Hospital, 4Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan Backgrounds: Although interferon-beta (IFN-β) is the first-line therapy in relapsing-remitting multiple sclerosis (RRMS), onethird of patients does not respond to IFN-β therapy. Recently, other disease modifying drugs (DMDs) such as Fingolimod　and Natalizumab are available. However, there are no appropriate biomarkers for the selection of DMDs. We previously reported that immune semaphorin Sema4A is increased in the sera of patients

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Disclosure Koda Toru: Nothing to disclose. Tatsusada Okuno: Nothing to disclose. Yuji Nakatsuji: Nothing to disclose. Kazushiro Takata: Nothing to disclose. Namba Akiko: Nothing to disclose. Kazuya Yamashita: Nothing to disclose. Josephe A. Honorat: Nothing to disclose. Satoru Tada: Nothing to disclose. Makoto Kinoshita: Nothing to disclose. Saburo Sakoda: Nothing to disclose. Atsushi Kumanogoh: Nothing to disclose. Hideki Mochizuki: Nothing to disclose. P632 The effects of natalizumab and fingolimod on clinical, neuropsychological and MRI measures in relapsing remitting multiple sclerosis: a one-year comparative study P. Preziosa1,2, M.A. Rocca1,2, G.C. Riccitelli1, M. Rodegher2, M. Copetti3, L. Moiola2, F. Mele1,2, A. Falini4, G. Comi2, M. Filippi1,2 1Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 2Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, 3Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, 4Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy Background: Natalizumab and fingolimod are second-line treatments approved for patients with active relapsing-remitting


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(RR) MS and they have been proven to be highly effective in reducing clinical relapses, disability progression and active lesion formation. Objectives: To compare the effects of natalizumab and fingolimod on clinical, neuropsychological and MRI measures in RRMS after one year of treatment. Methods: Forty-three RRMS patients starting natalizumab (n=19) or fingolimod (n=24) underwent 3T brain scans, clinical and neuropsychological evaluation (EDSS, Modified Fatigue Impact scale [MFIS], Montgomery-Asberg Depression Rating Scale [MADRS] and Rao’s battery) at baseline, and year 1 (Y1). T2-lesion volume (LV), T1-LV and cortical-LV as well as brain, white matter (WM), gray matter (GM) and deep GM volumes were measured. Results: At baseline, the two groups were clinically, neuropsychologically and neuroradiologically matched. At Y1, both groups showed similar disease activity and neuropsychological changes, whereas EDSS decreased significantly in fingolimod-patients (p=0.006). In natalizumab-patients, T2-LV, T1-LV and corticalLV remained stable at Y1, while T2-LV (p=0.0003 vs natalizumabpatients) and T1-LV (p=0.05 vs natalizumab-patients) increased significantly in fingolimod-patients. At Y1, WMV decreased significantly in both groups. Fingolimod-patients experienced significant thalamic (p=0.001) and caudate (p=0.03) atrophy. At Y1, MFIS psychosocial (MFISps) subscore improved in natalizumabpatients (p=0.02) and worsened in fingolimod-patients (p=0.02) (treatment-x-time interaction: p=0.001). MADRS scores were significant lower in natalizumab-patients vs fingolimod-patients at Y1 (p=0.04). In fingolimod-patients, 1-year changes of caudate (β=0.028;R2=0.25,p=0.01) and thalamic (β=0.036;R2=0.22,p=0.02) volumes predicted Y1-MADRS, whereas 1-year change of caudate volume (β=0.006;R2=0.36,p=0.001) predicted Y1-MFISps subscore. Conclusions: Natalizumab and fingolimod reduce disease activity in RRMS. Natalizumab could have a more significant effect on neuropsychological aspects including emotional and behavioural functions, possibly reducing brain damage accumulation, especially in cortico-subcortical circuits. Disclosure P. Preziosa, G. Riccitelli, M.E. Rodegher, M. Copetti, L. Moiola, F. Mele, A. Falini have nothing to disclose. M.A. Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed. G. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. M. Filippi has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis. P633 Predicting response to fingolimod in patients with relapsing-remitting multiple sclerosis M. Giuliani1, L. Prosperini1, F. Fanelli1, M.N. Hirsch1, F. De Angelis1,2, C. Pozzilli1

1Sapienza

University, Rome, Italy, 2University College London, London, United Kingdom Background: Fingolimod is an effective treatment for patients with relapsing-remitting multiple sclerosis (RRMS), and there is class I evidence that it is superior to standard care in reducing relapse rate. However, about two third of treated patients are not “disease free”, according to the 2-year data from a post-hoc analysis of the FREEDOMS trial. Objective: To determine which baseline (i.e. at treatment start) clinical and magnetic resonance imaging (MRI) variables are valuable tools to identify those patients who had no evidence of disease activity (NEDA) while on fingolimod treatment. Methods: We prospectively collected clinical and MRI data of RRMS patients treated with fingolimod and followed-up for at least 1 year. The proportion of patients who had NEDA, defined as a composite score consisting of absence of relapses, no sustained Expanded Disability Status Scale (EDSS) worsening and no radiological activity on MRI, was estimated. A Cox proportional hazards model was carried out to investigate which baseline characteristics were associated with NEDA status at the end of follow-up, including gender, age, disease duration, baseline EDSS score, number of relapses in the prior year, number of previously taken disease-modifying treatments (DMTs), and gadoliniumenhancement at baseline MRI scan. Results: We analysed data of 199 patients (139 F, 60 M) with mean (SD) age of 37.9 (9.4), mean disease duration of 8.8 (5.9) years, and median EDSS score of 2.0 (range 0-6.5). Twentyfour (12%) patients were treatment-naïve, while 115 (58%) and 60 (30%) were switched after failing a first-line DMT or as “exit strategy” from natalizumab treatment, respectively. Five patients who early discontinued fingolimod (bradycardia, n=2; leukopenia, n=2; macular oedema, n=1) were removed from the analysis. After a median follow-up time of 2 years (range 1-4), 118 (61%) patients had NEDA, while 76 experienced clinical activity (n=54) or isolated MRI activity (n=22). The risk of experiencing disease activity during follow-up was associated with a greater number of pre-treatment relapses (HR=1.36, p=0.02) and a greater number of previously failed DMTs (HR=1.47, p=0.004). Conclusion: Our findings suggest that fingolimod may lead to a complete remission of the disease if started in patients with less aggressive disease (i.e. few pre-treatment relapses) and in those who failed a lower number of DMTs, thus supporting the possible role of fingolimod as an early treatment for MS. Disclosure This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Manuela Giuliani: nothing to disclose. Luca Prosperini: consulting fees, and /or lecture fees, and/or travel grants from: Bayer Schering, Biogen Idec, Genzyme, Novartis and Teva. Fulvia Fanelli: nothing to disclose. Maria Neve Hirsch: nothing to disclose. Floriana De Angelis: nothing to disclose. Carlo Pozzilli: consulting and/or lecture fees and research grants and/or travel grants from Almirall, Biogen Idec, Bayer Schering, Merck Serono, Novartis, Roche, Sanofi Genzyme and Teva.


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Poster Session I, 21(S11) P634 A lesion topography-based approach to refine the value of new active lesions in predicting response to interferon beta in multiple sclerosis S. Galassi1, L. Prosperini2, L. De Giglio2, A. Logoteta2, M.N. Hirsch2, F. Fanelli2, M. Giuliani2, C. Pozzilli2 1Dept. of Neuroradiology Imaging, Bambino Gesù Children’s Hospital, 2Sapienza University, Rome, Italy Background: Several studies have suggested that the short-term treatment effect on magnetic resonance imaging (MRI) measures may predict the longer-term response to Interferon Beta (IFNB) in patients with multiple sclerosis (MS). However, none of these studies have investigated whether the topography of new lesions occurred early on-treatment may affect their predictive value in assessing the response to IFNB treatment. Purpose: To estimate the predictive value of new T2-hyperintense lesions, as evaluated after 1 year from IFNB start, on the risk of longer-term disability, by modelling the analysis for lesion topography (supratentorial, infratentorial or spinal cord level). Methods: Patients starting IFNB treatment between 2005 and 2010 as first-line disease-modifying treatment were regularly followed up to 4 years. Demographic, clinical and MRI data were collected at IFNB start and at 1 year of therapy. The count and location of new T2-hyperintense lesions was performed by two trained operators on the images taken at 1 year of treatment compared with the baseline scan. In case of disagreement, the questioned lesion was not included in the count. As main outcome measure we considered the sustained disability worsening, i.e. an increase of 1.0 point or more at the Expanded Disability Status Scale (EDSS) score from year 1 to 4 of follow-up. Results: Up to now we collected data from 387 patients (266 F, 121 M) with a mean age of 32.5+/-8.7 years, median disease duration of 2 years (range < 1-25), mean number of pre-IFNB relapses of 1.4+/-0.7 (1-4) and median EDSS score of 1.5 (range 0-3.5). Of them, 64 (16.5%) patients experienced a sustained disability worsening from year 1 to 4 of follow-up. A multivariable Cox proportional hazard regression model showed that a higher baseline EDSS score (HR=2.14, p< 0.001), the occurrence of relapses in the first year of treatment (HR=2.17, p=0.03), the appearance of new T2-hyperintense lesions at one-year MRI scan located in the spinal cord (HR=2.65, p=0.01) or infratentorial region (HR=2.97, p=0.006) were independently associated with a sustained disability worsening during the follow-up. The count of new lesions, as well as the presence of gadolinium enhancement at one-year MRI scan, did not contribute to better fit the model. Discussion: The early on-treatment occurrence of new lesions in sites representing anatomical bottle-necks predicted better than lesion count the future risk of IFNB treatment failure. Disclosure This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Luca Prosperini: consulting fees, and /or lecture fees, and/or travel grants from: Bayer Schering, Biogen Idec, Genzyme, Novartis and Teva. Laura De Giglio: travel grants from Novartis and Teva.

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Carlo Pozzilli: consulting and/or lecture fees and research grants and/or travel grants from Almirall, Biogen Idec, Bayer Schering, Merck Serono, Novartis, Roche, Sanofi Genzyme and Teva. Stefania Galassi, Alessandra Logoteta, Maria Neve Hirsch, Fulvia Fanelli, Manuela Giuliani: nothing to disclose. P635 Ambulatory motor fatigue in MS assessed by wearable inertial sensor metrics during the six minute walk C. Oberndorfer1, J. Barth2, R. Needham3, N. Chockalingam3, C. Herberz2, C.E.I. Westling4, B.M. Eskofier1, D. Roggen4, J. Klucken5, W. Rashid6, H.J. Witchel7 1Digital Sports Group, Pattern Recognition Lab, Department of Computer Science, Friedrich-Alexander University ErlangenNürnberg (FAU), 2ASTRUM IT, GmbH, Erlangen, Germany, 3CSHER, Staffordshire University, Stoke-on-Trent, 4University of Sussex, Brighton, United Kingdom, 5Department of Molecular Neurology, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany, 6Department of Neurology, Hurstwood Park Neurosciences Centre, Haywards Heath, 7Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom Background: Individuals with MS suffer from ambulatory motor fatigue; however, the degree of fatigue is often subjective and does not always mirror the degree of clinically assessed motor disability (as judged by EDSS). To complement patient reports of fatigue in MS, a range of objective performance metrics based on ambulation have been demonstrated as feasible, including a deceleration index. This potentially offers an additional and potentially sensitive characterisation of ambulatory motor fatigue. An affordable way to determine detailed aspects of walking (potentially including foot drop) would be based on wearable inertial sensors. Methods: Fully-ambulatory persons with multiple sclerosis (PwMS, N = 19) and age-matched healthy volunteers (N = 15) were instrumented with 7 sensors (placed on lateral aspects of shoes, ankles, thighs, and on the lumbar spine) with 3 axes of gyroscopy and accelerometry recording at 128 Hz (or 102.4 Hz). Participants performed a six minute walk (6MW), and strides from the full-speed straight-walking regions of the walk were recognised via machine learning and dynamic time warping. Results: Distance-dependent changes (slopes) of pre-determined metrics were assessed by least squares linear fitting of the metrics by individual. Significant differences in the distance-dependent slopes between PwMS and age-matched, healthy volunteers included the MS patients having a decreasing cadence (t = 2.26, P < 0.05), and increasing stride time (t = 2.10, P < 0.05). As MS patients progressed in the 6MW (but not healthy controls), the mean accelerometry signal from the shoe sensors in the vertical direction decreased (t = 2.21, P < 0.05), suggesting diminished foot drive. The slope of increase of stride time was correlated with subjective ratings on the Fatigue Severity Scale (rho = 0.44, P < 0.05), as was the slope of the mean accelerometry signal from the shoes sensors in the upward direction (rho = 0.423, P < 0.05). Conclusions: Wearable inertial sensors have the potential to provide specific metrics of ambulatory fatigue in MS with good face value. Future studies using these sensors have the potential to realise additional information on gait characterisation including


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specific deficits such as foot drop and may provide sensitive measures of gait abnormality associated with disease progression. Disclosure CO: Supported by German Academic Exchange Service (DAAD). No relevant commercial support. JB: Employed by ASTRUM IT, GmbH. Additional funding from Bavarian Research Foundation RN: supported by Staffordshire Univ. No relevant commercial support. JK: supported by Universitätsklinikum Erlangen, received research support from ASTRUM IT, FAU, Bavarian research foundation, Teva GmbH, LicherMT GmbH, and receives honoraria and/or serves on advisory boards for UCB, LicherMT, Ever Pharma, Teva Pharma, Desitin, GSK, Abbvie. NC: supported by Staffordshire Univ. No relevant commercial support. CH: employed by ASTRUM IT, GmbH. Commercially supported. CEIW: No relevant support. BME: supported by FAU Erlangen. Additional funding from ASTRUM IT DR: supported by University of Sussex. No relevant commercial support WR: supported by Brighton and Sussex University Hospital Trust. No relevant commercial support. HJW: supported by Brighton and Sussex Medical School. HJW also received funding from the Wellcome Trust and honoraria/ fees from ADR and ITV.

Treatment of progressive MS P636 Immunomodulatory therapy slows accumulation of disability in moderately advanced multiple sclerosis N. Lizak1, A. Lugaresi2, R. Alroughani3, J. Lechner-Scott4, M. Slee5, E. Havrdova6, D. Horakova6, M. Trojano7, G. Izquierdo8, P. Duquette9, M. Girard9, A. Prat9, P. Grammond10, R. Hupperts11, P. Sola12, F. Grand’Maison13, R. Bergamaschi14, E. Pucci15, C. Oreja-Guevara16, J.A. Cabrera-Gomez17, V. Van Pesch18, T. Petersen19, C. Boz20, C. Ramo21, M.E. Rio22, G. Iuliano23, R. Fernandez-Bolanos24, F. Granella25, D.L.A. Spitaleri26, F. Verheul27, M. Terzi28, C. Rozsa29, M.P. Amato30, J. Olascoaga31, S. Flechter32, E. Cristiano33, J.I. Rojas33, S. Hodgkinson34, V. Jokubaitis1, T. Spelman1,35, H. Butzkueven1,35,36, T. Kalincik1,35, on behalf of the MSBase Study Group 1Department of Medicine, University of Melbourne, Melbourne, VIC, Australia, 2Imaging and Clinical Sciences, University ‘G. d’Annunzio’, Chieti, Italy, 3Amiri Hospital, Kuwait City, Kuwait, 4Hunter Medical Research Institute, University Newcastle, Newcastle, NSW, 5Flinders University and Medical Centre, Adelaide, VIC, Australia, 6Department of Neurology and Center of Clinical Neuroscience, General University Hospital and Charles University in Prague, Prague, Czech Republic, 7Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy, 8Hospital Universitario Virgen Macarena, Sevilla, Spain, 9Hôpital Notre Dame, Montreal, 10Hotel-Dieu de Levis, Quebec, QC, Canada, 11Orbis Medical Center, Sittard-Geleen, The Netherlands, 12Nuovo Ospedale Civile S.Agostino/Estense, Modena, Italy, 13Hopital Charles

LeMoyne, Quebec, QC, Canada, 14Neurological Institute IRCCS Mondino, Pavia, 15Azienda Sanitaria Unica Regionale Marche, Macerata, Italy, 16University Hospital San Carlos, Madrid, Spain, 17Centro Internacional de Restauracion Neurologica, Havana, Cuba, 18Cliniques Universitaires Saint-Luc, Brussels, Belgium, 19Kommunehospitalet, Aarhus C, Denmark, 20Karadeniz Technical University, Trabzon, Turkey, 21Hospital Germans Trias i Pujol, Barcelona, Spain, 22Hospital S. Joao, Porto, Portugal, 23Ospedali Riuniti di Salerno, Salerno, Italy, 24Hospital Universitario Virgen de Valme, Seville, Spain, 25University of Parma, Parma, 26Azienda Ospedaliera di Rilievo Nazionale, Avellino, Italy, 27Groene Hart Ziekenhuis, Gouda, The Netherlands, 28Ondokuz Mayis University, Samsun, Turkey, 29Jahn Ferenc Teaching Hospital, Budapest, Hungary, 30University of Florence, Florence, Italy, 31Hospital Donostia, San Sebastian, Spain, 32Assaf Harofeh Medical Center, Beer-Yakov, Israel, 33Hospital Italiano, Buenos Aires, Argentina, 34Liverpool Hospital, Sydney, NSW, 35Department of Neurology, Royal Melbourne Hospital, 36Box Hill Hospital, Melbourne, VIC, Australia Introduction: Two large cohort studies have previously examined factors influencing disability accumulation in moderately advanced multiple sclerosis (MS), but displayed contradictory results. Aims: To examine the associations between early MS course and disability progression in moderately advanced MS and the effect of therapy on this progression. Methods: The primary analysis concerned the epoch between Expanded Disability Status Scale (EDSS) step 3 and 6. Two secondary analyses examined the EDSS 4-6 and 6-6.5 epochs. For each analysis, relapsing-remitting patients with a 6-month confirmed progression to the lower EDSS step and with a minimum of 12 months of pre-epoch data were selected from the MSBase cohort study. Annualised relapse rate (ARR) and proportion of time on disease-modifying therapy both prior to and during each epoch, age, and disease duration, were calculated. For each epoch, a multivariable Weibull survival model was used to examine progression to the outcome EDSS step confirmed at 3 months, and two sensitivity analyses were conducted: analysing patients with MRI data available prior to the epoch, and using the outcome EDSS step sustained for all available follow-up. Results: For the EDSS 3-6 epoch, 2,533 patients were identified. EDSS trajectories during the epoch were highly variable (-2.2 to +4.2 EDSS step per year) and correlated only weakly with the preepoch trajectories. Pre-epoch disease duration, ARR and therapy were not associated with the risk of EDSS progression. ARR (0.38; p< 0.001) and time on therapy during the epoch were associated with the probability of progression (-0.93 and -2.3 for the lower- and higher-efficacy therapy, respectively, p< 0.001). Similar results were observed for the EDSS 4-6 (n=2,578) and 6-6.5 (n=1,651) epochs. ARR during the EDSS 6-6.5 epoch was not associated with progression. Sensitivity analyses confirmed the results of all models. Conclusion: Disease progression during moderately advanced MS is largely amnestic to prior disease activity. However, increased therapy utilisation in moderately advanced MS is associated with a lower likelihood of accumulating significant disability, with higher efficacy therapies providing stronger protective effect. Increased ARR is associated with faster disability accrual in moderate but not in advanced MS.


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Poster Session I, 21(S11) Reaching EDSS steps 3, 4, or 6 should not preclude patients from receiving disease modifying therapy with the aim of mitigating disability accumulation. Disclosure Nathaniel Lizak did not declare any competing interests. Alessandra Lugaresi is a Bayer Schering, Biogen Idec, Genzyme, Merck Serono Advisory Board Member. She received travel grants and honoraria from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi and Teva, research grants from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi and Teva, travel and research grants from the Associazione Italiana Sclerosi Multipla. Raed Alroughani received honororia from Biologix, Bayer, Merck Sorono, Genpharm, GSK and Novartis, and served on advisory board for Biologix, Bayer, Novartis, Genzyme, Genpahrm and Merck Sorono. Jeannette Lechner-Scott has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment and also clinic support from Bayer Health Care, Biogen Idec, CSL, Genzyme Sanofi, Merck Serono and Novartis. Mark Slee has participated in, but not received honoraria for, advisory board activity for Biogen Idec, MerckSerono, BayerSchering, Sanofi Aventis and Novartis. Eva Havrdova received speaker honoraria and consultant fees from Biogen Idec, Merck Serono, Novartis, Genzyme and Teva, as well as support for research activities from Biogen Idec and Merck Serono. Dana Horakova received speaker honoraria and consulting fees from Biogen Idec, Merck Serono, Teva and Novartis, as well as support for research activities from Biogen Idec. Maria Trojano received speaking honoraria from Biogen-Idec, Bayer-Schering, Sanofi Aventis, Merck-Serono, Teva and Novartis; has received research grants from Biogen-Idec, MerckSerono, and Novartis. Guillermo Izquierdo received speaking honoraria from BiogenIdec, Novartis, Sanofi, Merck Serono and Teva. Pierre Duquette did not declare any competing interests. Marc Girard received consulting fees from Teva Canada Innovation, Biogen Idec, Novartis and Genzyme Sanofi; lecture payments from Teva Canada Innovation, Novartis and EMD Serono. Dr Girard has also received a research grant from Canadian Institutes of Health Research. Alexandre Prat did not declare any competing interests. Pierre Grammond is a Novartis, Teva-neuroscience, Biogen Idec and Genzyme advisory board member, consultant for Merck Serono, received payments for lectures by Merck Serono, Teva-Neuroscience and Canadian Multiple sclerosis society, and received grants for travel from Teva-Neuroscience and Novartis. Raymond Hupperts received honoraria as consultant on scientific advisory boards from Merck-Serono, Biogen-Idec, GenzymeSanofi and Teva, research funding from Merck-Serono and Biogen-Idec, and speaker honoraria from Sanofi-Genzyme and Novartis. Patrizia Sola did not declare any competing interests. Francois Grand’Maison received honoraria or research funding from Biogen Idec, Genzyme, Novartis, Teva Neurosciences, Mitsubishi and ONO Pharmaceuticals.

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Roberto Bergamaschi received speaker honoraria from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, Teva; research grants from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis, Teva; congress and travel/accommodation expense compensations by Almirall, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, Teva. Eugenio Pucci served on scientific advisory boards for Genzyme and Biogen-Idec; he has received honoraria and travel grants from Sanofi Aventis, UCB, Lundbeck, Novartis, Bayer Schering, Biogen Idec, Merck Serono, Genzyme and Teva; he has received travel grants from Associazione Marchigiana Sclerosi Multipla e altre malattie neurologiche. Celia Oreja-Guevara received honoraria as consultant on scientific advisory boards from Biogen-Idec, Bayer-Schering, MerckSerono, Teva and Novartis; has participated in clinical trials/other research projects by Biogen-Idec, GSK, Teva and Novartis. Jose Antonio Cabrera-Gomez did not declare any competing interests. Vincent Van Pesch has served on advisory boards for Biogen Idec, Novartis Pharma and Sanofi-Genzyme; has received travel grants and consultancy fees from Biogen Idec, Bayer Schering, Sanofi Aventis, Merck Serono, Sanofi-Genzyme and Novartis Pharma; has received research grants from Bayer Schering. Thor Petersen received funding or speaker honoraria from Biogen Idec, Merck Serono, Novartis, Bayer Schering, Sanofi-Aventis, Roche, and Genzyme. Cavit Boz received conference travel support from Biogen Idec, Novartis, Bayer-Schering, Merck-Serono and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. Cristina Ramo received research funding and compensation for travel from Biogen-Idec and Novartis. Maria Edite Rio did not declare any competing interests. Gerardo Iuliano had travel/accommodations/meeting expenses funded by Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis, and Teva. Ricardo Fernandez-Bolanos received speaking honoraria from Biogen-Idec, Novartis, Merck Serono and Teva. Franco Granella did not declare any competing interests. Daniele Spitaleri received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen Idec, Sanofi Aventis, Teva and Merck-Serono. Freek Verheul is an advisory board member for Teva Biogen Merck Serono and Novartis. Murat Terzi received travel grants from Merck Serono, Novartis, Bayer-Schering, Merck-Serono and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. Csilla Rozsa has received speaker honoraria from Bayer Schering, Novartis and Biogen Idec, congress and travel expense compensations from Biogen Idec, Teva, Merck Serono and Bayer Schering. Maria Pia Amato received honoraria as consultant on scientific advisory boards by Biogen-Idec, Bayer-Schering, Merck-Serono, Teva and Sanofi-Aventis; has received research grants by BiogenIdec, Bayer-Schering, Merck-Serono, Teva and Novartis. Javier Olascoaga did not declare any competing interests. Shlomo Flechter did not declare any competing interests. Edgardo Cristiano received honoraria as consultant on scientific advisory boards by Biogen-Idec, Bayer-Schering, Merck-Serono,


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Genzyme and Novartis; has participated in clinical trials/other research projects by Merck-Serono, Roche and Novartis. Juan Ignacio Rojas did not declare any competing interests. Suzanne Hodgkinson did not declare any competing interests. Vilija Jokubaitis has received conference travel support from Novartis. Tim Spelman received compensation for travel from Biogen Idec. P637 No evidence of disease activity achieved in patients with active relapsing-remitting multiple sclerosis who switched to alemtuzumab from subcutaneous interferon beta-1a: CARE-MS I and II extension studies H. Wiendl1, H.-P. Hartung2, E. Havrdova3, R.M.M. Hupperts4, D.H. Margolin5, L. Kasten6, D.A.S. Compston7, on behalf of the CARE-MS I and CARE-MS II Investigators 1University of Münster, Münster, 2Heinrich-Heine University, Düsseldorf, Germany, 3First Medical Faculty, Charles University in Prague, Prague, Czech Republic, 4Orbis Medisch Centrum, Maastricht University Medical Center, Sittard, The Netherlands, 5Genzyme, a Sanofi company, Cambridge, MA, United States, 6PROMETRIKA, LLC, Cambridge, MA, United States, 7University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom Background: In the CARE-MS studies, in active relapsing-remitting multiple sclerosis patients who were treatment-naive (CARE-MS I; NCT00530348) or had an inadequate response (⩾1 relapse) to a prior therapy (CARE-MS II; NCT00548405), alemtuzumab significantly improved relapse rate and magnetic resonance imaging (MRI) outcomes over subcutaneous interferon beta-1a (SC IFNB-1a). In CARE-MS II, alemtuzumab significantly reduced the risk of 6-month sustained accumulation of disability (SAD). In both CARE-MS studies, alemtuzumab patients were more likely than SC IFNB-1a patients to have no evidence of disease activity (NEDA) after 2 years. Goals: To examine alemtuzumab’s effect on NEDA after 2 years in patients who switched to alemtuzumab from SC IFNB-1a. Methods: In the initial 2-year, phase 3, head-to-head, raterblinded CARE-MS studies, SC IFNB-1a-treated patients received 44 µg 3 times/week for 2 years. These patients could enter the extension study (NCT00930553); upon enrolment, they received alemtuzumab 12 mg (infused on 5 consecutive days at extension study baseline and on 3 consecutive days 12 months later). Clinical disease activity (⩾1 relapse, or 6-month SAD [Expanded Disability Status Scale [EDSS] score increase from baseline of ⩾1.0; ⩾1.5 if baseline EDSS=0]), MRI activity (⩾1 new gadolinium-enhancing or new/enlarging T2 hyperintense lesion), and NEDA (absence of clinical disease and MRI lesion activity) were assessed annually before and after treatment with alemtuzumab. Results: 83% of SC IFNB-1a-treated patients in CARE-MS I (144/173) and CARE-MS II (146/175) enrolled in the extension. At Year 2 of the extension, the proportion of patients free of clinical disease activity of those who switched to alemtuzumab versus that of those on SC IFNB-1a in the core study increased by 12% for CARE-MS I (83% vs 74%) and 32% for CARE-MS II (84% vs 64%). The MRI lesion activity-free proportion increased by 38% for CARE-MS I (82% vs 59%) and by 73% for CARE-MS II

(81% vs 47%) patients. The proportion of patients achieving NEDA also increased, by 50% for CARE-MS I (70% vs 47%) and by 113% for CARE-MS II (67% vs 32%). Conclusion: In CARE-MS I and II patients who switched from SC IFNB-1a to alemtuzumab, there was a substantial increase in the proportion achieving NEDA. These findings demonstrate further improved outcomes with alemtuzumab versus SC IFNB-1a, and thus support the superior efficacy of alemtuzumab in patients who received prior disease-modifying therapy. Disclosure Study supported by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. HW: Honoraria for lecturing, travel expenses for attending meetings from Bayer Healthcare, Biogen Idec, Elan Corporation, Lilly, Lundbeck, Merck Serono, Novartis, Sanofi, and Teva Neuroscience), compensation for serving as a consultant (Biogen Idec, Merck Serono, Novartis Pharma, Sanofi), receiving research support (Bayer Schering Pharma, Biogen Idec, Elan Corporation, Merck Serono, Novartis, Novo Nordisk, and Sanofi). ). H-PH: Honoraria for consulting and speaking at symposia (Bayer Healthcare, Biogen Idec, CSL Behring, Genzyme, Merck Serono, Novartis, Octapharma, Roche, Teva, and Sanofi, with approval by the Rector of Heinrich Heine-University). EH: Honoraria and consulting fees (Bayer, GlaxoSmithKline, Genzyme, Biogen Idec, Sanofi, Merck Serono, Roche, Teva, and Novartis); consulting services, speaking and serving on scientific advisory boards and research support (Czech Ministry of Education). RMMH: Research grants, speaker´s fees and honoraria for advisory boards (BIOGEN, Genzyme-Sanofi, TEVA, Novartis, and Merck). DHM: Compensation as employee of Genzyme. LK: Provides statistical support as a consultant for Genzyme. DASC: Consulting fees and grant support (Genzyme) and lecture fees (Bayer Schering Pharma) on behalf of the University of Cambridge; and personal remuneration for lecture fees (Genzyme) from July 2014.

P638 Increasing levels of disability on objective measures of ambulation and upper extremity function are associated with increasing levels of patient-reported impairment in secondary progressive multiple sclerosis patients: baseline data from ASCEND D. Steiner1, H.P. Hartung2, R. Kapoor3, F. Sellebjerg4, D. Amarante1, Y. Chen1, Q. Dong1, D. Mikol1, on behalf of ASCEND Investigators 1Biogen, Cambridge, MA, United States, 2Heinrich-Heine University, Düsseldorf, Germany, 3National Hospital for Neurology & Neurosurgery, London, United Kingdom, 4Danish Multiple Sclerosis Center, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark Background: ASCEND is an ongoing, randomised, double-blind, placebo-controlled phase 3b study evaluating natalizumab treatment in patients with secondary progressive multiple sclerosis (MS). The primary endpoint is a composite of the following objective disability measures: the Expanded Disability Status


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Poster Session I, 21(S11) Scale, the Timed 25-Foot Walk (T25FW), and the 9-Hole Peg Test (9HPT). Objectives: To evaluate the degree of patient-reported impairment of ambulation and upper extremity function and the physical impact of MS on daily life in relation to objectively measured disability (T25FW and 9HPT) in the baseline ASCEND population. Methods: Of the composite endpoint measures, only those with continuous scales (T25FW and 9HPT) were analysed. For each of these measures, patients were grouped by quartile: cohort 1 (< 25th percentile), cohort 2 (25th to < 50th percentile), cohort 3 (50th to < 75th percentile), and cohort 4 (⩾75th percentile). Patient-reported instruments used were the MS Walking Scale (MSWS-12) (range 0-100; higher scores indicate more ambulatory impairment), the 56-item ABILHAND Questionnaire (range 0-100; higher scores indicate less difficulty with everyday manual activities), and the MS Impact Scale (MSIS-29) physical score (range 0-100; higher scores indicate greater impact of MS on daily life). Relationships between baseline objective and patientreported measures were evaluated by trend test across cohorts and Spearman rank correlation coefficient (rho). Results: Baseline mean (median [min, max]) T25FW time was 13.5 (11.2 [3.3, 82.4]) seconds (n=888); 9HPT times were 34.9 (28.6 [15.0, 300.0]) seconds for dominant hand (n=881) and 37.1 (29.6 [15.5, 426.2]) seconds for nondominant hand (n=868). Mean MSWS-12 scores increased by quartile from 55.3 (T25FW cohort 1) to 77.4 (T25FW cohort 4) (P< 0.0001) and were moderately correlated with T25FW times (rho 0.38) and MSIS-29 physical scores (rho 0.32). Mean ABILHAND scores decreased by quartile from 92.0 (9HPT dominant-hand cohort 1) to 74.1 (9HPT dominant-hand cohort 4) (P< 0.0001) and were moderately correlated with 9HPT times (rho: dominant hand, −0.47; nondominant hand, −0.37). More objectively impaired patients (T25FW and 9HPT cohorts 3 and 4) also had higher MSIS-29 scores. Conclusions: At ASCEND baseline, patients with longer T25FW and 9HPT times had greater perceived impairment of ambulatory function and everyday manual activities and a greater perceived impact of MS on their daily lives. Disclosure Supported by Biogen. DS, DA, YC, QD, DM: Employees of Biogen. HPH: personal compensation from Biogen, GeNeuro, Genzyme, Merck Serono, Novartis, Octapharma, Opexa, Roche, Teva for consulting services and speaking at scientific symposia. RK: personal compensation serving on scientific advisory boards and to support attendance at scientific meetings from Biogen, Genzyme, Novartis, Teva. FS: served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, Genzyme, Lundbeck, Merck Serono, Novo Nordisk, Novartis, Sanofi-Aventis, Schering Plough and Teva.

B. Kieseier1, A.N. Boyko2, D. Dive3, J. Lycke4, X. Montalban5, D.H. Margolin6, K. Thangavelu6, on behalf of the CARE-MS II Investigators 1Heinrich-Heine University, Düsseldorf, Germany, 2Pirogov’s Russian National Research University and Moscow Multiple Sclerosis Centre, Moscow, Russian Federation, 3University Hospital Centre of Liège, Liège, Belgium, 4University of Gothenburg, Gothenburg, Sweden, 5Vall d’Hebron University Hospital, Barcelona, Spain, 6Genzyme, a Sanofi company, Cambridge, MA, United States Background: In the CARE-MS II study (NCT00548405) of patients with active relapsing-remitting multiple sclerosis (RRMS) who had an inadequate response (⩾1 relapse) to a prior therapy, alemtuzumab significantly reduced the annualised relapse rate (ARR) by 49% versus subcutaneous interferon beta-1a (SC IFNB-1a) over 2 years. Goals: To examine alemtuzumab’s effect on relapse in patients who switched from SC IFNB-1a in the core study to alemtuzumab in the extension study (NCT00930553). Methods: Patients randomised to SC IFNB-1a 44 µg 3 times/ week in CARE-MS II could enter the extension; in the extension, they received 2 annual courses of alemtuzumab 12 mg (infused on 5 consecutive days at extension study baseline and on 3 consecutive days 12 months later), then as-needed retreatment based on evidence of disease activity (eg, relapse or magnetic resonance imaging activity). In the core study, relapses were confirmed per the protocol definition by an independent, blinded adjudication panel; in the extension, relapses were confirmed per protocol definition by the investigator. Endpoints included ARR, proportion of patients free of relapses, and relapse outcomes over 2 years in the subsets of patients who relapsed on SC IFNB-1a either any time during the core study or in Year 2 of the core study. Results: 83.4% of SC IFNB-1a-treated patients (n=146) from CARE-MS II entered the extension; of those, 131 (89.7%) received 2 alemtuzumab courses. Two years after their initial course of alemtuzumab, ARR decreased by 71% (0.52 vs 0.15). The proportion of patients who were relapse-free increased by 70%, from 47% of patients in the core study on SC IFNB-1a treatment to 79% of patients 2 years after switching to alemtuzumab. In those patients who relapsed on SC IFNB-1a any time during the core study (n=72), ARR decreased in the 2 years after switching to alemtuzumab (1.07 to 0.24), and 67% were relapse-free. Similar results were observed in SC IFNB-1a patients who relapsed in Year 2 of the core study (n=50; ARR 1.39 vs 0.311 [60% relapsefree for 2 years after switching to alemtuzumab]). Conclusion: Alemtuzumab treatment improved relapse outcomes in patients with RRMS compared with prior SC IFNB-1a treatment. Most patients who relapsed during SC IFNB-1a therapy became relapse-free after alemtuzumab. These findings, like those of the core study, demonstrate the benefit of switching to alemtuzumab for patients who had an inadequate response on prior disease-modifying therapy. Disclosure

P639 Improvement in relapse outcomes following switch from subcutaneous interferon beta-1a to alemtuzumab: CARE-MS II extension study

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Study supported by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. BK: Consulting fees (Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi, Teva Neuroscience); contracted


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research (Bayer Schering, Biogen Idec, Merck Serono, Teva Neuroscience). ANB: Consulting fees and participated in clinical trials (Bayer HealthCare, Biogen Idec, Genzyme, Merck Serono, Novartis,Sanofi Aventis, and Teva). DD: Institutional honoraria for advisory boards and participations and travel grants from Bayer, Novartis, Merck-Sereno, Teva and Genzyme. JL: Compensation for consulting, serving on scientific advisory boards and as a speaker for lectures from Biogen, Genzyme, Novartis and Teva. XM: Speaking honoraria and travel expenses for participation in scientific meetings, steering committee member of clinical trials or participation in advisory boards of clinical trials in the past years (Almirall, Bayer, Biogen Idec, EMD, Genentech, Geneuro, Genzyme, Merck, Neurotec, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals). DHM and KT: Compensation as employee of Genzyme. P640 Off-label rituximab in patients with secondary progressive multiple sclerosis Y. Naegelin1, P.R. Naegelin1, L. Kappos1,2, T. Derfuss1,2 1Neurology, Departments of Medicine, Biomedicine, Clinical Research and Biomedical Engineering, 2Laboratory of Clinical Neuroimmunology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland Background: Rituximab (RTX) is a monoclonal antibody against the B-cell-specific surface protein CD 20. Based on considerations about the role of B cells in the progressive phase of disease RTX might be an option in secondary progressive MS (SPMS). Objective: To evaluate the course of disease after initiation of treatment with RTX in a local cohort of patients with SPMS. Methods: Patients with active and/or rapidly progressive SPMS were treated off label with RTX and were included in this retrospective analysis if RTX had been given at least once and followup was at least one year. RTX was given in intervals of 6-12 months (m, once or twice 1’000mg intravenously within two weeks), based on the individual decision of the treating neurologist considering clinical course and CD-19-lymphocyte counts. Baseline (BL) was defined as the date of first rituximab infusion. Treatment duration was calculated to be 12 months after one infusion of RTX. Treatment Intensity (TI) was defined to be the total of administered RTX in mg divided by the duration of treatment in months. Standardized Neurostatus assessments (EDSS) were analysed on a yearly interval before BL and thereafter until a maximum of 12 m after last RTX dose. Results: 36 patients (19 females) treated in our center before May 2014 with RTX were included into this analysis. Mean (min-max) age at BL was 49.6 years (y, 23-71), disease duration (DD) was 17.9 y (3-40), EDSS 2 y before BL was 5.9 (2.5-7.5), at BL 6.4 (3.0-8.5), last EDSS under treatment or up to 1 year after having stopped treatment was 6.6 (3.5-8.5). Mean follow-up was 3.1 y (1-7). Mean TI was 168.4 mg/month (83.3-250). Worsening of EDSS occurred in 14 patients (38.9%). 6 patients (16.67%) reached confirmed progression during follow-up. In two patients (5.6%) treatment with RTX was stopped due to adverse events (microcytoclastic vasculitis, focal herpes zoster).

Conclusions: RTX treatment was generally well tolerated in this cohort of patients with active and/or rapidly progressing SPMS. Fewer patients than expected reached confirmed progression. Disclosure Naegelin Y has nothing to disclose. Naegelin PR has nothing to disclose. Derfuss T serves on scientific advisory boards for Novartis Pharma, Merck Serono, Biogen Idec, Genzyme, Mitsubishi Pharma, TEVA Pharma, GeNeuro, and Bayer Schering Pharma; has received funding for travel and/or speaker honoraria from Biogen Idec, Novartis, Merck Serono, and Bayer Schering Pharma; and receives research support from the Swiss National Research Foundation, Biogen Idec, Novartis Pharma, the European Union, and the Swiss MS Society. Kappos L: Institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: steering committee/consulting fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; royalties from Neurostatus Systems GmbH; grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis, Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society, and the Swiss National Research Foundation.

Others P641 Comparative gene expression profiling between Glatopa™ and Copaxone® J. D’Alessandro, J. Duffner, J. Pradines, C. Honan, T. Prod’homme, G. Kaundinya, T. Ganguly Momenta Pharmaceuticals, Cambridge, MA, United States Objectives: To contribute to the evaluation of biological equivalence between Copaxone® 20 mg and a generic version, Glatopa™, via expression profiling studies in T cells using microarrays. Background: Glatopa is the first US FDA-approved, substitutable generic version of Copaxone 20 mg. Momenta evaluated equivalence between Glatopa and Copaxone using a comprehensive set of physicochemical (structural) and biological (functional) assays. Design/methods: Gene expression changes induced by multiple lots of Glatopa, Copaxone, and a glatiramoid copolymer (negative control) related to media were examined on murine glatiramer acetate (GA)-specific T cells using Agilent 4x44k gene expression microarrays (24,263 different genes). Differences among treatment groups were examined by univariate methods (Student’s t-test; ANOVA) as well as by multivariate methods (principal component analysis and multidimensional scaling) accompanied by the appropriate permutation controls for false positives. In addition, discriminating genes were subjected to gene set enrichment analysis and the level of expression change was examined using T-helper Cell Differentiation Canonical Pathway from Ingenuity Pathway Analysis.


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Poster Session I, 21(S11) Results: As expected, GA primarily induced Th2-polarized cell expansion and related expression changes, whereas media alone did not. Glatopa and Copaxone exhibited similar levels of change in all Th2-relevant transcripts, while the negative control glatiramoid copolymer exhibited significantly different gene expression changes for IL-3 and IL-4. Conclusions: Momenta showed the biological equivalence of Glatopa and Copaxone across gene regulatory effects on T cells. These results were supportive of and consistent with results from a larger biocharacterization program, which consisted of multiple complementary molecular, cell-based, and in vivo assays across relevant biologic activities of GA. Disclosure All authors are employees of Momenta Pharmaceuticals, Inc. P642 Progressive multifocal leukoencephalopathy under treatment with dimethyl fumarate N.M. Dammeier1, V. Schubert1, T.K. Hauser2, A. Bornemann3, F. Bischof1 1Neurology, 2Neuroradiology, 3Institute for Pathology and Neuropathology, University Tuebingen, Tuebingen, Germany Background: Progressive multifocal leukoencephalopathy is a severe demyelinating disease caused by the polyoma JC virus in patients with reduced immunocompetence. A few cases of progressive multifocal leukoencephalopathy have been reported in patients treated with fumaric acid esters. Case: A 53-year-old Caucasian woman reported to our clinic with a first focal epileptic seizure and mild cognitive impairment. Since 1.5 years, she was treated with dimethyl fumarate for her psoriasis. During that time, her lymphocyte counts ranged between 450 and 750/ul. Cerebral magnet resonance imaging showed multifocal subcortical T2 hyperintense lesions with partial gadolinium enhancement. She did not have antibodies against human immunodefiency virus 1 and 2 and cerebrospinal fluid-polymerase chain reaction for viral infections including a sensitive JC-virus polymerase chain reaction were negative. The diagnosis of progressive multifocal leukoencephalopathy was established by histological analysis and detection of JC-virus desoxyribonucleic acid in brain biopsy specimens. Dimethyl fumarate was stopped and Mirtazapin and Mefloquin were initiated. Neurological examination and imaging remained stable. Conclusion: Progressive multifocal leukoencephalopathy can occur in patients with lymphocyte counts between 450 and 700/ul, produce only faint symptoms and is not excluded by negative JC-virus-polymerase chain reaction in cerebrospinal fluid. The incidence of progressice multifocal leukoencephalopathy may thus be underestimated and a more careful surveillance of patients would be necessary. Disclosure F Bischof receives compensation for serving on Scientific Advisory Boards for Bayer Healthcare, Biogen Idec, Genzyme and Novartis, speaker honoraria and travel support from Biogen Idec, Fresenius Medical Care, Genzyme and Novartis and research

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support from Novartis. The other authors declare that they have no competing interests. P643 The state of MS: treatment goals and challenges M. Tintoré1, M. Alexander2, K. Costello3, M. Duddy4, D. Jones5, N. Law6, G. O’Neill7, A. Uccelli8, R. Weissert9, S. Wray10 1Hospital Vall d’Hebron, MS Centre of Catalonia, Barcelona, Spain, 2European Multiple Sclerosis Platform, Brussels, Belgium, 3National Multiple Sclerosis Society, Denver, CO, United States, 4Royal Victoria Infirmary, Newcastle-upon-Tyne, United Kingdom, 5University of Virginia, Charlottesville, VA, 6Nancy Law Consulting LLC (formerly of National Multiple Sclerosis Society), Parker, CO, 7Biogen, Cambridge, MA, United States, 8University of Genoa, Genoa, Italy, 9University of Regensburg, Regensburg, Germany, 10Hope Neurology MS Center, Knoxville, TN, United States Background: Differences in the perception of the goals and challenges associated with disease modifying therapies (DMTs) between neurologists and people living with MS are likely to affect patients’ choices in initiating and persisting with treatment, and thus influence outcomes. Objectives: To gain insight into treatment goals and challenges in current MS care from the patient and neurologist perspective. Methods: An online survey using close-ended questionnaires surveyed neurologists who treat MS patients (n=900) and people living with MS (n=982) from Germany, Italy, Spain, the United Kingdom, and the United States (US) in 2014. Parallel questions were designed for patients and neurologists for comparison. Multiple answers were allowed per question. Results: Patients most commonly identified reducing relapse frequency (61%), slowing disability progression (60%), feeling better (53%), and reducing relapse intensity (50%) as treatment goals for their current MS DMT. Neurologists identified similar treatment goals but also selected the ability to live independently, maintaining cognitive function, reducing daily symptoms, preventing new brain/spinal cord lesions, and reducing neurodegeneration as important. Among patients who have been on a DMT, cost (personally or to the health care system), side effects or tolerability of the treatment, and uncertainty if the treatment is working represent the top challenges in managing their MS treatment. Personal cost was identified by more US patients than European Union (EU) patients (36% versus 20%, EU average). With the exception of cost, neurologists agreed on the top challenges for patients. However, about half of neurologists also cited a lack of acceptance of the disease, which patients themselves are much less likely to mention. Of the 51% of patients who skip DMT doses, 32% do not tell their healthcare provider. The main reasons for skipped doses were: forgot (43%); side effects (22%); and feeling better (15%). However, neurologists believe that their patients experiencing side effects (73%) represents the greatest cause of skipping. Conclusions: Overall, patients and neurologists identified similar treatment goals and challenges in managing DMTs. The impact of cost, a challenge for many patients, varied between the US and EU. Some identified treatment challenges may affect compliance; techniques to enable patients to remember to take their DMT may be as important as minimising treatment side effects.


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Disclosure Mar Tintoré: non-CME service/consulting fees from Biogen, EMD Merck Serono, Genzyme, Novartis, and Teva; educational/ research support from Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis Pharma AG, and Teva UK Ltd. Maggie Alexander: Nothing to disclose. Kathleen Costello: Nothing to disclose. Martin Duddy: Consulting fees and honoraria from Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis Pharma AG, and Teva UK Ltd; personal compensation as associate editor for the Multiple Sclerosis Journal; educational/research support from Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis Pharma AG, Roche, and Teva UK Ltd. David Jones: Consulting fees from Biogen, Genzyme, and Novartis. Nancy Law: Consulting fees from Biogen in her current role; no consulting fees were received in her former role as an employee of the National Multiple Sclerosis Society, Denver, CO, USA. Gilmore O’Neill: Employee of Biogen of and stockholder in Biogen. Antonio Uccelli: Speaker/consulting fees from Biogen, Genzyme, Merck Serono, Novartis, Roche, and Teva; research support from Biogen, Merck Serono, and Novartis. Robert Weissert: Consulting fees from Biogen, Genzyme, Merck Serono, and Novartis; speakers bureau for Biogen and Ärztlicher Kreisverband Weiden; contracted research for Novartis. Sibyl Wray: Consulting fees from Acorda, Biogen, EMD Serono, Genzyme, Novartis, Questcor, and Teva; speakers bureau for Acorda, Bayer HealthCare, Biogen, EMD Serono, Genzyme, Novartis, Questcor, and Teva; contracted research for Biogen, EMD Serono, Genzyme, Novartis, Receptos, and Roche. This study was funded by Biogen (Cambridge, MA, USA). Biogen provided funding for medical writing support in the development of this abstract. Karen Spach, PhD (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Harris Poll assisted with survey design, support, data collection, and data analysis. Biogen reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P644 Persistence and adherence to immunomodulators varies between Canadian provinces C. Evans1, R.A. Marrie2, S. Leung2, F. Zhu3, X. Lu4, H. Tremlett3 1University of Saskatchewan, Saskatoon, SK, 2University of Manitoba, Winnipeg, MB, 3University of British Columbia, Vancouver, BC, 4Saskatchewan Health Quality Council, Saskatoon, SK, Canada Background: Adherence to immunomodulators (IMDs) is believed to be problematic in individuals with multiple sclerosis (MS), but no large, population-based studies have examined this. Objective: To estimate the prevalence and predictors of adherence and persistence to IMDs in 3 Canadian provinces. Methods: We used population-based health administrative databases in British Columbia (BC), Saskatchewan (SK), and Manitoba (MB). All individuals who received an IMD (interferon-B-1b, interferon-B-1a subcutaneous and intramuscular, and glatiramer

acetate) between 1-January-1996 and 31-December-2011 were included. We estimated adherence using the proportion of days covered (PDC) at one year after the index date (date of first IMD dispensation). Persistence, defined as time to IMD discontinuation, was examined for both the initial and any IMD therapy. Multivariable regression models were used to assess independent predictors of adherence and persistence; results were pooled using random effects meta-analysis. Results: A total of 4830 individuals were included (BC, n=2323; SK, n=1297; MB, n=1210). Overall, 3614 (74.8%, 95% CI: 69.1%82.8%) individuals had good adherence (PDC ⩾80%) at one year after the index date. The proportion of good adherence varied between provinces, with SK having the highest (1041/1297, 80.3%, 95% CI: 75.4%-85.1%), followed by MB (948/1210, 78.3%, 95% CI: 73.4%-83.3%), and BC (1625/2323, 70.0%, 95% CI: 66.6%-73.3%). The median time to discontinuation of the initial IMD was 1.9 years (95% CI: 1.6-2.1), 2.8 years (95% CI: 2.53.0), and 4.0 years (95% CI: 3.5-4.6) for MB, BC and SK, respectively. Median time to discontinuation of any IMD was 4.6 years (95% CI: 4.1-5.0), 4.1 years (95% CI: 3.9-4.5), and 5.9 years (95% CI: 5.3-6.2) for MB, BC and SK, respectively. Age, sex and socioeconomic status were not associated with good adherence or persistence. Individuals who had ⩾4 physician visits during the year prior to the index date were more likely to exhibit good adherence compared to those with fewer (0-3) physician visits. Conclusion: Despite similar drug access and coverage criteria, adherence and persistence to IMDs differ across 3 Canadian provinces, and were not consistently associated with measured demographic characteristics or health care utilization. Variations in practice patterns and patient supports may explain these differences, and should be explored further. Disclosure Charity Evans receives grant support from the National MS Society (RG 4757-A-3). Ruth Ann Marrie has conducted clinical trials for Sanofi-Aventis Stella Leung: Nothing to disclose. Xinya Yu: Nothing to disclose. Feng Zhu: Nothing to disclose. Helen Tremlett is funded as a Canada Research Chair and has received research support from the National Multiple Sclerosis Society, the Canadian Institutes of Health Research, and the UK MS Trust and travel expenses to attend meetings or conferences from the Consortium of MS Centres (2013), the National MS Society (2012, 2014), Bayer Pharmaceuticals (2010), Teva Pharmaceuticals (2011), ECTRIMS (2011, 2012, 2013, 2014), UK MS Trust (2011), the Chesapeake Health Education Program, US Veterans Affairs (2012), Novartis Canada (2012), Biogen Idec (2014), American Academy of Neurology (2013, 2014, 2015). P645 The impact of adherence to immunomodulators on hospitalisations in multiple sclerosis C. Evans1, R.A. Marrie2, S. Leung2, F. Zhu3, X. Lu4, H. Tremlett3 1University of Saskatchewan, Saskatoon, SK, 2University of Manitoba, Winnipeg, MB, 3University of British Columbia, Vancouver, BC, 4Saskatchewan Health Quality Council, Saskatoon, SK, Canada


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Poster Session I, 21(S11) Background: Poor adherence to certain chronic medications has been associated with increased morbidity and mortality. However, few studies have examined the impact of adherence on health care utilization, and none have done so using a large, population-based cohort of individuals with multiple sclerosis (MS). Objective: To examine the association between optimal adherence to the immunomodulators (IMDs) for MS and hospitalisations in 3 Canadian provinces. Methods: We used population-based health administrative databases in British Columbia (BC), Saskatchewan (SK), and Manitoba (MB), and included all individuals who received an IMD (interferon-B-1b, interferon-B-1a subcutaneous or intramuscular, or glatiramer acetate) between 1-January-1996 and 31-December-2011. The date of the first IMD dispensation was considered the index date (Day 0). We estimated adherence using the proportion of days covered (PDC) for the one year after the index date. The primary outcome was the rate of all-cause hospital admissions in the subsequent year (Day 366-730). A secondary outcome was the number of MS-specific hospitalisations. Rate ratios (RR) were estimated using multivariable zero-inflated Poisson regression, with adjustment for age, sex, socioeconomic status, calendar year, and prior health care utilization; results were pooled using random effects meta-analysis. Results: A total of 4746 individuals were included (BC, n=2241; SK, n=1297; MB, n=1208); 3564 (75.1%, 95% CI: 69.6% 82.6%) individuals had optimal adherence (PDC ⩾80%) at one year after the index date. Overall, the rate of all-cause hospitalisations was lower for individuals who had optimal adherence compared to those with suboptimal (PDC < 80%) adherence (RR 0.72, 95% CI: 0.60 - 0.86). The association between adherence and hospitalizations was strongest in SK (RR 0.63, 95% CI: 0.46 - 0.85), followed by BC (RR 0.79, 95% CI: 0.53 - 1.17), and MB (RR 0.85, 95% CI: 0.57 - 1.27). A similar overall trend was seen when examining only inpatient all-cause admissions (RR 0.60, 95% CI: 0.36 - 1.00). MS-specific admissions were lower for individuals with good adherence, but were not significantly different from those with suboptimal adherence (RR 0.81, 95% CI: 0.22 - 2.93). Conclusion: Optimal adherence within the first year of IMD use appears to be associated with fewer all-cause hospitalizations in the subsequent year. Further work is needed to determine if this association is sustained over longer periods. Disclosure Charity Evans receives grant support from the National MS Society (RG 4757-A-3). Ruth Ann Marrie has conducted clinical trials for Sanofi-Aventis. Stella Leung: Nothing to disclose. Xinya Yu: Nothing to disclose. Feng Zhu: Nothing to disclose. Helen Tremlett is funded as a Canada Research Chair and has received research support from the National Multiple Sclerosis Society, the Canadian Institutes of Health Research, and the UK MS Trust and travel expenses to attend meetings or conferences from the Consortium of MS Centres (2013), the National MS Society (2012, 2014), Bayer Pharmaceuticals (2010), Teva Pharmaceuticals (2011), ECTRIMS (2011, 2012, 2013, 2014), UK MS Trust (2011), the Chesapeake Health Education Program, US Veterans Affairs (2012), Novartis Canada (2012), Biogen Idec (2014), American Academy of Neurology (2013, 2014, 2015).

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P646 Comparing dimethyl fumarate efficacy and tolerability among Caucasian-, African- and Hispanic-American MS patients L. Zhovtis Ryerson1, K. Pandey2, C. Sammarco1, L. Laing1, G. Confident1, R. Green2, B. Richter2, M. Elyashiv1, J. Kalina1, I. Kister1 1NYU Langone Medical Center, New York, NY, 2Barnabas Health System, Livingston, NJ, United States Background: Dimethyl fumarate (DMF) demonstrated significant efficacy in two randomized clinical trials for treatment of relapsing remitting multiple sclerosis (RRMS). However, trials included few patients of African-American (AA) and Hispanic backgrounds, who may have a different disease course. For example, AA have been reported to experience a more severe disease course and poorer response to disease modifying therapy. Objectives: To evaluate the efficacy and tolerability of DMF in patients with MS across different ethnic groups at 2 MS Centers, which serve ethnically diverse patient population. Methods: Retrospective chart review was performed of all clinic patients who were started on DMF in the first year of drug availability. Ethnicity was derived from patient self-description. Relapses and new T2 and Gad-enhancing lesions were recorded 1 year prior to and while on DMF therapy. Results of multivariate analyses will be presented. Results: 422 MS patients were started on DMF. Average age was 45 years (range 21 - 79); 74% were women. Ethnicity was available for 85% of patients, which was comprised of 56% Caucasians; 17%AA; 12% Hispanic. Mean duration of MS symptoms was 6 years (range 1-55). Mean duration of treatment was 8 months, (range 0-16). 12% of patients were drug naïve. DMF was discontinued by 17% of patients, most frequently due to GI side effects, 5%. Reduction in annual relapse rate (ARR) was seen across all ethnic groups when compared to ARR one year prior to start of DMF (Caucasians 0.31 to 0.11; AA 0.28 to 0.04; Hispanic 0.18 to 0.12). Similar reduction in new T2 lesion rate was seen across all groups: Caucasian 59%; AA and Hispanics 56%. Gadolinium enhancing lesions were reduced by 63% in Caucasian and Hispanic cohort, 64% in AA. Conclusions: Current study demonstrates DMF efficacy and tolerability appears to be similar across three main ethnic groups represented in our practice. Disclosure The study was funded by a research grant from Biogen Idec. Lana Zhovtis Ryerson: Research support from Biogen Idec; speaker´s bureau and served on scientific advisory board for Biogen Idec and Teva Pharmaceuticals Carrie Sammarco: Speaks for Biogen and Genzyme Lisa Laing: Nothing to disclose Krupa Pandey: Consults and speaks for: Acorda, Biogen and TEVA Gladyne Confident: Nothing to disclose Benjamin Richter: Nothing to disclose Rivka Green: Nothing to disclose Maayan Elyashiv: Nothing to disclose Jeniffer Kalina: Nothing to disclose


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Ilya Kister served on scientific advisory board for Biogen Idec and received research support from Guthy-Jackson Charitable Foundation, National Multiple Sclerosis Society, Biogen-Idec, Serono, and Navartis. P647 Use of multiple, high resolution, orthogonal assays for demonstration of biological and immunological equivalence of Glatopa™ and Copaxone® J. D’Alessandro1, K. Garofalo1, G. Zhao1, C. Honan1, J. Duffner1, J. Pradines1, I. Capila1, I. Fier1, G. Kaundinya1, D. Kantor2, T. Ganguly1 1Momenta Pharmaceuticals, Cambridge, MA, 2Neurologique, Pointe Vedra, FL, United States Background and objectives: Glatopa™ is the first FDAapproved, substitutable generic version of Copaxone® 20 mg. Momenta evaluated equivalence between the two drugs in terms of starting materials, manufacturing process signatures, and physicochemical properties. In addition, equivalence of biological and immunological properties was evaluated, as described herein. Methods: A comprehensive panel of >15 molecular, cellular, and in vivo biological assays assessed the major immunomodulatory mechanisms affected by glatiramer acetate (GA). These assays interrogated antigen presenting cell (APC) biology (MHC class II binding; MIG release) and T cell biology (proliferation; IL-2 release; T cell polarization). In vitro immunoreactivity to GA-specific monoclonal antibodies and in vivo antibody response (B cell biology) were used to demonstrate immunological equivalence. Other immunomodulatory effects (histamine release from basophils) were compared. Three EAE models compared the efficacy of Glatopa and Copaxone not covered by the mechanismspecific assays. Finally, genome-wide gene expression profiling was performed across 39,429 probes. Data from all studies were subjected to appropriate, rigorous statistical methods. Results: There were no statistically significant differences in direct head-to-head comparisons as well as cross over design studies between multiple lots of Glatopa and Copaxone with the above assays used to compare biological activity on APC, T cell, and B cell function. For example, in two EAE models, Glatopa and Copaxone significantly delayed mean disease onset relative to placebo (14.2 and 14.3 vs. 12.3 days, p< 0.01; 28.7 and 27.6 vs. 11.8 days, p< 0.001); no significant differences were observed between Glatopa and Copaxone. Conclusions: Using this comprehensive approach, Momenta showed equivalence of biological and immunological properties of Glatopa and Copaxone. Disclosure Josephine D’Alessandro, Kevin Garofalo, Ganlin Zhao, Christopher Honan, Jay Duffner, Joel Pradines, Ishan Capila, Ian Fier, Ganesh Kaundinya, and Tanmoy Ganguly are employees of Momenta. Daniel Kantor has been a consultant for Sandoz. P648 Pharmacokinetics, safety and tolerability of singledose siponimod (BAF312) in subjects with renal impairment versus matched healthy controls

A. Gardin1, A. Dodman1, S. Kalluri2, S. Neelakantham2, X. Tan3, E. Legangneux1, K. Shakeri-Nejad1 1Novartis Pharma AG, Basel, Switzerland, 2Novartis Healthcare Pvt. Ltd, Hyderabad, India, 3Novartis Institutes for BioMedical Research, Beijing, China Background: Patients with MS may present with varying degrees of age- or disease-related renal impairment (RI). While siponimod is predominantly eliminated via hepatic metabolic clearance, an indirect impact of RI on siponimod pharmacokinetics (PK) cannot be excluded. Objective: To investigate the PK of siponimod and selected metabolites (M3 and M5), the safety and tolerability of siponimod following administration of a single oral dose of 0.25mg (lowest conclusive dose and initial dose of siponimod dose-titration regimen) in subjects with varying degrees of RI compared with demographically matched healthy subjects (HS). Methods: This open-label, non-randomised, parallel-group study employed a top-down approach, starting with the enrolment of severe RI subjects (n=8) and matched healthy subjects (n=8). Enrolment of subjects with moderate and mild RI was to proceed only if interim analysis revealed ⩾50% increase in maximum plasma concentration (Cmax) or area under the curve (AUC) of total and/or unbound siponimod in subjects with severe RI vs. matched healthy controls. The study consisted of a 21-day screening period, a baseline period, a treatment period (Day 1) and ~13day follow-up period. PK parameters (Cmax, AUClast and AUCinf) and safety were evaluated. Results: All 16 subjects completed the study. Baseline characteristics were similar. Cmax was decreased by 8% and AUClast and AUCinf increased by 23% and 24%, respectively, in severe RI subjects vs HS. Siponimod plasma unbound (u) fraction was 7% higher in severe RI subjects. Cmax(u) was comparable whereas AUClast(u) and AUCinf(u) increased by 32% and 33%, respectively, in severe RI subjects vs HS. Changes in the PK parameters of siponimod plasma metabolites M3 (Cmax decreased by 9%; AUClast and AUCinf increased by 11%) and M5 (Cmax decreased by 26%; AUClast decreased by 16%) were also not clinically relevant. No AEs were reported; cardiac safety monitoring within the first 24 h of administration in subjects with severe RI did not reveal any significant bradycardia, bradyarrhythmic events or other cardiac rhythm abnormalities. Based on these results, investigation of PK, safety and tolerability in subjects with mild and moderate RI was not warranted. Conclusion: Single oral doses of siponimod 0.25mg were safe and well tolerated by subjects with severe RI. There were no clinically relevant variations in PK parameters of total or unbound siponimod or metabolites M3/M5 in subjects with severe RI. Disclosure Funding source This study is supported by Novartis Pharma AG, Basel, Switzerland. Anne Gardin is an employee of Novartis Pharma AG, Basel, Switzerland Angela Dodman is an employee of Novartis Pharma AG, Basel, Switzerland Sampath Kalluri is an employee of Novartis Healthcare Pvt. Ltd., Hyd, India Srikanth Neelakantham is an employee of Novartis Healthcare Pvt. Ltd., Hyd, India


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Poster Session I, 21(S11) Xuemei Tan is an employee of Novartis Institutes for BioMedical Research, Beijing, China Eric Legangneux is an employee of Novartis Pharma AG, Basel, Switzerland Kasra Shakeri-Nejad is an employee of Novartis Pharma AG, Basel, Switzerland P649 Siponimod (BAF312) for the treatment of secondary progressive multiple sclerosis (SPMS): baseline characteristics of the EXPAND study population L. Kappos1, A. Bar-Or2, B. Cree3, R. Fox4, G. Giovannoni5, R. Gold6, P. Vermersch7, P. Bhasin8, S. Arnould9, T. Sidorenko9, E. Wallstroem9 1Neurology, Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital, Basel, Switzerland, 2Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada, 3Multiple Sclerosis Centre, University of California San Francisco, San Francisco, CA, 4Mellen Centre for Treatment and Research in Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States, 5Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom, 6Department of Neurology, St. Josef-Hospital/ Ruhr-University Bochum, Bochum, Germany, 7Department of Neurology, University of Lille, Lille, France, 8Novartis Healthcare Pvt. Ltd., Hyderabad, India, 9Novartis Pharma AG, Basel, Switzerland Background: EXPAND is a phase 3, multicentre, randomised, double-blind, parallel-group, placebo-controlled study intended to demonstrate the efficacy, safety and tolerability of siponimod in treatment of secondary progressive multiple sclerosis (SPMS). Objective: To report the baseline demographic and disease characteristics of the EXPAND study population. Methods: Patients with SPMS (initial relapsing remitting disease course followed by progressive increase in disability over at least 6 months with or without occasional relapses, minor remissions, and plateaus) aged 18-60 years and an Expanded Disability Status Scale (EDSS) score from 3.0 to 6.5 at screening were enrolled. Eligible patients were randomised (2:1) to receive either siponimod with a 6-day dose titration (started at 0.25 mg and continued at 2 mg) or placebo. The primary efficacy variable was the time to 3-month confirmed disability progression measured by EDSS. The key secondary outcomes included MRI measurements, timed 25 foot walk test (T25FW) and safety assessments. Results: As of 27-March-2015, 1510 patients have been enrolled. Highest enrolling countries included Germany (n=247), Poland (n=107), Spain (n=103), Russia (n=94), USA (n=90), France (n=83) and Italy (n=80). Baseline mean (±SD) patient age was 47.9±7.8 years, and 60% were women. Median durations since MS diagnosis and conversion to SPMS were 11.6 and 2.6 years, respectively. At baseline, mean EDSS was 5.4±1.1 (median EDSS [range/IQR]: 6.0 [1.5-7.0/4.5-6.0]), with 53% of patients having EDSS score of 6.0-6.5. Other baseline clinical measures were (mean±SD): T25FW 17.2±28.2 seconds (s) and 9-Hole Peg Test (9HPT) dominant hand (DH) 33.9±31.1 s. At baseline, 75% of patients had no gadolinium (Gd)-enhancing T1 lesions, and the

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mean T2 lesion volume was 15103.5±15838.3 mm3. Relapses in the 2 years prior to study start were documented in 34.6% of the patients while 64.6% were free of clinical relapses; in both subgroups the majority of patients had no Gd-enhancing T1 lesions at baseline (70.9% for relapsing and 80.9% for non-relapsing patients; difference between subgroups [95% CI]: 10.0% [5.4;14.7]). Conclusion: Baseline age, EDSS and other disease characteristics including functional disability test scores are consistent with SPMS. Given the large enrolment, variable treatment duration regimen, and time-to-event endpoint the EXPAND study aims to elucidate the therapeutic potential of siponimod in SPMS. Disclosure Funding source This study is supported by Novartis Pharma AG, Basel, Switzerland. Ludwig Kappos’ institution (University Hospital Basel) has received in the last 3 years and used exclusively for research support: steering committee, advisory board, and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, Xenoport); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, Teva); support of educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva); royalties (Neurostatus Systems GmbH); grants (Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society, Swiss National Research Foundation). Amit Bar-Or has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Amplimmune, Biogen Idec, Diogenix, Genentech, Sanofi-Genzyme, GlaxoSmithKline, Novartis, Ono Pharma, Teva Neuroscience, Receptos Inc., Roche, and Merck/EMD Serono; Bruce Cree has received personal compensation for consulting from Abbvie, Biogen Idec, EMD Serono, MedImmune, Novartis, Genzyme/sanofi aventis, Teva Neurosciences and has received contracted research support (including clinical trials) from Acorda, Avanir, Biogen Idec, EMD Serono, Hoffman La Roche, MedImmune and Teva Neurosciences. Robert Fox has received compensation for serving as consultant or speaker or he or institution he works for has received research support from Allozyne, Avanir, Biogen Idec, Novartis, Questcor and Teva Pharmaceutical industries. Gavin Giovannoni has received fees for participation in advisory board for AbbVie Biotherapeutics Inc., Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, SanofiGenzyme, Synthon, Teva, and Vertex; speaker fees from AbbVie Biotherapeutics Inc., Biogen, Bayer HealthCare, Genzyme, Merck Serono, Sanofi-Aventis, and Teva; coeditor in chief of Multiple Sclerosis and Related Disorders; research support unrelated to study from Biogen, Genzyme, Ironwood, Merck Serono, and Novartis . Ralf Gold has received compensation for serving as consultant or speaker or he or institution he works for has received research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Patrick Vermersch has received honoraria, and consulting fees from Biogen Idec, Genzyme-Sanofi, Bayer, Novartis, Merck-Serono,


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GSK, and Almirall Research supports from Biogen Idec, GenzymeSanofi, Bayer, and Merck-Serono. Priya Bhasin, Sophie Arnould, Tatiana Sidorenko, and Erik Wallström are employees of Novartis. P650 Real-world effectiveness of natalizumab and fingolimod compared with injectable drugs in non-responders and in treatment-naïve patients with multiple sclerosis L. Prosperini1, S. Pontecorvo1, M. Giuliani1, F. Fanelli1, S. Haggiag2, S. Galgani2, A. Francia1, C. Pozzilli1, C. Gasperini2 1Sapienza University, 2S. Camillo-Forlanini Hospital, Rome, Italy Background: Despite the increased availability of treatments for multiple sclerosis, there is still no evidence to drive specific decision-making about which is the optimal therapy for non-responders (NR) to first-line drugs and for highly active treatment-naïve (TN) patients. Objective: To directly compare the effectiveness of natalizumab (NTZ), fingolimod (FNG) and injectable drugs, namely Interferon Beta (IFNB) and Glatiramer Acetate (GA), in NR and TN patients. Methods: In this post-marketing study, 409 NR (first dataset) and 155 TN (second dataset) were followed up to 2 years after starting NTZ, FNG or IFNB/GA. NR were patients who experienced either =/>2 relapses or 1 relapses associated with residual disability in the last year while on IFNB or GA. TN were patients who were never treated before and presented a highly active disease, i.e. =/>2 relapses in the last year and GD-enhancement on magnetic resonance imaging (MRI). The 2-year proportions of patients who had no evidence of disease activity (NEDA), defined as absence of relapses, disability worsening and MRI activity, were estimated. Since patients were not randomized to treatment group, propensity score inverse weighting-adjusted Cox models were built to control for potential confounders. Results: First dataset-after the first-line treatment failure, 184 and 105 patients were escalated to NTZ and FNG, respectively, while 120 were switched to the alternative class of injectable drug. The 2-year proportions of patients who had NEDA were: NTZ=67%, FNG=45%, IFNB/GA=22%, with hazard ratios (HR) for experiencing disease activity inferior in both NTZ and FNG than IFNB/GA (HR=0.35 and HR=0.53, respectively; p< 0.01). Moreover, the risk for disease activity was inferior even in NTZ vs FNG (HR=0.65, p=0.03). Second dataset-TN patients started high-dose IFNB-1a or 1b (n=97), FNG (n=24), or NTZ (n=34). The 2-year proportions of patients who had NEDA were: NTZ=67%, FNG=66%, IFNB=40%, with risk for disease activity slightly lower in NTZ (HR=0.51, p=0.06) and FNG (HR=0.55, p=0.12) than IFNB. No significant difference was found between NTZ and FNG (HR=0.87, p=0.93). Discussion: Our findings confirm that second-line escalation was the most effective choice after IFNB/GA failure, and NTZ was the best option. In TN patients we found a comparable effectiveness of NTZ and FNG in ensuring a better, although not significant, outcome than IFNB. A larger sample size of TN patients is warranted to confirm these latter data.

Disclosure This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Luca Prosperini: Consulting and/or lecture fees and/or travel grants from Bayer Schering, Biogen Idec, Genzyme, Novartis and Teva. Simona Pontecorvo: Travel grants and/or consulting fees and/or lecture fees from Almirall, Biogen idec, Genzyme, Novartis and Teva. Manuela Giuliani: Nothing to disclose. Fulvia Fanelli: Nothing to disclose. Shalom Haggiag: Nothing to disclose. Simonetta Galgani: Lecture fees and/or travel grants from Almirall, Biogen Idec, Genzyme, Merck Serono, Novartis and Teva. Ada Francia: Travel grants and/or consulting fees and/or lecture fees from Almirall, Biogen idec, Genzyme, Merck Serono, Novartis and Teva. Carlo Pozzilli: Personal fees and/or travel grants and/or research grants from Bayer Schering, Biogen Idec, Merck Serono, Novartis, and Teva and research grants from Almirall, Biogen Idec, Merck Serono, Novartis and Teva. Claudio Gasperini: Lecture fees and/or consulting fees from Merck Serono, Biogen, Idec, Teva, Bayer Schering and Novartis.

P651 Effect of laquinimod, a novel immunomodulator in development for treatment of multiple sclerosis, on cardiac repolarization in healthy subjects: a thorough QT/QTc study A. Elgart1, D. Mimrod1, L. Rabinovich-Guilatt1, E. Eyal2, J. Morganroth3, O. Spiegelstein1 1Phase-1 & Clinical Pharmacology, 2Global Biostatistics, TEVA Pharmaceutical Industries Ltd, Netanya, Israel, 3eResearch Technology, Inc, Philadelphia, PA, United States Laquinimod (TV-5600, Teva Pharmaceuticals) is a quinoline‑3‑carboxamide derivative in clinical development as a once daily oral treatment for Relapsing Remitting multiple sclerosis (MS), Primary Progressive MS, Crohn’s disease and Huntington’s disease. Objective: The primary objective of this study was to define the effect of laquinimod, on cardiac safety by assessing its effect vs placebo on the 12-lead electrocardiogram (ECG) with a focus on QTc duration. Moxifloxacin was also included to demonstrate assay sensitivity. Method: This randomized, double-blind study included 4 parallel-groups of healthy subjects. Subjects received a dose of either 0.6 or 1.2 mg/day laquinimod for 14 days, placebo for 14 days, or 13 days of placebo followed by a single dose of 400 mg moxifloxacin on Day 14. Continuous ECGs were recorded on Day 1 (baseline) and Days 14 to 17 and 4 ECGs were extracted at predefined time points. The primary endpoint was an analysis of variance of the time-matched change from baseline in individual placebo corrected QTc (ddQTcI) providing an estimate for each time point and its 2-sided 90% confidence interval (CI). Blood samples at each time point were collected for laquinimod pharmacokinetics. Linear mixed effects modeling was used to quantify the relationship between laquinimod plasma concentration and


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Poster Session I, 21(S11) ddQTcI. Safety assessments included adverse event monitoring, vital signs, clinical laboratory tests and physical examinations. Results: A total of 200 subjects were randomized and 195 were included in the ECG analysis. The upper limits of the 2-sided 90% CI for ddQTcI for both laquinimod doses were below 10 ms at all time points, whilst the lower limits for moxifloxacin exceeded 5 ms providing assay sensitivity. Laquinimod did not affect heart rate, PR or QRS interval durations. The relationship between ddQTcI and laquinimod plasma concentration showed no signal of change in ddQTcI from baseline with increasing laquinimod levels. The safety and tolerability of laquinimod were consistent with the known safety profile of laquinimod in healthy subjects and MS patients. Conclusions: Laquinimod does not affect the ECG and especially cardiac repolarization and is well tolerated at doses of 0.6 and 1.2 mg/day. Disclosure AE, DM, LRG, EE, and OS are employees of Teva Pharmaceutical Industries, Ltd, and received salary and/or stock options for the submitted work; JM is a Chief Cardiac Consultant at eResearch Technology, Inc, Philadelphia, PA, USA, which provides cardiac safety services including ECG analysis and consulting and was contracted by TEVA Pharmaceutical Industries, Ltd, for fees paid during the conduct of the study. P652 Inmunomodulator skin reactions: do anthropometric characteristics and lifestyle influence? M. Rus-Hidalgo1, E. Arellano Velázquez1, N. Becerril Rios1, A. Perez Luque2, J.A. Garcia Alonso1 1Virgen Macarena University Hospital, 2Hospital Universitario Virgen Macarena, Seville, Spain Background: Injection site reactions (ISRs) are one of the most common side effects in multiple sclerosis (MS) patients treated with subcutaneous disease modifying therapies (DMTs). Some studies show that ISRs are more common in women than in men, and are also related to the distribution of body fat. Objectives: To determine anthropometric factors, and dietary and exercise habits associated with the appearance of ISRs in patients treated with subcutaneous DMTs, to establish what type of ISRs are more frequent in our population with each type of drug. Method: An observational, cross-sectional and descriptive study was conducted on 194 patients who were selected by non-random systematic sampling. The variables studied were age, sex, body mass index, waist-hip ratio, skin phototype, diet, and level of physical activity. Results: About three-quarters (76%) of patients (85.6% females and 58% males) had some kind of ISRs (P < .001). Patients following a reasonable diet for health suffered less ISRs (P = .03). The duration of treatment in patients with ISRs was 74.65 months (SD 55.14), compared to 71.04 months (SD 59.68) (P = .71) for those free of ISRs. Conclusions: Our findings show that there are some protective factors for the onset of ISRs, such as being male and have a proper diet. No relationship was found between the other variables

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studied and the appearance of ISRs. A longer duration of treatment does not necessarily mean a higher frequency of ISRs. Disclosure Macarena Rus: Nothing to disclose. Elena Arellano: Nothing to disclose. Noelia Becerril: Nothing to disclose. Ana Perez: Nothing to disclose. Jose Antonio Garcia: Nothing to disclose. P653 Fingolimod efficacy in second-line treatment for RRMS: treatment outcome is independent from previous MRI or clinical activity M. Merschhemke1, Y. Zhang2, N. Putzki1 1Novartis Pharma AG, Basel, Switzerland, 2Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States Background: Fingolimod is licensed as a first-line treatment for relapsing multiple sclerosis (MS) in the US, while it is approved in the European Union (EU) for relapsing-remitting MS (RRMS) patients with high disease activity despite treatment with at least one disease-modifying therapy (DMT) or with rapidly evolving severe RRMS. The current EU label requires presence of both clinical features AND specific MRI criteria. MRI is increasingly recognized as an indicator of clinically relevant breakthrough disease. The decision to switch DMT in current clinical practice may occasionally be considered based on MRI activity only. Objective: To evaluate the efficacy of fingolimod in RRMS patients in relationship to their prior disease activity based on either MRI or clinical features. Methods: This post-hoc analysis from FREEDOMS and FREEDOMS II was conducted in patients with at least one prior DMT and with pre-baseline disease activity features, grouped as follows: imaging and clinical features (Group I+C), imaging or clinical features (but not both; Group I/C), imaging but no clinical features (imaging features only; Group I) and clinical but no imaging features (clinical features only; Group C). Imaging features were defined as at least one Gd+ T1 lesion at baseline and clinical features as relapse in the last 6 months of randomisation. Treatment effect (fingolimod 0.5 mg vs. placebo) was evaluated using annualised relapse rate (ARR) for each of the above four groups by negative binomial regression of number of confirmed relapses, with treatment as factor and Expanded Disability Status Scale score at baseline and number of relapses in the last 2 years before the study as covariates, adjusted by time on study. Results: The ARR (LS mean) for fingolimod 0.5 mg, as well as ARR ratio for fingolimod 0.5 mg vs. placebo in the pooled population (N=2355) was as follows: Group I+C, ARR 0.40, Ratio: 0.58 (95% CI 0.37; 0.92, p=0.019); Group I/C, ARR 0.24, Ratio: 0.61 (0.41; 0.92, p=0.018); Group I, ARR 0.11, Ratio: 0.25 (0.12; 0.52, p< 0.001); and Group C, ARR 0.30, Ratio: 0.87 (0.53; 1.43, p=0.581). Conclusions: The treatment benefit of fingolimod as second line therapy is independent of the definition of previous RRMS disease activity while on prior DMT. The relapse outcome on treatment is comparable across all groups regardless of whether


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‘disease activity’ was defined based on prior imaging and/or clinical features.

in self-management. Consistent with other studies, adherence was strongly associated with continuation rate.

Disclosure

Disclosure

Funding source: This study is supported by Novartis Pharma AG, Basel, Switzerland. Martin Merschhemke is an employee of Novartis Pharma AG, Basel, Switzerland. Ying Zhang is an employee of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Norman Putzki is an employee of Novartis Pharma AG, Basel, Switzerland.

Meritxell Sabidó-Espin is an employee of Merck KGaA, Darmstadt, Germany. Fernando Dangond is an employee of EMD Serono, Inc., Rockland, MA, USA.

P654 Factors associated with continuation of treatment with IFN ß-1a given subcutaneously three times a week: a US retrospective cohort study M. Sabidó-Espin1, F. Dangond2 1Global Drug Safety, Merck KGaA, Darmstadt, Germany, 2Neurodegenerative Diseases, EMD Serono, Rockland, MA, United States

P655 IL-17 neutralization by subcutaneous CJM112, a fully human anti IL-17A monoclonal antibody for the treatment of relapsing-remitting multiple sclerosis: study design of a phase 2 trial H. Wiendl1, F. Dahlke2, D. Bennett3, G. Rosenkranz2, C. Wolf4, A. Bar-Or5 1Department of Neurology, University of Münster, Münster, Germany, 2Novartis Pharma AG, Basel, Switzerland, 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States, 4Lycalis sprl., Brussels, Belgium, 5Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada

Background: Patients with multiple sclerosis (MS) with poor treatment adherence have a higher risk of relapse; however, few data for factors associated with continuation of treatment are available. Objective: Real-world data were used to estimate the continuation rate in US patients taking subcutaneous (sc) interferon (IFN) β-1a three times a week (tiw) and identify factors associated with this continuation. Methods: Retrospective cohort study using MarketScan© databases. Eligible subjects were ⩾18 years old with ⩾1 MS diagnosis recorded from 2006-2012, were sc IFN β-1a naïve, and had ⩾2 prescriptions. Subjects were followed from first prescription of sc IFN β-1a until date of discontinuation, switch, or end of insurance or observation period. Continuation was defined as prescription fills for sc IFN β-1a until end of insurance or end of observation period. Adherence was measured as medication possession ratio ⩾80%. Multivariable logistic regression was used. Results: Overall 9860 subjects were included: mean age (standard deviation) of 42.8 (10.8) years, 75.8% female. Overall, 5500 patients (55.8%) continued therapy with a median of 13 months (interquartile range: 5, 28), and 6690 were on treatment at 12 months (67.8%). Factors independently associated with continuation of sc IFN β-1a were female sex (odds ratio [OR]: 1.94, 95% confidence interval [CI]: 1.04-1.37), dose of 44 µg (vs. 22 µg; OR: 1.23, 95% CI: 1.08-1.38), adherence ⩾80% (vs. < 80%; OR: 81.06, 95% CI: 65.59-100.18), >2 hospital admissions (vs. 0-2; OR: 1.25, 95% CI: 1.16-1.35), antidepressant use during followup (OR: 1.46, 95% CI: 1.29-1.65), anxiolytics (OR: 1.32, 95% CI: 1.13-1.54), nonsteroidal anti-inflammatory drugs (OR: 1.89, 95% CI: 1.67- 2.15) and corticosteroid use (OR: 2.34, 95% CI: 2.05-2.67). Conclusions: Higher clinical disease activity may have a role in continuation as suggested by its association with patients on higher dose, hospitalisation episodes, and in particular, with the use of corticosteroids and other symptomatic therapies. Patients experiencing more symptoms could be more motivated to engage

Background: Interleukin (IL)-17A, is produced by proinflammatory Th17 cells, CD8+ and γδ T-cells, and by cells in the central nervous system, such as astrocytes and oligodendrocytes, in active areas of MS lesions. Evidence supports a central role of IL-17A in multiple sclerosis (MS) disease pathophysiology. A fully human anti-IL-17 monoclonal antibody (mAb), has demonstrated a reduction of MRI activity in relapsing-remitting multiple sclerosis (RRMS) patients in a proof-of-concept trial. CJM112 is a fully human anti-IL-17 mAb with high affinity to IL-17A in vitro. Objective: To evaluate CJM112 efficacy relative to fingolimod, in controlling brain MRI disease activity, in RRMS patients transitioning from natalizumab. Methods: MABINGO is a 6-month, double-blind, doubledummy, multi-centre, active-controlled, parallel-group study in approximately 360 patients (120 patients per treatment arm) from approximately 90 centres worldwide. The trial provides active treatment, irrespective of the treatment arm. Two doses of CJM112 (monthly subcutaneous application) will be compared to fingolimod (0.5mg oral, daily), in patients stopping natalizumab therapy. A data monitoring committee (DMC) will perform regular evaluations of safety and MRI efficacy data. There is a planned extension to obtain longer-term data. Results: The primary endpoint is the cumulative number of new Gd+ T1 lesions on the MRI scans at months 4, 5 and 6 after start of investigational treatment. Secondary endpoints include the cumulative number of new Gd+ T1 lesions on the MRI scans at months 1, 2, 3, 4, 5 and 6 after start of investigational treatment; on change of the total T2 lesion volume from Visit 1 to Month 6 of treatment, as well as safety and tolerability. Exploratory endpoints include parameters related to the occurrence of MS relapses and MS progression; potential biomarkers, which may identify responder subgroups related to the antiIL-17 pathway; immune cell-based assays to characterize cell subsets phenotypically and functionally. This includes assessment of cytokine response profiles upon stimulation, to identify


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Poster Session I, 21(S11) a signature which correlates with treatment response to antiIL-17 therapy. Conclusion: CJM112 efficacy should be at least as beneficial as fingolimod in treating a population with active disease and possess a relatively mild safety profile, in order to meet current medical needs in RRMS. Disclosure Funding source This study is supported by Novartis Pharma AG, Basel, Switzerland. Heinz Wiendl has received compensation for serving as a consultant or speaker for, or has received research support from: Bayer Schering Pharma, Biogen Idec/Elan Corporation, Merck Serono, Novartis, Novo Nordisk, Sanofi-Aventis and Teva Pharmaceutical Industries. Frank Dahlke is an employee of Novartis Pharma AG, Basel, Switzerland Debra Bennett is an employee of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Gerd Rosenkranz is an employee of Novartis Pharma AG, Basel, Switzerland. Christian Wolf has received honoraria for serving as a consultant for to-BBB, Desitin, Investitionsbank Berlin, Keyrus, Novartis, Synthon, and Teva. Amit Bar-Or has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Amplimmune, Biogen Idec, Diogenix, Genentech, SanofiGenzyme, GlaxoSmithKline, Novartis, Ono Pharma, Teva Neuroscience, Receptos Inc., Roche, and Merck/EMD Serono.

P656 Disease-modifying therapy improved depression symptoms in multiple sclerosis patients: the POSIDONIA study E. Montanari1, M. Conti2, D. Maimone3, V. Torri Clerici4, K. Plewnia5, M. Frigo6, A. Francia7, A. Pala8, A. Veneziano9, POSIDONIA Study Group 1U.O. di Neurologia, Ospedale di Fidenza, Fidenza, 2USSD Neuroimmunologia SM, Ospedale Papa Giovanni XXIII, Bergamo, 3U.O. Neurologia, Ospedale Garibaldi - Nesima, Catania, 4Centro Sclerosi Multipla - U.O. Neurologia 4, Fondazione Istituto Neurologico Carlo Besta, Milano, 5U.O. Neurologia, Ospedale Misericordia di Grosseto, Grosseto, 6Ambulatorio Neuroimmunologia Clinica Neurologica, Ospedale San Gerardo, Monza, 7Centro Sclerosi Multipla, Azienda Policlinico Umberto I, Roma, 8U.O. di Neurologia Ospedaliera, Presidio Ospedaliero A. Segni, Ozieri, 9Medical Department, Teva Italia S.r.l., Assago, Italy Background: Prevalence of depression in multiple sclerosis (MS) patients varies from 20% to 50%. The period surrounding diagnosis is described as psychologically demanding by MS patients and neurologists. Objectives: The POSIDONIA study was designed to evaluate depression and anxiety symptoms in recently diagnosed MS patients starting a disease-modifying therapy (DMT). Methods: This was a 12-month observational, prospective, multicenter study conducted in 40 Italian centers including 250 RRMS patients. Depression and anxiety symptoms were measured

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through validated scales and changes in the scores over time were assessed using repeated measures linear mixed models. A two sided p-value < 0.05 was considered as statistically significant. Results: The study enrolled 250 MS patients (74.4% females), with a mean age of 36.4±9.4 and a median Expanded Disability Status Scale of 1.5 (range 0.0-5.5). Glatiramer acetate was used by 47.6% patients while the remaining 52.4% used interferon. The statistical analysis has been performed on the Per Protocol (PP) population including 222 patients (88.8%) who completed all follow-up visits up to 12 months. The Hospital Anxiety and Depression Scale (HADS) total score decreased over time, from a mean baseline of 11.60±6.10 to 11.06±6.02 (-4.6%) at 12 months; almost reaching statistical significance (p=0.505). In contrast, the Hamilton Depression Rating Scale (HDRS) score significantly (p=0.0032) decreased from baseline (mean 6.77±5.96) to the 12-months follow-up visit (5.63±5.77; -16.8%). In addition, the Impact of Event Revised (IES-R) total score significantly (p=0.0009) decreased over time from baseline (mean 1.15±0.76) to the 12-months follow-up visit (0.96±0.78; -16.0%). Moreover, the Short Form 36 Health Survey (SF-36) mental health score slightly increased (p=0.068) over time from baseline (mean 66.14±20.22) to the 12-months follow-up visit (67.89±19.37; 2.65%). Conclusions: The significant changes in feelings of depression measured by the HDRS and the disease-related psychological distress measured with the IES-R, together with the encouraging changes observed in the HADS and SF-36 scores, suggest that the introduction of a DMT may support patients’ reaction to the feeling of uncertainty and distress following MS diagnosis, particularly in subjects with higher anxiety and depression scores at baseline. Disclosure The POSIDONIA study was funded by Teva Italia S.r.l. E. Montanari has been involved in activities sponsored by Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme, Teva M. Conti has been involved in clinical trials sponsored by Merck Serono, Novartis, Bayer, Biogen Idec D. Maimone has received speaker honoraria and travel grants from Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, and Teva M. Frigo has been involved in Advisory Boards organized by Biogen Idec and Novartis and in clinical trials sponsored by Teva, Merck Serono and Almirall A. Francia has been involved in activities sponsored by Teva, Novartis, Biogen Idec, Sanofi Genzyme A. Veneziano is an employee of Teva Italia S.r.l. Other authors have nothing to disclose P657 Enhanced migration of CD56bright NK cells across hCMEC/ D3 in interferon-beta-1a treated multiple sclerosis patients A. Harrer1, J. Wanek1, K. Oppermann1, M. Wimmer1, R. Zauner1, P.-O. Couraud2, I.A. Romero3, B. Weksler4, S. Afazel5, E. Haschke-Becher5, P. Wipfler1, G. Pilz1, E. Trinka1, J. Sellner1, J. Kraus6 1Department of Neurology, Paracelsus Medical University Salzburg, Salzburg, Austria, 2Institut Cochin, CNRS UMR 8104, INSERM U1016, Université Paris Descartes, Sorbonne Paris


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Cité, Paris, France, 3Department of Life, Health and Chemical Sciences, Open University, Milton Keynes, United Kingdom, 4Department of Medicine, Weill Medical College, New York, NY, United States, 5Department of Laboratory, Paracelsus Medical University Salzburg, Salzburg, 6Department of Neurology, Public Hospital Zell am See, Zell am See, Austria Background: Interferon-beta (IFN-β) treatment is associated with reduced percentages of total NK cells and expansion of the regulatory CD56bright NK cell subset in peripheral blood of multiple sclerosis (MS) patients. Here, we investigated the migration of NK cells versus other major lymphocyte subpopulations from IFN-β1a-treated MS patients across a brain endothelial cell layer. Methods: 13 MS patients de novo assigned to IFN-β1a (s.c.) treatment (untreated and on short-term (ST) treatment; median 3 months (range 1-7); IFN-β1a/ST), 13 MS patients on long-term (LT) IFN-β1a (s.c.) treatment; median 4.5 years (range 1-11); IFN-β/LT), and 13 normal controls (NC) were included. Blood was collected twice within three to six months and peripheral blood mononuclear cells (PBMC) were cryostored until analysis. PBMC (1*106) were allowed to migrate for 20 hours across hCMEC/D3 (immortalized human brain endothelial cells) grown to confluence on fibronectin-coated inserts (3 µm pore-size) of a 24-well cell culture system at 37°C/5%CO2. Remaining PBMC were allowed to rest under the same standard culture conditions. Percentages of T cells (CD3), B cells (HLA-DR), NK (CD56CD3-) and NKT (CD56CD3+) cells, and CD69 upregulation were determined from resting and migrated (pooled triplicates) cells by flow cytometry. Results: In migrated cells the proportion of NK cells was 2-3 fold higher and that of T cells 0.7-0.8-fold decreased compared to resting cells in all 3 groups. NK cell percentages of migrated cells were lower in long-term IFN-β1a-treated patients than in NC (PT1< 0.05; PT2< 0.05). CD56bright NK cell subset percentages were increased in long- and short-term IFN-β1a-treated but not in untreated patients compared to NC (IFN-β1a/LT: PT1< 0.005; PT2< 0.005; IFN-β1a/ST: PT1=0.724, PT2< 0.001). Moreover, NK cells from IFN-β1a-treated but not from untreated patients showed a lower CD69 upregulation compared to NC (IFN-β1a/LT: PT1< 0.01; PT2< 0.005; IFN-β1a/ST: PT1=0.960, PT2< 0.005). Discussion: We report a lower percentage of NK cells and higher proportion of the CD56bright NK cell subset in migrated lymphocytes from MS patients treated with IFN-β1a. This is in line with treatment effects in the peripheral blood. Enhanced migration of CD56bright NK cells implies a regulatory role also behind the blood-brain barrier thereby adding a new aspect to the mechanisms of action of IFN-β1a treatment. This study was supported by a scientific grant from Merck Austria. Disclosure AH received travel support for scientific meetings from Merck Serono, Genzyme, Novartis, and Teva. JW, MW, RZ, POC, IAR, BW, SA, have nothing to disclose. OK travel support for scientific meetings from Bayer, BiogenIdec, Genzyme, Merck Serono, and Sanofi-Aventis. EHB received financial support for research activities from Abbott Diagnostics, Roche Molecular Diagnostics, and Roche Diagnostics Austria.

PW received travel support for scientific meetings and speaker’s honoraria from Merck Serono, Biogen-Idec, Bayer, and Novartis. GP travel support for scientific meetings and speaker’s honoraria from Biogen-Idec, Bayer, Merck Serono, and Teva-Ratiopharm. ET received financial support for research activities and/or personal compensation for consulting services from Eisai, EverNeuropharma, Medtronics, Pfizer, Sunovion, New Bridge, Gerot-Lanacher, Biogen-Idec, Sanovi, Bial, Cyberonics, Novartis, Actavis, and UCB Pharma. JS received personal compensations for consulting services and/or speaker’s honoraria and/or support for congress presentations from Biogen-Idec, Terumo, Merck-Serono, Genzyme, Novartis, and Teva-Ratiopharm. JK received financial support for research activities and/or personal compensation for consulting services from Almirall, Bayer, Biogen-Idec, Genzyme, Medtronic, Merck-Serono, Novartis, Sanofi-Aventis, and TEVA ratiopharm. P658 Differences in patient characteristics, disease-modifying treatment utilization, and relapse by race/ethnicity in Texas medicaid patients with multiple sclerosis K.M. Richards1, K.A. Lawson1, T. Nazareth2, T.-C. Yu2, J.J. Ko2, E. Burton3, R. Sasane2 1College of Pharmacy, University of Texas at Austin, Austin, TX, 2Health Economics and Outcomes Research, 3US Medical Affairs, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States Background: Research has identified racial/ethnic disparities in multiple sclerosis (MS) treatment and outcomes. However, these studies are few and often include small numbers of non-white patients. This study investigated MS-related treatment and outcome disparities in the racially-diverse MS Medicaid population of Texas. Objectives: To identify and compare the demographic and clinical characteristics of Texas Medicaid (TX-M) patients with MS by race/ethnicity; and to compare disease-modifying treatments (DMTs), DMT adherence/persistence, and occurrence of MS relapse among racial/ethnic groups. Methods: A retrospective analysis was conducted using 20102013 TX-M medical and prescription data. The index date was defined as the date of the first DMT claim between 2010 and 2012, and patients were followed for 12 months. Included patients had an MS diagnosis, were 18-63 years of age at index, and were continuously enrolled in TX-M. Demographics, costs, and clinical variables were compared among cohorts using Kruskal-Wallis tests for continuous variables and chi-square tests for categorical variables. Results: Of 5,793 TX-M MS patients identified, 584 patients were included: 49.3% (n=288) White, 25.5% (n=149) African American (AA), and 25.2% (n=147) Hispanic. Patient cohorts were significantly different in mean age (p< 0.001), urban/rural residence (p=0.003), total MS-related costs (p=0.023), any relapse (p=0.010), and severe relapse (p< 0.001). Approximately 15% of Whites had >1 relapse compared to 27% and 23% of AAs and Hispanics, respectively. Patient cohorts also differed in index DMT (p< 0.001). Over half (51%) of AAs was taking an interferon DMT, compared to 39% of both Whites and Hispanics. In


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Poster Session I, 21(S11) addition, a smaller proportion of Hispanics (12%) was taking natalizumab compared to Whites (27%) and AAs (22%), while a larger proportion of Hispanics (46%) was taking glatiramer acetate compared to Whites (33%) and AAs (22%). One-year DMT adherence and persistence did not differ significantly among racial/ethnic groups. Conclusions: DMT use and MS relapse differed by racial/ethnic groups in TX-M MS patients. While DMT compliance was not significantly different among cohorts, the proportion of patients with relapse was higher in AAs and Hispanics compared to Whites. Follow-up studies are needed to confirm the findings and investigate the reasons for these disparities. Further, strategies are needed to improve outcomes for all MS patients. Disclosure KM Richards: Research support was provided by Novartis Pharmaceuticals. KA Lawson: Research support was provided by Novartis Pharmaceuticals. T Nazareth: Employed by Novartis Pharmaceuticals. T-C Yu: Employed by Novartis Pharmaceuticals. JJ Ko: Employed by Novartis Pharmaceuticals. E Burton: Employed by Novartis Pharmaceuticals. R Sasane: Employed by Novartis Pharmaceuticals. P659 Omega-3, Omega-6 PUFA and γ-Tocopherol in multiple sclerosis: PLP10 intervention efficacy and red blood cells’ membrane lipids composition I.S. Patrikios1,2, G.N. Loucaides3, M. Pantzaris2, M.A. Crawford4, K. Ghebremeskel5 1School of Medicine, European University Cyprus, 2Neurology, Clinic-C, 3Neurology, Clinic- C, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus, 4Department of Surgery & Cancer, Imperial College London, 5Lipidomics and Nutrition Research Center, London Metropolitan University, London, United Kingdom Introduction: We aimed to assess whether PLP10 novel intervention, comprising specific polyunsaturated fatty acids (PUFA) and vitamins reduce disease activity in relapsing remitting (RR) MS and correlate such activity with membrane’s lipid composition. Methods: We contacted a 30-month randomized, double-blind, placebo-controlled, proof-of-concept clinical study at the CING. Of a total of 80 patients, 20 were randomly assigned to receive intervention A (docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) (3:1w/w) omega-3, linoleic acid (LA)/gamma(g)-linolenic acid (GLA) (2:1w/w) omega-6 fatty acids, omega-3/omega-6 (1:1w/w), other specific PUFA, monounsaturated fatty acids (MUFA), minor quantity of specific saturated fatty acids (SFA), vitamin A and vitamin E), 20 to receive γ-tocopherol, intervention C, 20 to receive the combination of A and C, intervention B (PLP10) and 20 to receive placebo. Primary end point was the annualized relapse rate (ARR) and secondary the time to disability progression. Red blood cells (RBC) were used for correlation between efficacy and PUFA profile within the RBC membrane. ISRCTN87818535.

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Results: PLP10 reduced ARR by 70% (p=0.003), in relation to the baseline; placebo increased by 46% (p=0.354). For primary end point, PLP10 reduced ARR by 58% (95% CI 0.10-0.79, p=0.016) and for the secondary end point, significantly reduced the risk of sustained disability progression by 86% (Hr, 0.11; 95% CI 0.01-0.97, p=0.047) vs. placebo. More patients in the PLP10 group (72%) vs. placebo group (20%) were free from new or enlarging T2- MRI lesions. No adverse events were reported. Interventions A and C showed no significant efficacy. The RBC membrane lipid profile was supportive to the reported PLP10 efficacy. There was statistically significant increased quantitative content of the PUFA as well as significant increased release of arachidonic acid when γ-tocopherol was present. Discussion: PLP10 treatment significantly reduced the ARR and the risk of sustained disability progression. This is the first clinical study of System Medicine approach in RRMS. Disclosure All of the authors are the inventors of the plp10 and the study was funded by the Cyprus Ministry of Commerce, Industry and Tourism Kebreab Ghebremeskel and Kebreab Gebremeske: nothing to disclose P660 Cost-effectiveness of First-line disease-modifying treatments for relapsing-remitting MS E. Soini1, J. Joutseno2, M.-L. Sumelahti3 1ESiOR Oy, Kuopio, 2Genzyme, a Sanofi company, Helsinki, 3School of Medicine, University of Tampere, Tampere, Finland Background: Patients with relapsing-remitting MS (RRMS) are in need of therapies with improved efficacy, tolerability, and convenience than the widely used injectable disease modifying treatments (DMTs). Recently, general reimbursement was granted for 2 oral, first-line DMTs in Finland. Teriflunomide is the only firstline DMT with significant reduction in both relapses and 3-month disability progression in 2 pivotal clinical trials. Objectives: To evaluate the cost-effectiveness of the oral agents teriflunomide 14mg once daily and dimethyl fumarate (DMF) 240mg twice daily; subcutaneous therapies glatiramer acetate (GA) 20mg daily, interferon (IFN)β-1a 44µg 3x/week, and IFNβ-1b 250µg every other day; intramuscular IFNβ-1a 30µg once weekly; and best supportive care (BSC) as first-line treatments for RRMS in the Finnish healthcare payer setting. Methods: Markov cohort modelling with a 20-year time horizon (3%/year discount rate) was employed. The primary outcome was incremental cost-effectiveness ratio (ICER; cost [€] per qualityadjusted life year [QALY] gained vs non-dominated alternatives). During each 1-year modelling cycle, patients could maintain Expanded Disability Status Scale (EDSS) score or experience progression, develop secondary-progressive MS (SPMS), have EDSS progression in SPMS, or experience relapse with/without hospitalization or death. Specific annual adverse event risks were included. Patient characteristics, standardized mortality ratios, and a RRMS progression matrix were derived from a Finnish MS registry. A mixed-treatment comparison informed treatment effects. EQ-5D quality-of-life estimates and Finnish direct costs were associated


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with EDSS scores, relapses, and adverse events. Robustness of the base case results was tested with sensitivity analyses. Results: Teriflunomide was dominant (less costly, higher QALYs) compared with GA and IFNs, and had the lowest ICER of 17,326 vs BSC. DMF brought marginally more QALYs than teriflunomide (0.129 over 20 years), but the QALY difference was associated with relatively high costs, and the ICER for DMF vs teriflunomide was 78,092. In the probabilistic sensitivity analyses of teriflunomide vs other first-line DMTs, teriflunomide had over 50% probability to be cost-effective with willingness-to-pay values below €94,000/QALY gained. Conclusions: In our analysis, teriflunomide 14mg once daily was cost-effective compared with DMF twice daily, and dominated all other first-line DMTs for RRMS in Finland.

apparent Vss of ~58 mL/kg suggests compartmentalization was primarily in the vasculature. These values are consistent with findings from other therapeutic monoclonal human IgMs. The average ratio of CSF:Plasma concentration increased from 0.003% on Day 2 for both doses to 0.056% and 0.582% for 1.0 and 2.0 mg/kg on Day 29. Discussion: rHIgM22 PK parameters are typical for a human IgM. Of critical importance for the remyelinating antibody rHIgM22, is penetration into the CNS of MS patients. The increasing CSF:Plasma concentration ratio over time may reflect accumulation in the CNS. Work is on-going to examine molecular and radiologic correlates of remyelination that may be affected by rHIgM22 in this trial. Disclosure

Disclosure Study supported by Genzyme, a Sanofi company. ES works for and is a shareholder in a health economic consultancy (ESiOR Oy, Kuopio, Finland). ES declares no other potential conflict of interest. JJ works for the marketer of teriflunomide (Genzyme, a Sanofi Company, Helsinki, Finland). JJ declares no other potential conflict of interest. MLS has consultancies and memberships in advisory councils for Genzyme, Novartis and Biogen. MLS has received travel grant from Novartis. MLS declares no other potential conflict of interest. P661 Pharmacokinetics of a CNS-penetrating, putative remyelinating human monoclonal antibody, rHIgM22, in a Phase 1 clinical trial in patients with stable multiple sclerosis (MS) A. Eisen, D. Button, T.J. Parry, L. Wang, D. Shah, A. Blight, A.O. Caggiano Acorda Therapeutics, Inc., Ardsley, NY, United States Background: The monoclonal antibody rHIgM22 is being developed as a potential treatment for patients with MS, based on extensive preclinical evidence of its ability to stimulate remyelination. rHIgM22 was administered to 55 patients with clinically stable MS in a single ascending dose (0.025 - 2.0 mg/kg), doubleblind, placebo-controlled Phase 1 study [NCT01803867]. All doses tested of rHIgM22 were well-tolerated in this sample of MS patients. Here we report plasma pharmacokinetic (PK) parameters for rHIgM22 and its measurement in the cerebrospinal fluid (CSF) in the Phase 1 trial. Methods: A sensitive, specific and validated mass spectroscopic method, detecting a unique peptide of rHIgM22, was used to measure the concentration of rHIgM22 in plasma and CSF. The lower limits of quantitation of rHIgM22 for this method were 10.0 and 0.05 ng/ml in plasma and CSF, respectively. Following rHIgM22 infusion, blood was sampled frequently on Day 1 and once on Days 2, 4, 7, 14, 28 and 60. CSF was sampled on Days 2 and 29 from a cohort of 7 subjects at each of the two highest dose levels (1.0 and 2.0 mg/kg) and from 7 placebo-treated subjects. Results: Non-compartmental modeling demonstrated linear doseproportionality of both Cmax and AUC0-Last. Average plasma clearance and elimination half-life ranged from 1.05-0.45 mL/kg/h and 39-100 h, respectively, over the 0.025-2 mg/kg dose groups. An

Andrew Eisen is an employee and stockholder of Acorda Therapeutics, Inc. Donald Button is an employee and stockholder of Acorda Therapeutics, Inc. Tom J. Parry is an employee and stockholder of Acorda Therapeutics, Inc. Lu Wang is an employee and stockholder of Acorda Therapeutics, Inc. Dhara Shah is an employee and stockholder of Acorda Therapeutics, Inc. Andrew Blight is an employee and stockholder of Acorda Therapeutics, Inc. Anthony O. Caggiano is an employee and stockholder of Acorda Therapeutics, Inc. P662 Equimolar mixture of 50% oxygen and nitrous oxide inhalation reduces pain during lumbar puncture: a randomized control trial M.A. Sia, X. Moisset, B. Pereira, F. Taithe, E. Dumont, L. Bernard, P. Clavelou CHU Gabriel Montpied, Clermont Ferrand, France Background: Lumbar puncture (LP) is a daily diagnostic procedure in neurology, perceived as painful and stressful for patients. The aim of the study was to evaluate the efficiency of EMONO (equimolar mixture of 50% oxygen and nitrous oxide) compared to placebo to reduce pain and anxiety during LP. Methods: A monocenter, prospective, randomized and doubleblind controlled trial was performed on adult patients undergoing LP for cerebrospinal fluid analysis. Patients were randomly assigned to inhale either EMONO or Air. EMLA (euthetic mixture of local anesthetics) cream was systematically applied and pencil point 25G needles were used. The primary endpoint was to evaluate pain using a Numeric Rating Scale and anxiety evaluation was the main secondary outcome. Results: 66 patients were included from July 2014 to February 2015 in Clermont-Ferrand university hospital, 33 being allocated to EMONO and 33 to AIR. Intention to treat analysis was carried out and there was no lost to follow up. The maximal pain was 4.9±2.7 for the placebo group and 2.7±2.7 for the EMONO group (p=0.002). Similarly, the maximal LP-induced anxiety was 4.5±3.1 vs 2.6±2.6 (p=0.009). The number needed to treat to avoid one


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Poster Session I, 21(S11) patient undergoing significant pain (pain score ⩾4/10) was 2.75. No serious adverse effects were found. A significantly higher pain was found in patients with BMI>25 kg/m² (p=0.03) and the number of LPs’ attempts (p=0.02). Anxiety before LP was not a predictive factor for pain and anxiety induced by the procedure. Conclusion: EMONO associated with EMLA reduces significantly pain and anxiety during LP and should be proposed to every single patient necessitating LP. Disclosure SIA Mary Angel: received travel expenses from Lundbeck Xavier Moisset: received travel expenses from Merk-Serono, Biogen-Idec, Sanofi-Pasteur-MSD and Genzyme and received honoraria from Astellas and Institut UPSA de la douleur. Pierre Clavelou: received honoraria and travel expenses to conferences from and is a consultant to Teva-Pharma, Merck-Serono, Novartis, Biogen-Idec, LFB, Genzyme, Bayer, Almirall and Lundbeck. Frederic Taithe:received travel expenses from Bayer HealthCare SAS, Biogen-Idec, Merck-Serono and Genzyme and received honoraria from Astellas and Institut UPSA de la douleur.

Treatment of specific symptoms P663 Therapeutic software for the treatment of fatigue, depression and anxiety in multiple sclerosis M. Weiss Gaia Group, Hamburg, Germany Fatigue, depression, and anxiety are common symptoms among persons with multiple sclerosis (PwMS), with average prevalence estimates ranging from 26% for depression to 32% for anxiety and 76% for fatigue. Treatment of these symptoms remains challenging, particularly given concerns about the safety and efficacy of psychopharmacological approaches among PsMS. Our research group (Gaia, Hamburg) has developed three therapeutic software programmes, all of which have been evaluated in randomized controlled trials (RCT). These programmes are delivered via secure, password-protected websites and are highly tailored to match individual patient requirements. The first programme introduced here is termed Elevida and targets symptoms of fatigue. An RCT led by the University Medical Center Hamburg-Eppendorf with N=224 PsMS has recently shown that Elevida achieves significant fatigue reductions (Chalder scale) over 8 weeks, with a moderate effect size. The second programme introduced here is termed Deprexis and targets symptoms of depression. Efficacy for Deprexis has been demonstrated in six RCTs to date, with a recent trial showing a moderate effect size among PsMS (N=90; Fischer et al., 2015, Lancet Psychiatry). A third programme, termed Velibra, targets anxiety (generalized anxiety, panic disorder, social phobia). A first RCT on the efficacy of Velibra is conducted by the University Berne and has recently been completed; main results will be briefly presented. In summary, accruing evidence suggests that the therapeutic software presented here can be used to target fatigue, depression, and anxiety in PsMS. However, this does not mean that any or all online programmes are useful or effective; it is incumbent upon every physician to employ only software that has demonstrated its safety and efficacy in methodologically

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sound RCTs. The evidence for these programmes is very encouraging, though, and suggests that effective software could revolutionize the treatment of fatigue, depression, and anxiety in PwMS. Future studies ought to investigate the impact of these softwarebased treatments on biological outcomes, including cortical inflammatory lesions as measured by MRI. Disclosure The author is founder and CEO of Gaia Group, the company that developed, owns, and operates the therapeutic software described in this presentation. P664 Prolonged-release fampridine treatment improved patient-reported impact of multiple sclerosis: item-level analysis of the MSIS-29 C. Gasperini1, J. Lycke2, M. McNeill3, J. Zhong4, L.R. Mehta4, J. Elkins4 1San Camillo-Forlanini, Rome, Italy, 2Institute of Neuroscience and Physiology, The Sahlgrenska Academy, Gothenburg, Sweden, 3Biogen, Maidenhead, United Kingdom, 4Biogen, Cambridge, MA, United States Background: Prolonged-released (PR) fampridine tablets (dalfampridine extended-release in the United States) improve walking in multiple sclerosis (MS). Benefits of PR-fampridine to ambulatory function have been demonstrated; however, questions persist on the role of PR-fampridine on the psychological and physical function of MS given its purported mechanism of action of blocking potassium channels, which are distributed widely in the central nervous system. Objective: To evaluate the effect of PR-fampridine versus placebo on patient-perceived psychological and physical health impact of MS based on the individual items of the 29-item MS Impact Scale (MSIS-29) assessed during the MOBILE study. Methods: MOBILE was a 24-week, randomised, double-blind, phase 2 study that enrolled patients in Canada and Europe. Patients were randomised to PR-fampridine 10 mg tablets (n=68) or placebo (n=64) twice daily. Patient-perceived impact of MS on physical and psychological health was assessed at baseline and each study visit using the MSIS-29. Mean changes from baseline for each of the 9 items of the MSIS-29 psychological (PSYCH) and 20 items of the physical (PHYS) impact subscale were calculated using all post-baseline visits up to 24 weeks. Reported here is the proportion of patients with any mean improvement over weeks 2 to 24. Treatment differences were assessed in a post-hoc analysis using logistic regression adjusting for mean baseline item score. Results: A higher proportion of patients treated with PR-fampridine demonstrated benefits in 6 of the 9 PSYCH items versus placebo over 24 weeks. Benefits were significant in one item: worries related to your MS (63% vs 41%; P=0.006). Similarly, PR-fampridine demonstrated benefits in 16 of the 20 PHYS items versus placebo over 24 weeks, with significant improvements in four items: difficulty doing things spontaneously (56% vs 38%; P=0.012), difficulties moving around indoors (62% vs 41%; P=0.013), having to depend on others to do things (57% vs 39%; P=0.017), and taking longer to do things (62% vs 45%; P=0.040).


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Conclusions: The patient-reported impact of MS on several psychological and physical health domains were improved in patients taking PR-fampridine versus placebo. These results support that the mobility benefits associated with PR-fampridine are clinically meaningful and translate into both physical and psychological gains for MS patients. Disclosure C. Gasperini has received compensation for consulting from Biogen and Bayer HealthCare and as a speaker for lectures from Merck Serono, Biogen, Teva, Novartis, Genzyme, and Bayer HealthCare. J. Lycke has received compensation for consulting, serving on scientific advisory boards and for lectures from Biogen, Novartis, Teva, and Genzyme. M. McNeill, J. Zhong, L.R. Mehta, and J. Elkins are full time employees of Biogen. This study was funded by Biogen. Biogen provided funding for medical writing support in the development of this abstract. Maria Hovenden, (Excel Scientific Solutions, Southport, CT, USA) wrote the first draft of the abstract based on input from authors. Biogen reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P665 The effect of different assistive devices on gait and walking in persons with multiple sclerosis-related walking difficulty E.T. Cohen1, D.A. Barone2, S. Soliman2, C. Beswick2, E. Goldwasser2, A. Caruana2, A. Manzoor2, N. Parikh2 1Rehabilitation and Movement Sciences, Rutgers, The State University of New Jersey, 2Rowan University, School of Osteopathic Medicine, Stratford, NJ, United States Purpose: To compare temporal-spatial parameters of gait in persons with multiple sclerosis (MS) using three assistive devices (AD): single-point cane (SPC), four-point cane (FPC), and trekking pole (TP). Methods: 19 persons with MS (16 women, 3 men; mean age=52 years), and Extended Disability Severity Scale scores of 2.5-6.0 (median=4.0, IQR=1.75). A randomized, crossover, design was used. Participants were randomly assigned the AD order. Each participant was provided with an AD and instructed in its use. They were then instructed to regularly utilize the AD until the next visit 1-2 weeks later. This was repeated for all AD. Participants walked across a 4.9-meter GAITRite walkway (CIR Systems, Sparta, NJ) three times with each AD. Data was collected using PKMAS software (Protokinetics, Havertown, PA). Data for each pass in each condition was combined using PKMAS resulting in averaged values. Measures were step length (SL), stride length (STL), step time (ST), stride width (SW), stride velocity (SV), cycle time (CT), stance-time percent (STT%), swing-time percent (SWT%), singlelimb-support percent (SLS%), double-limb support percent (DLS%), walking velocity (WV) and cadence (CAD). Data was analyzed with ANOVAs and planned pairwise comparisons. Greenhouse-Geisser correction was used when spehericity was violated. Results: Differences were found between AD conditions for all parameters except SW. SL was larger with the SPC (p=.03) and TP

(p=.000) then the FPC. STL was larger with the TP (p=.001) than the FPC. STT was faster with the SPC (p=.008) and TP (p=.000) than the FPC. SV was faster with the SPC (p=.001) and TP (p=.000) than the FPC. CT was faster with the SPC (p=.01) and TP (p=.000) than the FPC. SLS% was greater with the SPC (p=.047) and TP (p=.002) than the FPC. DLS% was lesser with the TP (p=.015) than the FPC. WV was faster with the SPC (p=.001) and TP (p=.000) than the FPC. CAD was greater with the SPC (p=.002) and TP (p=.000) than the FPC. The difference in ST% and SW% did not persist in the pairwise comparisons. Conclusions: Participants generally performed better with the SPC and TP than with the FPC. These may be useful AD options for persons with MS. A previous study showed that the SPC and TP have a more positive psychosocial impact than the FPC. The combination of better gait performance and lower negative psychosocial impact should make the SPC or TP firstline options for persons with MS who may benefit from the use of a walking AD. Disclosure Cohen: No potential conflict to disclose Barone: No potential conflict to disclose Soliman: No potential conflict to disclose Beswick: No potential conflict to disclose Goldwasser: No potential conflict to disclose Caruana: No potential conflict to disclose Manzoor: No potential conflict to disclose Parikh: No potential conflict to disclose P666 Objective and subjective impact of dalfampridine on ambulation in multiple sclerosis S. Klineova, R. Farber, J. Friedman, C. Farrell, S. Phelps, C. Hannigan, F.D. Lublin, S.C. Krieger Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY, United States Objective: To assess the qualitative impact of dalfampridine on walking function and the relationship to objective walking speed change. Background: We have previously presented utilization of dalfampridine in clinical practice and its objective impact on Timed 25 Foot Walk (T25FW). We have shown T25FW improvement in 57% of patients, of which only 15% achieved clinically significant improvement of >20%. Despite this, 89% of patients continued dalfampridine therapy. To further explore this discrepancy, we have assessed the subjective impact of dalfampridine on walking ability. Design/methods: Modified Multiple Sclerosis Walking Scale (MSWS-12) questionnaire was sent to all participants in our established database of patients with dalfampridine treatment ⩾ 3 months, and minimum of two T25FW measurements within one year pre- and post- treatment. Our modified questionnaire assessed dalfampridine impact on overall walking ability and specific gait related features. The T25FW data were extracted from the original dataset. We used descriptive statistics and linear regression to analyze our data.


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Poster Session I, 21(S11) Results: The questionnaire was sent to 59 patients with a return rate of 66% (39 patients). Our sample consisted of 26 females (67%); 25 patients had progressive MS (64%). Twenty- one patients (54%) showed objective T25FW improvement; in only 4 patients (11%) the improvement was >20%. Thirty-four patients (87%) continued dalfampridine treatment. Twenty- eight patients (72%) reported improvement by the MSWS-12. The average MSWS-12 score was 41 (SD = 9). We found a statistically significant correlation between T25FW change and dalfampridine impact measured by MSWS-12, controlling for disease type (R = .526, p < 0.002). Dalfampridine showed highest impact on patient reported walking ability (impact score 3.85), walking distance (3.54), effort to walk (3.54) and walking speed (3.49). Conclusions: Our cohort reported a beneficial impact of dalfampridine on gait by MSWS-12, moderately correlating with objective change in T25FW. These data support that the T25FW is an insensitive measure of actual therapeutic response to dalfampridine, and the addition of a qualitative assessment of treatment response further elucidates the therapeutic response to dalfampridine in our cohort. Disclosure S. Klineova has received compensation for advisory board work with Teva. R. Farber has received compensation for consulting and advisory board work for Teva and for MedPage Today. J. Friedman has nothing to disclose C. Farrell has nothing to disclose S. Phelps has nothing to disclose C. Hannigan has nothing to disclose S.C. Krieger has received compensation for consulting and advisory board work with Acorda Therapeutics Inc.; Bayer; Biogen Idec; EMD Serono (Merck & Co., Inc.); Genentech; Genzyme; Novartis; Questcor Pharmaceuticals, Inc; and Teva Pharmaceutical Industries Ltd. and has given non-promotional lectures with Biogen Idec and Genzyme. F.D. Lublin has served on Scientific Advisory Boards for Acorda Therapeutics Inc.; Actelion Pharmaceuticals Ltd.; Bayer; Biogen Idec; EMD Serono, Inc. (Merck & Co., Inc.); F. Hoffman-La Roche Ltd.; Facilitate, LTD; Forward Pharma; MedImmune, LLC; Novartis; Osmotica Pharmaceutical Corp.; Questcor Pharmaceuticals, Inc.; Receptos Inc.; Revalesio Corporation; Teva Pharmaceutical Industries Ltd.; XenoPort, Inc.; and sanofi-aventis. P667 THC:CBD oromucosal spray in multiple sclerosis spasticity: end of treatment, frequency, reasons and moments J. Koehler Multiple Sclerosis Dept., Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gemeinnützige GmbH, Berg, Germany Background: Spasticity is a common disabling symptom of multiple sclerosis (MS). The approval of THC:CBD oromucosal spray (Sativex) provides a new option for patients with moderate to severe MS spasticity who are resistant to other medications. It is important to identify the features of THC:CBD discontinuation in these patients to tackle them properly.

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Aim: Quantify the % of patients that discontinue THC:CBD treatment, moment and reasons, in MS sites with vast experience with this medication in Germany, Italy and Spain. Methods: Retrospective data collection through a survey recording THC:CBD spray treatment discontinuation parameters: percentage of patients receiving training for medication use and/or patient diaries, slowing down titration, re-adjusting dose over time (after titration), discontinuing treatment (abandonments, withdrawals), moments and reasons of discontinuation and % switching from THC:CBD treatment and to another antispastic drug and which one. Results: Seven centers (3 Italy, 2 Germany, 2 Spain) treating 1852400 (mean 1176) MS patients a year and 54-224 (mean 93) patients with THC:CBD a year participated (overall THC:CBD patients sample, n=645). 81% of patients received medication training and 28% used a diary. 10% of patients stopped and restarted titration. Post-titration dose adjustment happened in 40% of cases. 30% (SD 14) of patients treated with THC:CBD stopped the treatment, 2/3 after patients’ decision. 52% of these discontinuations happened during the first 6 weeks of treatment. The main reported reason was lack of effectiveness (35%), followed by different known side effects: sleepiness and/or drowsiness (24%), dizziness and/or nausea (20%) and/or taste alterations (10%). Only in 36% of patients who ended THC:CBD treatment a new antispastic treatment was prescribed afterwards. Baclofen, gabapentin and botulinum toxin were most commonly used in this limited subset. Conclusions: Our study confirms the possibility of a more intensive training and patients’ diary use in the beginning of THC:CBD spray treatments. The given titration schedule is generally helpful to avoid side effects, documented by a low percentage of abandoning patients when slowing it down. If THC:CBD fails, few treatments, some with potentially more side effects, are left, so it seems important to use it properly. Therefore discontinuations of THC:CBD should be carefully analysed and further re-treatments should be tried with continuously monitoring. Disclosure The author has received honoraria from different pharma companies, including fees for advice and clinical studies from Almirall S.A., the EU commercializator of the medication from which this work provides new data.

P668 Effectiveness of THC:CBD oromucosal spray in multiple sclerosis spasticity. First data from a large observational study in Italy M. Trojano, MOVE 2 Italy Investigators’ Group Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy Background: A cannabinoid oromucosal spray containing THC and CBD at a 1:1 ratio has been licensed in Italy since Q3 2013 as add-on therapy for moderate to severe resistant MS spasticity (MSS) symptoms. Aims: Description of clinical outcomes from MSS patients receiving routine treatment with THC:CBD spray in Italy.


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Methods: Thirty-three MS specialized Italian centres are prospectively collecting through an e-CRF and patient’s diary MSS data at baseline (BL) and after 1 and 3 months of medication use. Effectiveness is measured by rates of treatment continuation and changes of MSS 0-10 NRS and 0-4 Ashworth modified scale scores. Proactive questions on tolerability are posed. Interim analyses from patients with 1 and 3 month available data have been performed while the study is still ongoing. Results: Interim analyses included 322 patients (58.3% female, mean age 51.1 y -SD 10.2-). BL antispasticity drugs to whom the new medication was added were baclofen (71.1%) gabapentin/pregabalin (10.9%), benzodiazepines (6.8%) and tizanidine (5.9%). About 50% of patients were receiving physiotherapy. Mean THC:CBD spray doses were 6.1 +/- 2.5 sprays/day at the 1st month visit and 5.1 +/- 2.6 (ranges 1-12 sprays/day), at the 3rd month visit. Rates of treatment discontinuation were 8.7% and 22.16% at the 1st and the 3rd month visits, respectively. Patient discontinuation causes were lack of effectiveness (42%), lack of tolerability (42%), pregnancy + other reasons (16%). Mean BL NRS score (6.8; SD 1.9) improved of at least 20% in 82.9% of patients at the 1st month visit, and of at least 30% in 24.6% of them at the 3rd month visit (p< 0.001). In ongoing patients, mean BL MSS NRS score decreased of 1.6 points (19.1%) at the 3rd month visit (p< 0.001). Mean BL Ashworth scale score (2.6; SD 0.8) decreased (p< 0.001) to 2.2 and to 2.3 at the 1st and 3rd month visits, respectively. About thirteen per cent of MS patients (41/320 patients) reported at least one adverse event (AE), all mild to moderate but 3 serious AEs (1 unrelated). AEs with incidence ⩾1% were dizziness (5.6%), confusion (2.5%), nausea (1.25%) and somnolence (1.25%). Conclusions: THC:CBD oromucosal spray provides relief of MSS in a relevant number of previously resistant patients, reproducing or surpassing in everyday clinical practice the clinical trials results with lower mean daily doses. The less sensitive Ashworth scale shows aligned results. No new tolerability concerns appeared. Final data expected by Q2 2016.

reduces responsiveness to excitation, we hypothesized that transient receptor potential channel (TRP) activation could yield sufficient excitatory input to dampen motor neuron hyperexcitability. Methods: We conducted human studies to assess the effectiveness of TRP activation in inhibiting cramps of the foot. Cramp of the flexor hallucis brevis muscle was elicited via external stimulation. The intensity and duration of the cramp was recorded by EMG in timecourse studies. Results: An oral solution containing TRP activators prevented cramps within minutes of ingestion, lasting up to 6-8 hrs. The aggregated results from 3 independent, randomized, blinded clinical studies showed a significant reduction in cramp intensity by 3-fold (p< 0.0001). Cramps were reproducibly elicited with little intra-subject variation for threshold settings and cramp profile. However, EMG patterns varied between subjects. Cramp profiles fell under several sub-types: 1) low intensity but sustained for several minutes on EMG, 2) high intensity with a rapid return to baseline, 3) delayed onset, 4) high intensity and sustained, and 5) multi-phasic sustained. There was no difference between the threshold settings to induce cramp and cramp profile. The Flex proprietary formulation was effective at reducing cramp intensity across all cramp subtypes. Conclusions: These results suggest that TRP activators may be an effective new treatment for individuals suffering from cramps/ spasticity associated with MS. As such, Flex Pharma plans to initiate a multi-center, randomised, blinded, 14-day cross-over study to investigate the effects of Flex’s proprietary formulation in patients with symptoms of spasticity and cramps due to MS. Patients will be assessed over a 2-week treatment period for changes in their cramps, measures of spasticity, quality of life, and sleeping patterns with safety/tolerability monitored. The results from pre-clinical and ongoing clinical research will be presented. Disclosure

Disclosure The author has received honoraria from different pharma companies, including fees for advice and clinical studies participation from Almirall S.A., the company commercializing in EU the presented study medication P669 TRPV1 and TRPA1 activators reduce muscle cramping. Potential new treatment for MS symptoms B.W. Hegarty, G. Short, B. Bean, R. MacKinnon, T. Wessel, C. Westphal, J. Cermak Flex Pharma, Boston, MA, United States Background: Muscle cramps and spasticity can be painful and debilitating for patients suffering with MS. A Boston-based biotechnology company, Flex Pharma, is developing innovative treatments for neuromuscular conditions. Recent studies have demonstrated that hyperexcitability of α-motor neurons in the spinal cord is likely the underlying cause of cramps and spasticity. Objectives: Based on a general property of neuronal circuits, whereby strong excitatory input increases inhibitory tone and

The authors Brooke Hegarty, Christoph Westphal, Glenn Short, Jennifer Cermak are employees and stock holders of Flex Pharma. Rod MacKinnon and Bruce Bean are scientific founders and stock holders. Rod MacKinnon is a Board of Director member. P670 Relapse management in RRMS: real-world characteristics of steroid-treated patients R.J. Fox1, J.R. Acot2, B.A. Lesher3, M. Malhotra4 1Mellen Center for MS, Cleveland Clinic, Cleveland, OH, 2Medical Data Analytics, Parsippany, NJ, 3Pharmerit International, Bethesda, MD, 4Mallinckrodt Pharmaceuticals, Hayward, CA, United States Background: Few studies have described real-world management patterns of clinical relapses, a hallmark of multiple sclerosis (MS). We conducted a retrospective, observational chart review documenting the real-world management of MS relapses. Methods: With ethics approval, 44 neurologists participated in the chart review of 3 recent relapses (at least 1 in the past 12 months) among 106 adults with relapsing remitting MS from their


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Poster Session I, 21(S11) clinical practice. At least 1 relapse in each patient needed to be treated with corticosteroids, but not ACTH. Academic- and community-based neurologists were recruited from a national physician database. A standardized case report form was used to characterize each relapse. Results: 318 relapses were investigated. Mean age was 41 years; 66% were female; 74.5% Caucasian; mean annualized relapse rate since diagnosis was 0.9; and 95.3% were receiving long-term MS disease modifying therapy. The mean relapse was 3.7 weeks, 41.5% of relapses were mild, 49.7% moderate, and 8.8% severe according to published criteria. Common relapse symptoms included numbness (38.7%), weakness (33.0%), loss of balance (31.1%), and paresthesia (29.2%). On average, severe relapses lasted 5.4 weeks, moderate 4.3 weeks, and mild 2.7 weeks. Relapse evaluation included MRI in 51.6% of relapses, with new lesions identified in 57.3% of those. 16.4% of relapses were not treated; 74.5% were treated with 1-line and 9.1% treated with 2-lines of therapy. Most relapses were treated with intravenous (IV) (65.7%) or oral (24.8%) corticosteroids. IV immunoglobulins and plasmapheresis were each prescribed in 0.9% of relapses. The most common reason cited for IV (89.5%) and oral (63.3%) steroid therapy was proven treatment efficacy. AEs were reported in 28.1% of IV and 35.4% of oral steroid courses; frequently reported AEs were anxiety (7.1% IV/5.1% oral), insomnia (7.1%/13.9%), behavior/moods swings (6.7%/6.3%), and hyperglycemia (5.2%/6.3%). Only 2.9% of IV and no oral steroid courses were discontinued for AE management. The majority of patients (96.2%) did not have complete symptom resolution by one month after onset. Conclusion: Sensory, motor, and coordinating deficits are similarly common in relapse presentation. Mild relapses are shorter duration than moderate or severe relapses. One month after onset, the majority of relapses have persistent or unresolved symptoms. The incomplete recovery suggests that additional treatment options for relapse management are needed. Disclosure Robert Fox has received personal consulting fees from Actelion, Biogen Idec, Mallinckrodt, MedDay, Novartis, Teva, and XenoPort. J. Robert Acot is an employee of Medical Data Analytics, a division of Market Certitude LLC, which is providing health economics and outcomes research services as consultant to the study sponsor, Mallinckrodt Pharmaceuticals. Beth Lesher is an employee of Pharmerit International, which provided services to Medical Data Analytics. Manoj Malhotra is an employee of Mallinckrodt Pharmaceuticals. P671 Use of patient case scenarios to assess current practice patterns of MS relapse assessment and treatment among MS specialists in the United States A. Javed1, R. Berkovich2, B. Hendin3, A. Miller4, C. Tornatore5 1University of Chicago School of Medicine, Chicago, IL, 2Keck School of Medicine, University of Southern California, Los Angeles, CA, 3Good Samaritan Hospital, Phoenix, AZ, 4Corinne Goldsmith Dickinson Center for Multiple Sclerosis, New York, NY, 5MedStar Georgetown University Hospital, Washington, DC, United States

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Background: The clinical presentation of multiple sclerosis (MS) relapse is highly variable (manifesting as subjective symptoms, objective signs, or both), and research is needed to evaluate whether consensus exists in how MS specialists currently assess and treat MS relapse events. Objective: To gain a better understanding and explore consensus of current MS relapse assessment and treatment practice patterns among MS specialists in the United States (US) using patient case scenarios. Methods: A survey was recently conducted as part of the MS Relapse Practice Patterns Project to gather insights on current MS relapse management practice patterns among 74 MS specialists in the US. One section of the survey used patient cases involving motor, sensory, and visual systems to evaluate practice patterns of MS relapse assessment and treatment. Each case had 2 scenarios that differed in severity of symptoms. A consensus opinion was defined as ⩾75% agreement. Results: In one case, a 28-year-old woman with relapsing-remitting MS experienced new right leg weakness over 5 days, making it difficult for her to walk and participate in normal activities. Neurological exam showed 3/5 leg muscle strength in scenario 1 and 5−/5 muscle strength (with no noticeable effect on her walking) in scenario 2. In both scenario 1 and 2, there was consensus among MS specialists that the event was an MS relapse (100% and 93%, respectively). In scenario 1, respondents differed in categorizing relapse severity and need for magnetic resonance imaging (MRI), but consensus was reached for treating with high-dose intravenous corticosteroids (94%). In scenario 2, there was consensus that the relapse event was mild in severity (91%), while respondents differed on the need for MRI or treatment. There was also disparity in whether MS specialists would treat a patient who reports subjective symptoms of motor relapse but shows no objective signs during neurological exam. Two additional patient cases were used to identify assessment and treatment practice patterns for relapses of differing severity in sensory and visual systems, each case showing points of consensus and disparity. Conclusion: Significant heterogeneity exists among MS specialists in the US in practice patterns for assessment and treatment of MS relapse, suggesting a need for improved clinical guidelines. Supported by Mallinckrodt Pharmaceuticals. Disclosure Regina Berkovich is a consultant for Acorda, Avanir, Bayer, Biogen, Genzyme, Novartis, Mallinckrodt, and Teva. Barry Hendin has received research support from Biogen, Genentech and Teva; is a consultant for Biogen, Genzyme, EMD Serono, Mallinckrodt, Novartis; he serves on a speakers bureau for Acorda, Biogen, Genzyme, Mallinckrodt, Novartis and Teva. Adil Javed has received consulting fees from Biogen, Novartis, Bayer, Mallinckrodt, Teva, and Genzyme. Aaron Miller is a consultant for Acorda, Accordant Health Services, Alkermes, Biogen, Caremark, EMD Serono, Genentech, Genzyme/Sanofi-Aventis, GlaxoSmithKline, Novartis, Mallinckrodt, Roche, and Teva; is on an advisory board for Sanofi; has received speaker honoraria from Biogen; and received research support from Biogen, Genentech, Genzyme, Novartis, Mallinckrodt, Sanofi-Aventis, and Roche. Carlo Tornatore has received grant support from and is on the advisory councils for Biogen, Novartis and Genzyme. He is also on the speaker bureau for Biogen.


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P672 A double blind clinical trial of the effect of coenzyme Q10 on oxidative stress, depression and fatigue in multiple sclerosis patients F. Seifar1, M. Khalili2, M. Sanoobar3, A. Azimi4, F. Modarresi5 1Neuroscience Research Centre, Student Research Committee, Tabriz University of Medical Sciences, 2Neuroscience Research Centre, Tabriz University of Medical Sciences, Tabriz, 3School of Nutrition and Dietetics, Tehran University of Medical Sciences, 4Multiple Sclerosis Research Center, Tehran University of Medical Sciences, Tehran, 5Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran Background: Multiple sclerosis (MS) is a diminutive inflammatory disease resulting in progressive disorders such as depression, fatigue and tremor. There is not still a specific pharmacological treatment for such symptoms. The aim of this study was to evaluate the effect of oral Coenzyme Q10 supplementation on oxidative stress, and patients’ symptoms of depression and fatigue in multiple sclerosis. Methods and materials: 48 patients with multiple sclerosis were enrolled, and randomized into two groups: the first group took CoQ10 supplements (500 mg/day) and the second group received placebo for 12 weeks. Treatment was evaluated using the Fatigue Severity Scale (FSS) and the Beck Depression Inventory (BDI). In addition antioxidant enzyme (superoxide dismutase) [SOD] and glutathione peroxidase [GPx]) activities were compared before and after the trial to determine anti-inflammatory effect of CoQ10 supplement. Results: After 12 weeks, CoQ10-treated patients had a significant reduction in FSS and BDI compared to the placebo group. (P=0. 001, P=0. 01 respectively). SOD activity (P=0.01) was significantly improved after the treatment, while glutathione peroxidase activity didn’t show a significant difference between two study groups. Conclusion: CoQ10 supplements (500mg/day) can be regarded as a novel treatment to modify oxidative stress and improve depression and fatigue in multiple sclerosis patients.

an EDSS score between 4-7, but less than 50% are responders in clinical studies. Longterm outcome is not yet known in these patients. Objective: To monitor the longterm progression in MS patients treated with Fampridine up to three years. Methods: Multimodal gait assessment was made by an electronic walkway system (GAITRite), the Timed-25 Foot Walk Test, the 2-minute walk test and the Multiple Sclerosis Walking Scale-12 at the beginning of the treatment, 2 weeks after beginning of treatment and every year. EDSS was also obtained in the same fashion. For patients who became unable to walk during the span of the study, EDSS alone was obtained. Results: 201 patients were included, of which 127 (63.2%) were female and 74 (36,8%) were male. Their mean age was 53,19 (±11,05 SD), mean EDSS of all patients at baseline was 5,27 (± 1,28 SD); 5,18 (± 1,33 SD) for Responders (Rs) and 6,39 (± 1,15 SD) for Non-Responders (NRs); Mean EDSS of patients with diagnosis of RRMS was 4,40 (± 1,28 SD) and 5,30 (± 1,11 SD); 5,72 (± 1,13 SD) and 5,60 (± 1,25 SD) for SPMS patients and 5,84 (± 0,89 SD) and 5,43 (± 1,16 SD) for PPMS patients, Rs and NRs, respectively, at baseline. After three years, their mean EDSS was 5,59 (± 1,34 SD) for all patients, 6,75 (± 1,07 SD) and 5,44 (± 1,43 SD) for all Rs and NRs, respectively; 4,62 (± 1,37 SD) and 5,65 (± 1,10 SD) for RRMS patients; 5,81 (± 1,32 SD) and 6,25 (± 0,91 SD) for SPMS patients, and 6,38 (± 0,74 SD) and 5,59 (± 1,30 SD) for PPMS patients, Rs and NRs, respectively. At baseline, NRs (38,46%RRMS; 36,92% SPMS; 24,62% PPMS) had a higher mean EDSS, and showed greater EDSS increase during the following 3 years. SPMS NRs showed the greatest EDSS progression in contrast to PPMS and RRMS NRs. In GAITRite analysis, NRs showed a constant decrease over time in Functional Ambulation Profile (FAP) score, Velocity, Cadence and stride length, most remarkably during the first year. Conclusion: In a large cohort in real world, Fampridine has shown significant improvement in gait parameters in responder patients. Long-term effects showed a relative improvement in gait parameters in responders, while disease progression (worsening of EDSS) affected all patients, especially those non responding to Fampridine.

Disclosure

Disclosure

This research project was fully sponsored by Tehran University of medical sciences. Fatemeh Seifar: Nothing to disclose Mohammad Khalili: Nothing to disclose Meisam Sanoobar: Nothing to disclose Amirreza Azimi: Nothing to disclose Faezeh Modarresi: Nothing to disclose

Francisco Rodriguez-Leal: Nothing to disclose Katja Thomas: Has received honorarium from Novartis, Bayer and Biogen idec. Raimar Kern: Nothing to disclose Judith Eisele: Nothing to disclose Thorsten Schultheiss: Nothing to disclose Tjalf Ziemssen: Is on the scientific advisory board for Bayer Healthcare, Biogen Idec, Novartis, Merck-Serono, Teva, Genzyme, and Synthon; has received speaker honorarium from Bayer Healthcare, Biogen Idec, Genzyme, MSD, GSK, Novartis, Teva, Sanofi, and Almirall; and has received research support from Bayer Halthcare, Biogen Idec, Genzyme, Novartis, Teva, and Sanofi.

P673 Longterm discapacity progression in MS patients treated with fampridine F.A. Rodriguez-Leal, K. Thomas, R. Kern, J. Eisele, T. Schultheiss, T. Ziemssen Multiple Sclerosis Center, Center of Neurological Science. University Hospital Carl Gustav Carus, Dresden, Germany Introduction: Multiple Sclerosis (MS) is a chronic inflammatory and degenerative disease, often presenting with gait impairment. Fampridine is a symptomatic treatment used in MS patients with

P674 Depression and fatigue improve after mindfulness training C. Oreja-Guevara1, A. Muñoz-San José2, S. Cebolla-Lorenzo2, L. Carrillo2, I. González-Suárez1, N. Sanz-Velasco2, T. SotoLópez2, A. Irimia-Nores2, B. Rodriguez-Vega2, C. Bayón-Pérez2


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Poster Session I, 21(S11) 1Neurology,

University Hospital San Carlos, 2Psiquiatría, Hospital Universitario La Paz, Madrid, Spain Introduction: Recent research supports that behaviour interventions for stress management like mindfulness, might produce significant reductions in depression, anxiety, fatigue and quality of life improvements among patients with chronic diseases. Objectives: To compare the efficacy over anxiety and depression of a group Mindfulness-Based Stress Reduction (MBSR) program against a group psychoeducative intervention in MS patients and the efficacy over fatigue of a group MBSR program against a group psychoeducative intervention in MS patients at 8 weeks of treatment. Material and methods: A randomized clinical trial has been designed for studying the effect of both interventions on anxiety and depression (HADS), quality of life (SF-36) and fatigue (visual analogue scale), at the beginning, at the moment of ending both interventions (8 weeks) and 24 weeks after the end of both programs. Both interventions are taught in a group over 8, weekly 1.5 hour sessions. A maximum of 15 participants were admitted in each group. The effect of each intervention over anxiety and depression (Hospital Anxiety and Depression Scale (HADS)) and fatigue (visual analogue scale) was studied. Results: We study 41 patients with RRMS, 21 randomized to mindfulness intervention and 20 to psychoeducative program. No difference in sociodemographical characteristics has been found between the groups. Medium age was 43 and 46 years old respectively. In both groups the level of educaction was high school graduate at least. In HADS: patients randomized to mindfulness intervention show a mean score of 22.1 (SD 8.3) at baseline, while the mean score at 8 weeks was 9.1 (SD 5.5); patients in the psychoeducative program obtained a mean score of 18 (SD 8.6) at the baseline, and 7 (SD 5.5) at 8 weeks. In depression subscale (HADS-D), participants randomized at MBSR group had a basal mean score of 9.9 (DS 4.8) and 7 (DS 5.2) at 8 weeks. Mindfulness group mean scores in visual analogue scale of fatigue were 4.1 at basal evaluation and 3.8 at week 8; in the psychoeducative group scores were 4.1 and 3.4 respectively. Conclusion: The results support the beneficial effects in depression, anxiety and fatigue of mindfulness in patients with multiple sclerosis. Disclosure Celia Oreja-Guevara received honoraria for speaking and/or consultancy from Biogen, Genzyme, Bayer, Merck-Serono, Roche, Teva and Novartis. A. Muñoz-San José: Nothing to disclosure. Ines González-Suárez received honoraria for speaking from Biogen. S Cebolla-Lorenzo: Nothing to disclosure. N Sanz-Velasco: Nothing to disclosure. L. Carrillo: Nothing to disclosure. A Irimia Nores: Nothing to disclosure. C Bayón-Pérez: Nothing to disclosure. B Rodriguez Vega: Nothing to disclosure.

P675 Fampridine modulates thalamic resting state functional connectivity and ameliorates fatigue in multiple sclerosis patients

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M. Filippi1,2, P. Valsasina1, B. Colombo2, P. Preziosa1,2, L. Vacchi1, V. Martinelli2, A. Falini3, G. Comi2, M.A. Rocca1,2 1Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 2Department of Neurology, 3Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy Background: Functional imaging studies have supported the hypothesis of a central origin of MS-related fatigue, by showing a dysfunction of cortico-subcortical circuits, involving frontoparietal regions and the basal ganglia. Currently, different pharmacological agents are used for treatment for fatigue in MS (including fampridine and amandatine). However, there is still no clear evidence supporting the efficacy of such treatments. Objectives: To investigate the effects of fampridine and amantadine on thalamic resting state (RS) functional connectivity (FC) in MS patients with fatigue. Methods: Forty-five fatigued MS patients were randomly, blindly assigned to undergo treatment with fampridine (n=15), amantadine (n=15) or placebo (n=15) and underwent clinical, neuropsychological (including fatigue assessment) and 3T RS fMRI at baseline (T0) and after four weeks (W4) of treatment. Fifteen matched healthy controls were also studied. RS FC analysis was done using the left thalamus as seed region and SPM8. Results: At T0, compared with controls, MS patients showed decreased thalamic RS FC with temporal, occipital, frontal and cerebellar regions. At W4, fampridine patients showed significantly increased global, physical and cognitive MFIS (p=0.003/0.004/0.02), while no significant MFIS changes were observed in amantadine patients. Placebo patients showed improved global, physical and psycho-social MFIS (p=0.02/0.01/0.02). In fampridine patients, increased thalamic RS FC at W4 was detected with bilateral temporal, frontal and parahippocampal regions, while amantadine patients and healthy controls showed no significant RS FC modifications. In placebo patients, small clusters of increased thalamic FC with frontal and parietal regions were identified. Compared to the other groups, fampridine patients showed a significant RS FC increase over time in the left insula and fusiform gyrus, and right precentral and hyppocampal gyrus. Physical MFIS improvements were associated with increased thalamocerebellar FC, while cognitive MFIS improvements were associated with increased thalamo-frontal FC. Conclusions: Treatment with fampridine ameliorates fatigue in MS patients possibly through a modulation of thalamic functional connections. Disclosure Partially supported by a grant from Italian Ministry of Health (GR-2008-1138784). P. Valsasina, B. Colombo, P. Preziosa, L. Vacchi, V. Martinelli, A. Falini have nothing to disclose. M. Filippi has received compensation for consulting services and/ or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis. G. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for


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speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. M.A. Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed. P676 PR-Fampridine improves walking and quality of life in people with severe MS-related walking impairment R. Ewe1, H. Louissaint2, H. Bleasdale3, K. Bull2, R. Farrell2,4,5 1UCL Medical School, 2UCLH NHS Foundation Trust, 3UCL NHS Foundation Trust, 4UCL Institute of Neurology, 5NIHR Biomedical Research Centre, London, United Kingdom Background: Walking impairment is a common and disabling symptom in people with Multiple Sclerosis (MS). Walking impairment is associated with unemployment, falls, reduced independence and quality of life. Prolonged release (PR) Fampridine has been shown to improve walking speed and quality of life in people with MS. Objectives: To observe the long-term efficacy of PR-Fampridine on walking, quality of life and functional ability when used in routine clinical practice. Methodology: People with MS and walking impairment were reviewed in a specialist ambulation clinic comprised of neurologists and specialist physiotherapists. Treatments offered included PR-Fampridine, functional electrical stimulation, spasticity and orthotics review. Outcomes included: Timed 25 Foot Walk (T25FW), Multiple Sclerosis Walking Scale (MSWS-12), healthrelated quality of life using the EuroQol 5-dimension instrument, 5-level version (EQ-5D-5L), Visual Analogue Scale (VAS) walking, falls log and functional goals of treatment. Those treated with PR-fampridine were evaluated for this study. Responder status was defined by ⩾20% increase T25FW velocity compared to baseline with concomitant MSWS-12 improvement. Treatment response was monitored over time. Results: 65 female subjects and 33 males were included (n=98). Mean age 51.4 years [34-73 years], Mean Expanded Disability Status Score (EDSS) 6.5 [6.0-7.0]: 50 SPMS, 14 had RRMS, 30 had PPMS and 4 were uncategorised. After 2 weeks, 74.8% walked ⩾20% faster than baseline. Mean change in T25FW velocity was 81.3% [21.2 - 453 %, p< 0.0001] in responders versus -6.80% [-31.9-12.8%, p< 0.0001] in non-responders. Responders continued walking faster than baseline at 6 months (54.2%, p=0.431). The bottom quartile of patients (slowest) at baseline walked 126.9% faster at 2 weeks, while the top quartile walked 59.7% faster (p=0.011). At 2 weeks, MSWS-12 improved more in responders (-27.8, p< 0.0001) than non-responders (-10.0) (p=0.186), EQ-5D-5L index changed by +0.136 [-0.402 - +0.807, p< 0.0001] in responders and - 0.053 [-0.464 - +0.206] in nonresponders (p=0.02). At 6 months, responders’ improvement of the EQ-5D-5L index was maintained (0.134, p=0.0046) and 87% of responders achieved their functional goals of treatment. Conclusion: In an open label study of people with severe walking impairment, PR-Fampridine improves walking speed, subjects’ perception of walking ability and quality of life. Disclosure Rachel Farrell - Honoraria /Hospitality from GW Pharma ltd, Canbex therapeutics ltd., Teva pharmaceuticals ltd., Biogen Idec ltd, Novartis ltd, Almirall ltd, Merck Serono ltd.

Renee Ewe, Hannah Steadman, Helen Bleasdale, Kate Bull: Nothing to disclose

P677 High-dose intravenous methylprednisolone induced hepatotoxicity in multiple sclerosis patients: three case reports M. Hidalgo de la Cruz1, J.A. Miranda Acuña1, A. Lozano Ros1, M. Vega Catalina2, M.L. Martinez Ginés1, G. Clmente Ricote2, E. Salinero Paniagua3, C.D. De Andrés Frutos1 1Neurology, 2Gastroenterology, 3Cell Biology, Hospital General Universitario Gregorio Marañón, Madrid, Spain High-dose intravenous methylprednisolone (IVMP) corticosteroid therapy is the conventional and most effective treatment employed for Multiple Sclerosis (MS) exacerbations. Adverse events, such as hyperglycemia, tachycardia, insomnia and gastric damage are known. However, hepatotoxicity has not been described. We present three MS patients that developed hepatotoxicity after IVMP infusion. First patient is a 28-year-old woman. In February 2012 she presented with an exacerbation in the left side of her body and was treated with a total dose of 4,500 mg IVMP, without adverse events. In April 2012, due to cerebellar damage, she was given 7,000 mg IVMP. 50 days later, the patient presented with an episode of clinical severe acute hepatitis with liver enzyme elevation (ALT 2,642 U/L) and histological damage. In September 2012, treatment with fingolimod was initiated. In June 2013, she presented with a cervical spinal cord damage that improved after treatment with 3,000 mg IVMP. 30 days later, she presented with another severe acute hepatitis episode with similar findings to that observed previously. Second patient is a 37-year-old man. In September 2012, he was hospitalized for an exacerbation due to cervical spinal cord damage. He was treated with 5,000 mg IVMP. In September 2013, he presented with worsening of his residual spinal cord damage and was treated with 5,000 mg IVMP. 43 days later, in a routine examination a liver enzyme elevation was observed (ALT 328 U/L). Hepatic biopsy was normal. Third patient is a 35-year-old woman. In April 2014 she presented with cervical spinal cord damage. She was treated with 5,000 mg IVMP. Three days later, a routine blood analysis showed high liver enzyme levels (ALT 850 U/L), but the patient was clinically asymptomatic. Other etiological causes were excluded. Reevaluation showed that IVMP had been given during the weeks prior to acute hepatitis episodes. Therefore, it was reasonable to hypothesize that IVMP was possible cause and was avoided in following exacerbations. Since then, they have not experienced any subsequent hepatic symptoms or liver enzyme elevations. We conclude that hepatic damage is an adverse event of IVMP treatment that should be considered. Consequently, more studies are needed to determine the underlying mechanisms. Additionally, we emphasize the importance of finding alternative drugs or medical procedures for these disease exacerbations. Disclosure Nothing to disclose


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Poster Session I, 21(S11) P678 Differences in use and perceptions on effectiveness of marijuana for MS: a survey of NARCOMS participants S.S. Cofield1, A.R. Salter1, T. Tyry2, C. Crowe3, S. McNeal1, G.R. Cutter1, R.J. Fox4, R.A. Marrie5, NARCOMS 1Biostatistics, University of Alabama at Birmingham, Birmingham, AL, 2Dignity Health, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, 3University of Alabama at Birmingham, Birmingham, AL, 4Neurology, Cleveland Clinc, Cleveland, OH, United States, 5University of Manitoba, Winnipeg, MB, Canada Background: Research on marijuana in multiple sclerosis (MS) is limited but suggests some effectiveness for treatment of spasticity and related pain. Objective: To characterize perceptions about effectiveness of marijuana for MS symptoms by current use and current symptoms. Methods: In August 2014, active participants (12,260) in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry were invited to complete an online, anonymous questionnaire about current behaviors and attitudes on marijuana use, including current severity of spasticity, tremor, pain, and MS disease status. Marijuana referred to smoking, ingesting, or any controlled substance derived from marijuana or synthetic marijuana. Results: Of 5665 respondents, 78.3% were women. Men were older than women (median 58.0 vs 54.9 years, p< 0.0001), but did not differ in age at diagnosis (38 vs 37, p=0.44). A higher proportion of men had used marijuana before MS diagnosis (66.5 vs 62.7, p=0.017), had discussed use with their doctor (25.8 vs 18.5, p< 0.0001), and currently used it for their MS (30.7 vs 23.9, p< 0.0001). The median days of use in the last 30 days for those that use (20 days, p=0.59) or proportion that think it should be legal (91.5% legal overall) did not differ by sex. A higher proportion of men than women did not think marijuana improved any symptoms (9.5 vs 5.9, p< 0.0001). A higher proportion of men reported spasticity (81.0 vs 74.6, p< 0.0001) but a lower proportion thought marijuana was an effective treatment (72.8 vs 77.0, p=0.003). A higher proportion of men reported tremor (34.4 vs 25.9, p< 0.0001) but perceived effectiveness of marijuana for tremor did not differ from women (38.8 vs 39.1, p=0.89). A higher proportion of women compared to men reported experiencing headaches (31.2 vs 18.0), anxiety (41.3 vs 33.1), and nausea/GI issues (24.6 vs 19.0) and thought that marijuana improved these symptoms (females 32.3 vs 26.4 males), anxiety (54.3 vs 45.0), nausea/GI issues (39.6 vs 30.3, all p< 0.0001). Differences persisted adjusting for type of MS, age and duration of disease, and current marijuana usage. Conclusion: More men report current use of marijuana and have spoken to their physician about it but fewer men think it improves symptoms associated with MS than women. Disclosure Dr. Cofield has received support for consulting services from the American Shoulder and Elbow Society, DSMB service from MedImmune, and/or grant support for various entities; no direct conflicts. Dr. Salter has received support for consulting services and grant support; no direct conflicts.

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Dr. Fox has received support for consulting fees from Actelion, Biogen, MedDay, Novartis, Questcor, Teva, and XenoPort; no direct conflicts. Dr. Marrie has conducted clinical trials for sanofi-aventis; no direct conflict. Dr. Tyry has nothing to disclose. Ms. McNeal has nothing to disclose. Ms. Crowe has nothing to disclose. Dr. Cutter has consulting and/or DSMB commitments in Past 12 months. Participation of Data and Safety Monitoring Committees: All of the below organizations are focused on medical research: Apotek, Biogen-Idec, Cleveland Clinic(Vivus), Glaxo Smith Klein Pharmaceuticals, Gilead Pharmaceuticals, Horizon Pharmaceuticals, Modigenetech/Prolor, Merck/Ono Pharmaceuticals, Merck, Merck/ Pfizer, Neuren, Sanofi-Aventis, Teva, NHLBI (Protocol Review Committee), NINDS, NICHD (OPRU oversight committee). Consulting, Speaking fees & Advisory Boards: Consortium of MS Centers (grant), D3 (Drug Discovery and Development), Genzyme, Genentech Jannsen Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, Novartis, Opexa Therapeutics, Receptos, Roche, EMD Serono, Spiniflex Pharmaceuticals, Somahlution, Teva pharmaceuticals, Transparency Life Sciences. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. Sources of funding: NARCOMS is supported by the CMSC and the Foundation of the CMSC. P679 Remotely-supervised cognitive remediation is feasible and effective: results of a pilot study L.E. Charvet, L. Haider, M. Shaw, W. Fang, K. Sherman, P. Melville, L.B. Krupp Neurology, Stony Brook Medicine, Stony Brook, NY, United States Cognitive impairment represents a critical unmet treatment need in multiple sclerosis (MS). Having to travel to an outpatient office for cognitive rehabilitation treatment often presents a barrier to participation. Computer-based cognitive remediation programs target deficits similar to those seen in MS, and can be accessed outside of the outpatient setting. However, controlled evaluation is needed to determine potential benefit and guide optimal use. Our goal was to develop a protocol for remotely-supervised cognitive remediation that enables individuals with MS to participate from home while the standards for clinical study are maintained. MS participants (n=20, all relapsing remitting, treated with fingolimod) were randomized to either an active web-based cognitive remediation program (n=11, a research program using the Lumosity platform to target MS-specific deficits) or an active control condition of ordinary computer games (n=9). Participants were provided a study laptop to complete daily cognitive remediation sessions for 5 days per week over 12 weeks, targeting a total of 30 hours. Technical support was available throughout the week, and each participant had weekly phone contact with the study technician. The full group averaged 24.4 hours of program use, 81% of the targeted use, and program usage did not significantly differ between active and control conditions (24.8 vs. 24.0 hours). The treatment effect was


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measured by a composite score from the cognitive testing battery (complex attention, verbal and visual learning). The active group significantly improved on test performance at follow-up compared to the control condition (change in composite z score of 0.38 ±0.51 improvement vs. -0.11 ± 0.49 decline, p=0.04). Additionally, more participants in the active vs. control condition reported improved cognitive functioning (p=0.04). Remotely-supervised cognitive remediation accessed at home is feasible for clinical study with potential for cognitive benefit in MS. Disclosure Study funded by Novartis AG with support from The Lourie Foundation Inc. The cognitive remediation program was provided by Lumos Labs, Inc. Leigh Charvet has received research funding from Novartis. Lauren Krupp has received either consulting fees, honoraria, or royalty payments from the following: J&J, Biogen, Novartis, Teva, Bayer, Multicell, Quintiles, EMD Serono, Medidata, and Pfizer and research funding from Novartis and Teva Neurosciences. Patricia Melville is on the Teva Pharmaceutical speaker´s bureau. Lamia Haider: nothing to disclose Michael Shaw: nothing to disclose Wendy Fang: nothing to disclose Kathleen Sherman: nothing to disclose

Quality of life P680 Using techniques of positive psychology as an intervention to address the challenges of living with MS: an examination of the National MS Society’s Everyday Matters: living your Best Life Program K. Koch1, S.A. Tompkins2 1National Multiple Sclerosis Society, Denver, 2Madipen, LLC, Fort Collins, CO, United States Multiple sclerosis (MS) impacts more than 2.3 million people worldwide and is known to have a substantial negative impact on quality of life (Yamout et al., 2013). People living with MS experience a wide range of symptoms, including loss of mobility, increased stress, and feelings of isolation and depression (Cecil, 2014; Marrie et al., 2009). Interventions aimed at cultivating positive feelings, behaviors and emotions have resulted in significant enhancement in well-being and decreases in depressive symptoms (Sin & Lyubomirsky, 2009); implications for the MS population include improved ability to better face disease specific challenges. In response to a void of proactive programs, the National Multiple Sclerosis Society developed Everyday Matters: Living Your Best Life with MS. Over the course of 5 sessions (2-hr per/wk) the program aims to increase participants’ knowledge about positive psychology and how to apply these tenets to addressing the everyday challenges of living with MS. Program data is from pre (254), post (209), 3-month follow-up surveys (164), and 12-month surveys (100). Baseline sample: PwMS (80%), diagnosed < 5 yrs (34%), RRMS diagnosis (70%) and (41%) reporting sometimes experiencing depression. Paired sample t-test run on pre and 12-month responses* showed significant increases in satisfaction with life scale (SWLS; t(74) = 4.57, p< .05); MS specific self-efficacy

(MSSE; t(70) = 2.31, p< .05); positive/optimistic outlook (t(77) = 6.12, p< .05; *PwMS only as 12-month sample was not sufficient for support partners). Additional findings include benefits for support partners at 3-months post, usage of positive psychology, MS related resources and action plans. Everyday Matters is one of the few MS-specific programs being offered using the principles of positive psychology to assist in addressing life challenges. Results demonstrate evidence of program success in multiple outcomes. Specifically, increased self-efficacy or feelings of control may lessen the psychological and emotional impact of living with MS leading to improved disease management (Trojan et al., 2007; Bol et al., 2009). Additional implications of increasing positive constructs are better medication adherence, less morbidity and increased longevity (Cuffee et al., 2012). The Society has created an effective positive psychological intervention for the MS population, improving both MS specific and general positive constructs. Disclosure Kimberly Koch: Nothing to disclose Sara Anne Tompkins: Nothing to disclose P681 A revolutionary new way of looking at the link between quality of life (QoL) and multiple sclerosis (MS) progression R. Devy1, P. Lehert2, M. Genty3, G. Edan4 1Association DNS, Saumur, France, 2University of Louvain, Louvain, Belgium, 3Centre Thermal, Yverdon les Bains, Switzerland, 4CHU Rennes, Rennes, France Introduction: QoL is known to be influenced by MS progression. Our study assessed if QoL influences the disability of MS patients. Material: A standard therapy currently used in MS demonstrated a significant delay of MS progression and relapse reduction with no benefit on QoL. Our study assessed the extent to which a specific Behavioral Cognitiv Therapy (BCT) with the addition of an Interferon β (Iβ) is superior to Iβ alone in QoL improvement. Methods: We conducted a longitudinal one year, multi-center controlled, multi-variate matched study on Relapsing-Remitting MS patients (EDSS < 4, MS duration < 2 years) in 11 french centers. All were treated with Iβ. 19 of the group was treated with Iβ plus BCT. QoL measured by TLS-QoL10 scale at month 0-3.6 and 12. A double-mixed linear Model with autoregressive assumption (MLA) assessed the effect of EDSS at time t-1 (EDSS t-1) on QoL at time t (QoL t) and conversely the effects of QoL at time t-1 (QoL t-1) on EDSS at time-t (EDSS t). Results: 51 matched MS patients took part in the trial. The BCT effect resulted in a significant QoL increase of 1.10 (95% CI [0.31-1.89], p = .009). The two dependent MLA models provided evidence that QoL, adjusted for QoL t-1 is negatively affected by EDSS t-1 (-0.95 [-1.2l-0.63]). However EDSS t adjusted for EDSS t-1 was also found to be influenced by QoL t-1. (-0.10[-0.14- -0.06].


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Poster Session I, 21(S11) Conclusion: MS progression impacts Patients’ QoL. Our study provides the first conclusive evidence that QoL has a direct effect on disability. This bi-directional effect QoL-EDSS has important implications in routine medical practice: a- QoL is a key indicator in predicting MS progression. b- Unlike EDSS, QoL deterioration could be treated by BCT. c- Consequently a regular monitoring of QoL is a simple, useful tool to anticipate MS progression. d- This could help the strategic management of the disease to improve Single Patient Perspective. Disclosure The authors have no conflict of interest

P682 The relationship between beliefs about illness causes and well-being among persons with multiple sclerosis and their caregivers M. Bassi1, M. Falautano2, S. Cilia3, B. Goretti4, M. Grobberio5, M. Pattini6, E. Pietrolongo7, R.G. Viterbo8, M.P. Amato4, M. Benin5, A. Lugaresi7, E. Minacapelli9, E. Montanari6, F. Patti3, M. Trojano8, A. Delle Fave1, The Care System Group 1University of Milan, 2Neurology, IRCCS San Raffaele Hospital, Milano, 3University of Catania, Catania, 4University of Florence, Firenze, 5Hospital S. Anna, Como, 6Hospital of Vaio, Fidenza, 7University G. d’Annunzio, Chieti, 8University of Bari, Bari, 9IRCCS San Raffaele Hospital, Milano, Italy Background: Illness beliefs of patients and their caregivers can deeply affect their bio-psycho-social functioning. In particular, beliefs about disease causes have been associated with quality of life, medication adherence, and help-seeking behaviour in conditions like obstructive pulmonary disease and myocardial infarction. Little however is known about the relationship between causal attributions and the well-being of persons with multiple sclerosis (P) and their caregivers (CG), as the unknown etiology of MS may challenge individuals’ perceived locus of control and sense of agency in illness adjustment. Aim: To investigate the relation between perceived illness causes and well-being among P and their CG. Methods: Questionnaires assessed participants’ illness causes (revised Illness Perception Questionnaire), psychological wellbeing (Psychological Well-Being Scales), life satisfaction (Satisfaction with Life Scale), and hedonic balance (Positive Affect and Negative Affect Schedule). Regression analyses examined the contribution of illness causes (psychological attributions, risk factors, environmental causes, genetic cause, immunity, luck) to participants’ well-being. Results: Data were analyzed for 71 P and 71 CG from 7 MS centres in Italy. Analyses revealed that only psychological attributions and luck contributed to participants’ well-being. CG’s psychological attributions were negatively related to their own life satisfaction (B=-.34, p< .05), and to P’s life satisfaction (B=.29, p< .05) and psychological well-being (B=-.40, p< .01). In addition, CG’s attribution to luck was negatively related to P’s life satisfaction (B=-.31, p< .01). Finally, an interaction effect between P’s and CG’s psychological attributions on CG’s hedonic balance

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was observed (B=-.25, p< .05): when both CG and P attributed MS more to psychological causes, CG reported lower hedonic balance; when a mismatch between P’s high and CG’s low psychological attributions was observed, CG reported higher hedonic balance. Conclusions: Perceived illness causes are related to the wellbeing of P and CG in complex ways. P were mostly susceptible to CG’s causal attributions which may lead them to experience a sense of self-blame or helplessness. Intervention is needed to provide P and CG with better understanding of their mutual illness views and of available sources of control which can provide them with a deeper sense of empowerment in disease adjustment. Disclosure Marta Bassi declares that she has no conflict of interest. Sabina Cilia declares that she has no conflict of interest. Monica Grobberio declares that she has no conflict of interest. Francesco Patti declares that he has no conflict of interest. Marianna Pattini declares that she has no conflict of interest. Rosa Gemma Viterbo declares that she has no conflict of interest. Maria Pia Amato declares that she has no conflict of interest. Enrico Montanari declares that he has no conflict of interest. Antonella Delle Fave declares that she has no conflict of interest. Monica Falautano is member of the scientific committee of Fondazione Italiana Sclerosi Multipla (FISM) and received travel grants from FISM. Benedetta Goretti received speaker’s honoraria and grants from FISM. Erika Pietrolongo received speaker’s honoraria and travel and research grants from FISM. Miriam Benin received honoraria as consultant for Associazione Italiana Sclerosi Multipla (AISM) - Section Como. Alessandra Lugaresi received speaker’s honoraria from FISM. Eleonora Minacapelli received travel grants from AISM. Maria Trojano received speaker’s honoraria from FISM. Study was supported by FISM - Fondazione Italiana Sclerosi Multipla - Cod. 2011/R/5 P683 Home-based palliative approach for people with severe multiple sclerosis and their carers (PeNSAMI): ongoing study A. Solari1, A. Giordano1, M.G. Grasso2, P. Confalonieri3, F. Patti4, A. Lugaresi5, L. Palmisano6, R. Amadeo7, G. Martino7, M. Ponzio8, G. Casale9, C. Borreani10, R. Causarano11, S. Veronese12, P. Zaratin8, M.A. Battaglia8, PeNSAMI project 1Unit of Neuroepidemiology, Foundation IRCCS Neurological Institute C. Besta, Milan, 2Multiple Sclerosis Unit, Foundation IRCCS S. Lucia Rehabilitation Hospital, Rome, 3Unit of Neuroimmunology, Foundation IRCCS Neurological Institute C. Besta, Milan, 4MS Center, Neurology Clinic, University Hospital Policlinico Vittorio Emanuele, Catania, 5Department of Neuroscience, Imaging and Clinical Sciences, G. d’Annunzio University of Chieti-Pescara, Chieti, 6Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, 7Associazione Italiana Sclerosi Multipla, 8Fondazione Italiana Sclerosi Multipla, Genoa, 9Antea Charitable Association, Rome, 10Unit of Clinical Psychology, Foundation


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IRCCS Istituto Nazionale per la Cura dei Tumori, 11Unit of Palliative Care-Hospice, Niguarda Ca’ Granda Hospital, Milan, 12FARO Charitable Foundation, Turin, Italy Background: There is very limited proof that palliative care in patients with severe multiple sclerosis (MS) is beneficial. Objective: To determine the effectiveness of a home-based palliative approach (HPA) for people with severe MS and their carers. Methods: This is a multicenter single-blind randomized controlled trial with a nested qualitative study (ISRCTN73082124). Results: Seventy-five severe MS-carer dyads are being randomized to HPA or usual care (UC) in a 2:1 ratio. Primary outcome measures are changes in: Palliative Outcome Scale - Symptoms MS; and the Schedule for the Evaluation of Individual Quality of Life-Direct Weighting (not assessed in patients with severe cognitive compromise). Other outcomes are changes in patient functional status and mood; changes in carer quality of life, mood and caregiving burden; costs; incorporation with standard care; unplanned hospital admissions; referrals to hospice; and deaths. The experience of participants (HPA arm only) will be scrutinized by patient and carer individual interviews, and focus group meetings of caring physicians. Between 13 January - 19 May 2015, 42 patients have been randomized (56% of target; 28 to HPA and 14 to UC). No drop outs have been reported so far; two serious adverse events (accesses to emergency room without hospitalization) occurred: one in the HPA group, and one in the UC group. Conclusion: The results of our study will show whether the HPA is feasible and beneficial to people with severe MS and their carers living in the three Italian geographic areas. The nested qualitative study will add to the understanding of the strengths and limitations of the intervention. Disclosure The study is funded by the Fondazione Italiana Sclerosi Multipla (grant no. 2014/S/1 to AS). AS has been a board member of Biogen Idec and Novartis, and has received speaker honoraria from Genzyme, Merck Serono, the Fondazione Serono and Excemed. MGG has received research funding from Merck Serono and consulting and speaking fees from Biogen Idec. PC has been a board member of Biogen Idec, received travel grants from Sanofi Aventis, Biogen Dompe’ and Merk Serono. FP received honoraria for speaking activities from Bayer Schering, Biogen Idec, Merck Serono, Novartis, and Sanofi Aventis. He has served as advisory board member of the following companies: Bayer Schering, Biogen Idec, Merck Serono, and Novartis. AL has been a Bayer Schering, Biogen Idec, Merck Serono and Genzyme advisory board member. She received travel grants and honoraria from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis and Teva and research grants from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis and Teva. She has also received travel and research grants from the Associazione Italiana Sclerosi Multipla and was a consultant of Fondazione Serono. LP, RA, and MAB are board members of the Fondazione Italiana Sclerosi Multipla (charitable organization). All other authors declare that they have no competing interests.

P684 Impact of walking impairment on healthcare resource utilisation in multiple sclerosis patients: an updated analysis from 2015 Y. Liu1, J. Pike2, A. Lee1, M. Y. Huang 1Biogen, Cambridge, MA, United States, 2Adelphi Real World, Manchester, United Kingdom, 3Biogen, Zug, Switzerland Background: Multiple sclerosis (MS) is a chronic, progressive disease. Mobility and walking impairment affect up to 90% of MS patients. In clinical trials, walking impairment is often measured by walking speed (WS). The impact of walking impairment on direct and indirect healthcare resource utilization (HCRU) and support resources, such as walking aids and home/workplace modifications, provides important information on burden of MS-related symptoms for healthcare decision makers. Objectives: This analysis sought to investigate association between WS, measured by timed 25 foot walk test (T25FW), and direct HCRU, walking aid use, and modifications to daily living at home and work using a cross-sectional study from 2015. Methods: Data were obtained from 490 neurologists in France, Germany, Italy, Spain, UK and US. Neurologists completed 10-15 prospective records for consulting MS patients. Of the total 5397 MS patients, 512 had a T25FW score, and of these, 162 returned a self-completion form reporting on the utilization of support services. Mean age was 44.01 years. Mean time since diagnosis was 5.63 years. Logistic, ordered logistic, negative binomial and probit (with sample selection) regressions assessed the relationship between WS and physician-reported data on direct patient HCRU and patient-reported data on walking aids and home and workplace modifications. Covariates were age, sex, body mass index, time since MS diagnosis and relevant concomitant conditions. Results: Reduced WS was associated with increased level of nonprofessional and professional caregiver need (p=0.001), and an increased number of visits to ER in the last 12 months (p=0.009). Reduced WS was also associated with increased need for walking aids (p=0.001) and home modification (p=0.003). Conclusions: Reduction in WS is associated with increased HCRU and additional support requirements. This updated analysis generally confirmed results from a similar analysis using 2014 data. Therapies that improve patients’ WS may be beneficial to reduce economic burden associated with reduced WS. Disclosure A. Lee, Y. Liu, C. Hibbert are full time employees of Biogen. J. Pike and B. Hoskin are full time employees of Adelphi. This study was funded by Biogen. Biogen provided funding for medical writing and editorial support in the development of this abstract. Eddie Jones of Adelphi Real World provided writing support in the development of the abstract. Biogen reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content.

P685 Daclizumab HYP reduced psychological impact of multiple sclerosis versus intramuscular interferon beta-1a in the DECIDE trial


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Poster Session I, 21(S11) B. Turner1, T. Vollmer2, E. Havrdova3, S. Lynch4, S. Wray5, C. Ford6, P. Wang7, Y. Liu7, J. Elkins7, W. Castro-Borrero7 1Barts NHS Trust, London, United Kingdom, 2University of Colorado Denver, Aurora, CO, United States, 3First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, 4Department of Neurology, University of Kansas Medical Center, Kansas City, KS, 5Hope Neurology MS Center, Knoxville, TN, 6University of New Mexico Health Sciences Center, Albuquerque, NM, 7Biogen, Cambridge, MA, United States Background: DECIDE was a randomised, double-blind, activecontrolled study comparing daclizumab high-yield process (DAC HYP) 150mg subcutaneous (SC) every 4 weeks with interferon (IFN) beta-1a 30mcg intramuscular (IM) once weekly for 96-144 weeks in patients with relapsing-remitting multiple sclerosis (RRMS). Objective: To evaluate patient-reported impact of DAC HYP vs IM IFN beta-1a on the Multiple Sclerosis Impact Scale (MSIS-29) psychological subscale (PSYCH), as well as the 9 individual PSYCH items. Methods: The MSIS-29 was assessed at baseline and weeks 24, 48, 72, and 96 in DECIDE. Negative changes in MSIS-29 PSYCH indicate improvement. Between-treatment comparison for mean change from baseline in MSIS-29 PSYCH score at Week 96 (preplanned analysis) was analysed using analysis of covariance adjusted for baseline covariates. MSIS-29 PSYCH subscale items have 5 response options expressing degree of bother (1=Not at All to 5=Extremely). In a post hoc analysis of individual items, change from baseline in percentage of patients reporting Not at All bothered at Week 96 was examined for each treatment group. Results: Mean baseline MSIS-29 PSYCH scores were 28.8 (DAC HYP; n=904) and 28.6 (IFN beta-1a; n=912). Mean improvement from baseline in MSIS-29 PSYCH score at Week 96 was significantly greater for the DAC HYP vs IFN beta-1a groups (-4.20 vs -2.57; P=0.039). The items with the greatest percentage of patients reporting any bother (responses 2 through 5) at baseline were: worries related to your MS (76.6%, DAC HYP; 77.9%, IFN beta1a), feeling irritable/impatient/short tempered (74.7%, DAC HYP; 72.0%, IFN beta-1a), and feeling anxious/tense (73.1%, DAC HYP; 73.0%, IFN beta-1a). At Week 96, the increase from baseline in percentage of patients reporting Not at All bothered (response 1) was numerically higher in DAC HYP vs IFN beta-1a patients for 6 of the 9 items (feeling irritable/etc. [10.2% vs 6.9%]; feeling depressed [8.2% vs 4.8%]; problems sleeping [5.8% vs -1.6%]; feeling unwell [5.0% vs 3.4%]; lack of confidence [4.2% vs 2.8%]; and problems concentrating [4.1% vs 3.9%]). Conclusion: DAC HYP resulted in greater mean improvement relative to baseline vs IFN beta-1a in the patient-reported psychological impact of MS in DECIDE at Week 96. The increase in percentage of patients reporting no psychological impact of MS at Week 96 was numerically greater for DAC HYP vs IFN beta-1a across most PSYCH items, notably problems sleeping and feeling depressed. Disclosure Benjamin Turner received honoraria and Clinical Grants from Biogen, Novartis, Genzyme, TEVA, Merck Serono, and compensation for advisory boards from Biogen, Novartis, Genzyme, and Roche.

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Timothy Vollmer received consulting fees from Biogen, Genentech, Novartis, Novartis Canada, Teva, Teva Canada, and Xenoport and research funding from: Acorda, Biogen, EMD Serono, Genzyme, Jensen Research, MedImmune, the National Institutes of Health, Novartis, Ono, Teva, and Vaccinex. Eva Havrdova received speakers’ honoraria and research grant support from Bayer Schering Healthcare, Biogen, Genzyme, Merck Serono, Novartis, and Teva, and compensation for advisory board activities from Biogen, Genzyme, Merck Serono, Novartis, and Teva. Sharon Lynch received research grant support from: Biogen, Genzyme, Genentech, Roche, Teva, Novartis, Actelion, Acorda, Medimmune, Sun Pharma, Vaccinex, NIH, and NMSS. Sibyl Wray has received honoraria and research funding from Biogen, Genzyme, Novartis, and EMD Serono; research funding from: Genentech, Ono, and Receptos; and speaker’s honoraria from Accorda, Bayer, and Teva. Corey Ford received consulting fees from Biogen, Novartis, Teva and research funding from Acorda, Biogen, Merck Serono, Genzyme, MedImmune, Novartis, Ono, Roche, Sanofi-Aventis, and Teva. Ping Wang is a full-time employee of Biogen. Ying Liu is a full-time employee of Biogen. Jacob Elkins is a full-time employee of Biogen. Lou Barbato is a full-time employee of Biogen. This study was funded by Biogen and AbbVie Biotherapeutics Inc. Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this abstract. Rebecca Jarvis (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content. P686 Relapse rates and quality of life among patients receiving disease modifying therapy for multiple sclerosis S. Naoshy1, J. Pike2, E. Jones2, C. Watson1 1Biogen, Cambridge, MA, United States, 2Adelphi Real World, Manchester, United Kingdom Background: Multiple Sclerosis (MS) registry data and previous real world studies suggest that treatment with natalizumab results in lower rate of relapse versus other disease modifying therapies (DMTs). Furthermore, treatment with natalizumab has been shown to improve quality of life. Objective: To compare relapse rates and quality of life using the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS) questionnaire between MS patients treated with natalizumab or platform therapies (interferons and glatiramer acetate). Methods: Relapsing Remitting MS (RRMS) patients receiving natalizumab or platform therapies for greater than 12 months were identified from the 2015 Adelphi MS Disease Specific Programme, a global (United States, United Kingdom, Spain, Italy, France and Germany) cross-sectional study of MS patients. Average treatment effects (ATEs) for 867 patients (156 natalizumab, 711 platform) were estimated and adjusted utilizing a propensity score generated from age, gender, Expanded Disability Status Scale


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(EDSS) score at current treatment initiation, line of therapy, body mass index (BMI), duration of current treatment, time since MS diagnosis, and number of comorbid conditions. Physicianreported relapses in the previous 12 months and HAQUAMS were compared across treatments. Results: Relapse and HAQUAMS data were available for 739 (122 natalizumab, 617 platform) and 278 (55 natalizumab, 223 platform) patients, respectively. Natalizumab patients suffered fewer relapses than platform therapy patients (ATE=-0.21 vs. 0.48, p=0.020). The HAQUAMS analysis demonstrated that patients receiving natalizumab reported significantly less mobility/lower limb impairment (ATE=-0.42 vs. 1.91, p< 0.001), mood impairment (ATE=-0.25 vs. 2.43, p=0.033) and overall impairment than those on platform therapies (ATE=-0.19 vs. 1.96, p=0.023). Conclusion: Treatment with natalizumab was associated with a lower relapse rate and a significantly better quality of life compared to platform therapies. Disclosure Study was funded by Biogen. SN: Employee of Biogen. JP: Employee of Adelphi Real World, which has a research consultancy agreement with Biogen. EJ: Employee of Adelphi Real World, which has a research consultancy agreement with Biogen. CW: Employee of Biogen. P687 Burden and depression in caregivers and patients with multiple sclerosis. MS-feeling study J. Meca-Lallana1, M. Mendibe2, R. Hernández-Clares1, A.B. Caminero3, J. Mallada4, P. Dávila5, M. Garcés Redondo6, M. Gómez7, J. Millán8, G. Soriano9, M.D.C. Amigo10 1Hospital de Virgen de la Arrixaca. Murcia. Cátedra de Neuroinmunología Clínica y Esclerosis Múltiple. UCAM Universidad Católica San Antonio de Murcia, Murcia, 2Hospital de Cruces, Barakaldo, Vizcaya, 3Hospital Nuestra Señora de Sonsoles Complejo Asistencial de Ávila, Ávila, 4Hospital de Elda, Alicante, 5Hospital Comarcal de Manacor, Manacor, Islas Baleares, 6Hospital de Tortosa, Tortosa, Tarragona, 7Hospital San Pedro de Alcántara, Cáceres, 8Hospital de Alcázar de San Juan y Hospital General de Tomelloso, Ciudad Real, 9Hospital de Navarra, Pamplona, 10Hospital Provincial CHOP, Pontevedra, Spain Background: Little is known about the degree of burden and depression in caregivers and patients with relapsing-remitting multiple sclerosis (RRMS) in Spain. Burden and depression may influence treatment effectiveness by decreasing medication adherence. Objectives: To assess the burden and depression in caregivers and patients with RRMS, and describe their satisfaction with treatment. Methods: Multicenter, observational, cross-sectional study conducted from 09/12 to 04/14 in RRMS patients⩾18 years(y) and treated for ⩾1y. Burden was assessed with the Zarit Burden Interview, depressive symptoms with the Center for Epidemiologic

Studies Depression Scale-short form(CESD-7), and treatment satisfaction of caregivers and patients with ad-hoc questionnaire and treatment Satisfaction Questionnaire for Medication(TSQM), respectively. Multivariate analyses were performed for caregiver burden and depression. Results: 180 patients (mean[SD] age 41[11]y; 66% female) and caregivers (48[12]y; 56% female; 67% employed). Most caregivers were relatives (59% spouse;25% parent) living with the patient (86%);32% assisted to administer medication. Median(Q1-Q3) time since diagnosis: 7(4-10)y and between diagnosis and first treatment: 0.3(0.2-1.3)y. Most patients received monotherapy (92%: interferon beta[51%], glatiramer acetate[20%], natalizumab[14%], fingolimod[7%]). Median EDSS: 2.5(1-4). 19% of caregivers reported burden (median score:10[7-15]). Factors associated (odd ratio[OR]) with burden were: EDSS Score (OR[95% confidence interval]:1.6 [1.2-2.0]), time as caregiver (OR:1.1 [1.0-1.2]) and number of assisted medication administrations (OR:4.1 [1.2-13.5]). 42.2% of patients and 20.6% of caregivers had depression. Factors associated with caregiver depression were: patient age (OR:0.9 [0.8-0.9]), daily time as caregiver (OR:1.2 [1.1-1.5]) and female gender (only the tendency, OR:4.4 [0.99-19.9]). 90% of patients and caregivers were satisfied/very satisfied with treatment. Conclusions: Around 1 in 5 caregivers had burden, which proportionally increased with disease severity, years as caregiver and number of assisted medication administrations. About 1 in 5 caregivers and 2 in 5 patients had depression. Caregiver depression proportionally decreased with patient age and increased with daily time as caregiver. Also, 9 in 10 patients and caregivers were satisfied/very satisfied with RRMS treatment. Disclosure José Meca-Lallana: Nothing to disclose. Mar Mendibe: Nothing to disclose. Rocío Hernández-Clares: Nothing to disclose. Ana Belén Caminero: Nothing to disclose. Javier Mallada: I have received speaking honoraria from Novartis, Genzyme and Merck-Serono. I have received support for congresses from Novartis. Pablo Dávila: Nothing to disclose. Moisés Garcés Redondo: Nothing to disclose. Monserrat Gómez: I have participated like speaker in meetings with Biogen, Novartis, Shering, Genzyme, Teva and Merk Serono. Jorge Millán: Nothing to disclose. Gerardo Soriano: Nothing to disclose. María del Campo Amigo: Nothing to disclose. Source of funding: Novartis Farmacéutica, S.A., Spain. P688 The burden of multiple sclerosis and patients’ cooping strategies L. Lorefice1, G. Fenu2, J. Frau2, G. Coghe2, M.G. Marrosu3, E. Cocco2 1Multiple Sclerosis Centre, Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, 2Multiple Sclerosis Centre, Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, Italy, 3Multiple Sclerosis Centre, Department of Medical Sciences, University of Cagliari, Italy, Cagliari, Italy


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Poster Session I, 21(S11) Multiple Sclerosis (MS) is a chronic disease that afflicts mainly young people, affecting different aspects of life. MS patients experience several emotional responses to changed perception of themselves, managing the situation in a variety of ways focused to control, tolerate, or reduce the overall burden of the disease.1 The present study aimed to evaluate the differences between MS patients and healthy controls (HCs) in coping styles, exploring which of the MS clinical features influence the adaptive responses. Methods: MS patients, according to the McDonald 2010 criteria,2 and HCs, were recruited. Coping strategies were assessed using the Italian version of the questionnaire “Coping Orientation to the Problems Experienced” (COPE-NVI).3 The intergroup comparison was obtained by using Mann-Whitney U-test. Results: 135 MS patients (female: 89/135; 65,9%) and 94 HCs (female: 64/94; 68%) were enrolled. MS patients are less inclined to use of coping strategies that involved seeking Social Support and Problem Solving than HCs (p < 0,005). In MS group, women are found to be more socially oriented than men (p 0,02) and Social Support worsen with increasing of disease duration (p 0,01). An association between level of disability and avoidance strategies was reported (p 0,005). Conclusions: The results of this study highlight the issue of “difficulties of living with MS”, including the negative impact on social relationships. Therefore a psychosocial intervention is needed to increase the adaptive way by MS patients cope with their disease and to provide patients with the best care and quality of life. Keywords: Multiple Sclerosis; coping strategies; psychosocial intervention; quality of life 1. Brassington JC, et Al. Neuropsychol Rev. 1998 Jun;8(2):43-77 2. Polman CH, et Al. Ann Neurol.;69:292-302 3. Claudio Sica. Psicoterapia Cognitiva e Comportamentale Vol. 14 - n. 1 • 2008 (pp. 27-53) Disclosure Conflict of Interest No conflict of interest exists regarding the present paper. Dr. Lorefice received speaker fee from Teva and serves on scientific advisory boards for Biogen. Dr. Fenu received honoraria for consultancy from Novartis and for speaking from Merck Serono and Teva. Dr. Frau serves on scientific advisory boards for Biogen, received honoraria for speaking from Merck Serono and Teva. Dr. Coghe received speaker fee from Teva. Professor Marrosu and Professor Cocco have received honoraria for consultancy or speaking from Bayer, Biogen-Idec, Novartis, Sanofi-Genzyme, Serono and Teva. P689 The role of positive coping and hopefulness in predicting quality of life in multiple sclerosis C.A. Young1,2, A. Tennant3, TONiC Group 1Walton Centre NHS Trust, 2University of Liverpool, Liverpool, United Kingdom, 3Swiss Paraplegic Research, Nottwil, Switzerland Background: Hope facilitates coping with the unpredictable nature of multiple sclerosis (MS) and improves mood. Coping mechanisms can improve the patients´ quality of life (QoL). How does either construct impact upon QoL?

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Methods: The TONiC study is an ongoing, multi-centre, UK study to investigate the trajectories of outcomes in MS. It incorporates many Patient Reported Outcome Measures, including measures of hopefulness (MS-Hope-12) and positive coping (MS-Cope-12). Both have a score range of 0-36 (Rasch transformed), which can be divided into tertials, giving rise to lowmedium-high groups. The Leeds MS QoL scale can be divided using the lower tertial range to indicate a good quality of life. Logistic regression was used to examine the odds ratios for the effect of high positive coping and hopefulness on quality of life, adjusted for disease type. Results: Of 722 people with MS analysed, 71.9% were female. 66.4% reported relapsing-remitting MS; 23.3% secondary progressive MS; and 10.3% primary progressive MS. Almost three- fifths (58%) reported a strong hopeful perspective (upper tertial); whereas just less than one-quarter (24.3%) reported a strong positive coping style. Just over one third (34.2%) reported a good QoL. 15% displayed low levels of positive coping, and there appeared to be no specific association with levels of hopefulness. There was no association between the type of MS and the level of coping, but those with progressive MS were more likely to have low levels of hopefulness, and less likely to display high levels than those with the relapsing remitting type (Chi-Square 25.9; P < 0.001).Both coping and hopefulness were shown to be predictive of QOL, with the increased odds of good QoL for high coping group being 4.3 (CI: 2.1-8.8) and 4.1 for the high hope group (CI:1.5-11.3). The odds were adjusted for each other and for disease type, also shown to be a significant predictor of QoL (p=0.024) (Nagelkerke R Square 0.213; Hosmer & Lemeshow Test 0.866; correct classification 72.1%). Conclusion: Both positive coping skills and hopefulness have been shown to be indicative of good quality of life in MS, adjusted for MS type. While high levels of coping and hopefulness appear to go together, this is not the case for low levels of coping skills. The results suggest that helping patients to improve positive coping, and achieve a sense of hopefulness, will also improve their quality of life. Disclosure Young CA has received financial support for research and educational purposes, hospitality, fees for speaking and advisory boards, from Biogen Idec, Genzyme, Novartis, Roche, and Teva. Tennant A: nothing to disclose. The TONiC study was supported by unrestricted grant support from NIHR, MNDA, Walton Neuroscience Charity, Biogen, Novartis, Roche, Teva. P690 Work, fatigue and cognition: a correlational analysis using the QUIPSEP, a cognitive ergonomic questionnaire for work holding in multiple sclerosis patients G. Delrue1, A. Blavier2, R. Berkail2, J. Hennen2, P. Calay1, E. Lommers1, V. Delvaux1, P. Maquet1, A.-S. Nyssen2 1MS Group - Neurology, CHU Liege, 2Lecit, ULG, Liège, Belgium We have constructed and previously presented the QUIPSEP (ECTRIMS 2012), a questionnaire designed to focus on cognitive-ergonomic difficulties encountered by multiple sclerosis


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(MS) patients at work. It is divided in three parts : description of one’s work cognitive load, encountered disturbances and social support. We postulate that the QUIPSEP should be correlated with subjective fatigue and cognitive dysfunctions. We attempted to validate this assumption by comparing answers to the QUIPSEP with cognitive functioning and fatigue complaints of 32 MS patients with no other inclusion criteria than being actively working. These patients underwent an extensive cognitive battery (including a french version of the Brief International Cognitive Assessment for MS - BICAMS) and answered to QUIPSEP. Correlation analyses were conducted between QUIPSEP scores and cognitive scores. Depression and anxiety were also evaluated using Hamilton Anxiety and Depression Scale scores (HAD) and fatigue was evaluated by the Modified Fatigue Impact Scale (MFIS) and the Fatigue Scale for Motor and Cognitive functions (FSMC). There was no significant correlation between QUIPSEP scores and HAD scores but significant correlations between ‘encountered disturbances’ scores and fatigue measures (MFIS p< 0,001; FSMC p< 0,001). No significant correlation at all was found between BICAMS scores and QUIPSEP scores. However, we found significant correlations between different attentional and executive scores from specific TAP battery (Test of Attentional Performance). These correlations were mostly found for ‘social support’ part of the QUIPSEP. These results highlight different important findings. First, screening for cognitive dysfunctions may lead to underscore the functional impact of light cognitive disturbances. Second, our patients are actually in a compensating way of coping with their work, not so inefficient, but feeling increasing fatigue and more tied to social support. Third, the only isolated correlations found between ‘encountered disturbances’ score of the QUIPSEP and our extensive cognitive testing emphasizes the need for a specific focus on individual work situation of our patients and their potential daily working handicap. These preliminary results encourage us to go on with including a specific eye on working situation of our patients, beyond our usual clinical tools. Disclosure This study has been founded by King Baudouin Foundation and the Belgian National Multiple Sclerosis League. P691 Fatigue and quality of life in multiple sclerosis: the mediating effect of activity limitation and the moderating effect of gender and disease type C.A. Young1,2, A. Tennant3, TONiC Group 1Walton Centre NHS Trust, 2University of Liverpool, Liverpool, United Kingdom, 3Swiss Paraplegic Research, Nottwil, Switzerland Introduction: Fatigue has shown to be a common symptom in MS, impacting upon activities and quality of life. Models such as path analysis may help to explore these relationships. Methods: The current analysis from the TONiC study uses Neurological Fatigue Index-MS (NFI-MS); MS Impact Scale (MSIS29) and Leeds MS Quality of Life scale (LMSQoL) to examine the mediating effect of activity limitation upon the relationship between fatigue and quality of life, and how such relationships may

be moderated (interaction effect) by gender and disease type. Data from the scales were included in the model as single indicator latent variables derived from Rasch analysis. Age and duration were available as independent contextual factors, and gender and disease type as moderators. A Sobel-Goodman mediation test first assessed the mediating effect of activity, and a path analysis then assessed the invariance of gender and disease type for the relationships so identified. A non-significant ChiSquare test of the model was considered a valid result. Analysis was undertaken in STATA13. Results: Of 565 patients analysed, mean age was 48.5 years (SD 11.6) and mean duration of disease was 11.4 years (SD 8.8). 72.6% were female, and 31.2% had a progressive form of the disease. The Sobel-Goodman mediation test showed a strong partial mediation for activities, with 39.3% of the total effect of Fatigue upon Quality of Life mediated in this way. The basic model, including age and duration, showed good fit in the path analysis (Chi-Square 2.616; df 2; p=0.270; RMSEA 0.023; CFI 0.999; TLI 0.997) with no evidence that path coefficients differed significantly by gender. However, significant differences were found for disease type across all paths except age and duration. For the progressive type, the effects of fatigue upon QoL were fully mediated, showing no significant direct effect, unlike with the relapsing-remitting type, where the partial mediation was still strong, showing both direct and indirect (through activities) effect (Chi-Square 2.603; df 4; p=0.626; RMSEA 0.000; CFI 1.000; TLI 1.000). Conclusion: This study shows that the effects of fatigue upon QoL are differentially mediated by activities, depending upon whether the patient has progressive MS. In progressive MS, the full effect of fatigue is manifest through the activity limitations experienced by the patient, whereas for those with relapsing-remitting form of the disease, there is also a significant direct effect. Disclosure Young CA has received financial support for research and educational purposes, hospitality, fees for speaking and advisory boards, from Biogen Idec, Genzyme, Novartis, Roche, and Teva. Tennant A: nothing to disclose. The TONiC study was supported by unrestricted grant support from NIHR, MNDA, Walton Neuroscience Charity, Biogen, Novartis, Roche, Teva. P692 The impact of urinary dysfunction in multiple sclerosis: rasch analysis of the SF-Qualiveen K. Milinis1,2, R. Mills3, A. Tennant4, C. Young1,2, the Trajectories of Outcome in Neurological Conditions (TONiC) Study Group 1The Walton Centre NHS Foundation Trust, 2University of Liverpool, Liverpool, 3Royal Preston NHS Trust, Preston, United Kingdom, 4Swiss Paraplegic Research, Nottwil, Switzerland Background: The Qualiveen was a 40-item scale developed in France in 2001 specifically to assess the impact of neurogenic bladder dysfunction on quality of life in spinal cord injury by simple self-report. A short-form, 8-item scale (SF-Qualiveen) was adapted in multiple sclerosis (MS) in 2008 and comprised 4 domains of limitations/inconvenience, constraints/restrictions, fears and feelings/impact on daily life, with both English and


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Poster Session I, 21(S11) French versions. The validity of the scale has not been previously examined using modern psychometric techniques. Objective: To assess the construct validity of the English 8-item SF-Qualiveen by application of the Rasch measurement model. Methods: The SF-Qualiveen was given to patients with clinically definite MS as part of the TONiC study, a multicentre, UK study of factors affecting quality of life in MS. The data were randomly split into a development sample and a sample set aside for validation. Results: 705 patients completed the questionnaire (response rate 61.7%). The scale failed to meet the expectations of the Rasch model with a highly significant overall chi square probability and several misfitting items. An item-based solution could only be achieved across both the development and validation samples by the deletion of four items (1, 5, 6 and 8) and accepting weak reliability (person separation index 0.75). A testlet solution was employed, which retained all the items, by grouping into 2 testlets (items 2, 3, 4, 7 and 1, 5, 6, 8). This achieved good fit with good reliability, was unidimensional and free of differential item function for important person factors. No variance was shed and there were acceptable levels of intertestlet dependency. Conclusions: The SF-Qualiveen was shown to have construct validity for use in MS. Urinary dysfunction is likely to have a significant impact on quality of life and this simple self-report scale could be used as a variable in modelling quality of life in MS. Further work is needed to compare the scale’s agreement with objective urodynamic measures. Disclosure Milinis K, Mills RJ, Tennant A and Young CA declare no conflicts of interest for this work. The TONiC study was supported by unrestricted grant support from NIHR, MNDA, Walton Neuroscience Charity, Biogen, Novartis, Roche, Teva. P693 Suboptimal disability measurement in multiple sclerosis clinical trials: limitations of existing patient-reported outcomes measures J. Petrillo1, D. Cadavid1, S. Cano2, S. Cleanthous2, E. Kinter1, P. Marquis2, D. Mikol1, S. Naoshy1, G. Sabatella1, D. Steiner1, C. Wakeford1, C. Watson1, J. Hobart3 1Biogen, Cambridge, 2Modus Outcomes, Newton, MA, United States, 3Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, United Kingdom Background: Multiple sclerosis (MS) clinical trials frequently use patient-reported outcome measures (PROs) to evaluate treatment efficacy and determine its clinical significance. The ability to detect changes and differences should be optimized for specific study populations. Goals: To evaluate, using Rasch Measurement Theory, how precisely 4 PROs (MS Walking Scale, MSWS-12; MS Impact Scale, MSIS-29; ABILHAND-56; National Eye Institute Visual Functioning Questionnaire, NEI VFQ-25) target populations using data from 3 trials (RENEW, ADVANCE, ASCEND).

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Methods: We examined scale-to-sample targeting (reported in logits) of the MSWS-12, MSIS-29 (physical [PHYS] and psychological [PSYCH]), ABILHAND-56, and NEI VFQ-25 in data from RENEW (NEI VFQ-25; n=82), ADVANCE (MSIS-29; n=1512) and ASCEND (ABILHAND-56, MSWS-12, MSIS-29; n=889). RENEW enrolled patients with their 1st unilateral AON episode (an early MS symptom). ADVANCE enrolled patients with relapsing remitting MS. ASCEND enrolled patients with secondary progressive MS. For the MSIS-29, MSWS-12 and ABILHAND-56, lower scores=better function; for the NEI VFQ25, higher scores=better function. Results: For all 3 trials, PRO scale-to-sample targeting was suboptimal. Person location range (sample distribution) was wider than item location range (scale measurement range), indicating participants with lower disability levels were measured less precisely than those with greater disability levels. The MSIS-29 PHYS was: -5.68 to 5.53 (person) vs -3.41 to 3.11 (items) in ADVANCE compared with -5.19 to 5.11 (person) vs -3.43 to 2.58 (items) in ASCEND. The targeting range for the MSIS-29 PSYCH was -5.18 to 4.86 (person) vs -3.17 to 2.66 (items) in ADVANCE and -4.26 to 4.30 (person) vs -2.00 to 2.10 (items) in ASCEND. Using ASCEND data, the targeting range was -5.01 to 5.77 (person) vs -2.99 to 4.10 (items) for the MSWS-12 and -7.31 to 1.83 (person) vs -5.75 to 4.27 (items) for the ABILHAND-56. The targeting range for the NEI VFQ-25 using RENEW data was -1.43 to 6.27 (person) vs -3.48 to 4.58 (items). Conclusion: The PROs examined did not adequately (or precisely) reflect the level of disability for patients at the lower end of the range of disability (those with less disability). Changes in disability for less disabled patients may be underestimated by these PROs. A modification of the scoring rubric and/or addition of items may better enable detection of changes in impairment for patients who are less disabled. Disclosure Jennifer Petrillo is a full-time employee of Biogen. Diego Cadavid is a full-time employee of Biogen. Stefan Cano is an employee of Modus Outcomes and receives consulting fees from Biogen. Sophie Cleanthous is an employee of Modus Outcomes and receives consulting fees from Biogen. Elizabeth Kinter is a full-time employee of Biogen. Patrick Marquis is an employee of Modus Outcomes and receives consulting fees from Biogen. Dan Mikol is a full-time employee of Biogen. Sarah Naoshy is a full-time employee of Biogen. Guido Sabatella is a full-time employee of Biogen. Deb Steiner is a full-time employee of Biogen. Craig Wakeford is a full-time employee of Biogen. Crystal Watson is a full-time employee of Biogen. Jeremy Hobart receives consulting/advisor fees or honoraria from Acorda, Biogen, Merck Serono, and Novartis. This study was funded by Biogen. Biogen provided funding for medical writing support in the development of this abstract. Rebecca Jarvis, PhD (Excel Scientific Solutions, Southport, CT) wrote the first draft of the abstract based on input from authors. Biogen reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract, and provided their final approval of all content.


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Neuro-ophthalmology

1Department

P694 Study of subclinical oculomotor disturbances by video oculography in patients with clinically isolated syndromes A. Ferraro1, E. Thouvenot2, X. Ayrignac1, D. Renard2, C. Carra Dallière1, P. Labauge1, G. Castelnovo2 1Neurology, CHU Gui de Chauliac, Montpellier, 2Neurology, CHU Caremeau, Nimes, France Introduction: The clinically isolated syndrome (CIS) is a first clinical episode with features suggestive of multiple sclerosis (MS). We studied the prevalence of subclinical ocular motor disorders in CIS with video-oculographic analyses (Eyebrain tracker). Methods: Consecutive CIS patients followed in Nimes and Montpellier MS centers were invited to undergo video-oculography. Patients with oculomotor abnormalities on physical examination and/or with a brainstem or cerebellum MRI lesion were excluded. Eye movements were recorded using the Mobile Eyebrain Tracker head-mounted. Patients were tested for fixation, horizontal and vertical reflexive saccades and horizontal and vertical smooth pursuit Three main characteristics of reflexive saccades were analysed: initiation time (latency), velocity (both mean and peak velocities between the beginning and the end of the saccade were assessed), and gain (corresponding to accuracy of the saccade). Analyses were done for each eye in each horizontal and vertical direction, and compared with age-matched healthy controls. Latency, mean velocity, peak velocity, and gain were called abnormal when values differed > 2SD from controls. Horizontal smooth pursuit was studied with a slow moving target moving 20°/s towards a lateral angle of 19.5°. For vertical smooth pursuit, the moving target was studied at 8°/s towards a vertical angle of 10.1°. Smooth pursuit was called pathological when a clear degradation of the sinusoidal pattern to a saccadic pattern was observed in one or more of the sine wave cycles. Results: Twenty-seven CIS patients were explored. Oculomotor abnormalities were found in 74% of patients, mainly consisting in abnormal horizontal saccades (48,2%). Saccadic dysmetria and/or reduced saccadic velocity were identified in 33% of patients. Saccadic intrusions were present in 37% of patients. Unilateral subclinical internuclear ophtalmoplegia was founded in 18.5% of patients. Horizontal smooth pursuit was pathological in only 2 patients (7.4%). Conclusions: Our study shows that CIS patients frequently have subclinical eye movements disorders on video-oculography. The oculomotor abnormalities observed indicate a brainstem or cerebellar dysfunction not visible on MRI. Follow-up of our patients is necessary to analyse if video-oculography may contribute to establish spatial diffusion criterion in patients after a first event suggestive of MS. Disclosure No conflict of interest. P695 Difference in recovery from optic neuritis between neuromyelitis optica and multiple sclerosis patients H. Masuda1, M. Mori1, A. Uzawa1, M. Muto1, T. Uchida1, R. Otani1, R. Akiba2, H. Yokouchi2, S. Yamamoto2, S. Kuwabara1

of Neurology, Graduate School of Medicine, Chiba University, 2Department of Ophthalmology, Graduate School of Medicine, Chiba University, Chiba, Japan Objective: To investigate difference in recovery from optic neuritis (ON) between neuromyelitis optica (NMO) and multiple sclerosis (MS) patients and to clarify factors associated with ON recovery and severity in NMO. Methods: Records of the visual acuity (VA) of 75 NMO patients and 179 MS patients at attack with other clinical data were reviewed. We compared VA immediately before attack, at nadir, and 1 and 3 months after attack. Patients showing ON and decreased VA, and taking a neuro-ophthalmic evaluation follow-up in at least two points in those periods were included. Then, we compared time from ON relapse to nadir and basement VA in NMO and MS. We also investigated the time in the first ON and relapsed ON and the time in patients treated and not treated with some type of treatment in NMO. Results: Fifty two eyes of 21 NMO patients and 44 eyes of 17 MS patients were included. Ten NMO patients and six MS patients relapsed more than twice. Intravenous methylprednisolone pulse therapy, occasionally followed by plasmapheresis, low-dose steroid therapy or no treatment was performed. VA was better at all points in the MS group than in the NMO group. The improvement of VA at 3 months did not differ between the groups. KaplanMeier analysis revealed that the frequency of VA regaining the baseline was greater in the MS group than in the NMO group. The relapsed ON patients showed worse recovery and tended to reach nadir earlier than the first ON patients in NMO. Treatment showed no statistical differences in both MS and NMO. Conclusions: Recovery from ON was worse in NMO than in MS. Preventing ON relapses is important for preserving VA in NMO patients. Disclosure Hiroki Masuda: Nothing to disclose. Masahiro Mori: Nothing to disclose. Akiyuki Uzawa: Nothing to disclose. Mayumi Muto: Nothing to disclose. Tomohiko Uchida: Nothing to disclose. Ryohei Otani: Nothing to disclose. Ryutarou Akiba: Nothing to disclose. Hirotaka Yokouchi: Nothing to disclose. Shuichi Yamamoto: Nothing to disclose. Satoshi Kuwabara: Nothing to disclose. P696 Failure of smooth pursuit as a marker of early multiple sclerosis N.S. Lizak1,2, M. Clough1,3, L. Millist1, O.B. White1,4, J. Fielding1,3,4 1Ocular Motor Laboratory, Department of Neurology, Royal Melbourne Hospital, 2Faculty of Medicine, 3School of Psychological Sciences, Monash University, 4Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia Background: Studies have demonstrated significant abnormalities of saccadic behaviour in patients with multiple sclerosis (MS), including those with a clinically isolated syndrome (CIS)


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Poster Session I, 21(S11) suggestive of MS, which worsen with disease progression. Although saccades and pursuit have been postulated as different outcomes of the same neural processes, it is unclear whether smooth pursuit is similarly affected. Aims: To determine whether smooth pursuit integrity is affected in CIS and clinically definite MS (CDMS), and examine whether deficits of smooth pursuit may be indicative of disease state. Methods: 15 CIS patients, 13 patients with early CDMS (⩽7 years from diagnosis) and 15 healthy controls were recruited and assessed at the Royal Melbourne Hospital, with the intention of expanding sample size and including a late CDMS group. Each participant completed 36 trials of Rashbass’ step-ramp paradigm, evenly split by ramp direction (left/right) and speed (8.65, 17.1 and 25.9 deg/s), and with greater step magnitude at greater ramp speed (1.4, 2.69 and 4.12 deg respectively). Closed-loop pursuit gain (CLPG) and average summed saccade amplitude (ASSA) were compared between groups. Results: At the fastest ramp speed (25.9 deg/s) mean CLPG was significantly greater for controls (0.56) compared to CIS patients (0.41; p=0.012). At medium ramp speed (17.1 deg/s) median CLPG was significantly greater for controls (0.89) compared to CIS patients (0.61; p=0.008). For early CDMS patients, CLPG was not significantly different to either group at fast and medium speeds (0.48 and 0.79 respectively). At 8.65 deg/s there was no difference between groups (p=0.144). Mean ASSA was significantly greater for early CDMS patients compared to controls (4.6° vs. 3.6° respectively, p=0.047). The difference in mean ASSA between controls and CIS patients (4.4°) nearly reached significance (p=0.069). Conclusion: Preliminary results indicate that smooth pursuit abnormalities, manifesting as decreased CLPG at higher pursuit speed and as increased saccadic tendency, may be a marker of early disease. Saccadic interruption of unsuccessful pursuit may be a compensatory mechanism for more significant pursuit failure with advancing disease. Pursuit deficits are potentially a sensitive discriminator of widespread network dysfunction in CIS patients, and may well indicate pathology that is clinically and radiologically undetectable. This may prove to aid in the diagnosis of MS. Disclosure Nathaniel Lizak: Nothing to disclose. Meaghan Clough: Nothing to disclose. Lynette Millist: Nothing to disclose. Owen White and Joanne Fielding: Have both received research support from Biogen Idec and Novartis. P697 The Pulfrich Phenomenon: a signature of visual system pathophysiology in multiple sclerosis R. Agarwal1, M.J. Sobhanian1, D. Conger1, A. Conger1, L.J. Balcer2,3, O. White4,5, T. Frohman1, J. Ooi1, S.C. Beh1, R.L. Rennaker6, E.M. Frohman1,6,7 1Neurology, University of Texas Southwestern Medical Center, Dallas, TX, 2Neurology, 3Ophthalmology, NYU Langone Medical Center, New York, NY, United States, 4Neurology, Royal Melbourne Hospital, 5Medicine, University of Melbourne, Parkville, VIC, Australia, 6Biomedical Engineering, University of Texas at Dallas, Richardson, 7Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, United States

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Introduction: The Pulfrich Phenomenon (PF) is the illusory perception that an object moving linearly along a 2-D plane, appears instead to move in an elliptical 3-D trajectory. The PF is thought to reflect inter-eye differences, in the transmission properties in the visual information-processing network. We have developed an innovative method by which we can identify both the presence and magnitude of the PF. Methods: Thirty-three subjects participated in the study, consisting of 10 healthy controls and 23 patients carrying a diagnosis of multiple sclerosis (MS) with a history of optic neuropathy (ON), 20 of which had a history of unilateral acute optic neuritis; AON; 1 patient exhibited unilateral subclinical optic neuropathy, and 2 with bilateral AON, were asked to indicate whether movement of a pendulum bob followed a 2D linear versus a 3D elliptical trajectory. In the latter case, subjects were asked to ascertain the magnitude and direction of the 3D motion by virtue of the bob’s approximation to one of five colored equidistant wires, oriented parallel to the frontal plane, in close proximity to the bob. Control subjects were asked to make the same approximations following monocular application of graduated neutral density filtering (G-NDF). Results: Twelve (52%) of the MS patients with ON experienced the PF, whereas none of the control subjects spontaneously experienced this illusion. However, the monocular application of G-NDF produced the illusion of the PF in all control subjects. The magnitude of the PF intensified corresponding to the serial escalation in the level of filter tinting. Alternately, the systematic application of incremental G-NDF to the less affected eye of MS patients experiencing the PF, was employed until the illusion was attenuated or abolished. Conclusions: We have designed a method by which to identify the presence and magnitude of the induced PF illusion (via G-NDF) in normal subjects, and the spontaneous phenomenon in MS patients with ON, and asymmetry in the visual processing network. Our future investigations will be aimed at the objective characterization of the pathobiological underpinnings of this phenomenon in MS patients. A dividend of these studies, will include the development of a pathophysiologic signature-biomarker, with both face and construct validity, signaling discrete derangements in visual system architecture, and their corresponding functional consequences. Disclosure Rohit Agarwal: Nothing to disclose. Millad J. Sobhanian: Nothing to disclose. Darrel Conger: Nothing to disclose. Amy Conger: Nothing to disclose. Laura J. Balcer has received honoraria for consulting on development of visual outcomes for MS trials from Biogen-Idec, Novartis, Acorda, Vaccinex and Bayer. She is on a clinical trial advisory board for Biogen-Idec. Owen White: Nothing to disclose. Teresa Frohman has received speaker and consultant fees from Genzyme, Novartis and Acorda. Jason Ooi: Nothing to disclose. Shin C. Beh: Nothing to disclose. Robert L. Rennaker: Nothing to disclose. Elliot M. Frohman has received speaking and consulting fees from, TEVA Neuroscience, Genzyme, Acorda, and Novartis.


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P698 Retinal oximetry: a novel visual biomarker of retinal metabolic dysfunction in MS S.C. Beh1, M. Lucero1, D. Conger1, A. Conger1, V. Stokes1, T.C. Frohman1, P.A. Calabresi2, R. Rennaker3, L.J. Balcer4, E.M. Frohman1 1Neurology, UT Southwestern Medical Center, Dallas, TX, 2Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 3University of Texas Dallas, Dallas, TX, 4Neurology, New York University School of Medicine, New York, NY, United States Background: Optic neuropathy occurs very commonly in multiple sclerosis (MS) patients. Optical coherence tomography (OCT) has been shown to be a sensitive, and precise method of quantifying structural retinal changes that occur in MS. It is very likely, however, that metabolic dysfunction precedes such structural changes in the retina; therefore, a method of detecting and measuring these metabolic changes (for example, retinal oxygen utilization) would result in a more sensitive visual biomarker of MS disease activity. Objective: To measure retinal vascular oximetry (oxygen saturation [SatO2] and partial oxygen pressure [PaO2]) in MS patients using a novel technology - the Oxymap® T1 Retinal Oximeter. Methods: We recruited 11 healthy controls, and 13 MS patients. All subjects underwent assessments with high- and low-contrast letter acuity (2.5%), and spectral-domain OCT. Further, using the Oxymap®, we measured the mean retinal vessel SatO2, and PaO2. Results: Using a generalized estimating equation (GEE) analysis, we found that MS patients had significantly higher mean retinal SatO2 (p = 0.039), and PaO2 (p = 0.034) when compared to normal subjects. Although the mean arteriolar SatO2 was higher in MS eyes, this difference was not significant. However, MS patients had significantly higher venular SatO2 (p = 0.02) compared to healthy controls. In a patient who presented with left acute optic neuritis (AON), we found that higher retinal SatO2 and PaO2 preceded changes in OCT-derived metrics by 3 months. Conclusions: To our knowledge, we report the first application of objective, in vivo, ascertainment of retinal oxygenation in the eyes of patients with MS, and confirm significant differentiation from measures derived from control subjects. In the single AON patient in our study, it is noteworthy that retinal oxygen utilization was altered before any structural changes were detected by OCT. We hypothesize that the pathobiological mechanisms affiliated with MS, culminate in retinal ganglion cell neuron damage and dysfunction, thereby resulting in a reduced retinal metabolic demand, and thus, decreased oxygen extraction. As such, the application of retinal oximetry may prove to be a highly sensitive biomarker of retinal metabolic activity in MS, which would begermane to the identification of novel neurotherapeutic and remyelination strategies in MS treatment trials. Disclosure Shin Beh, MD: nothing to disclose. Marlen Lucero: nothing to disclose. Amy Conger, COA: nothing to disclose. Darrel Conger, CRA: nothing to disclose. Victoria Stokes, RN: nothing to disclose.

Teresa Frohman, PA-C: speaker and consultant fees from Biogen Idec, Novartis and Acorda and consulting fees from Genzyme. Rob Rennaker, PhD: owner of Vulintus LLC. Peter A. Calabresi, MD: personal compensation from Vertex and Abbott; and has received research funding from Biogen-IDEC, Abbott, Vertex, Novartis, and Bayer. Laura J. Balcer, MD MSCE: honoraria from Biogen-Idec, Novartis, Acorda, Vaccinex and Bayer, is on a clinical trial advisory board for Biogen-Idec. Elliot M. Frohman, MD PhD: speaking and consulting fees from Biogen Idec, TEVA, Acorda, Novartis and consulting fees from Genzyme and Abbott. P699 Neuromyelitis optica spectrum disorders in Algeria S. Daoudi1, M. Bouzar2 1Neurology, Nedir Mohamed Hospital, 2Medicine, Mouloud Mammeri University., Tizi-Ouzou, Algeria Background: Neuromyelitis optica (NMO) is a disabling inflammatory condition that targets astrocytes in the optic nerves and spinal cord. Recent advances led to the individualization of a set of conditions now referred as NMO spectrum disorder (NMOSD). Objective: To describe the frequency and the characteristics of NMO SD in Algeria. Patients and methods: The present study is a retrospective and descriptive work which took place in Nedir Mohamed teaching hospital, Tizi-Ouzou Algeria. 232 patients with optic neuritis and/ or myelitis were reviewed. Patients who met the 2015 NMO criteria were selected and analyzed. Results: 08 patients (3,4%) met the NMOSD criteria, 3/8 (37,5%) was positive to AQ4-IgG and 5/8 (62,5%) have a negative AQ4IgG status. Mean age of onset was 29 years, female to male ratio was 3:1, cerebral MRI was normal in 71% of cases and longitudinally extensive transverse myelitis was found in 75% of cases. 37/232 patients (15,9%) were considered at high risk of NMO however lack of AQ4-IgG or a concomitant MRI to a relapse do not permit a clear diagnosis of this cases. Conclusion: The non availability of AQ4-IgG test in Algeria is the major obstacle for the diagnosis of NMOSD. 2015 criteria have brought interesting new radio-clinical elements in cases of AQ4-IgG unknown status and will allow an easier diagnosis in our region. Disclosure Nothing to disclose. P700 Dyschromatopsia in multiple sclerosis points to retinal ganglion cell damage E. Lampert, M. Andorra, R. Torres-Torres, S. Ortiz-Perez, S. Llufriu, M. Sepúlveda, N. Sola, A. Saiz, B. Sanchez-Dalmau, P. Villoslada, E.H. Martinez-Lapiscina Hospital Clinic and Institut d Investigació August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain Background: Multiple Sclerosis (MS) frequently results in dyschromatopsia, color vision impairment, regardless of a previous


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Poster Session I, 21(S11) history of acute optic neuritis (AON). However, the exact location of the injury leading to dyschromatopsia in eyes without previous AON (NON-eyes) of MS patients has not yet been clarified. Aim: To identify the anatomical region leading to acquired dyschromatopsia in MS patients’ eyes without previous AON. Methods: We studied the association between color vision and measures of thickness/volume of different regions in the afferent visual pathway in a cohort of 106 MS patients by using Spearman Rank Correlations. Each region with a significant association was included in multiple logistic models to assess its independent role in the development of dyschromatopsia in NON-eyes of MS patients. We also ran a model including global lesion load and Normalized Brain Parenchymal volume (NBPV) as markers of diffuse neuroaxonal damage, which is related to disease severity. Dyschromatopsia was defined as color vision impairment in either eye except for in patients with a prior history of AON, for whom only the fellow eye was considered. We evaluated color vision using Hardy-Rand-Rittler plates (HRR). Macular Raster scans from Optical Coherence Tomography and layer segmentation were used to evaluate retinal damage. We ran SIENAX(FSL) to quantify NBPV, FIRST(FSL) for the volumes of thalamus and Freesurfer for primary, secondary and associative visual cortex areas, including occipitaltemporal regions such as the fusiform and lingual gyrus. Results: We found moderate yet significant correlations with macular retinal nerve fiber layer (RNFL) (rho=0.289, p=0.003), macular ganglion cell complex (GCC) (rho=0.353, p< 0.001), thalamus volume (rho=0.334 p< 0.001) and lesion volume within the optic radiations (OR) (rho=-0.230 p=0.030). We did not find correlations in any other regions. In the logistic regression model including the above parameters, only GCC thickness remained statistically significant [p=0.019]. In the final model that also included global lesion load and NBPV, GCC thickness remained independently associated with a higher probability of dyschromatopsia [OR=0.88 95%IC (0.80-0.97) p=0.016]. Conclusions: Dyschromatopsia in non-AON eyes is due to Retinal Ganglion Cell (RGC) damage in MS. Color vision impairment, as measured by HRR plates, can serve as an accurate and sensitive marker of RGC damage in MS, independently of AON. Disclosure Erika Lampert: nothing to disclose. Magi Andorra: nothing to disclose. Ruben Torres-Torres: nothing to disclose. Santiago Ortiz-Perez: nothing to disclose. Maria Sepúlveda: nothing to disclose Sara Llufriu: nothing to disclose Nuria Sola: nothing to disclose Albert Saiz: nothing to disclose. Bernardo Sánchez-Dalmau: nothing to disclose. Pablo Villoslada has received consultancy fees from Heidelberg Engineering regarding the clinical applications of OCT. Elena H Martinez-Lapiscina: nothing to disclose. P701 20/40 or better visual acuity after optic neuritis: not as good as we once thought! R.C. Nolan1, K.M. Galetta2, S. Sabadia1, J.A. Wilson2, P.A. Calabresi3, E.M. Frohman4, S.L. Galetta1, L.J. Balcer1

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NYU School of Medicine, New York, NY, 2University of Pennsylvania, Philadelphia, PA, 3Johns Hopkins University School of Medicine, Baltimore, MD, 4University of Texas Southwestern Medical Center, Dallas, TX, United States Background: While it has been reported patients with acute optic neuritis (ON) recover high-contrast visual acuity (VA) to 20/40 or better in 95% of eyes affected, vision-specific quality of life (QOL) has been shown to be reduced even years following the event. Additionally, retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thinning can be seen very early in the course of optic neuritis. Goals: The aim of this study was to examine vision-specific QOL scores in a cohort of multiple sclerosis (MS) patients with ON among the sub-group of subjects with recovery of high-contrast VA to 20/40 or better in both eyes. Methods: Participants with MS and a history of ON completed the 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and the 10-Item Neuro-Ophthalmic Supplement, as well as VA and low-contrast letter acuity (LCLA) testing, in an ongoing collaborative study of visual outcomes. Peripapillary RNFL and macular ganglion cell+inner plexiform layer thickness (GCL+IPL) were measured using spectral-domain optical coherence tomography. Results: Analyses of data from 135 patients with MS and a history of ON confirmed vision-specific QOL scores were reduced compared to disease-free controls even among the specific subgroup with recovery of high-contrast VA to 20/40 or better in both eyes (n=119, p< 0.001 for NEI-VFQ-25 composite and 10-Item Supplement, linear regression, accounting for age). NEI-VFQ-25 scores were 83.6±15.1 (compared to 98.1±1.9 for controls), with Supplement scores 74.6±17.4 (vs. 96.4±5.2 for controls). Eyes in this sub-group, and even in the subgroup with high-contrast VA 20/20 or better, had significant thinning of the RNFL (79.8 vs. 92.2 microns for controls, p< 0.001) and GCL+IPL (69.6 vs. 80.0 microns, p< 0.001, accounting for age and within-patient, intereye correlations). Those with greater binocular LCLA reported better vision-specific QOL scores (2.5%: p=0.02; 1.25%: p=0.006, accounting for age). Conclusions: Clinically meaningful reductions in vision-specific QOL occur in MS patients with a history of acute ON, even with recovery of high-contrast VA of 20/40 or better. Further, significant degrees of retinal axonal and neuronal loss manifest in this subgroup. Therefore, optic neuritis remains an unmet need in clinical trials. Disclosure Rachel C. Nolan: nothing to disclose. Kristin M. Galetta: nothing to disclose. Sakinah Sabadia: nothing to disclose. James A. Wilson: nothing to disclose. Peter A. Calabresi: compensation for activities with Abbott, Vaccinex, and Vertex. Dr. Calabresi has received research support from Novartis and Biogen Idec. Elliot M. Frohman: compensation for activities with Teva Neuroscience, Acorda, and Novartis. Steven L. Galetta: consulting for Biogen and Genzyme. Laura J. Balcer: consulting for Biogen and Genzyme; clinical trial advisory board for Biogen.


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Biomarkers P702 CSF biomarker levels of inflammation and degeneration in relapsing MS following switch to fingolimod from other disease modifying therapies M. Axelsson1, L. Novakova1, M. Khademi2, H. Zetterberg1, K. Blennow1, C. Malmeström1, F. Piehl2, T. Olsson2, J. Lycke1 1Sahlgrenska University Hospital, Gothenburg, 2Karolinska Institutet, Stockholm, Sweden

Background: The effect from switching disease modifying therapy (DMT) in relapsing-remitting multiple sclerosis (RRMS) is usually monitored clinically and by MRI. However, the DMTs all have different mechanism of action and the specific influence from changed therapy on inflammatory and degenerative processes is largely unknown. Investigation of biomarkers of cerebrospinal fluid (CSF) have revealed changed levels of immune cells and proteins that reflect different parts of the immunopathogenesis of MS. Objective: To investigate the effect on CSF biomarkers levels of inflammation and degeneration following switch to fingolimod from other disease modifying treatments. Material and method: We included 43 RRMS patients. Three were treatment naïve, and 40 had previously been on DMT; 19 interferon beta, 5 glatiramer acetate (GA), 2 teriflunomide, and 14 natalizumab treatment. They were clinically examined and CSF was collected prior and 6-12 months after fingolimod treatment. CSF from 39 healthy subjects served as controls. We analyzed B-cell activity (CXCL13), monocyte/memory T-cell/dendritic cell recruitment (monocyte chemotactic protein 1, MCP1), microglial activation (chitinase 3-like 1 or YKL-40), astrogliosis (glial fibrillary acidic protein, GFAP) and axonal damage (neurofilament light protein, NFL) in CSF by ELISA. Results: CSF levels of NFL, CXCL13, MCP1 and YKL-40 decreased significantly (p< 0.05) after 6-12 months of fingolimod treatment. Subgroup analysis revealed significant reduction of NFL (p< 0.001), CXCL13 (p=0.001) and YKL-40 (p< 0.001) in patients previously treated with first line therapies (interferon beta, GA and teriflunomide). However, the levels of these biomarkers were still significantly higher after fingolimod treatment compared to controls (p< 0.05). In contrast, the levels of all analyzed biomarkers were essentially unchanged pre- and post fingolimod treatment in patients who switched from natalizumab treatment. Conclusions: We found improved anti-inflammatory (CXCL13, YKL-40) and reduced degenerative (NFL) activity in patients switching from first line DMTs to fingolimod. In patients who switched from natalizumab to fingolimod the CSF levels of these biomarkers remained at low levels. Except for astrogliosis (GFAP), fingolimod treatment seemed to reduce all of the investigated pathological processes. Disclosure Markus Axelsson have had compensation for lectures and/or advisory boards from Biogen, Genzyme and Novartis. Lenka Novakova, Mohsen Khademi, Henrik Zetterberg, Kaj Blennow, Clas Malmeström have no discloures. Tomas Olsson has received unrestricted MS research grants from Biogen, Genzyme, Novartis and Astra zeneca. Compensation for

lectures and/or advisory boards from biogen, Genzyme and Novartis. Research support from Swedish research council, the Swedish Brain foundation, the AFA foundation and Knut and Alice Wallenberg foundation. Fredrik Piehl has received unrestricted academic research grants from BiogenIdec and Novartis, and compensation for lectures and/or participation in advisory boards from Biogen, Merck Serono, Novartis, Sanofi and Teva, which have been exclusively used for the support of research activities. Jan Lycke has received travel support and/or lecture honoraria from Biogen, Novartis, Teva and Genzyme/SanofiAventis; has served on scientific advisory boards for Almirall, Teva, Biogen, Novartis and Genzyme/SanofiAventis; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, Novartis and Teva. P703 Can optic nerve MTR and OCT distinguish between multiple sclerosis and neuromyelitis optica? L. Magnollay, F. De Angelis, V. Wottschel, A. Toosy, C. Tur, M. Yiannakas, R. Cortese, D.H. Miller, O. Ciccarelli Neuroinflammation, NMR Unit, UCL Institute of Neurology, London, United Kingdom Introduction: Optic neuritis (ON) occurs in both multiple sclerosis (MS) and neuromyelitis optica (NMO), but is usually more severe in NMO. This study compared optic nerve magnetic transfer ratio (MTR) and retinal nerve fibre layer (RNFL) thickness, obtained with optic coherence tomography (OCT), of the affected and fellow eye between NMO and relapsing-remitting (RR) MS patients. In the patient groups, the relationships between MTR and OCT biomarkers and visual acuity (VA) were explored. Methods: 14 NMO and 3 NMOSD (spectrum disorder) patients (13F, mean age 49yrs±12, median EDSS 4 (range 2-6), 7 with unilateral and 5 bilateral ON), 12 RRMS patients (8F, mean age 40yrs±10, median EDSS 3.5 (range 1-7.5), 5 with unilateral and 1 bilateral ON) and 21 healthy controls (HC) (10F, mean age 33yrs±10) were scanned at 3T and RNFL was measured on a Spectralis OCT. The MTR of the optic nerves were calculated and analysed using automated ROIs. VA was assessed in patients with letter charts and 100-hue test. Multiple linear regressions adjusted for age, gender and disease duration were used to compare MTR and OCT biomarkers between the different groups. Results: NMO patients showed lower MTR in the affected optic nerves than HC (regression coefficient (RC) -5.23, 95%CI -7.6, -2.87, p< 0.001) and borderline evidence for lower MTR in the affected optic nerves than RRMS (RC -4.23, 95%CI -9.17, 0.7, p=0.09). Similarly NMO patients showed lower MTR in the fellow eye than HC (RC -2.18, 95%CI 4.56, -0.52, p=0.02) and RRMS (-2.67, 95%CI -4.78, -0.58, p=0.013). RRMS did not have a lower MTR in the affected and fellow eyes than HC. RNFL thickness in the affected eye was lower in RRMS than HC (RC -22.2, 95%CI -39.1, -5.31, p=0.012) and in NMO than HC (RC -29.4, 95%CI -50.9, -7.9, p=0.009), but did not differ between NMO and RRMS. The RNFL thickness in the fellow eye did not differ between groups. In patients, the VA of the affected eye was associated with the corresponding optic nerve MTR (NMO: RC -0.12, p< 0.001, MS: RC -0.04, p< 0.001). This association was stronger in NMO patients (p< 0.001). VA in the unaffected eye was associated with optic nerve MTR but only in MS (RC -0.04, p< 0.001).


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Poster Session I, 21(S11) Conclusion: Optic nerve MTR seems to distinguish between MS and NMO more effectively than OCT, though the use of OCT in NMO was limited by the low visual acuity of some patients. Optic nerve MTR is associated with visual acuity and could become a useful outcome measure for clinical trials in NMO. Disclosure L. Magnollay, V. Wottschel, F. De Angelis, M. Yiannakas and Rosa Cortese have nothing to disclose. O. Ciccarelli receives research grant support from the Multiple Sclerosis Society of Great Britain and Northern Ireland, the Department of Health Comprehensive Biomedical Centre, the International Spinal Cord Research Trust (ISRT) and the Engineering and Physical Sciences Research Council (EPSRC); she serves as a consultant for Novartis, Biogen and GE and payments are made to UCL Institute of Neurology. A. Toosy has received speaker honoraria from Biomedia, Sereno Symposia International Foundation and Bayer. C. Tur received a McDonald Fellowship (from the Multiple Sclerosis International Federation) in 2007, and has received an ECTRIMS post-doctoral research fellowship in 2015. She has also received honoraria and support for travelling from BayerSchering, Teva, Merck-Serono and Serono Foundation, Biogen, Sanofi-Aventis, Novartis, and Ismar Healthcare. D.H. Miller has received honoraria, through payments to UCL Institute of Neurology, for Advisory Committee and/or Consultancy advice in multiple sclerosis studies from Biogen Idec, GlaxoSmithKline, Novartis, Merck, Chugai, Mitsubishi Pharma Europe and Bayer Schering Pharma and has received compensation through payments to UCL Institute of Neurology for performing central MRI analysis of multiple sclerosis trials from GlaxoSmithKline, Biogen Idec, Novartis and Merck.

P704 Combination of YKL-40 and GFAP in CSF predicts disability progression in relapsing-remitting forms of multiple sclerosis M.A. Mañé-Martínez1,2, B. Olsson3, L. Bau2, M. Elisabet2, Á. Cobo-Calvo2, K. Blennow3, L. Romero-Pinel2, H. Zetterberg3,4, S. Martínez-Yélamos2 1Department of Neurology, Hospital Universitari de Tarragona Joan XXIII. Universitat Rovira i Virgili, Tarragona, 2Multiple Sclerosis Unit, Department of Neurology, Hospital Universitari de Bellvitge; Universitat de Barcelona, L’Hospitalet del Llobregat, Spain, 3Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden, 4Institute of Neurology. University College London, London, United Kingdom Objective: To evaluate whether the combination of CSF levels of chitinase 3-like 1 protein (YKL-40) and Glial fibrillary acidic protein (GFAP) from diagnostic lumbar puncture in relapsing-remitting forms of multiple sclerosis (MS) patients correlates with disability progression. Methods: CSF samples from 280 relapsing-remitting forms of MS patients were included. CSF levels of YKL-40 and GFAP were analysed by enzyme-linked immunosorbent assays. Multiple Sclerosis Severity Score (MSSS), progression index (PI) and MS

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severity rank were evaluated based on the Expanded Disability Status Scale (EDSS) and disease duration at last follow-up. Results: The mean MSSS, the mean PI and the median MS Base rank at the end of the follow-up were higher in patients with high levels of YKL-40 and GFAP compared to patients with low levels of YKL-40 and low levels of GFAP. MSSS: high YKL-40 and GFAP levels: 2.9±2.4; low YKL-40 and GFAP levels: 1.6±1.6 (p < 0.0001). Progression index: high YKL-40 and GFAP levels: 0.25±0.24; low YKL-40 and GFAP levels: 0.16±0.16 (p = 0.004). MS Base rank: high YKL-40 and GFAP levels: 39 (19-70); low YKL-40 and GFAP levels: 24 (17-47) (p = 0.001). Conclusion: The combination of high CSF levels of YKL-40 and GFAP in the early stages of the disease could be useful to predict a worse disability progression in relapsing-remitting forms of MS patients. Disclosure M Alba Mañé Martínez: Received research support from the Fundació Hospital Universitari de Tarragona Joan XXIII and Fundació Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), and received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma. Received honoraria compensation to participate in Advisory Boards and scientific communications from Teva Pharmaceutical Industries LTD and Bayer Schering Pharma. Bob Olsson: Nothing to disclose Laura Bau: Received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma. Elisabet Matas: received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma. Álvaro Cobo Calvo: Received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma. Ulf Andreasson: Nothing to disclose Kaj Blennow: Has served on Advisory Boards for Innogenetics, Belgium. Lucia Romero-Pinel: Received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma. Henrik Zetterberg: Nothing to disclose Sergio Martínez-Yélamos: Received honoraria compensation to participate in Advisory Boards, collaborations as a consultant and scientific communications from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma, and received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma. P705 Autoantibodies to myelin-oligodendrocyte glycoprotein antibodies in a small proportion of adult multiple sclerosis patients


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M. Spadaro1, L.A. Gerdes1, B. Ertl-Wagner2, M. Krumbholz1, F. Hoffmann1, E. Schuh1, R. Hohlfeld1,3, E. Meinl1, T. Kümpfel1 1Institute of Clinical Neuroimmunology, 2Department of Radiology, LMU München, 3Munich Cluster for Systems Neurology (SyNergy), München, Germany Background: Antibodies to myelin-oligodendrocyte glycoprotein (MOG ab) mediate demyelination in animals and presumably also humans. Antibodies to MOG are detected in a proportion of patients with pediatric multiple sclerosis (MS), in anti-aquaporin-4 (AQP-4) seronegative neuromyelitis optica (NMO) spectrum disease (NMOSD), and in recurrent optic neuritis (ON). Objective: To determine the presence of antibodies to MOG in adult patients with MS. Methods: We used a sensitive cell-based assay to detect antibodies to MOG and analyzed: 1) 104 adult relapsing remitting MS (RRMS) patienst selected for having recurrent severe episodes of optic neuritis (ON), myelitis and/or brainstem encephalitis. 2) 55 age- and sex-matched RRMS patients unselected for a specific phenotype. Results: MOG ab were found in 5/104 of the selected MS patients (4,8%) but in none of the unselected MS patients. All MOG ab positive patients had a long-lasting diagnosis of RRMS according to the revised McDonald criteria, showed typical findings on cerebral MRI fulfilling the Barkhof criteria, had positive oligoclonal bands in the cerebrospinal fluid and were negative for APQ-4 ab in the serum. Phenotypes of the MOG ab positive patients were as follows: three had recurrent severe ON, five had recurrent myelitis (four with LETM) and four had severe brainstem/midbrain involvement. All had highly active RRMS and failed to several immunotherapies. Three patients had been treated with plasma exchange for severe relapses in the past and had shown a favourable response. Longitudinal analysis for up to six years in three patienst revealed fluctuations of anti-MOG reactivity, which appeared only transiently. Conclusion: Few adult MS patients with a phenotype similar to NMOSD have antibodies to MOG and may benefit from plasma exchange therapy. Disclosure M. Spadaro has nothing to disclose L.A. Gerdes has nothing to disclose B. Ertl-Wagner has nothing to disclose M. Krumbholz has nothing to disclose F. Hoffmann has nothing to disclose E. Schuh has nothing to disclose Prof. R. Hohlfeld has nothing to diclose E. Meinl has nothing to disclose T. Kümpfel has nothing to disclose P706 Multiple sclerosis clinical characteristics in molecularly-defined patient populations A. Enayetallah, R. Hosur, R.M. Ransohoff, J. Goyal Biogen, Inc., Cambridge, MA, United States Background: Relapsing-remitting multiple sclerosis (RRMS) is a heterogeneous disease, in regard to clinical presentation, disease

course, disability progression and treatment response. Post-hoc analyses of clinical trial data may afford insights into the pathophysiology associated with this heterogeneity, facilitating better individual prognosis formulation and treatment decision-making. Goals: To establish molecularly-defined RRMS patient populations and determine their association with 2-year clinical and radiological measures of disease activity and severity, including relapses, disability progression, gadolinium-enhancing lesions and T2 lesion burden. Methods: Whole blood genome-wide expression from 570 RRMS patients from the placebo arms of the simultaneous phase 3 studies DEFINE and CONFIRM were analysed. Analytical methods such as causal reasoning were used to generate individual-specific putatively-mechanistic disease profiles. Unsupervised clustering of patients by their mechanistic profiles was performed. The patient clusters were tested for associations with baseline clinical or MRI characteristics and on-study relapses or disability progression. Finally, the molecular profiling and clustering was replicated in a treated RRMS patient cohort at baseline and the impact of treatment was compared in the molecularly-defined patient groups. Results: Baseline mechanistic profiles from RRMS patients provided distinct molecularly defined patient groups. At baseline, distinct mechanisms included immune and inflammatory signals, oxidative stress, and differential B-cell and T-cell biology. At least 120 predicted molecular activities (e.g. NFE2L2, IFNG, IL2) could distinguish among these patient groups. These prospectively defined patient groups exhibited a distinct range of baseline and subsequent clinical and radiological variables with up to 20-fold differences between the extremes. Notably, “Time to relapse”, “Time to disability progression” and “Brain volume change”; were found to significantly associate with specific patient groups. Conclusion: Utilizing data from two large prospective RRMS trials, we identified molecularly-distinct patient groups that correlated with mild and severe extremes of disease status and outcome. Mechanistic understanding of groups that were well differentiated within the extremes of the clinical and radiological covariates will be further evaluated to provide markers that distinguish such populations. Supported by: Biogen Disclosure All Biogen employees P707 Molecular markers predicting JCV-antibody switch in natalizumab treated multiple sclerosis patients A. Achiron, G. Miron, R. Falb, D. Magalashvili, M. Dolev, Y. Stern, M. Gurevich Multiple Sclerosis Center, Sheba Medical Center, Ramat-Gan, Israel Background: The presence of anti-John Cunningham Virus (JCV) antibodies in Natalizumab treated multiple sclerosis (MS) patients is a risk factor for the development of progressive multifocal leukoencephalopathy (PML). Estimating the individual risk of JCV antibody negative MS patients to become antibody positive during Natalizumab treatment is a major challenge.


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Poster Session I, 21(S11) Objective: Identify molecular markers that detect MS patients predisposed to JCV antibody switch under Natalizumab treatment. Methods: Peripheral blood mononuclear cells were obtained from JCV-negative relapsing-remitting MS patients before initiation of Natalizumab treatment and after 1 year of treatment and subjected to gene expression microarrays analysis. Patients were followed up to 3 years and those that serologically converted from JCV antibody negative to positive were defined as JCV-switchers. The transcriptional changes induced by Natalizumab at one year of treatment versus baseline were compared between JCVswitchers and non-switchers. In accordance, pre-treatment baseline samples were analyzed to verify whether the identified transcriptional profile determine differences between JCVswitchers and non-switchers. Results: Following three years of Natalizumab treatment, 23% of JCV antibody negative MS patients switched to become JCV antibody positive. Prior to initiation of Natalizumab treatment JCVswitching patients were characterized by transcriptional signature enriched by mechanisms of viral entry into host cells that were also enhanced by Natalizumab treatment, as demonstrated by enrichment in Macropinocytosis, Endocytic, Clathrin-mediated and Caveolar-mediated Endocytosis. Specifically, JCV-switchers characterized by up-regulation of viral entry related genes like TFRC, HIP1R, EPS15, VLA-4, AP1G2, RAB5B, HERC, FLOT, and FLNB. Conclusion: Our findings enabled the identification of 77% of Natalizumab treated MS patients that will remain JCV antibody negative allowing safe continuation of the treatment. Disclosure Anat Achiron: Nothing to disclose Gadi Miron: Nothing to disclose Rina Falb: Nothing to disclose David Magalashvili: Nothing to disclose Mark Dolev: Nothing to disclose Yael Stern: Nothing to disclose Michael Gurevich: Nothing to disclose Source of funding: The study was supported by a research grant from Medison Pharma SRL, Israel. P708 Clinically suspected neuromyelitis optica associated to anti-MOG antibodies L.M.O. de Paula Salles1, D.K. Sato1,2, S.L. Apóatolos-Pereira1, R.F. Simm1, F.M.H. Jorge1, K. Fujihara2, D. Callegaro1 1Neurology, University of São Paulo, Sao Paulo, Brazil, 2Department of Multiple Sclerosis Therapeutic, Tohoku University Graduate School of Medicine, Sendai, Japan Background: Bilateral, severe or recurrent optic neuritis, and longitudinally extensive transverse myelitis (LETM) are some features of patients with neuromyelitis optica spectrum disorders (NMOSD). The positivity to to anti-aquaporin-4 antibodies confirms the diagnosis of NMOSD. However, some patients who were suspected of having NMOSD are seronegative to anti-aquaporin-4, and a portion of these cases are positive to antibodies to myelin-oligodendrocyte glycoprotein (MOG), but the predominance of clinical phenotypes and the proportion of patients with relapses have not been systematically evaluated.

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Objective: To evaluate clinical characteristics of anti-MOG+ clinically suspected NMOSD with a high-risk of relapses. Methods: We included anti-MOG+ patients suspected of having NMOSD followed at Hospital das Clinicas, Faculty of Medicine, University of Sao Paulo between 2011 and 2015. All patients were preAnti-MOG tested using a cell-based assay with live full-length MOG transfected HEK293 cells. Results: Among 23 patients, 43.5% (10/23) were males with a female/ male ratio of 1.3. The median onset age was 32 (range 3 - 50) years. Fifteen out of 23 patients (65.2%) were Mullatoe, 4 were Caucasians, 3 were Africans, and 1 was Indian. Five of 23 (21.7%) had LETM, 60.9% (14/23) had bilateral or recurrent optic neuritis (ON) and 17.3 % (4/23) had features compatible with definitive NMO (both ON and LETM). Two out of 5 (40%) patients with LETM had a single attack, but 60% (3/5) had relapses. The median disability measured by EDSS was 6 (range 5 - 8) on recurrent cases and 2 (range 1 - 3) in patients with a single attack. Central spinal cord lesion was found in all patients with LETM. Among patients with isolated ON 57.1% (8/14) had more than one attack, 21.4% (3/14) had bilateral ON. Only one patient had no light perception (NPL) at the last follow-up. In patients diagnosed with definitive NMO, NPL was present in 1 of 4 (25%), and 4 of these patients had relapses. Only one of 23 patients had MRI compatible with multiple sclerosis. Conclusions: Optic neuritis is the most common clinical phenotype associated with anti-MOG antibodies, and more than half these patients had recurrent attacks. Patients diagnosed with definitive NMO represented a small fraction of anti-MOG+ patients, but they have similarities to the other patients with attacks restricted to ON or LETM. MRI features resembling multiple sclerosis are rarely seen in anti-MOG+ cases. Disclosure Dr de Oliveira: Nothing to disclose Dr Sato has received scholarship from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, research support from CAPES/Brasil and speaker honoraria from Novartis. Dr Apostolos-Pereira: Nothing to disclose Dr Callegaro: Nothing to disclose Dr Simm: Nothing to disclose Dr Jorge: Nothing to disclose Dr. Fujihara serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, Medimmune and Medical Review; has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical; serve as an editorial board member of Clinical and Experimental Neuroimmunology (2009-present) and a advisory board member of Sri Lanka journal of Neurology; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical,Ono Pharmaceutical, Nihon Pharmaceutical, and Genzyme Japan; is funded as the secondary investigator (#22229008, 2010-2015) by the Grants-in-Aid for


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Scientific Research from the Ministry of Education, Science and Technology of Japan and as the secondary investigator by the Grants-in-Aid for Scientific Research from theMinistry of Health, Welfre and Labor of Japan (2010-present).

at onset and longer disease duration were significantly associated with JCV seropositivity. The annual risk of seroconversion against JCV is higher than what had been published in the literature. Disclosure

P709 Seroprevalence and risk of seroconversion against JC virus among multiple sclerosis patients in Eastern Mediterranean region: a multi-national study R. Alroughani1,2, S. Akhtar3, S. Ahmed4,5, S. Khoury6, M. Sahraian7, M. Al-Jumah8,9, M. Zeineddin6, J. Al-Hashel3,4, B. Yamout6 1Amiri Hospital, 2Dasman Diabetes Institute, 3Kuwait University, 4Ibn Sina Hospital, Kuwait, Kuwait, 5Minia University, Minia, Egypt, 6American University of Beirut Medical Center, Beirut, Lebanon, 7Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran, 8KAIMRC, King Saud Ben Abdulaziz University for Health Sciences, NGHA, 9Prince Mohammed Ben Abdulaziz Hospital, Riyadh, Saudi Arabia Background: JC virus (JCV) serological testing has been increasingly used to stratify multiple sclerosis (MS) patients to different disease modifying therapies. However, there is a paucity of published data on JCV seroprevalence and risk of conversion against JCV in the Middle East. Objectives: To estimate JCV seroprevalence and annual risk of seroconversion against JCV among MS patients in the Eastern Mediterranean region (EMR). Methods: This was a multi-center study conducted among MS patients in four regional counties by implementing; i) a cross-sectional design to assess JCV seroprevalence and evaluate factors associated with JCV sero-status and ii) a longitudinal design to assess the risk of sero-conversion against JCV. Data on demographics, clinical variables and JCV serology were collected. JCV seroprevalence was computed based on the results of first serological test. Annual risk of seroconversion against JCV was computed among patients who were JCV seronegative on first test but seroconverted against JCV in subsequent tests. The relationship of demographic and clinical variables with JCV seropositivity was evaluated using univariable and multivariable logistic regression analyses Results: Of 581 MS patients in the study sample, 64.9% patients were females. The mean age and the mean disease duration were 33.9 ± 9.9 and 8.4 ± 6.5 years respectively. JCV seroprevalence was 51.3%. Multivariable logistic regression analysis showed that male gender (adjusted odds ratio (OR)) = 2.15; p = 0.002), age at onset (adjusted OR = 1.05; p =0.001) and disease duration of 2 or more years (adjusted OR = 12.03; p = 0.007) were significantly associated with JCV seropositivity. Among patients (n=125) who were tested at least twice during one year of follow-up, the annual risk of JCV seroconversion was 17.6% (95% CI: 11.4% - 25.4%). There was statistically significant difference in the mean MS duration between JCV seroconverted and seronegative patients (9.9 ± 6.9 versus 7.1 ± 4.7 years; p = 0.021). 63.6% of the seroconverters had titers < 1 while 5.8% of seronegative patients had transient seropositivity with titers < 0.6 Conclusions: JCV seroprevalence among MS patients in EMR is comparable to other international figures. Male gender, higher age

Dr. Alroughani received speaker`s honoraria from Bayer, Biogen, Biologic, Novartis, GSK, Merck-Serono, Genzyme, Genpahrm and he received honoraria for serving in scientific advisory boards for Bayer, Biogen, Biologix, Novartis, Merck-Serono, Genzyme and Genpahrm. Dr. Akhtar has nothing to disclose. Dr. Ahmed has nothing to disclose. Dr. Khoury reports grant support from Novartis Pharmaceuticals. Dr. Sahraian received educational, research grants, lecture honorarium, consultation fee from Biogen-Idec, Merck-Serono, BayerSchering- Novartis, Cinnagen and Genzyme. Dr. Al-Jumah received research and speaker´s honoraria from Bayer, Merck-Serono, Biogen, Genpharm, Genzyme and Novartis. Dr. Zeineddine has nothing to disclose. Dr. Al-Hashel has nothing to disclose. Dr. Yamout received speaker´s honoraria from Bayer, Genzyme, Merck-Serono, Novartis, Genpharm, Biogen; he received research grants from Bayer, Merck-Serono, Novartis, Biogen, Pfizer; and he received advisory board honoraria from Bayer, Novartis, Merck-Serono, Biogen, Genzyme, Genpharm.

P710 Analysis of lymphocytic DNA damage in early multiple sclerosis by automated gamma-H2AX and 53BP1 foci detection L. Rasche1,2,3, L. Heiserich4, J.R. Behrens1,2, K. Lenz5, C. Pfuhl1,2,3, K. Wakonig1,2, R.M. Gieß1,2,3, E. Freitag1,2, C. Eberle4, P. Bauer4, J. Bellmann-Strobl1,2,6, F. Paul1,2,3, D. Roggenbuck4,7, K. Ruprecht2,3 1NeuroCure Clinical Research Center, CharitéUniversitätsmedizin Berlin, 2Clinical and Experimental Multiple Sclerosis Research Center, Charité-Universitätsmedizin Berlin, 3Neurology, Charité-Universitätsmedizin, Berlin, 4Medipan GmbH, Berlin-Dahlewitz, 5Medical Biometrics and Clinical Epidemiology, Charité-Universitätsmedizin Berlin, 6Experimental and Clinical Research Center, CharitéUniversitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, 7Faculty of Science, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany Background: In response to DNA double strand breaks, the histone protein H2AX becomes phosphorylated at its C-terminal serine 139 residue, then called gamma-H2AX. Formation of gamma-H2AX foci is associated with recruitment of p53-binding protein 1 (53BP1), a regulator of the cellular response to DNA double strand breaks. gamma-H2AX foci in peripheral blood mononuclear cells (PBMCs) were recently proposed as a diagnostic and disease severity marker for multiple sclerosis (MS). Objective: To evaluate the significance of gamma-H2AX and 53BP1 foci in PBMCs as diagnostic and disease severity markers in patients with clinically isolated syndromes (CIS) and early


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Poster Session I, 21(S11) relapsing-remitting MS (RRMS) using automated gamma-H2AX and 53BP1 focus detection. Methods: Immunocytochemistry was performed on freshly isolated PBMCs of patients with CIS/RRMS (n=25) and healthy controls (n=27) with gamma-H2AX and 53BP1 specific antibodies. Nuclear gamma-H2AX and 53BP1 foci were determined using a fully automated reading system, which assesses the numbers of gamma-H2AX and 53BP1 foci per total number of cells and the percentage of cells with foci among the total number of cells. All patients underwent contrast enhanced cranial 3 Tesla magnetic resonance imaging (MRI) and clinical examination including expanded disability status scale (EDSS) score. Levels of gammaH2AX and 53BP1 foci were compared between groups by MannWhitney test. EDSS and MRI parameters were correlated with gamma-H2AX and 53BP1 foci by Spearman correlations. Results: The median (range) number of gamma-H2AX (0.04 [0-0.5]) and 53BP1 (0.005 [0-0.2]) foci per cell across all study subjects was low and within the range of previously reported values of healthy individuals. For both gamma-H2AX and 53BP1, the cellular focus number as well as the percentage of positive cells did not differ between patients with CIS/RRMS and healthy controls. Levels of gamma-H2AX and 53BP1 foci per cell and the percentage of positive cells neither correlated with the number or volume of T2-weighted and contrast enhancing lesions nor with the EDSS score. gamma-H2AX and 53BP1 were not influenced by immunotherapy, tobacco smoking, or age. Conclusion: Our findings suggest that gamma-H2AX and 53BP1 foci do not seem to be promising diagnostic or disease severity biomarkers in patients with early MS. Furthermore, lymphocytic DNA double strand breaks are unlikely to play a major role in the pathophysiology of MS. Disclosure LR has received a travel grant from Bayer Healthcare unrelated to this study. LH is an employee of Medipan GmbH. JRB received travel grants by Biogen and speaking fees from Novartis. KL has nothing to disclose. CP has nothing to disclose. KW has nothing to disclose. RMG has received a travel grant from Novartis. EF has nothing to disclose. CE is an employee of Medipan GmbH. PB is an employee of Medipan GmbH. JBS has received speaking fees and travel grants from Bayer Healthcare, sanofi-aventis/Genzyme, and Teva Pharmaceuticals unrelated to this study. FP has received travel grants, research support and personal compensation for activities with Alexion, Bayer, MerckSerono, Teva, Sanofi Genzyme, MedImmune, Chugai, BiogenIdec and Novartis. FP is supported by the Deutsche Forschungsgemeinschaft (DFG EXC257), the Bundesministerium für Bildung und Forschung (BMBF Competence Network Multiple Sclerosis) and the Guthy Jackson Charitable Foundation. DR is a shareholder of and has a managerial position at Medipan GmbH. KR received research support from Novartis as well as speaking fees and travel grants from Guthy Jackson Charitable Foundation,

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Bayer Healthcare, Biogen Idec, Merck Serono, sanofi-aventis/ Genzyme, Teva, and Novartis; and is supported by the German Ministry of Education and Research (BMBF/KKNMS, Competence Network Multiple Sclerosis). P711 Cerebrospinal fluid kynurenines in multiple sclerosis: relation to disease course and neurocognitive symptoms S. Ståhl1, S. Aeinehband1, P. Brenner1, M. Bhat2, M.D. Fidock2, M. Khademi1, T. Olsson1, G. Engberg3, J. Jokinen1,4, S. Erhardt3, F. Piehl1 1Department of Clinical Neuroscience, Karolinska Institutet Karolinska University Hospital, Solna, 2Research & Development, Innovative Medicines, Personalized Healthcare & Biomarkers, AstraZeneca, Stockholm, 3Department of Physiology and Pharmacology, Karolinska Institutet, Solna, 4Department of Clinical Sciences, Umeå University, Umeå, Sweden MS is a chronic inflammatory and neurodegenerative CNS disease, with a high rate of neurocognitive symptoms for which the molecular background is still uncertain. There is accumulating evidence for dysregulation of the kynurenine pathway (KP) in across several psychiatric and neurodegenerative conditions. We here report the first comprehensive analysis of cerebrospinal fluid (CSF) kynurenine metabolites in MS patients of different disease stages and with a variable degree of neuropsychiatric symptoms, as compared to controls (MS n=85; controls n = 33). CSF levels of tryptophan (TRP), kynurenine (KYN), quinolinic acid (QUIN) and kynurenic acid (KYNA) were determined. At the group level MS patients did not differ in absolute levels of any metabolite compared to controls. Stratification of patients into different disease courses revealed that both absolute QUIN levels and the QUIN/KYN ratio were increased in relapsing-remitting MS (RRMS) patients in relapse. Interestingly, the KP was down-regulated in secondary progressive MS (SPMS), while primary progressive (PPMS) patients displayed increased levels of all metabolites. In a second cohort recently diagnosed MS patient were evaluated for neuropsychiatric symptoms and correlation with KP was investigated, where low TRP levels were found in depressed patients. In addition, clustering of these patients according to their KP profile resulted in five subgroups, resembling the distribution found in the first cohort. These results demonstrate that clinical disease activity and differences in disease courses in MS are reflected by changes in KP metabolites. Disclosure Sara Ståhl: post doc funded by Astra Zeneca, Shahin Aeinehband: nothing to disclose, Philip Brenner: nothing to disclose, Maria Bhat: Employed by Astra Zeneca, Mark D Fidock: Employed by Astra Zeneca, Mohsen Khademi: nothing to disclose, Tomas Olsson: has received unrestricted MS research grants from Biogen, Genzyme, Novartis and Astra zeneca. Compensation for lectures and/or advisory boards from biogen, Genzyme and novartis.Research support from Swedish research council, the Swedish Brain foundation, the AFA foundation and Knut and Alice Wallenberg foundation..


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Göran Engberg: nothing to disclose, Jussi Jokinen: nothing to disclose, Sophie Erhardt: was supported by Swedish Research Council Grants 2009-7052, 2011-4795 and an independent research grant from Astra Zeneca. Fredrik Piehl: has received unrestricted academic research grants from BiogenIdec and Novartis, and compensation for lectures and/or participation in advisory boards from Biogen, Merck Serono, Novartis, Sanofi and Teva, which have been exclusively used for the support of research activities.

P712 Cerebrospinal fluid lactic dehydrogenation enzyme levels in acute attacks of inflammatory demyelinating diseases S. Nishiyama1, T. Misu2, Y. Takai1, R. Takano1, T. Takahashi3, I. Nakashima1, K. Fujihara1, M. Aoki1 1Department of Neurology, Tohoku University Graduate School of Medicine, 2Department of Neurology, Hachinohe National Hospital, Sendai, 3Department of Neurology, Yonezawa National Hospital, Yonezawa, Japan Background: Neuromyelitis optica spectrum disorders (NMOsd) is characterized by severe optic neuritis and transverse myelitis. The extensive loss of aquaporin-4 (AQP4) and glial fibrillary acidic protein (GFAP) were revealed in pathological studies in NMOsd, especially in the perivascular regions with complement and immunoglobulin depositions. An in vitro study demonstrated that sera from NMO patients caused an elevated level of lactic dehydrogenation enzyme (LDH) elevation in the culture media, but the clinical significance of tissue damage measured by LDH in NMOsd and the other inflammatory demyelinating disease are unknown. Objective: To examine the usefulness of cerebrospinal fluid (CSF) -LDH level as a tissue damage marker in acute phase of inflammatory demyelinating diseases (e.g.: NMOsd, multiple sclerosis (MS), tumefactive demyelinating disease (TDD), and Neuro-Behcet’s disease). Methods: We conducted a cross-sectional studyof 91 patients who were diagnosed as inflammatory demyelinating diseases and 9 healthy control cases. Their CSF-LDH, CSF-GFAP and CSF-myelin basic protein (MBP) in acute attacks were measured by sandwich ELISA kits. The data was analyzed by Graphpad Prism 5. Results: CSF-LDH was elevated in 46.8% of AQP4-IgGseropositive NMOsd, 24.2% of MS, 16.7% of TDD, and 60% of Neuro-Behcet’s disease. CSF-LDH correlated with CSF-GFAP but not with CSF-MBP in AQP4-IgG-seropositive NMOsd. CSFLDH was higher in myelitis patients, and correlated with length of spinal cord lesion. Besides, CSF-LDH correlated with CSF-MBP in MS. Conclusion: CSF-LDH levels are often elevated in the acute phase of NMOsd and other inflammatory demyelinating diseases, and may reflect the total tissue damage. Further studies are expected to clarify the clinical and pathological relevance distinct from other cellular damage markers. Disclosure Nothing to disclose

P713 From genetic variations to plasma cytokine receptor levels during MS treatment S.K. Bedri, K. Fink, W. Lundström, T. Olsson, A. Glaser, J. Hillert Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden Genome wide association studies (GWAS) have identified genetic variants within some of the cytokine receptor genes to be associated with MS susceptibility, including the soluble interleukin-7 receptor alpha (sIL-7Rα) and soluble interleukin-2 alpha receptor (sIL-2Rα) coding genes. As these genes are expressed by cells targeted by immune-modulatory drugs in use for MS, we explored their potential role as biomarkers in monitoring MS disease activity and MS treatment. Here we specifically assessed how natalizumab and fingolimod influenced their protein expression patterns. In addition we included the soluble interleukin-6 receptor (sIL-6R) and the soluble glycoprotein 130 (sgp130). We measured the protein expression of the selected soluble receptors using enzyme-linked immunosorbent assay (ELISA) in 4-8 serial plasma samples from 49 MS patients who had been switched from natalizumab to fingolimod. The patients were sampled before initiation of natalizumab treatment, while on natalizumab and after switching to fingolimod and followed with regard to clinical response. All patients were clinically stable on natalizumab and decisions to switch to fingolimod were made to avoid risk of progressive multifocal leukoencephalopathy (PML). We assumed that the analysis of serial samples would benefit our study by minimizing inter-individual differences. Preliminary data showed a decline in protein levels for the sIL-2Rα and sIL-6R during treatment with fingolimod compared to the previous period before and during natalizumab treatment. The levels of sgp130 increased during treatment with fingolimod compared to natalizumab. The levels of sIL-7Rα showed no statistically significant changes during the entire treatment period. We saw no difference in protein expression between patients who remained clinically stable on fingolimod (N=25) and those that had signs of insufficient treatment response on fingolimod (N=12). Building on the MS associated risk variants and utilizing the extensive clinical resources we have access to, we hope to elucidate the pharmacodynamics of treatments with the aim to identify biomarkers for treatment effects. Moreover the layout of this study could be a blueprint for identifying biomarkers for the response to treatments. Disclosure Sahl Khalid Bedri: nothing to disclose. Katharina Fink received an unrestricted research grant from Biogen. Wangko Lundström: nothing to disclose. Tomas Olsson has received unrestricted research grants or honoraria for lectures or advisory boards from Biogen, Novartis, Merck Serono, Teva and Genzyme a Sanofi Company. Dr Glaser is receiving research support from Biogen. Dr Hillert received honoraria for serving on advisory boards for Biogen and Novartis and speaker’s fees from Biogen, MerckSerono, Bayer-Schering, Teva and Sanofi-Genzyme. He has served as P.I. for projects sponsored by, or received unrestricted research support from, Biogen, Sanofi-Genzyme, Merck-Serono, TEVA,


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Poster Session I, 21(S11) Novartis and Bayer-Schering. His MS research is funded by the Swedish Research Council and the Swedish Brain Foundation. P714 Platelet-derived genes are altered in MS patients M. Axelsson, M. Jernås, I. Nookaew, C. Malmeström, H. Wadenvik, J. Lycke, B. Olsson University of Gothenburg, Gothenburg, Sweden Background: Platelets are small anucleated cells that play a critical role in the initiation of coagulation. There is a growing body of evidence to suggest that platelets contain vast amounts of proteins and genetic material involved in inflammation and immunity. Objective: Our aim was to explore platelet gene expression profiles in Multiple Sclerosis. Methods: EDTA-blood was obtained from 10 MS patients (7 female, 3 male, mean age 32.1±4.1 years) and 10 healthy controls (7 female, 3 male, mean age 48.7±4.2 years). Platelet was isolated without leukocyte contamination, RNA was prepared using the Chomczynski method, followed by RNeasy clean-up (Qiagen, Hilden, Germany). Twenty ng RNA was amplified with Ovation RNA Amplification SystemV2 (NuGEN, San Carlos, CA), and cDNA was synthesized using Encore Biotin Module kit (NuGEN). After standard labelling each sample was hybridized to Affymetrix U133Plus 2.0 Human Genome array (Santa Clara, CA). Results: In the DNA microarray analysis we identified 1992 decreased and 808 increased differentially expressed genes between MS patients and healthy controls. The top three genes; NR4A2, PPP2R2B and USP28 were all down-regulated. ● Three orphan nuclear receptors (NR4A) are immediate early genes that play an important role in maintaining cellular homeostasis. There is increasing evidence for the role of these receptors in metabolic, cardiovascular, neurological, inflammatory and cancer diseases. ● Protein phosphatase 2A is one of four major classes of serine/threonine phosphatases. It has been determined that induction of phosphatase 2 regulatory subunit B (PPP2R2B) is deficient in systemic lupus erythematosus. ● Oxidative stress contributes to pathology associated with inflammatory brain disorders and under oxidative stress there is a reactive oxygen species-dependent down-regulation of the ubiquitin-specific protease 28 (USP28). Conclusion: Our findings imply that platelet-derived genes are altered in MS patients compared with healthy controls. The role of NR4A2, PPP2R2B and USP28 in MS platelets needs to be further evaluated. We are currently performing functional studies and verify differentially expressed genes and corresponding proteins with RT-PCR and ELISA. Disclosure Markus Axelsson has received travel support and/or lecture honoraria from Biogen, Novartis. has served on scientific advisory boards for Biogen and Novartis. He has had compensation for lectures from Biogen, Genzyme and novartis. Jan Lycke has received travel support and/or lecture honoraria from Biogen, Novartis, Teva and Genzyme/SanofiAventis; has served on scientific advisory boards for Almirall, Teva, Biogen, Novartis and Genzyme/SanofiAventis; serves on the editorial

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board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, Novartis and Teva. Margareta Jernås, Intawat Nookaew, Hans Wadenvik and Bob Olsson has nothing to disclose. P715 Relationships between CSF biomarkers of inflammation and degeneration in RRMS are also found in healthy controls L. Novakova1, M. Axelsson1, M. Khademi2, H. Zetterberg1, K. Blennow1, C. Malmeström1, F. Piehl2, T. Olsson2, J. Lycke1 1Sahlgrenska University Hospital, Gothenburg, 2Karolinska Institutet, Stockholm, Sweden Background: In relapsing-remitting multiple sclerosis (RRMS) evidence is accumulating that early signs of CNS degeneration is dependent on inflammatory activity. The levels of several cerebrospinal fluid (CSF) biomarkers seem to reflect disease activity or are reduced during intervention with disease modifying therapies (DMT). Better understanding of their relationships could lead to the appropriate implementation of biomarkers in clinical practice and their use in treatment monitoring. Objective: To explore possible relationships between CSF biomarkers of inflammation and degeneration in RRMS. Material and methods: We included 72 RRMS patients, 4 were treatment naïve, and 68 were on disease modifying therapy (DMT); 36 interferon beta, 9 glatiramer acetate (GA), 2 teriflunomide, 2 intravenous immunoglobulin, and 19 natalizumab. Thirtynine healthy persons served as controls (HC). We analyzed B-cell activity (CXCL13), monocyte/memory T-cell/dendritic cell recruitment (monocyte chemotactic protein 1, MCP1), glial activation (chitinase 3-like 1 or YKL-40), astrogliosis (glial fibrillary acidic protein, GFAP) and axonal damage (neurofilament light protein, NFL) in CSF by ELISA. Results: RRMS had higher levels of YKL-40, CXCL13 and NFL compared to HC (p< 0.001). Subgroup analysis showed higher CXCL13 and NFL in patients treated with first line therapies (n=47, interferon beta, GA, teriflunomide) compared to natalizumab (n=19, p=0.001 and p=0.002, respectively). With few exceptions, the interrelation analysis of the biomarkers in RRMS showed significant correlations between inflammatory and degenerative biomarkers. The strongest relationships were found between YKL-40 and GFAP and NFL (r=0.426, p< 0.001 and r=0.689, p< 0.001, respectively). Interestingly, similar and even stronger correlations were found for these biomarkers in HC (r=0.721, p< 0.001 and r=0.742, p< 0.001, respectively). Conclusions: RRMS had higher CSF levels of both inflammatory and degenerative biomarkers compared to HC (CXCL13, YKL-40, NFL) and the levels (CXCL13, NFL) reflected the efficacy of ongoing DMTs. Interestingly, the strongest relationships were found between the glial activator (YKL-40) and structures of axons (NFL) and astrocytes (GFAP) in both RRMS and in HC. YKL-40 has previously been suggested to be involved in MS inflammation. However, our results indicate that YKL-40 may also have other roles e.g. metabolic in CNS during normal conditions. Disclosure Markus Axelsson have had compensation for lectures and/or advisory boards from Biogen, Genzyme and Novartis.


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Lenka Novakova, Mohsen Khademi, Henrik Zetterberg, Kaj Blennow, Clas Malmeström have no discloures. Tomas Olsson has received unrestricted MS research grants from Biogen, Genzyme, Novartis and Astra zeneca. Compensation for lectures and/or advisory boards from biogen, Genzyme and Novartis. Research support from Swedish research council, the Swedish Brain foundation, the AFA foundation and Knut and Alice Wallenberg foundation. Fredrik Piehl has received unrestricted academic research grants from BiogenIdec and Novartis, and compensation for lectures and/or participation in advisory boards from Biogen, Merck Serono, Novartis, Sanofi and Teva, which have been exclusively used for the support of research activities. Jan Lycke has received travel support and/or lecture honoraria from Biogen, Novartis, Teva and Genzyme/SanofiAventis; has served on scientific advisory boards for Almirall, Teva, Biogen, Novartis and Genzyme/SanofiAventis; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, Novartis and Teva. P716 The urine proteome profile is different in neuromyelitis optica compared to multiple sclerosis H.H. Nielsen1,2, H.C. Beck1,2, L.P. Kristensen3, N. Heegaard2,3,4, Z. Illes1,2 1Dept of Neurology, Odense University Hospital, Odense C, 2Institute of Clinical Research, University of Southern Denmark, 3Center for Clinical Proteomics, Odense University Hospital, Odense, 4Dept of Autoimmunology & Biomarkers, Statens Serum Institute, Copenhagen, Denmark Background: Inflammatory demyelinating diseases of the central nervous system (CNS) comprise a broad spectrum of diseases like neuromyelitis optica (NMO), NMO spectrum disorders (NMO-SD) and multiple sclerosis (MS). Despite clear classification criteria differentiation can be difficult. However, early differentiation is of vital importance since misclassification can lead to deterioration of the condition due to incorrect medication. Objectives: We hypothesized that analysis of ”omics” in urine may have the capacity to yield quantitative biomarkers. In addition, MS and NMO/NMO-SD patients may exhibit specific differences in the molecular composition (proteins, posttranslational modifications) of the urine, which reflect the pathogenesis, and may enable early differentiation. Specifically, the hypothesis is tested by a thorough and unbiased analysis of the whole proteome. Methods: Urine samples from anti-aquaporin 4 (AQP4) seropositive NMO/NMO-SD patients (n=32), patients with MS (n=46) and healthy subjects (HS, n=31) were examined by liquid chromatography- tandem mass spectrometry (LC-MS/MS). Results: The analysis identified a total of 1112 proteins of which 333 were shared by all 109 subjects. Cluster analysis revealed differences in the proteome of NMO compared to both HS and MS, but no clear clusters when MS was compared to HS. Principal component analysis and false discovery rate adjustments suggested that the NMO proteome is useful for classification and indicated a panel of 31 proteins significant for NMO/HS discrimination, 4 for NMO/MS discrimination and 1 for MS/HS discrimination. Significant up-regulation of immunoglobulin components (IgG, 3 heavy chain and light chains) in the urine differentiated

NMO from both HS and MS. Multivariat logistic regression analysis revealed a 3-protein profile for NMO/HS discrimination, a 6-protein profile for NMO/MS discrimination and an 11-protein profile for MS/HS discrimination. Conclusion: The proteome profile of the urine in patients with NMO is different from urine of healthy subjects and MS patients. This may reflect differences in the pathogenesis of NMO and MS and suggest that urine may be a useful starting point for identifying biomarkers for MS and NMO. Disclosure Helle H Nielsen: nothing to disclose. Hans C. Beck: nothing to disclose. Lars P. Kristensen: nothing to disclose. Niels Heegaard: nothing to disclose. Zsolt Illes: nothing to disclose.

P717 Cerebrospinal fluid and serum levels of interleukin-6, interleukin-8, interleukin-10, beta2-microglobulin and orosomucoid at the time of first clinical symptoms in MS patients Z. Matejčíková1, J. Mares1, V. Sladkova2, T. Svrcinova2, J. Klosova2, S. Skalska2, J. Dolakova2, P. Kanovsky2 1Neurology, 2University Hospital and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic, Olomouc, Czech Republic Backround: Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system Although MS is according to McDonald’s revised diagnostic criteria primarily a clinical diagnosis, paraclinical investigation methods are an important part in the diagnosis of MS. In common practice, magnetic resonance imaging of the brain and spinal cord, examination of cerebrospinal fluid and examination of visual evoked potentials are used. There are an increasing number of studies dealing with biomarkers in CSF and their role in etiology of MS. We studied five inflammatory markers (interleukin-6, interleukin-8, interleukin-10, beta-2-microglobulin, orosomucoid). Methods: The study was based on CSF and serum examination in patients with MS and control group (patients with non-inflammatory disease). In the MS patients, the lumbar puncture was performed at the time of the first clinical symptoms compatible with MS. None of our patients had been treated by corticosteroids before lumbar puncture. There were no signs of inflammation at time of lumbar puncture in both groups. The aim of the study was to assess CSF and serum levels of inflammatory markers (IL-6, IL-8, IL-10, beta2-microglobulin, orosomucoid) and compare these levels between MS group and control group. Results: We investigated group of 204 patients. CSF and serum examination was performed in 102 patients with newly diagnosed MS (70 females, 32 males; median 40 years) and 102 control group patients (79 females, 23 males; median 37,5 years). Significantly higher CSF levels of IL-8 (median 59,1; min- max (5,0-188); p< 0.0001, Mann-Whitney U test) and beta-2-microglobulin (median 1,27; min-max (0,69-5,49); p< 0.0001, Mann-Whitney U test) in MS patients group were found.


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Poster Session I, 21(S11) Significantly lower serum levels of IL-8 (median 8,00; min-max (0-43,8), p=0,018, Mann-Whitney U test) were found. Conclusion: The levels of two studied inflammatory markers were found to be increased at the time of first clinical symptoms of MS. IL-8 seems to be an important chemokine in the inflammatory phase of MS. This thesis was also confirmed in other studies. The second marker with elevated levels was beta-2-microglobulin, for which, however, other studies in MS patients have yielded inconsistent results. As the etiology of MS is still unknown, research on inflammatory and neurodegenerative markers in MS should continue. Disclosure Zuzana Matejcikova: nothing to disclose P718 Galectin 8 autoantibodies are associated with relapsing remitting phenotype of multiple sclerosis and with higher disability scores E. Ciampi1,2, R. Uribe1,2, C. Carcamo3, E. Pardo4, C. Curkovic4, P. Cortes4, A. Soza4, A. Gonzalez4 1Neurology, Pontificia Universidad Católica de Chile, 2Neurology, Hospital Dr. Sótero del Río, 3Pontificia Universidad Católica de Chile, 4Departamento de Inmunología Clínica y Reumatología, Facultad Medicina, Centro de Envejecimiento y Regeneración (CARE), Facultad Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile Background: Establishing diagnostic and prognostic biomarkers in Multiple Sclerosis (MS) is necessary for predicting clinical course, treatment response and disability. Galectins are modulators of the immune response and have been associated with specific anti-inflammatory mechanisms in some autoimmune disease. Galectin 8 autoantibodies (anti-Gal8-ab) may block these regulatory features and thus perpetuate inflammation and neurodegeneration. Goals: To study the presence of anti-Gal8-ab in MS patients and their correlation with clinical variables. Methods: Fifty eight patients (36 relapsing-remitting, 22 progressive, 72% female, mean age 39 year, mean disease duration 6.3 years, median EDSS 1 (mean 2.4, range 0-8) were recruited from the Universidad Católica MS Programme between 2011 and 2014. Clinical assessments were performed by a trained neurologist including EDSS and relapses every 3 to 6 months, as well as yearly Magnetic Resonances. Patients were naïve to treatment or had stopped medication at least 6 months prior blood samples were taken. Presence of anti-Gal8-ab was analysed by western blot, and function-blocking activity of anti-Gal8-ab was assessed by cell adhesion assays. Clinical, radiological and laboratory associations were also assessed. Results: Anti-Gal8-ab were detected in the sera of 47% of RRMS versus 9% of progressive MS patients (p=0.004). We confirmed blocking properties of anti-Gal8-ab using lymphocyte adhesion assays. RRMS with positive anti-Gal8-ab (n=17) had higher Expanded Disability Status Scale (EDSS) scores after 12 months of follow-up (mean EDSS anti-Gal8-ab positive 1.5 vs. antiGal8-ab negative 0, p=0.02), and were more prone to develop confirmed EDSS worsening at the end of follow-up (anti-Gal8-ab

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positive 5/17 vs. anti-Gal8-ab negative 0/19, p=0.01). We found no other differences between baseline clinical or radiological variables. Conclusions: Blocking anti-Gal8-ab are present mainly in patients with relapsing-remitting MS, and are associated with worse disability scores early in the disease, suggesting a potential value as a serum biomarker for predicting poor prognosis, instauration of early aggressive treatment, and prevention of disability. Disclosure Financed by Fondecyt 1131122, Financing Program Basal (PFB12/2007) EC received educational grants from the ECTRIMS Clinical Training Fellowship Programme 2013-2014. She has served as an advisory board member for Genzyme and Biogen, as well as professional travel and accommodation stipends from Novartis and Merck. RU has served as an advisory board member for Genzyme, as well as professional travel and accommodation stipends from Biogen, Novartis, Merck, Teva. CC has served as an advisory board member for Genzyme, Merck Serono LATAM, and Novartis Chile. She has received reimbursement for developing educational presentations for, Merck Serono LATAM, Bayer and Novartis Chile, as well as professional travel and accommodation stipends. EP, CC, PC, AS and AG report no conflict of interest. P719 Serum neurofilament light chain levels are associated with brain atrophy in early MS - analysis from the randomized controlled phase II trial of riluzole in early MS S. Gnanapavan1, D. Grant2, S. Morant3, B. Nourbakhsh4, N. Revirajan4, C. Azevedo5, D. Pelletier5, E. Waubant4, G. Giovannoni1, J. Kuhle6 1Queen Mary University of London, 2Institute of Neurology. University College London, London, 3Independent Statistician, Haddenham, United Kingdom, 4Department of Neurology, University of California San Francisco, San Francisco, 5University of Southern California, Los Angeles, CA, United States, 6University Hospital Basel, Basel, Switzerland Background: Neurofilaments are major cytoskeletal elements of axons and are released in to the cerebrospinal fluid and blood during injury. Neurofilament heavy chain (NfH) which is heavily phosphorylated is predominantly found in large myelinated neurones, whilst light chains (NfL) are distributed in dendrites. Our work alludes to the hypothesis that in early MS the damage involves dendrites resulting in NfL release and is a predictor of early brain atrophy. Methods: Riluzole trial in early MS was a two-year randomized (1:1), double-blind, placebo-controlled trial in clinically isolated syndrome or relapsing-remitting MS with disease onset less than 12 months prior to enrollment. A standard dose of riluzole (50mg twice daily) as add-on therapy to weekly i.m. interferon beta-1a was tested in 43 treatment naive patients (5 drop outs). The primary outcome was change in brain volume (data was available over two years in 29 patients). Serum samples were collected in addition to MRI, OCT and clinical data. NfL and NfH analyses


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were performed using previously reported immunoassays. Comparisons between NfL/NfH in the treatment and placebo cohorts was performed using mixed models after log transformation of the neurofilaments levels as was changes in neurofilaments with other paraclinical measures. Results: There was no detectable treatment effect of the riluzole on the change in neurofilament levels. Higher serum values of NfL but not NfH was associated with greater brain volume loss by SIENA (p< 0.001). Brain volume fell by 0.55% (95% CI -0.68% - -0.43%) per year in people with average NfL levels, and by a further 0.60% (-0.91% - -0.29%) per year if their serum NfL was ten times greater than average. Summary: This is the first study showing an association between baseline serum NfL levels and subsequent brain volume loss. Serum NfL may be a more sensitive marker of brain atrophy in the initial stages of MS than NfH. This has wider implications for the type of axonal injury occurring during the inflammatory demyelination and potentially the usefulness of this serum biomarker as a measure of ongoing disease activity in early MS. Disclosure Conflicts: The authors report no conflict of interest. Source of funding: Emaneulle Waubant, Bardia Nourbakhsh, Nisha Revirajan, Danielle Pelletier, Christina Azevedo, Sharmilee Gnanapavan NMSS Research Grant Gavin Giovannoni: NMSS Research Grant, research grant support from Bayer-Schering Healthcare, Biogen-Idec, GW Pharma, Merck-Serono, Merz, Novartis, Teva and Sanofi-Aventis. Jens Kuhle: supported by an ECTRIMS Research Fellowship Programme and by the Forschungsfonds of the University of Basel, Switzerland; has received research support from the Swiss MS Society, Swiss ALS Society, Protagen AG, Roche, and Novartis. Donna Grant, Steve Morant: nothing to disclose P720 Soluble TREM-2 in cerebrospinal fluid from patients with multiple sclerosis treated with natalizumab or mitoxantrone A. Öhrfelt, M. Axelsson, C. Malmeström, L. Novakova, A. Heslegrave, K. Blennow, J. Lycke, H. Zetterberg University of Gothenburg, Gothenburg, Sweden Background: Microglia-mediated proteolysis of the triggering receptor expressed on myeloid cells (TREM-2) produces soluble TREM-2 (sTREM-2) that can be measured in cerebrospinal fluid (CSF) samples. Loss-of-function mutations in TREM2 or in the gene encoding its adaptor protein cause the rare Nasu-Hakola disease (NHD). Multiple sclerosis (MS) is an autoimmune disease that in common with NHD is characterized by demyelination and microglial activation. Objective: To investigate the potential utility of sTREM-2 as a biomarker for MS and to follow treatment effects. Methods: Soluble TREM-2 was analyzed in CSF samples from subjects with MS (N=59); relapsing-remitting MS (RRMS) (N=36), secondary progressive MS (SPMS) (N=20) and primary progressive MS (PPMS) (N=3), and controls (N=27). CSF levels of sTREM-2 were also assessed before and after treatment of patients with natalizumab or mitoxantrone.

Results: CSF levels of sTREM-2 were significantly increased in patients with RRMS, SPMS and PPMS compared with controls. After natalizumab treatment, the levels of sTREM-2 were normalized to control levels. The levels of sTREM-2 were also reduced after mitoxantrone treatment. Conclusion: Increased CSF levels of sTREM-2, a new marker of microglial activation, in MS and normalization upon treatment with either natalizumab or mitoxantrone support a role for microglial activation in active MS. Disclosure Jan Lycke has received travel support and/or lecture honoraria from Biogen, Novartis, Teva and Genzyme/SanofiAventis; has served on scientific advisory boards for Almirall, Teva, Biogen, Novartis and Genzyme/SanofiAventis; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, Novartis and Teva. Markus Axelsson has received travel support and/or lecture honoraria from Biogen and Novartis. Has recieved lecture honoraria from Biogen and Novartis. P721 Glial and neuronal markers in cerebrospinal fluid in different multiple sclerosis types M.A. Mañé-Martínez1,2, B. Olsson3, L. Bau4, E. Matas4, Á. Cobo-Calvo4, U. Andreasson3, K. Blennow3, L. Romero-Pinel4, H. Zetterberg3,5, S. Martínez-Yélamos4 1Hospital Universitari de Tarragona Joan XXIII. Universitat Rovira i Virgili, 2Hospital Universitari de Bellvitge; Universitat de Barcelona, Tarragona, Spain, 3Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden, 4Multiple Sclerosis Unit, Department of Neurology, Hospital Universitari de Bellvitge; Universitat de Barcelona, L’Hospitalet del Llobregat, Spain, 5Institute of Neurology. University College London, London, United Kingdom Objective: To investigate glial and neuronal biomarkers in CSF samples from patients with different multiple sclerosis (MS) types. Methods: CSF levels of neurofilament light protein (NFL), total-tau (t-tau), tau phosphorylated at threonine 181 (p-tau), glial fibrillary acidic protein (GFAP), S-100B protein (S-100B), chitinase 3-like 1 protein (YKL-40), monocyte chemoattractant protein (MCP-1), α-cleaved soluble amyloid-precursor protein (α-sAPP), β-cleaved soluble amyloid-precursor protein (β-sAPP), and 38, 40 and 42 amino acid long fragments of amyloid β (Aβ38, Aβ40, Aβ42) were analysed in 109 clinically isolated syndrome (CIS) patients, 192 relapsing-remitting MS (RRMS), 6 secondary progressive MS (SPMS) and 17 primary progressive MS (PPMS) patients. Results: The CSF levels of NFL were significantly higher in RRMS patients compared to PPMS [RRMS: 1330ng/L (6152312) vs PPMS: 550ng/L (475-710); p = 0.008]. CSF levels of GFAP were lower in CIS than PPMS [CIS: 270 ng/L (190-400) vs PPMS: 420 ng/L (320-605); p = 0.05]. CSF levels of YKL-40 were higher in the PPMS group but no significant differences were found after Bonferroni correction. No significant differences were found for any of the biomarkers between the RRMS and CIS


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Poster Session I, 21(S11) groups. YKL-40, MCP-1, S1000B, t-tau, p-tau and amyloidal cleavage proteins Aβ38, Aβ40, Aβ42 showed no significant differences among the various MS types. Conclusion: The CSF biomarker profile was similar within different types of MS with the exception of the NFL. Disclosure M Alba Mañé Martínez: received research support from the Fundació Hospital Universitari de Tarragona Joan XXIII and Fundació Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), and received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma. Received honoraria compensation to participate in Advisory Boards from Bayer Schering Pharma and scientific communications from Teva Pharmaceutical Industries LTD. Bob Olsson: nothing to disclose. Laura Bau: received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma. Elisabet Matas: received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma. Álvaro Cobo Calvo: received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma. Ulf Andreasson: nothing to disclose. Kaj Blennow: has served on Advisory Boards for Innogenetics, Belgium. Lucia Romero-Pinel: received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma. Henrik Zetterberg: nothing to disclose. Sergio Martínez-Yélamos: received honoraria compensation to participate in Advisory Boards, collaborations as a consultant and scientific communications from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma, and received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma. P722 Cerebrospinal fluid/serum CXCL13 ratio: an early prognostic marker of conversion to clinically definite multiple sclerosis I. Dujmovic1,2, V. Gredler3, K. Schanda3, S. Mesaros1,2, J. Dackovic2, J. Vitas4, T. Pekmezovic5, F. Deisenhammer3, T. Berger3, J. Drulovic1,2, M. Reindl3 1Department of Neurology, University of Belgrade School of Medicine, 2Clinic of Neurology, Clinical Centre of Serbia, Belgrade, Serbia, 3Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria, 4University of Belgrade School of Medicine, 5Institute of Epidemiology, University of Belgrade School of Medicine, Belgrade, Serbia

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Background: Cerebrospinal fluid (CSF) level of CXCL13, a potent B-cell chemoattractant, has been recently suggested to be a potential marker of conversion to multiple sclerosis (MS) in patients with clinically isolated syndrome suggestive of MS (CIS). Aim: We analyzed the prognostic significance of CSF and serum CXCL13 levels in CIS patients for conversion to clinically definite (CD) MS. Patients and methods: CXCL13 levels were measured by Enzyme-linked Immunosorbent Assay in paired CSF and serum samples obtained from 55 CIS patients at a median of 21 days from symptom onset (baseline (BL)). CSF/serum CXCL13 ratio and CSF/serum CXCL13 index were calculated to assess intrathecal CXCL13 synthesis. Routine CSF analyses were done by standard methods. The Expanded Disability Status Scale (EDSS) was used to assess disability. All patients were followed clinically for a median of 4.2 years (range, 2.2-6.2 years). Results: CIS patients who converted to CDMS during follow-up had significantly higher BL CSF CXCL13 levels (p< 0.0001), CSF/serum CXCL13 ratio (p< 0.0001) and CSF/serum CXCL13 index (p=0.0007) compared witn non-converters. BL serum CXCL13 levels were similar in converters and non-converters and did not correlate significantly with CSF CXCL13 levels. BL CSF CXCL13 levels, CSF/serum CXCL13 ratio and CSF/serum CXCL13 index correlated significantly with markers of intrathecal immunoglobulin G (IgG) synthesis (oligoclonal IgG bands and IgG index) but did not correlate significantly with BL EDSS score. In the multivariate Cox model, a higher BL CSF/serum CXCL13 ratio (HR,1.001; 95% CI, 1.000-1.001; p< 0.0001) was an independent predictor of CIS conversion to CDMS over a median of 4.2 years of disease duration. Conclusion: In CIS patients, CXCL13 contributes to the intrathecal B-cell mediated autoimmune activation. CSF/serum CXCL13 ratio at the disease onset is a potential predictor of clinical CIS conversion to MS and deserves further studies in larger patient cohorts. Disclosure I. Dujmovic has received lecture fees and/or travel grants from Merck Serono, Bayer, Medis, Teva Pharmaceuticalsand Boehringer Ingelheim and has been supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant No 175031). V. Gredler: nothing to disclose. K. Schanda: nothing to disclose. S. Mesaros has received travel grants and honoraria for speaking from Merck Serono, Novartis, Bayer Schering, Medis and Genzyme-Sanofi and has received a research grant support from the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant No 175031). J. Dackovic has received a travel grant from Teva Pharmaceuticals. J. Vitas: nothing to disclose. T. Pekmezovic has been supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant No 175087). F. Deisenhammer has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Bayer Healthcare, Biogen Idec, Genzyme-Sanofi, Merck, Novartis Pharma, and Teva-Ratiopharm. His institution has received financial support for participation in randomized controlled trials of


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INFb-1b (Betaferon, Bayer Schering Pharma), INFb-1a (Avonex, Biogen Idec; Rebif, Merck Serono), glatiramer acetate (Copaxone, Teva Pharmaceuticals), Natalizumab (Tysabri, Biogen Idec), in multiple sclerosis. He is section editor of the MSARD Journal (Multiple Sclerosis and Related Disorders). T. Berger has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for multiple sclerosis: Almirall, Bayer, Biogen, Genzyme, Merck, Novartis, Octapharma, Ratiopharm, Sanofi Aventis, TEVA. His institution has received financial support in the last 12 months by unrestricted research grants (Biogen, Bayer, Merck, Novartis, Ratiopharm, Sanofi Aventis) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Octapharma, Sanofi Aventis, TEVA. J. Drulovic serves on scientific advisory boards for Bayer Schering Pharma and Merck Serono, and has received speaking honoraria and travel expenses for scientific meetings, from Bayer Schering Pharma, Merck Serono, Medis, Teva Pharmaceuticals, and Novartis. She has been supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant No 175031). M. Reindl: nothing to disclose. P723 Predicting optimal response to B-cell depletion with rituximab in multiple sclerosis using biomarkers E. Alvarez1,2, L. Piccio2, R.J. Mikesell2, K. Trinkaus2, S. Lancia2, B.J. Parks2, R.T. Naismith2, A.H. Cross2 1University of Colorado Denver, Aurora, CO, 2Washington University in St Louis, Saint Louis, MO, United States Background: B cell depleting drugs are being investigated for treating multiple sclerosis (MS). Objective: We sought predictors of optimal response to rituximab, a B cell depleting antibody, to help guide therapy selection. Methods: This is a post-hoc study of 30 relapsing MS patients who had breakthrough disease while on beta-interferon or glatiramer acetate and were treated with add-on rituximab. Standardized neurologic examinations, brain MRI, and cerebrospinal fluid were obtained before and after rituximab. Tissue biomarkers were measured using ELISA. Optimal responders had no evidence of disease activity (NEDA). Results: At baseline, optimal responders performed better on the 9-hole peg test (p=0.007), 25 foot timed walk (p=0.001), and Expanded Disability Status Scale (p=0.002). Optimal responders had more contrast enhancing lesions (p=0.002), higher IgG indices (p=0.041), and higher CXCL13 indices ([CSF CXCL13/ serum CXCL13]/albumin index; p=0.024). Rituximab treatment resulted in reduced CSF biomarkers of tissue destruction myelin basic protein (p=0.046), neurofilament light (p< 0.001), and inflammation (CXCL13 index [p=0.042]). Conclusions: MS patients with optimal response to rituximab had less disability and more evidence of CNS inflammation at baseline. Rituximab treatment decreased markers of tissue damage and inflammation in most patients. This study helps identify relapsing MS patients who will respond optimally to B cell depletion.

Disclosure Dr. Alvarez has received consulting honoraria from Teva Neurosciences, Biogen IDEC, and Genzyme. Mr. Mikesell has nothing to disclose. Dr. Parks has received speaking honoraria and consulting fees from Biogen-Idec, EMD Serono, Novartis and Teva Neuroscience. Dr. Naismith has received speaking honoraria for speaking and consulting for Acorda, Bayer, Biogen-Idec, EMD Serono, and Teva Neurosciences, and research support through Acorda. Dr. Cross has received consulting honoraria from Teva Neurosciences, Biogen-Idec, Roche, Novartis, and Sanofi Aventis/Genzyme. AHC serves on advisory boards for the National MS Society and the NIH. AHC was supported in part by the Manny and Rosalyn Rosenthal-Dr. John L. Trotter Chair in Neuroimmunology. P724 Specificity of serum and cerebrospinal fluid chitinase-3 like protein 1 (CHI3L1) for multiple sclerosis diagnosis R. Boitet1, S. Finge2, C. Demattei3, G. Hinsinger4,5, P. Corbeau2,5, P. Marin5,6, E. Thouvenot1,5,6 1Neurology Department, 2Laboratory of Immunology, 3BESPIM, CHRU Caremeau, Nîmes, 4Functional Proteomics Platform, Institut de Génomique Fonctionnelle, UMR 5203, 5Université Montpellier, 6Neuroproteomics and Physiopathology of Neurological and Psychiatric Diseases, Institut de Génomique Fonctionnelle, UMR 5203, Montpellier, France Background: Chitinase-3 like protein 1 (CHI3L1) has been identified by several studies as a sensitive cerebrospinal fluid (CSF) and serum biomarker of multiple sclerosis (MS), and elevated CSF CHI3L1 levels are predictive of conversion to MS after a CIS. Objectives: To evaluate the diagnostic value of CSF and serum CHI3L1 in routine in MS and in different neurological inflammatory and non-inflammatory diseases, compared with classical immunological CSF parameters (oligoclonal bands -OCBs- and IgG index). Methods: We performed a retrospective monocentric study in Nîmes Hospital, France, including consecutive patients with lumbar puncture and immunological CSF analysis from March to December 2014. Patients were classified as clinically isolated syndrome (CIS), MS, inflammatory neurological disease controls (INDC), peripheral inflammatory neurological disease controls (PINDC), non inflammatory neurological disease controls (NINDC) and symptomatic controls (SC). CSF and serum CHI3L1 concentrations were determined by ELISA and CSF OCBs by immunoelectrophoresis. Results: 202 patients (17 MS, 35 CIS, 17 INDC, 12 PINDC, 62 NINDC et 59 SC) were analyzed. Mean age of each group varied from 34 to 47 years old and sex ratio (F/M) from 0.71 to 4.67. CSF protein levels and CSF white blood cells count were comparable in all groups except for INDC, some of whom had meningitis. CSF CHI3L1 levels were significantly increased in all groups compared to SC (p< 0.05), except for PINDC. CSF CHI3L1 levels were lower in CIS patients than in MS patients and INDC, though not significantly (p=0.19 and p=0.06 respectively). In serum, CHI3L1 levels were significantly elevated in NINDC compared to SC and CIS patients (p< 0.05 and p< 0.01 respectively).


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Poster Session I, 21(S11) Presence of CSF OCBs was significantly more frequent in CIS and MS patients compared to other groups (p< 0.05). Discussion: This study shows a poor specificity of CSF and serum CHI3L1 levels in routine to decipher MS and CIS patients from other neurological inflammatory and non-inflammatory diseases, while OCBs are more specific of MS and CIS. However, CSF CHI3L1 levels show a great sensitivity to discriminate SC from all other pathological conditions, while OCBs are only present in 12% of INDC and 25% of PINDC and NINDC. Conclusion: together, CHI3L1 and OCBs provide complementary information and should be combined for the diagnosis of neurological inflammatory diseases in routine.

Conclusion: Our study provides novel insights into the impact of adipsin on MS and indicate that dysregulation of alternate complement pathway plays a role in the pathophysiology of RRMS.

Disclosure

MRI and cognition

E Thouvenot has received honoraria, travel grants or research grants from the following pharmaceutical companies: Biogen, Genzyme, Merck Serono, Novartis, Teva pharma. R Boitet, S Finge, C Demattei, G Hinsinger, P Corbeau and P Marin have nothing to disclose. This study was funded by the CHRU Caremeau, Nîmes, France. P725 Adipokines in multiple sclerosis and clinically isolated syndrome: a follow-up study S. Hagman1, R. Natarajan1, M. Hämäläinen2, T. Leppänen2, P. Dastidar3, E. Moilanen2, I. Elovaara1,4 1Neuroimmunology Unit, School of Medicine, 2Immunopharmacology Research Group, School of Medicine, University of Tampere, 3Department of Radiology, Medical Imaging Centre, 4Department of Neurology, Tampere University Hospital, Tampere, Finland Background: Accumulating evidence indicates that adipose tissue-derived molecules, adipokines, are involved in regulation of immune system and therefore may be important factor in the pathogenesis of immune-mediated diseases including multiple sclerosis (MS). Dysregulation of adipokines during obesity as well as some autoimmune diseases has been reported, but only very little is known of their impact on MS. Aims: To assess whether the levels of adipokines in the plasma of patients with MS and clinically isolated syndrome (CIS) are associated with inflammatory disease activity and disease progression in different phenotypes of MS. Methods: The study included 80 patients with different subtypes of MS (n=65) and CIS (n=15) that were followed-up annually over two years. The levels of adiponectin, adipsin, leptin and resistin in the plasma were determined using ELISA methodology. The data obtained were correlated with disease activity, neurological disability expressed by Expanded Disability Status Score (EDSS) and volumes of T1-weighted and Fluid-attenuated inversion recovery (FLAIR) lesions on magnetic resonance imaging. Results: In patients with relapsing- remitting MS (RRMS), the levels of adipsin appeared to be lower than in primary progressive MS [(60.3(52.3-71.2) vs. 80.8 (69.5-93.6) p< 0.001)] and correlated with EDSS (r=0.523, p=0.003) and the volume of T1 (r=0.418 p=0.030) and FLAIR (r=0.631 p< 0.0001) lesions as well as the changes of T1 lesion volumes (r=0.561 p=0.004) detected over follow-up period.

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Disclosure Hagman: nothing to disclose; Natarajan: nothing to disclose; Hämäläinen: nothing to disclose; Leppänen: nothing to disclose; Dastidar: nothing to disclose; Moilanen: nothing to disclose; Elovaara: nothing to disclose.

P726 The link between thalamic volume and cognition in multiple sclerosis is mediated by premorbid intelligence J.F. Sumowski1, M.A. Rocca2, G. Riccitelli2, A. Meani2, G. Comi2, M. Filippi2 1Neuropsychology and Neuroscience, Kessler Foundation, West Orange, NJ, United States, 2Vita-Salute San Raffaele University, Milan, Italy Background: Cognitive decline is common among persons with multiple sclerosis (MS), and mounting evidence establishes a link between cognitive impairment and both global and regional cerebral atrophy. In particular, several studies have identified normalized thalamic volume as a particularly strong correlate of cognitive status in MS patients, presumably due to disease-related thalamic atrophy. Importantly, however, recent evidence in healthy persons identifies the thalamus as the subcortical substrate of intelligence, which may help explain why thalamic volume is linked to cognition. Based on these recent advances, we investigated whether premorbid intelligence (Pre-IQ) explains (mediates) the very strong link between thalamic volume and cognitive status in MS patients. Methods: High-resolution 3.0T T1-weighted MRIs were acquired in 102 relapse-onset MS patients, and normalized measures of total brain and deep grey matter (thalamus, caudate, putamen, hippocampus) were derived. We performed a partial correlation between Pre-IQ (estimated with word-reading) and normalized thalamic volume, controlling for demographics and cerebral atrophy. Cognitive status was measured in a representative subsample (n=73). We examined the correlation between thalamic volume and cognitive status, and if this relationship is mediated by Pre-IQ. (Other deep grey structures were analyzed to demonstrate specificity.) Results: Higher Pre-IQ predicted larger thalamic volume (R2=.100, p=.001), but not other grey matter volumes (caudate, putamen, hippocampus). Larger thalamic volume predicted better cognitive status (R2=.182, p< .001), but one third of this relationship was explained by Pre-IQ, which mediated the link between thalamic volume and cognitive status (Sobel z=2.02, p=.044). Note that higher Pre-IQ strongly predicted better cognitive status (R2=.249, p< .001), and this relationship was largely unchanged when controlling for thalamic volume, thereby supporting the model of Pre-IQ mediating the relationship between thalamic volume and cognitive status. Conclusion: Thalamic volume is a strong predictor of cognitive status in MS, but much of this relationship is explained (mediated)


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by the link between thalamic volume and Pre-IQ. Findings help explain the very strong relationship between thalamic volume and cognitive status in MS patients. Our findings also highlight thalamic volume as a potential neuroanatomical substrate of cognitive reserve. Disclosure Funding: None. JF Sumowski: Nothing to disclose. MA Rocca: Received speakers honoraria from Biogen Idec, Serono Symposia International Foundation, and Novartis and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. G Riccitelli: Nothing to disclose. A Meani: Nothing to disclose. G Comi has received consulting fees for participating in advisory boards from Novartis, Teva Pharmaceutical Industries Ltd, Sanofi-Aventis, Merck Serono, Bayer Schering Pharma, Actelion Pharmaceuticals Ltd and GeNeuro, and lecture fees from Novartis, Teva Pharmaceutical Industries Ltd, Sanofi-Aventis, Merck Serono, Biogen-Dompé, Bayer Schering Pharma and Serono Symposia International Foundation; he has received honoraria from Bayer HealthCare, Biogen Idec, Merck Serono and Teva; he is editor-in-chief of Therapeutic Advances in Neurological Disorders and has received a license fee from Biogen Idec (no future rights). M Filippi is Editor-in-Chief of the Journal of Neurology; serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., has received funding for travel from Bayer Schering Pharma, Biogen Idec, Merck Serono, and Teva Pharmaceutical Industries Ltd.; serves as a consultant to Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Pepgen Corporation, and Teva Pharmaceutical Industries Ltd.; serves on speakers´ bureaus for Bayer Schering Pharma, Biogen Idec, Merck Serono, and Teva Pharmaceutical Industries Ltd.; receives research support from Bayer Schering Pharma, Biogen Idec, Novartis, Merck Serono, Teva Pharmaceutical Industries Ltd., Fondazione Italiana Sclerosi Multipla, the Italian Ministry of Health, CurePSP, and the Jacques and Gloria Gossweiler Foundation (Switzerland). P727 Corpus callosum structural changes associated with Kawashima Nintendo Brain Training in patients with multiple sclerosis L. De Giglio1, N. Upadhyay1, F. De Luca2, F. Tona1, L. Prosperini1, N. Petsas1, C. Pozzilli1,2, P. Pantano1,3 1Neurology and Psychiatry, ‘Sapienza’ University of Rome, Rome, 2MS Centre, A.O. Sant’Andrea, Roma, 3IRCSS Neuromed, Pozzilli (IS), Italy We recently reported a beneficial effect of a cognitive training based on the Kawashima Nintendo Brain Training (KNBT) on cognitive performance in patients with multiple sclerosis (MS), and a correlation between clinical improvement and functional modifications of thalamic connectivity in treated patients. Since damage of corpus callosum (CC) may play a crucial role in cognitive impairment due to MS, we aim at investigating whether the clinical improvement induced by KNBT correlates with measures of white matter (WM) integrity of the CC.

Diffusor Tensor Images (DTI) were acquired with a 3T MRI scanner before and after an 8-week training with KNBT. Pre- and postprocessing of DTI data were performed using the FSL 5.0 toolbox. Body, splenium and genus of CC were virtually dissected by creating regions of interest (ROIs) that were then non-linearly registered by using a standard WM atlas (JHU-ICBM-FA-2mm.nii.gz and JHU-ICBM-labels-2mm.nii.gz) into each subject native diffusion space. ROIs were thresholded and labeled on the basis of automatically segmented WM tracts in JHU atlas. DTI measures of the whole CC, including fractional anisotropy (FA), mean, axial and radial diffusivity (MD, AD, RD), were then calculated for each patient and imported in SPSS toolbox for statistical analysis (SPSS Version 22.0, Chicago). Data from 9 patients who participated in our previous study (age 44+3.3, educational level 18+3.3, disease duration 12+8.4 years) were available for this analysis. Baseline mean DTI values of CC were: FA: 0.64+0.042, AD: 0.0015+0.0003 mm^2/s, MD: 0.0008+0.00006 mm^2/s, RD: 0.0005+.00007. Baseline AD and MD inversely correlated with baseline Paced Additional Serial Task (PASAT) score (r=-0.69 and r=-0.68, respectively; p< 0.045). There were no other correlations between DTI measures of CC and other cognitive scores, i.e. Symbol Digit Modalities Test (SDMT) and Stroop Test (ST), at baseline. Paired T-test showed a significant decrease in pre-post training AD (p=0.038). Finally, we found a correlation between increased PASAT scores and decreased AD values after training (r=0.860, p=0.003). Our data show that KNBT training may induce significant changes of CC structural connectivity associated with clinically improvement in PASAT performance. Analysis of correlations with other cognitive tests (SDMT and ST) could have been influenced by the small sample size. Further analysis are requested to confirm these results. Disclosure L. De Giglio, nothing to disclose N. Upadhyay, nothing to disclose F. De Luca, nothing to disclose F. Tona, nothing to disclose L. Prosperini, consulting fees, and /or lecture fees, and/or travel grants from: Bayer Schering, Biogen Idec, Genzyme, Novartis and Teva N. Petsas, lecture fees from Biogen Idec C. Pozzilli consulting and/or lecture fees and research grants and/ or travel grants from Almirall, Biogen Idec, Bayer Schering, Merck Serono, Novartis, Roche, Sanofi Genzyme and Teva. P. Pantano nothing to disclose P728 Cognitive rehabilitation in MS. Evidence for neuroplasticity. A fMRI study J. Campbell1, D. Langdon2, M. Cercignani1, W. Rashid3 1University of Sussex, Brighton, 2Neuropsychology, University of London, London, 3Brighton and Sussex University Hospitals NHS Trust, Brighton, United Kingdom Introduction: Neuroplasticity may play an important role in ameliorating the effects of accumulating pathology in multiple sclerosis (MS). Cognitive impairment is known to affect between 40-60% of individuals with MS and has been shown to be present


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Poster Session I, 21(S11) at all stages and in all subtypes of MS. The effectiveness of cognitive rehabilitation in MS remains uncertain but may act to promote neuroplasticity and improve cognitive function in some individuals. Objectives: To explore the feasibility and efficacy of computerised, home-based cognitive rehabilitation in patients with multiple sclerosis using neuropsychological assessment, advanced structural and functional MRI techniques. Methods: 38 patients with MS and evidence of cognitive impairment on the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) test battery (defined as scores below the 5th centile for normative data) were enrolled in the study. Patients were randomly assigned to undergo 45-minutes of computerised cognitive rehabilitation (RehaCom software, n = 19) three times weekly for six weeks or to a control condition (natural history DVDs, n = 19). All patients underwent MRI at baseline (time 1) and post-intervention (time 2). Changes in cortical activations were explored using a visual n-back fMRI paradigm. Participants also underwent repeat cognitive testing at follow up. Results: The n-back task was associated with robust cortical activations in known working memory networks. At time 2 the treatment group exhibited a significant group-by-time interaction with decreased activation in the left orbitofrontal cortex and bilateral insula relative to control group at time 2 (p< 0.05 FWEcorr). Compared to time 1, a significantly higher proportion of patients in the treatment group showed 10% or greater improvement in the Symbol Digits Modality Test (SDMT) at time 2 (χ2 = 0.008). Conclusion: This study supports the hypothesis that home-based, computerised cognitive rehabilitation may be a feasible and effective approach to improving cognitive performance in patients with MS. The reductions in cortical activation are likely to represent more efficient neural processing. Disclosure Jamie Campbell: Nothing to disclose Waqar Rashid: I have accepted educational grants and travel bursaries from Genzyme, Biogen-Idec, Novartis and Teva. I have also participated on advisory boards with Bayer, Novartis, Biogen-Idec and Genzyme. Dawn Langdon: Research grants: Bayer, Novartis, BiogenConsultancy: Bayer, Novartis, Teva. Speaker Bureau: Teva, Roche, Bayer, Novartis, Biogen Mara Cercignani: Nothing to disclose P729 Functional connectivity and frequency-specific variability of cognitive networks in primary-progressive MS M. Petracca, C. Saiote, H. Bender, F. Arias, C. Farrell, A. Miller, F. Lublin, M. Inglese Icahn School of Medicine at Mount Sinai, New York, NY, United States Background and objectives: A wide range of cognitive deficits affecting processing speed/attention, executive functions and working and verbal memory have been reported in patients with primaryprogressive MS (PP-MS) as well as alterations in functional connectivity (FC) in the resting-state (RS) default-mode network

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(DMN). In contrast, neuronal variability (as measured by standard deviation - SD) in the different networks like DMN and other brain networks involved in cognitive functions remains to be investigated in PP-MS with and without cognitive impairment. The goal of our study was to explore FC and variability abnormalities in RS networks involved in cognitive functions in patients with PP-MS. Methods: All subjects underwent MRI at 3 T. The MRI protocol included T2-, 3D T1- weighted sequences and EPI for RS fMRI (TR/TE: 2304/27 ms, 150 volumes, voxel size: 3 mm3, whole brain coverage). A seed-based analysis of FC and variability was performed using AFNI. FC and neuronal variability - of DMN, salience network (SN), executive control network (ECN) and dorsal attention network (DAN) were measured in different frequency bands (Standard, Slow 5 and Slow 4) in 25 patients with PP-MS, and 20 healthy controls (HC). Results: In the standard frequency band, altered connectivity was found in all networks in PP-MS patients compared to HCs. Additionally, reduced FC (p< 0.05) in slow 5 was found in the DMN, ECN and SN while reduced FC (p< 0.05) in Slow 4 was found in the DMN and SN. Finally, PP-MS patients showed higher variability than controls (p< 0.05) in all studied networks. Conclusions: Abnormalities in frequency-specific resting state neuronal variability were found in DMN, ECN and SN of patients with PP-MS suggesting a widespread dysfunction of cortical reorganization that involves not only the DMN but also other RS networks that control cognitive processes. The investigation of the impact of FC and variability abnormalities on cognitive functions is under investigation. Disclosure M Petracca has nothing to disclose C Saiote has nothing to disclose H. Bender has nothing to disclose F. Arias has nothing to disclose C. Farrell has nothing to disclose A Miller has served as a consultant and/or participant in advisory board meetings for Genzyme/Sanofi-Aventis, Biogen Idec, Glaxo Smith Kline, EMD Serono (Merck Serono), Novartis, ONO, Acorda, Nuron Biotech, Teva, Questcor, and Accordant Health Services. He has received research support from Acorda, Novartis, Genentech, Genzyme/Sanofi-Aventis, Biogen Idec, Roche, and Questcor. He has served as Editor of Continuum, a continuing medical education publication of the AAN, and currently serves as Editor of Continuum audio. He is a member of the editorial board of Multiple Sclerosis and Related Disorders. He occasionally performs expert reviews of medical records or serves as an expert witness in medical malpractice cases. F. Lublin: sources of funding for research: Acorda Therapeutics, Inc., Biogen Idec, Novartis Pharmaceuticals Corp., Teva Neuroscience, Inc., Genzyme, Sanofi, Celgene, NIH, NMSS; consulting agreements/advisory boards/DSMB: Bayer HealthCare Pharmaceuticals, Biogen Idec, EMD Serono, Inc., Novartis, Teva Neuroscience, Actelion, Sanofi-Aventis, Acorda, Questcor, Roche, Genentech, Celgene, Johnson & Johnson, Revalesio, Coronado Bioscience, Genzyme, MedImmune, Bristol-Myers Squibb, Xenoport, Receptos, Forward Pharma; co-chief editor: Multiple Sclerosis and Related Diseases; stock ownership: Cognition Pharmaceuticals, Inc. M Inglese has received research grants from NIH, NMSS, Novartis Pharmaceuticals and Teva Neuroscience


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P730 Gray matter correlates of cognitive performance differ between relapsing-remitting and primary-progressive multiple sclerosis L. Jonkman1, D.M. Rosenthal2, M.P. Sormani3, L. Miles2, J. Herbert2, R.I. Grossman2, M. Inglese4 1VU Medical Center, Amsterdam, The Netherlands, 2New York University School of Medicine, New York, NY, United States, 3University of Genoa, Genoa, Italy, 4Mount Sinai School of Medicine, New York, NY, United States Background: In MS, 80-85% of patients experience a relapsingremitting (RR) course, while about 15-20% of patients experience a primary progressive (PP) course. Cognitive impairment (CI) affects approximately 40-70% of all MS patients and differences in CI between RR-MS and PP-MS have been found. Furthermore, both pathological and MRI studies have shown that cortical demylination and gray matter (GM) atrophy are more prominent in PP-MS than in RR-MS. Nevertheless, only a few studies have investigated the cognitive-MRI characteristics of PP-MS patients in comparison to RR-MS patients. Objective: We aimed to compare RR-MS and PP-MS patients in terms of cognitive performance, and to investigate the MRI correlates of cognitive impairment in the two groups using measures of brain volumes and cortical thickness. Methods: Fifty-seven patients (42 RR-MS, 15 PP-MS) and thirtyeight matched controls underwent neuropsychological (NP) testing and MRI. Cognitive functioning was assessed using the FAS, CLVT-II, SDMT, PASAT-3 secs, D-KEFS inhibition and D-KEFS inhibition switching. Patients were defined as CI when their Z-score on a minimum of two NP tests was at least 1.65 standard deviations below the norm. 3T MRI sequences included a T2 dual-echo turbo spin-echo, a 3D T1-weighted MPRAGE and a Post-Gd T1-weighted spin-echo. Lesion (T1 and T2) volumes and normalized, gray and white matter brain volumes (NBV, GMV, WMV) were assessed and cortical thickness of seven composite areas and of six deep gray nuclei volume were measured using Freesurfer software. Results: PP-MS patients scored lower than RR-MS patients on most of the NP tests, but only on “verbal learning & memory” this reached significance (p = 0.028). Although PP-MS patients had less cortical thickness than RR-MS patients in all seven regions, none of these reached the required level of significance. In regards to deep GM volumes, PP-MS patients had greater volume reductions in nearly all areas (cerebellum, thalamus, caudate, putamen, hippocampus and amygdala), but only the difference in caudate volume was significant (p = 0.041). Regarding MRI correlates of CI, a prevalent association with MRI measures of cortical GM injury in RR-MS patients and with subcortical GM injury in PP-MS patients was observed. Conclusion: Although cognitive impairment results from several factors, cortical and subcortical GM injury may play a different role depending on the disease course. Disclosure L.E. Jonkman has nothing to disclose D.M. Rosenthal has nothing to disclose MP Sormani has received personal compensation for consulting services and for speaking activities from Genzyme, Merck Serono, Teva, Synthon, Actelion, Novartis and Biogen Idec.

L. Miles has nothing to disclose J. Herbert has nothing to disclose R. I. Grossman has received research grant support from NIH. M. Inglese serves on the editorial board of MS International, Journal of World Radiology Frontiers in Aging Neuroscience, and the Scientific Advisory Board of the Italian MS Society and has served as a consultant for Celgene Cellular Therapeutics and Vaccinex, Inc. MI has received research grant support from NIH, NMSS, Novartis Pharmaceuthicals and Teva Neurosciences. P731 Association of cognitive impairment with optical coherence tomography and magnetic resonance imaging changes in multiple sclerosis patients N. Giedraitiene1, R. Kizlaitiene1, G. Kaubrys1, E. Mockeviciute2, M. Noreikyte2, R. Strupaite1, A. Cimbalas1, A. Liveikiene1, R. Asoklis1 1Vilnius University Hospital Santariskiu Clinics, 2Vilnius University Faculty of Medicine, Vilnius, Lithuania Objectives: To investigate the correlation between cognitive impairment, retinal nerve fiber layer (RNFL) thickness and linear brain atrophy markers in multiple sclerosis (MS) patients. Methods: A Brief International Cognitive Assessment for MS (BICAMS), which included Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R), California Verbal Learning Test, second edition (CVLT-II), was administered in all persons. From routine Magnetic resonance imaging (MRI) in MS patients we measured three linear brain atrophy markers: third ventricle width (TVW), Huckman´s index (HI) and inter-caudate distance (ICD). RNFL in MS patients was measured with OCT. Statistical analysis was performed using SPSS statistical software (version 22.0). P< 0.05 was considered significant. Results: A total of 88 persons were included: 52 patients with relapsing remitting (n=51; 98.1%) and secondary progressive (n=1; 1.9%) MS and 36 control persons. The mean age of MS patients was 42.8±10.9 years, of the control group - 39.9±12.8 years. The mean EDSS score of MS patients was 3.5±1.3. Mean scores of the BICAMS were significantly higher in control group, younger MS patients and patients with lower degree of disability (p< 0.05). Significant correlations were found between all neuropsychological test scores and MRI measures, the strongest correlation between TVW and CVLT (r= -0.57; p=0.00). Cognitive functions and OCT results revealed a significant correlation between SDMT and the left eye temporal segment (r=0.32; p=0.03) and papillomacular bundle (PMB) (r=0.36; p=0.01) thickness. There was not statistically significant relation between RNFL and MRI indexes (p>0.05). Conclusions: Cognitive impairment depends on brain atrophy with the most represent third ventricle width and correlates with retinal temporal segment and maculopapular beam thicknesses measured with OCT. Cognitive dysfunction depends on age and physical disability in MS patients, but changes of RNFL thickness do not reflect brain atrophy directly. Disclosure Nothing to disclose


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Poster Session I, 21(S11) P732 Hippocampal microstructural damage and memory impairment in clinically isolated syndrome V. Planche1,2,3, A. Ruet1,2,4, P. Coupé5, D. Hamel1,2, M. Deloire4, F. Munsch1,2, A. Saubusse4, J. Charré-Morin4, N. Moscufo6, D. Meier6, C.R. Guttmann6, V. Dousset1,2,4, B. Brochet1,2,4, T. Tourdias1,2,4 1University of Bordeaux, 2Inserm U862 - Neurocentre Magendie, Bordeaux, 3Clermont-Ferrand University Hospital, ClermontFerrand, 4Bordeaux University Hospital, 5Laboratoire Bordelais de Recherche en Informatique, UMR CNRS 5800, Bordeaux, France, 6Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States Objective: Memory impairment is correlated to hippocampal atrophy in multiple sclerosis (MS) but the substrate of early memory deficit, prior to atrophy, is unknown. We investigated whether early hippocampal alterations are already present at the stage of clinically isolated syndrome suggestive of MS (CIS) and whether they are related to memory performance. Methods: 37 CIS patients were prospectively included in a crosssectional study and compared to 32 MS patients and 36 healthy controls. Information processing speed (IPS), working memory and episodic verbal memory were assessed. A 3T-MRI protocol was performed including FLAIR, T1-weighted and diffusion-tensor imaging. Results: While there was no hippocampal atrophy in the CIS group, hippocampal fractional anisotropy (FA) was already significantly decreased, independently of T2 lesions. Hippocampal FA declined further in MS patients together with increased mean diffusivity (MD). In CIS, hippocampal MD was sensitively and specifically correlated with the delayed-recall task of episodic verbal memory test (r=-0.57, p=0.0002) but not with cognitive tasks unrelated to hippocampal function. Hippocampal MD was the only variable discriminating memory-impaired from memory-preserved CIS patients (AUC=0.77; sensitivity 90.0%; specificity 70.3%). In the MS group, hippocampal volume was correlated with episodic verbal memory performances, but hippocampal FA and MD were associated with global brain damage at this stage and in turn correlated with IPS scores (r=0.36, p=0.04 and r=-0.52, p=0.002). Conclusion: Hippocampal microstructural damage precedes atrophy in CIS patients and is strongly correlated with their long term memory impairment. It suggests that an early neuropathological process contributing to memory deficit occurs in the hippocampus during the course of MS. Disclosure BB or his institution received research grants and/or consulting fees from Biogen, Bayer, Novartis, Genzyme, Roche, Medday, Merck-Serono, and Teva. AR or her institution received research grants and/or consulting fees from Novartis, Biogen-Idec, MerckSerono, Bayer Healthcare, Roche, and Teva. VP thanks ClermontFerrand University Hospital and the Inserm MD-PhD program (Ecole de l’Inserm - Liliane Bettencourt) for personal support awards. Other authors: nothing to disclose. P733 Structural MRI substrates of cognitive impairment in neuromyelitis optica

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Y. Liu1,2,3, Y. Fu3, M.M. Schoonheim4, F. Barkhof2, F.-D. Shi3 Hospital, Capital Medical University, Beijing, China, 2Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands, 3Tianjin Medical University General Hospital, Tianjin, China, 4Department of Anatomy and Neurosciences, VU University Medical Center, Amsterdam, The Netherlands

1Xuanwu

Objective: Cognitive impairment (CI) is frequently seen in neuromyelitis optica (NMO) patients but poorly understood. This study aims to identify the clinical and structural MRI markers for predicting CI in patients with NMO. Methods: A total of 54 patients with NMO and 27 healthy controls (HC) underwent extensive neuropsychological testing and multimodal 3.0T MRI. The patient group was divided into CI and cognitively preserved (CP) patients, using a criterion of ⩽1.5 SD on at least two cognitive domains. MRI measurements included prevalence of brain white matter (WM) lesions and lesion volume; grey matter (GM), WM and deep GM (DGM) volume; cortical thickness, and the severity and extent of reduced WM integrity. Groups were compared using a multivariate general linear model, and clinical and MRI measurements were related to average cognition Z-scores by partial correlations and stepwise linear regression model. Results: Twenty-six (48.2%) NMO patients were classified as CI and showed disrupted WM integrity, and GM especially DGM atrophy compared to HC. CP patients also showed WM integrity loss but without significant GM atrophy. Compared to CP, CI patients demonstrated a lower level of education and decreased hippocampal volume. In the whole patient group, average cognition Z-scores were best predicted by the level of education and hippocampal volume (R2=0.46, p< 0.001). Conclusion: In NMO patients, WM integrity disruption was identified in both CP and CI groups. GM atrophy particularly in the DGM was only found in CI group. Hippocampal volume was the main MRI predictor of cognition in the entire NMO group. Disclosure Dr. Yaou Liu was supported by was supported by the ECTRIMSMAGNMIS Fellowship from ECTRIMS. Dr. Menno M. Schoonheim is sponsored by the Dutch MS Research foundation, grant nr 13-820, and has received consultation fees for Genzyme, Novartis, Merck Serono and Excemed. Dr. Frederik Barkhof serves as a consultant for Bayer-Schering Pharma, Sanofi-Aventis, Biogen Idec, Teva, Merck Serono, Novartis, Roche, Synthon, and Jansen Research. Dr. Ying Fu and Dr. Fu-Dong Shi report no disclosures. P734 White matter tract abnormalities are associated with cognitive dysfunction in secondary progressive multiple sclerosis K.A. Meijer1,2, N. Muhlert2,3, M. Cercignani4, V. Sethi2, M.A. Ron2, A.J. Thompson2,5, D.H. Miller2,5, D. Chard2,5, J.J.G. Geurts1, O. Ciccarelli2,5 1Department of Anatomy and Neurosciences, VU Medical Centre, Amsterdam, The Netherlands, 2NMR Research Unit, Queen Square MS Centre, University College London Institute of Neurology, London, 3School of Psychology and Cardiff


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University Brain Research Imaging Centre, Cardiff University, Cardiff, 4Clinical Imaging Centre, Brighton and Sussex Medical School, Brighton, 5NIHR University College London Hospitals Biomedical Research Centre, London, United Kingdom Background: Secondary progressive (SP) multiple sclerosis (MS) is associated with greater cognitive deficits than relapsing remitting MS (RRMS). Whilst our knowledge of WM pathology underlying cognitive impairment in relapsing remitting (RR) MS is increasing, equivalent understanding in those with SPMS lags behind. Objective: To examine whether the extent and severity of WM tract damage differ between cognitively impaired (CI) and cognitively preserved (CP) SPMS patients. Method: Thirty SPMS patients (20 women, mean age 54 yrs, range 36-65) and thirty-two healthy controls (HCs) (20 women, mean age 41 yrs, range 21-65) underwent a whole-brain imaging protocol on a 3T scanner, including diffusion weighted imaging. Cognitive assessment included comprehensive testing spanning five cognitive domains that are commonly affected in MS patients. Patients who scored at least 2 standard deviations below the mean of the HCs on a minimum of 2 out of 5 tested cognitive domains were designated as CI. Tract-based spatial statistics (TBSS) was used to perform voxel-based diffusion tensor MRI analyses between groups. Lesional voxels where 10% or more patients showed T2 lesions were calculated and mapped onto the TBSS skeleton. Results: Twelve patients were defined as cognitively impaired and processing speed was the most commonly affected cognitive domain. Cognitive performance in SPMS was significantly predicted by premorbid IQ, age and gender (R2=0.42 p=0.002). After accounting for demographic factors, of the examined MRI measures, RD explained the most additionally variance. The regression model including the demographic factors and RD explained 6 percent more variance (R2=0.48, p=0.002), than a model including solely the demographic factors. Relative to HCs, CI and CP patients showed a widespread loss of WM integrity throughout the WM skeleton. Relative to CP patients, CI patients showed more extensive and severe damage of several WM tracts, including the fornix, superior longitudinal fasciculus and forceps major. Conclusion: Damage to WM tracts connecting grey matter regions involved in cognitive function may be a potential mechanism for cognitive impairment in SPMS, possibly through a “disconnection syndrome”. The present study showed that loss of WM integrity assessed using TBSS helps to explain cognitive decline in SPMS patients. Disclosure K.A. Meijer, N. Muhlert, M. Cercignani and M. Ron report no disclosures. V. Sethi receives research support from Biogen Idec and Novartis. A. Thompson has in the last 3 years received honoraria and support for travel for consultancy, serving on advisory boards, or speaking from Biogen Idec, Genzyme, medDay, Novartis, Teva, Remedica, and Excemed. He is editor-in-chief for Multiple Sclerosis Journal, for which he receives an honorarium. D.H. Miller has received honoraria from Biogen Idec, Novartis, GlaxoSmithKline, and Bayer Schering, and research grant support for doing MRI analysis in multiple sclerosis trials sponsored by GlaxoSmithKline, Biogen Idec and Novartis.

D. Chard receives research support from the Multiple Sclerosis Society of Great Britain. J.G.G. Geurts serves on the Scientific Advisory Board of the Dutch MS Research Foundation and of MS Academia, Merck Serono, and has served as a consultant for Merck Serono, Biogen Idec, and Teva Pharmaceuticals. O. Ciccarelli receives research grant support from the Multiple Sclerosis Society of Great Britain and Northern Ireland, the Department of Health Comprehensive Biomedical Centre, the International Spinal Cord Research Trust (ISRT) and the Engineering and Physical Sciences Research Council (EPSRC), and she has received honoraria from Bayer Schering and GE. P735 Functional cognitive control load in multiple sclerosis L. Vacchi1, M.A. Rocca1,2, A. Meani1, M. Rodegher2, V. Martinelli2, G. Comi2, A. Falini3, M. Filippi1,2 1Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 2Department of Neurology, 3Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy Background: According to the load theory, an active mechanism of cognitive control is involved in maintaining current task goals and reducing additional processing of irrelevant information. Objectives: To investigate clinical, behavioural and functional MRI correlates of N-back task performance in MS patients with the main relapse-onset clinical phenotypes. Methods: A block-design N-back task was administered to 72 MS patients (12 clinically isolated syndromes [CIS], 38 relapsingremitting [RR] and 22 secondary progressive [SP]) and 24 ageand gender-matched healthy controls (HC). Regions showing load-dependent activations/deactivations with increasing task difficulty (0- to 3-back and LOAD contrast) were modelled using SPM8. Correlation with clinico-behavioural, cognitive and structural MRI measures were performed. Results: Compared to HC, MS patients had worse task performance and significant brain atrophy. All groups activated frontoparietal and cerebellar regions and deactivated areas part of the default-mode network. Compared to HC, MS patients had higher recruitment of the right inferior parietal cortex and fronto-mesial areas during low cognitive load conditions as well as decreased recruitment of posterior regions during higher load conditions. The analysis of the LOAD contrast showed that, compared to HC and RRMS, CIS patients had increased activations of anterior brain areas and right hippocampus and decreased recruitment of left superior temporal and postcentral gyri. Compared to RRMS, SPMS patients had a decreased recruitment of left putamen. Compared to cognitively preserved patients, those with cognitive impairment (n=22) had higher recruitment of the right cuneus, insula and cerebellum as well as a decreased activation of right superior parietal gyrus and left cerebellum. Better accuracy was significantly correlated to left precentral gyrus activity (r=0.42), whereas higher T2 lesion volume correlated with left superior temporal gyrus activity (r=0.4). Conclusions: Load-dependent modifications of executive network recruitment occur in MS patients. These abnormalities vary across the stages of the disease and contribute to clinical and cognitive deficits. Increased recruitment of fronto-parietal regions,


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Poster Session I, 21(S11) which occurs mostly in CIS, was associated to better performances. Conversely, posterior brain region recruitment is present in SPMS patients and is likely modulated by focal WM lesions. Disclosure Partially supported by grants from Italian Ministry of Health (GR2008-1138784/GR-2009-1529671) and Fondazione Italiana Sclerosi Multipla (FISM2012/R/8). L. Vacchi, A. Meani, M.E. Rodegher have nothing to disclose. V. Martinelli received personal compensation for consulting services and for speaking activities from Biogen-Idec, MerckSerono, Bayer, TEVA, Novartis, Genzyme. M.A. Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed. G. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. M. Filippi has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis.

P736 Cerebellar sub-structures in cognitive impairment: volumetric and microstructural analyses at different stages of multiple sclerosis A. Moroso1,2, A. Ruet1,2, D. Hamel2, F. Munsch2, M. Deloire1, P. Coupé3, J.-C. Ouallet1, V. Planche2, N. Moscufo4, D. Meier4, T. Tourdias1,2, C. Guttmann4, V. Dousset1,2, B. Brochet1,2 1Bordeaux Hospital University Center, 2Inserm U 862 Neurocentre Magendie, 3Laboratoire Bordelais de Recherche en Informatique, Unité Mixte de Recherche CNRS (UMR 5800), Bordeaux, France, 4Center for Neurological Imaging, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States Background: Recent studies have demonstrated the impact of cerebellar lesion load and atrophy on cognitive impairment in multiple sclerosis (MS) that might result from functional disconnection in the fronto-cerebellar loop and local modulation. However, structural alterations in posterior lobules, in which cognitive functioning seems preponderant, are still unknown. Objectives: To compare grey matter volume (GMv) and diffusion metrics in lobules VI to VIIIb between clinically isolated syndrome (CIS), MS patients and healthy controls (HC) according to cognitive status. Methods: Sixty nine patients (37CIS, 32MS) and 36 matched HC underwent a 3T MRI scan including 3D T1 weighted and diffusion-weighted images. Cerebellum was isolated and lobules were automatically segmented using SUIT 3.0 to estimate their normalized GMv. Fractional anisotropy (FA) and mean diffusivity (MD) were calculated within each lobule and cerebellar peduncles using FSL 5,0. Rao´s battery was completed with attentional, working memory (WMem), executive functions (EF) and information processing speed (IPS) testing to evaluate cognitive domains using z-scores. We investigated correlations between cognitive outcomes

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and cerebellar sub-structures GMv on the one hand, and diffusion parameters on the other. Results: Attention, WMem and IPS scores were impaired in MS patients compared to CIS, but not significantly different between CIS and HC. Cerebellar, lobule VI, CrusI, right CrusII and VIIb GMv were decreased in MS patients compared to CIS and HC. FA was generally lower and MD higher in the cerebellum and specifically in vermis CrusII, lobules VIIb and VIIIa/b in MS. GMv and FA estimations in CIS tended to be higher than in HC. Considering all patients, we found correlations between IPS z-score and cerebellum (p< 0,001, r=0,44), lobules VI, CrusII, and vermis VIIIa GMv. IPS was positively correlated with FA in the cerebellum (p< 0,001, r=0,55), lobules VI and VIIIb in all patients (as in MS subgroup in right lobule VIIIb) and negatively correlated with MD in vermis CrusII (p< 0,001, r=-0,45). Increased MD and decreased FA in superior and medium peduncles were associated with IPS and WMem respectively. Conclusion: Cerebellar GM atrophy and DTI indicators of microstructural damage are associated with cognitive deficits in MS. Alterations in posterior lobules were associated with reduced IPS. CIS patients had minor cognitive disability but GMv and FA changes may suggest adaptive mechanisms. Disclosure Pr B. Brochet or his institution received research grants and/or consulting fees from Biogen, Bayer, Novartis, Genzyme, Roche, Medday, Merck-Serono, and Teva. Dr A. Ruet or her institution received fees for research and symposium from Novartis, Biogen-Idec, Merck-Serono, Bayer Healthcare, Roche, and Teva. Dr J-C. Ouallet JCO has received consultancy fees, speaker fees,research grants (non-personal), and honoraria from Novartis, Biogen-Idec, Merck-Serono, Bayer Schering, Roche, Almirall, Teva and GenzymeSanofi-Aventis. Amandine Moroso received a research grant from the Fondation pour la recherche médicale (DEA20140630564) Coupé P., Deloire M., Dousset V., Guttmann C., Hamel D., Meier D., Moscufo N., Munsch F., Ouallet J-C., Planche V., Tourdias T.: nothing to disclose P737 Differential contribution of cerebellar resting state functional connectivity abnormalities to cognitive impairment in pediatric and adult patients with multiple sclerosis M.A. Rocca1,2, P. Valsasina1, L. Vacchi1, L. Moiola2, A. Ghezzi3, P. Veggiotti4, R. Capra5, M.P. Amato6, A. Fiorino2, L. Pippolo3, M.C. Pera4, G. Comi2, A. Falini7, M. Filippi1,2 1Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 2Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, 3Multiple Sclerosis Center, Ospedale di Gallarate, Gallarate, 4Fondazione ‘Istituto Neurologico Casimiro Mondino’, Pavia, 5Multiple Sclerosis Center, Spedali Civili of Brescia, Brescia, 6Department of Neurology, University of Florence, Florence, 7Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy Background: The human cerebellum is a complex structure engaged in motor and cognitive functions.


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Objectives: We investigated whether resting state (RS) functional connectivity (FC) abnormalities of different functional subregions (right and left CrusI, CrusII and dentate nucleus) of the cerebellum contribute to cognitive impairment in pediatric and adult patients with MS. Methods: RS fMRI scans were acquired from 49 pediatric MS patients, 40 adult MS patients, 27 pediatric healthy controls (HC) and 40 adult HC. Patients with abnormalities in ⩾3 neuropsychological tests at an age- and disease-tailored cognitive evaluation were classified as cognitively impaired (CI). Results: Ten (20%) pediatric and 9 (22%) adult MS patients were classified as CI. In pediatric and adult HC and CP MS patients, within group analysis of RS FC of the right dentate, CrusI and II showed a distributed pattern of correlations with several regions of the bilateral cerebellum, basal ganglia and fronto-parieto-temporal lobes. Conversely, pediatric and adult CI MS patients had a “reduced” pattern of RS FC between cerebellar subregions and a few frontal and temporal areas. For each cerebellar subregion, compared to pediatric HC, adult HC had a decreased RS FC in a distributed network of anterior areas. Compared to HC, MS patients experienced significant reduction of RS connectivity between the cerebellum and the basal ganglia, which was independent from age and did not contribute to cognitive performance. In pediatric MS patients, decreased RS FC between the cerebellum and fronto-parietal-temporal regions was related to the presence of cognitive deficits. In adult MS patients, a more complex pattern of RS FC abnormalities was detected, characterized by the concomitant presence of regions of increased and decreased connectivity, both contributing to cognitive decline. Conclusions: Different patterns of cerebellar RS FC abnormalities contribute to cognitive deficits in pediatric and adult patients with MS, possibly due to the level of maturation of cerebellar connections. Disclosure Partially supported by a grant from Italian Ministry of Health (GR-2009-1529671). P. Valsasina, L. Vacchi, L. Moiola, P. Veggiotti, A. Fiorino, L. Pippolo, M.C. Pera, A. Falini have nothing to disclose A Ghezzi has served on scientific advisory boards for Merck Serono, Biogen Idec Teva Pharmaceutical Industries Ltd; has received speaker honoraria from Merck Serono, Biogen Idec, Bayer Schering Pharma, and Novartis, Serono Symposia International; served as a consultant for Novartis; and receives research support from Sanofi-Aventis, Biogen Idec, and Merck Serono. R Capra received consulting fees fromNovartis, Merck Serono, BiogenIdec and lecture fees fromBayer, BiogenIdec, Genzyme, and Sanofi-Aventis. MP Amato: serves on scientific advisory boards for Biogen-Idec, Merck Serono, Bayer Schering and Sanofi Aventis and receives research support and honoraria for speaking from Biogen-Idec, Merck Serono, Bayer Schering and Sanofi Aventis. M.A. Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed. G. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. M. Filippi has received compensation for consulting services and/or

speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis.

Cognitive assessment and development P738 An improved computerized symbol digit modalities test: introducing distracters V.P. Patel1,2, A. Zambrana3, L. Walker3, A. Feinstein1,2 1Psychiatry, Sunnybrook Health Sciences Centre, 2University of Toronto, Toronto, 3Neuropsychology, The Ottawa Hospital, Ottawa, ON, Canada Background: Cognitive dysfunction affects 40-70% of people with MS and exerts a deleterious effect on employment, leisure pursuits and relationships. Detection of even subtle deficits is therefore important. Objective: To improve an existing method of cognitive assessment by adding distracters (telephone ring, car horn) to a validated computerized version of the Symbol Digit Modalities Test (c-SDMT). Methods: A sample of 82 individuals with MS and 43 demographically matched healthy control participants completed a modified version of the c-SDMT. Half of the participants in each group completed the c-SDMT with auditory distracters and half without. The MS group also underwent comprehensive neuropsychological testing with the Minimal Assessment of Cognitive Functioning in MS (MACFIMS). Results: There were no demographic or neurologic differences between MS groups completing the distracter and non-distracter c-SDMT tasks. The mean times on both the distracter and nondistracter c-SDMT were significantly greater in MS participants compared to healthy controls (p=0.001, both versions). In MS participants, the mean time on the distracter c-SDMT was 17.2 seconds and 16.0 seconds on the non-distracter (p=0.45). For healthy controls, the equivalent times were 12.8 and 12.5 seconds, respectively (p=0.64). In total, 46% of MS participants were impaired on the distracter c-SDMT versus 34% on the non-distracter version (p=0.26). Among MS participants receiving the distracter c-SDMT, the impairment rate on the traditional SDMT (part of the MACFIMS) was significantly lower than the impairment rate on the distracter c-SDMT (32% vs. 46%, p=0.03). Those receiving the non-distracter c-SDMT displayed similar impairment rates to the traditional SDMT (34% vs. 32%, respectively p=0.99). Global cognitive impairment rate on the MACFIMS was 46% and increased to 51% when the traditional SDMT was replaced with the distracter c-SDMT (p=0.99). Conclusion: The incorporation of distracters into the c-SDMT revealed a significantly higher rate of impairment compared to the traditional SDMT. The use of distracters therefore offers the promise of boosting the sensitivity of traditional cognitive tests. Real world distracters could also, in theory, enhance the ecological validity of the psychometric data. Disclosure Viral Patel: Nothing to disclose. Aaron Zambrana: Nothing to disclose.


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Poster Session I, 21(S11) Lisa Walker: Nothing to disclose. Anthony Feinstein: I have served on scientific advisory boards for Merck Serono and Avanir Pharmaceuticals; have received speaker honoraria from Merck Serono, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Biogen Idec; serve on the editorial boards of Multiple Sclerosis and the African Journal of Psychiatry; receive publishing royalties for The Clinical Neuropsychiatry of Multiple Sclerosis (Cambridge University Press, 2007); chair the Medical Advisory Committee for the Multiple Sclerosis Society of Canada; conduct neuropsychiatric evaluation, cognitive testing, and brain imaging in neuropsychiatry in my clinical practice; and receive research support from the Canadian Institute of Health Research, the Multiple Sclerosis Society of Canada and Teva Pharmaceuticals Industries Ltd. P739 Proposal for a new measure of cognitive fatigability derived from Symbol Digit Modalities Test: the Information Processing Speed Deceleration Index (IPSDI) L. De Giglio1, F. De Luca2, L. Porosperini1,2, F. Fabiano2, I. Ferrante2, L. Castelli2, F. Gurreri2, C. Pozzilli1,2 1Neurology and Psychiatry, ‘Sapienza’ University of Rome, Rome, 2MS Centre, A.O. Sant’Andrea, Roma, Italy Background: Fatigability is defined as an objective change while performing a motor or cognitive task, and is one of the most debilitating symptoms of multiple sclerosis (MS). Few techniques have been developed to objectively measure cognitive fatigability (CF), and a widely accepted method is still lacking. We aimed to find an easy tool to measure CF, based on the Symbol Digit Modalities Test (SDMT), and to investigate its correlation with subjective cognitive fatigue. Methods: We included 55 (34 F, 25 M) patients with MS aged between 18 and 65 years, and 44 (25 F, 20 M) healthy subjects (HS) to be used as controls. The SDMT was administered twice in a row (SDMT1 and SDMT2), recording the number of correct answers (NCA) for each test in 3-time intervals (time-1: 0-30 s; time-2: 30-60 s; time-3: 60-90 s). We estimated the “Information Processing Speed Deceleration Index” (IPSDI) with the following equation: (NCA time-3 - NCA time-1/NCA time-1)*100. The Multiple Sclerosis Fatigue Impact Scale (MFIS) was also administered. Differences in NCA and IPSDI at SDMT1 and 2 were tested with unpaired t-tests, and a two-way analysis of the variance to test the time by group effect. Relationship between IPSDI and MFIS was investigated by the Spearmen coefficient. Results: MS and HS did not show significant differences in age and education (p>0.5). As expected, MS performed worse than HS in terms of mean NCA at both SDMT1 (34.9+/-14.1 vs. 50+/13.5, p< 0.001) and SDMT2 (36.2+/-14.2 vs. 51.4+/-11.4, p< 0.001). However, considering the NCA at different time-points, we did not find a significant time by group interaction at SDMT1 (F=1.32, p=0.3); by contrast, we found a significant time by group interaction (F=4.28, p=0.015) at SDMT2, indicating that NCA decreased over time only in MS. We also found a significant difference in MS and HS in mean IPSDI at SDMT2 (6.8+/-24.4 vs. -3.4+/-25.3, p=0.045), while difference in mean IPSDI at SDMT1 did not reach the statistical significance (9.4 +/-20 vs 0.2+/- 33, p=0.1). In MS group, IPSDI was correlated with MFIS total score (rho=-0.461; p< 0.001) and its subscales (cognitive rho=-0.315;

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p=0.019; psychosocial rho=-0.376 p=0.005; physical rho=-0.447; p< 0.001). Conclusions: The administration of SDMT twice in a row may unmask the occurrence of cognitive fatigability in MS. We suggest that the IPSDI could be used as an easy tool to measure of cognitive fatigability, and further evaluations are needed to confirm its validity. Disclosure Laura De Giglio: Nothing to disclose Francesca De Luca: Nothing to disclose Luca Prosperini: Consulting fees, and /or lecture fees, and/or travel grants from: Bayer Schering, Biogen Idec, Genzyme, Novartis and Teva. Fabiano Francesca: Nothing to disclose Ferrante Ilaria: Nothing to disclose Castelli Letizia: Nothing to disclose Gurreri Flavia: Nothing to disclose Carlo Pozzilli: Consulting and/or lecture fees and research grants and/or travel grants from Almirall, Biogen Idec, Bayer Schering, Merck Serono, Novartis, Roche, Sanofi Genzyme and Teva.

P740 The utility of BICAMS in detecting cognitive impairment in the outpatient clinic. Associations with employment and quality of life measures J. Campbell1, M. Cercignani1, D. Langdon2, W. Rashid3 1University of Sussex, Brighton, 2Neuropsychology, University of London, London, 3Brighton and Sussex University Hospitals NHS Trust, Brighton, United Kingdom Introduction: Cognitive impairment is known to affect between 40-60% of individuals with multiple sclerosis (MS) and has been shown to be present at all stages and in all subtypes of MS. Cognitive dysfunction may negatively impact upon employment independent of the physical limitations imposed by the disease. Rates of unemployment in MS may be up to 80%. Objectives: To explore the utility of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) in the outpatient setting and to examine the relationship between cognitive impairment and conventional measures of disability, neuropsychological, psychosocial and quality of life measures (QOL) in MS as well as vocational status. Methods: 62 patients with MS were assessed using the BICAMS test battery for cognitive impairment. Data was obtained on vocational status and quality of life and other measures including; Fatigue Severity Score (FSS), Multiple Sclerosis Neuropsychological Questionnaire Self-report (MSNQ-S), Hospital Anxiety and Depression Scale (HADS) the Functional Assessment of MS (FAMS) as well as on the EuroQOL five dimension questionnaire (EQ-5D). Results: Cognitive assessment revealed 44 subjects (65%) had evidence of cognitive impairment on one or more of the BICAMS tests. In comparison with cognitively unimpaired patients, cognitively impaired patients were significantly more likely to be unemployed (p = 0.004). In the secondary regression analysis, the Symbol Digits Modality Test (SDMT) score and gender were found to be


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the most significant predictors of unemployment accounting for between 44-59% of the variance. Of the three cognitive tests employed, the SDMT was found to correlate most closely with FAMS and EQ-5D QOL outcome measures. Patients with cognitive impairment had significant lower FAMS scores (p=0.001) and higher EQ-5D scores (p< 0.001) indicative of lower QOL. Such patients also had higher MSNQ-S (p=0.004) scores in keeping with a greater subjective perception of cognitive impairment. Conclusion: BICAMS provides a sensitive and easy to administer screening test for cognitive impairment within the outpatient setting. The level of cognitive impairment found in our cohort is comparable to other studies and the presence of such impairment (particularly with the SDMT) in addition to gender (male) is the strongest predictor of unemployment rather than physical disability or disease duration. Disclosure Jamie Campbell: Nothing to disclose. Waqar Rashid: I have accepted educational grants and travel bursaries from Genzyme, Biogen-Idec, Novartis and Teva. I have also participated on advisory boards with Bayer, Novartis, Biogen-Idec and Genzyme. Dawn Langdon: Research grants: Bayer, Novartis, BiogenConsultancy: Bayer, Novartis, Teva Speaker Bureau: Teva, Roche, Bayer, Novartis, Biogen Mara Cercignani: Nothing to disclose. P741 The sound lateralization test demonstrates slowed processing speed in MS patients with minimal to mild disability and shows no learning effects in multiple testing sessions over a 1-year period J. Bacon1,2, T. Bacon2, Z. Rimler2, I. Kister2 1Psychology, Stern College for Women, Yeshiva University, 2Neurology, NYU Langone Medical Center, New York, NY, United States Objectives: To investigate the stability of the Sound Lateralization Test (SLT) over a 1-year period in patients with multiple sclerosis (MS) and healthy controls (HC) and to assess for the presence of learning effects in the SLT. Background: We have previously described a technically simple test, the SLT, that utilizes Interaural Time Difference (ITD) thresholds to measure processing speed, and have shown that IDT thresholds were significantly higher in MS patients with minimal to mild disability (Expanded Disability Status Scale (EDSS) < 3) compared to HCs. In theory, the SLT, which is designed to test primarily integrity of brainstem auditory pathways, should not be subject to learning effects as are higher cognitive function tests such as the Symbol Digit Modality Task (SDMT). Design and analysis: 43 patients with EDSS < 3 and 30 HCs completed 4 visits in 3-month intervals. At each visit, the SLT and SDMT were administered, and treating neurologists performed the EDSS and evaluated patient’s clinical status (relapse/treatment history). The data from the 4 testing sessions (TS) and two groups (HC and MS patients) were analyzed using a 4X2 split-plot Analysis of Variance with age and gender as covariates. Separate analyses were conducted for the SLT and the SDMT.

Results: A significant main effect for groups was observed for SLT (MMS= 83.7, MHC= 63.7; p=0.03), indicating that MS patients required a longer ITD than HC. There was no significant effect for TS (p>0.05) or for the interaction of Groups X TS (p>.05) indicating that, over the 4 testing sessions, IDT scores for MS and HC did not improve and the difference between them remained constant. In contrast, the results for the SDMT showed no main effect for groups (MMS=61.5, MHC=61.6; p>.05), but a highly significant main effect for TS (MTS1=57.1, MTS2= 62.6, MTS3 = 62.4,MTS4= 64.1; p=.001) and a highly significant TS x Group interaction (p=.002), indicating that though baseline SDMT for the MS group was lower than HC scores, both groups improved to an equal performance level over the three subsequent testing sessions. Conclusions: Although both SLT and SDMT baseline scores were worse for MS patients compared to HC, only the SLT scores continued to document worse performance in the MS group throughout the 1-year observation period. Moreover, SLT showed no learning effects and thus may be a particularly suitable measure of therapeutic intervention outcomes. Disclosure Joshua Bacon: This research was supported by a Grant for Multiple Sclerosis Innovation (GMSI) award (Serono EMD) Tamar Bacon: Nothing to disclose. Zoe Rimler: Nothing to disclose. Ilya Kister: Served on scientific advisory board for Biogen Idec and received research support from Guthy-Jackson Charitable Foundation,National Multiple Sclerosis Society, Biogen-Idec, Serono, and Navartis

P742 Cognitive evolution in Tysabri treated multiple sclerosis patients F. Jacques1, B.T. Harel2,3, A.J. Schembri4, C. Paquette1, B. Bilodeau1, P. Kalinowski4 1Clinique Neuro-Outaouais, Gatineau, QC, Canada, 2Cogstate, 3Yale Child Study Center, New Haven, CT, United States, 4Cogstate, Melbourne, VIC, Australia Background: Cognitive dysfunction affects up to 65% of MS patients and progresses over time. Natalizumab has shown to be superior to placebo in preserving cognitive function for the first two years of therapy. Objectives: The objectives of this study are to understand the impact of natalizumab on cognition beyond two years of therapy and to investigate whether baseline characteristics are predictive of clinical response. Methods: This is a single-center, 24-month, observational study. Sixty-three patients treated with natalizumab were assessed prior to monthly infusions using a Cogstate battery and the SDMT. A Beck Depression Index (BDI) was administered every 4 months. Patient demographics, including EDSS, MSSS, education level, age, MS disease duration, BDI scores, natalizumab treatment duration and presence of cognitive impairment, were collected at baseline. A linear mixed model was conducted with duration of natalizumab therapy as a between-subjects factor (< =2 or >2 years), assessment as a within-subjects factor, and MSSS as a covariate. All patients in the < =2 years group were treated with


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Poster Session 2, 21(S11) natalizumab for less than two years prior to baseline. All patients in the >2 years group were treated with natalizumab for at least two years prior to the baseline (mean 3.6 years). Results: There were no statistically significant differences between the key demographic variables aside for the MSSS (p=.0074). No patient showed evidence of sustained cognitive deterioration over the 24 month period. Irrespective of time on natalizumab, significant improvements were observed at the group level in executive function, verbal memory and working memory, whereas processing speed and attention remained unchanged. Impaired cognition or any other baseline parameter did not influence the trajectory of cognitive change over 24 months. Conclusions: Our results suggest that natalizumab preserves cognitive function, including the ability to learn, for 4 years and beyond of continuous therapy. This occurs irrespective of baseline characteristics.

to CDMS, 2005 and 2010 criteria respectively. In a multivariate analysis, the number of periventricular lesions is the only predictor of conversion according to all 3 criteria (p< 0.001), while presence of at least one T1-enhanced lesion after Gadolinium injection is predictive of conversion according to the 2010 criteria only (p< 0.0001). In a univariate analysis, presence of cerebrospinal fluid oligoclonal bands is predictive of conversion according to 2005 criteria (p< 0.05) but not according to 2010 criteria (p=0.051). Sixteen patients (14%) with MS at first MRI were proposed a disease modifying drug before conversion according to the 2005 criteria. Conclusions: This prospective cohort provides real-life data and confirms that 2010 criteria are more sensitive for MS diagnosis than 2005 criteria and CDMS. However, they seem to accelerate treatment initiation only for a little part of patients with MS at first MRI. Disclosure

Disclosure Dr. Jacques has received honorariums from several companies. Clinique Neuro-Outaouais operates an infusion clinic where Tysabri is administered. Drs. Harel, Schembri and Kalinowski are full time employees of Cogstate, the company that provided the tests used in this study. The study was funded by an unrestricted grant from Biogenidec.

E Thouvenot has received honoraria, travel grants or research grants from the following pharmaceutical companies: Biogen, Genzyme, Merck Serono, Novartis, Teva Santé. D Audry-Chaboud, G Castelnovo, R Benrabah and M Coustans received honoraria from Teva Santé. B Salin is employee of Teva Santé. N Lemaire has nothing to disclose. This study was funded by Teva Santé.

Poster Session II

P743 Characteristics of a French prospective cohort of 233 clinically isolated syndrome patients and predictive factors of conversion to multiple sclerosis E. Thouvenot1,2,3, D. Audry-Chaboud4, G. Castelnovo1, R. Benrabah5, N. Lemaire6, B. Salin7, M. Coustans8 1CHRU Caremeau, Nîmes, 2Institut de Génomique Fonctionnelle, UMR 5203, 3Université Montpellier, Montpellier, 4Cabinet de Neurologie, Dijon, 5CHNO des Quinze-Vingts, Paris, 6Axonal, Nanterre, 7Teva Santé, La Défense, 8CHI de Cornouaille, Quimper, France

P744 STAR-MS study: single test to ARrive at MS diagnosis. A prospective, investigator blinded pilot study, assessing the accuracy of a single 3 Tesla MRI scan in predicting multiple sclerosis in cases of diagnostic uncertainty: study protocol A.P. Samaraweera1, M. Clarke2, Y. Falah1, O. Mougin3, A. Pitiot4, C.R. Tench1, R.A. Dineen5, P.S. Morgan6, N. Evangelou1 1Division of Clinical Neuroscience, University of Nottingham, 2Clinical Neurology, Nottingham University Hospitals NHS Trust, 3Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, 4School of Psychology, University of Nottingham, 5Radiological Sciences, 6Medical Physics, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

Background: 2010 McDonald’s criteria allow performing multiple sclerosis (MS) diagnosis on a single MRI after a clinically isolated syndrome (CIS), but treatment initiation seems to be limited at this stage of the disease. Objectives: To describe the explorations and management of CIS patients in a prospective cohort and describe the conversion rate at 2 years according to their initial characteristics. Methods: 252 patients with a CIS were prospectively included by 59 neurologists from public and private sectors over a 9-months period. Initial and prospective follow-up clinical and MRI data allowed comparing the conversion rate to MS according to clinically definite MS (CDMS), 2005 and 2010 criteria, as well as MRI parameters, disability progression (EDSS), lab tests results and initiation of disease modifying drugs. Results: Complete data were available for 233 patients, 26.2% of which had MS according to their first MRI (2010 criteria). Conversion rates at 2 years were 38.4%, 46.8 and 55.2% according

Background: There is no Magnetic Resonance Imaging (MRI) biomarker for the diagnosis of multiple sclerosis (MS). However the presence of white matter lesion (WML) central veins (CV) detected using T2* weighted imaging is proving promising. Objectives: To confirm in a prospective study with a cohort of patients with diagnostic difficulties, if there is a difference in the proportion of CV:WMLs in patients with MS and non-MS. This group has been chosen, as they provide uncertainty for patients and clinicians and we believe this is where the test will be most useful. Method: We want to identify a difference in the proportion of CV:WMLs in patients with MS and non-MS (based on previous data that estimated a mean proportion of approximately 60% in MS patients and 6% in ischaemic patients) with an alpha level of 0.05 and power of 80%. Patients with ambiguous diagnoses but possible demyelination are being scanned once using 3D FLAIR, T2*, PSIR and DIR. We aim to recruit 60 patients in one year.

Diagnosis and differential diagnosis

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Sensitivity, specificity, positive and negative predictive values and receiver operating characteristic curves will be calculated to identify the optimum proportion of CV:WMLs to make a diagnosis of MS. Patients will be followed up by their treating neurologist until a diagnosis is confirmed. The MRI will then be reviewed and a diagnosis of MS or non-MS made, based on the proportion of CV:WMLs. The diagnostic value of central veins will be compared with DIR/PSIR detected cortical lesions. The study is supported by the Nottingham University Hospitals Charity (Research Ethics Committee number: 15/NW/0286). Discussion: To our knowledge this is the first prospective study using T2* weighted imaging and clinically available 3T MRI scanners to confirm if the central vein sign is specific for MS.

Results: In the autopsy case, perivascular inflammation dominated by CD4+ T cells was not only detected in brainstem and cerebellum but also in brain areas with normal appearance on 3.0 T MRI, including supratentorial regions and cranial nerve roots. There was no evidence of lymphoma in any of the 4 patients. 7.0 T MRI revealed supratentorial lesions and perivascular pathology in vivo with most of the contrast enhancing lesions being centered around a small vessel. Ultrahigh field MRI also disclosed prominent T1 hypo-intensities in the brainstem, which were not seen on 3.0 T MRI. This corresponded to neuropathological detection of axonal injury in the autopsy case. Conclusion: Our findings suggest a more wide-spread perivascular inflammation and postinflammatory axonal injury in patients with CLIPPERS.

Disclosure Dr Samaraweera: nothing to disclose; Margareta Clarke: nothing to disclose; Dr Falah: nothing to disclose; Dr Mougin: nothing to disclose; Dr Pitiot: nothing to disclose; Dr Tench: nothing to disclose; Dr Dineen: nothing to disclose; Professor Morgan: nothing to disclose; Dr Evangelou: nothing to disclose. P745 CLIPPERS as a differential diagnosis to multiple sclerosis: evidence from pathology and 7T MRI M. Blaabjerg1,2, K. Ruprech3,4, T. Sinnecker4,5, D. Kondziella6, T. Niendorf7,8, B.M. Kerrn-Jespersen9, M. Lindelof9, H. Lassmann10, B.W. Kristensen11, F. Paul4,5,7, Z. Illes1,2 1Odense University Hospital, Dept of Neurology, 2Institute of Clinical Research, University of Southern Denmark, Odense, Denmark, 3Dept of Neurology, Charité - Universitätsmedizin Berlin, 4Clinical and Experimental Multiple Sclerosis Research Center, Charité - Universitätsmedizin Berlin, 5NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany, 6Dept of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, 7Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, 8Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine, Berlin, Germany, 9Dept of Neurology, Herlev Hospital, Herlev, Denmark, 10Center for Brain Research, Medical University of Vienna, Vienna, Austria, 11Dept. of Pathology, Odense University Hospital, Odense, Denmark Background: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) was recently described as a rare neuroinflammatory disorder of the brainstem and surrounding structures. While few case reports suggested the possibility of other diseases such as multiple sclerosis and a pre-lymphoma state, the cause of the disease is unknown and in-depth pathological and radiological studies are scarce. Methods: We performed a detailed neuropathological examination in 4 cases including one autopsy case, and studied two additional patients by ultrahigh field MRI at 7.0 Tesla (T).

Disclosure Dr. Morten Blaabjerg has received travel grants and speaking fees from Biogen Idec, Merck Serono, Sanofi-aventis/Genzyme, Teva Pharmaceuticals, and UCB. Dr. Zsolt Illes has received research support from Biogen Idec and travel grants and speaking fees from Bayer Healthcare, Biogen Idec, Merck Serono, Sanofi-aventis/Genzyme, Teva Pharmaceuticals, and Novartis. Dr. Friedemann Paul has travel reimbursement, speaker honoraria, personal compensation for serving on steering committees and advisory boards and research support from Biogen, Bayer, Teva, Alexion, MedImmune, Chugai, Novartis, Merck, SanofiGenzyme. Dr. Klemens Ruprecht has received research support from the German Ministry of Education and Research (BMBF/KKNMS, Competence Network Multiple Sclerosis) and Novartis as well as travel grants from the Guthy Jackson Charitable Foundation and speaking fees and travel grants from Bayer Healthcare, Biogen Idec, Merck Serono, Sanofi-aventis/Genzyme, Teva Pharmaceuticals, and Novartis. Dr. Thoralf Niendorf is founder and CEO of MRI.TOOLS GmbH, Berlin, Germany. Dr. Tim Sinnecker has received travel grants from Novartis, Bayer and Teva. Drs. Bjørg Morell Kerrn-Jespersen, Daniel Kondziella, Mette Lindelof, Bjarne Winther Kristensen and Hans Lassmann have nothing to disclose. Study funding: Lundbeckfonden and Scleroseforeningen (Denmark) to ZI; Deutsche Forschungsgemeinschaft (Exc 257) and the German Ministry for Education and Research (BMBF Competence Network Multiple Sclerosis) to FP. German Ministry for Education and Research (BMBF Competence Network Multiple Sclerosis) to KR. P746 Use of multiple biomarkers to improve the prediction of multiple sclerosis in patients with clinically isolated syndromes V. Martinelli, G. Dalla Costa, M.J. Messina, G. Di Maggio, L. Moiola, M. Rodegher, B. Colombo, L. Leocani, R. Furlan, G. Comi Neurological Department, San Raffaele Hospital, Milan, Italy Background: The early identification of CIS patients at high risk of Clinically Definite Multiple Sclerosis (CDMS) represents the


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Poster Session 2, 21(S11) main purpose of diagnostic criteria and of clinicians in everyday clinical practice. Objective: To investigate whether the incorporation of different biomarkers in a model with established MRI criteria improves the prediction of MS. Methods: We evaluated baseline clinical data as well as MRI, multimodal evoked potentials and cerebrospinal fluid (CSF) data of patients with a first demyelinating episode. We used discrimination and calibration characteristics and reclassification of risk categories to assess incremental utility of different biomarkers for CDMS prediction. Results: During follow-up (median 7.2 years), 127 of the 243 participants in our study (mean age 31.6 years) developed a second clinical attack (CDMS). In Cox proportional-hazards models adjusted for established MRI criteria, age at onset, number of T1 lesions and presence of CSF oligoclonal bands significantly predicted the risk of developing MS within 2 and 5 years. The C-statistic increased significantly when the three biomarkers were incorporated into a model with established MRI criteria, both at 2 years (C-statistic with biomarkers vs. without biomarkers, 0.74 vs. 0.69) and at 5 years (0.70 vs. 0.66). The use of multiple biomarkers led to a 29% net-reclassification improvement at 2 years (p < 0.001) and 30% at 5 years (p < 0.001). Conclusions: The simultaneous addition of several biomarkers improves the risk stratification for MS in patients with clinically isolated syndromes beyond that of a model that is based only on MRI criteria. Disclosure V. Martinelli has received personal compensation for activities with Biogen Dompe, Merck Serono, Bayer Schering, Teva and Sanofi Aventis as a speaker. G. Dalla Costa, M.J. Messina, G. Di Maggio, L. Moiola, M. Rodegher, B. Colombo, L. Leocani, R. Furlan report no disclosures. G. Comi has received compensation for consulting services and/or speaking activities from Bayer Schering Pharma AG, Serono Symposia International Foundation, Merck Serono International, Teva, Sanofi-Aventis and Biogen Dompe.

MS Variants P747 Antibody to myelin oligodendrocyte glycoprotein in adults with inflammatory demyelinating disease of the CNS S.-M. Kim1, M. Woodhall2, J.-S. Kim3, S.-J. Kim4, K.S. Park5, A. Vincent2, B. Kim1, S. Cheon1, K.-W. Lee1, P. Waters2 1Neurology, Seoul National University College of Medicine, Seoul, Republic of Korea, 2Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxfordshire City, United Kingdom, 3Korea University Guro Hospital, 4Department of Ophthalmology, Seoul National University College of Medicine, Seoul, 5Neurology, Seoul National University Bundang Hospital, Seoung Nam City, Republic of Korea Background: Several recent studies have shown the presence myelin-oligodendrocyte glycoprotein antibodies (MOG-Ab) in the serum of adult patients with the NMOSD phenotype. However, the clinical relevance of MOG-Abs among adult patients with inflammatory demyelinating disease (IDD) is not yet clear, and

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there are some differences between the assays used. Here, using an improved cell based assay method a large number of sera from adults with IDD, and controls, were tested for antibodies to MOG and AQP4. Objective: To evaluate the clinical relevance of myelin-oligodendrocyte glycoprotein antibody (MOG-Ab) in a large cohort of consecutive adult patients with IDD of the CNS. Methods: Live cell based assays for antibodies to MOG-Ab (IgG1 antibodies only) and aquaporin-4 (AQP4-Ab) were performed in a cohort of 288 adult patients with IDD and in 72 controls. Results: Eighteen patients with IDD (6.3%) had MOG-Ab and fifty patients (17.4%) had AQP4-Ab; none had both antibodies. The MOG group tended to manifest with symptoms of isolated optic neuritis (15/18, 83%). All relapses in the MOG group involved only the optic nerve and those that relapsed did so within 1 year of disease onset. At onset, MRI in the MOG group uniquely demonstrated extensive peri-neural enhancement (6/18; 33%). They had fewer brain abnormalities and less periventricular lesions than the MS group, and fewer patients with spinal involvement than the AQP4 groups. There was no female bias in the MOG group and none of them met the criteria for definite NMO. In the MOG group, 3/13 monophasic patients suffered a poor visual outcome (< 0.2) or paraplegia from the initial attack, while 1/5 relapsing patient suffered poor visual outcome due to repeated optic neuritis. Conclusions: MOG-Ab may be a disease specific biomarker in adult patients with IDD who have a disease distinct from NMO or MS. Some patients with MOG-Ab may be left with severe disability, most often after the initial attack suggesting the need for early active immune modulating or suppressing treatment. Disclosure Sung-Min Kim: nothing to disclose Mark Woodhall: nothing to disclose Ji-Sun Kim: nothing to disclose Seong-Joon Kim: nothing to disclose Kyung Seok Park: nothing to disclose Angela Vincent: nothing to disclose Bongje Kim: nothing to disclose Soyoung Cheon: nothing to disclose Kwang-Woo Lee: nothing to disclose Patrick Waters: nothing to disclose P748 Novel multiple sclerosis phenotypes are associated with differences in cognitive disability A. Fontes-Villalba1, Y.-C. Lee1, E.K.Y. Cheung2, A.J. Schembri3, W.R. McMahon3, J. Parratt4 1Neurology, Royal North Shore Hospital, 2University of Sydney, Sydney, NSW, 3Cogstate Ldt., Melbourne, VIC, 4Royal North Shore Hospital, Sydney, NSW, Australia Background: Cognitive decline is common among multiple sclerosis (MS) patients and is associated with cerebral atrophy and lesion load. The distribution of lesions within the brain exerts some influence over the pattern of cognitive deficit but more broadly, the effects of MS lesion topography on cognition are unknown.


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Objective: To identify differences in cognitive function between novel phenotypes of MS using lesion topography for classification. Methods: Sixty nine patients with clinically definite MS (RRMS=57, SPMS=10, PPMS=2) underwent a computerized neuropsychological assessment (Cogstate) consisting of the Detection (DET), Identification (IDN), One Card Learning (OCL) and One Back (ONB) tasks, and the Groton Maze Learning Test (GMLT). These tasks measured information processing speed, visual attention, visual learning, working memory and attention, and spatial working memory, respectively. The results were correlated with five phenotypes based on the distribution of lesions enumerated by MRI - the clinico-radiological class (CRC) composing of cortical (cMS=4), deep white matter (dwMS=28), brain stem/cerebellar (bcMS=2), spinal-predominant (sMS=11), and generalized (gMS=24) MS. Other covariates included Lublin’s phenotypes, EDSS and level of education. The data were analysed using ANOVA and ANCOVA accounting for multiple tests and interactions with a p value set at < 0.05. Results: The GMLT differed significantly (sig < 0.001) between the CRC with the best performance for bcMS (mean = 38.0, SD = 11.3) and the worst for cMS (mean = 93.8, SD = 97.6) but the CRC did not influence other cognitive parameters. Progressive forms of MS had significantly worse GMLT scores (mean = 75.7, SD = 57.0 in SPMS/PPMS vs. mean = 52.1, SD = 17.4 in RRMS), IDN (mean = 2.8, SD = 0.1 vs. mean = 2.7, SD = 0.1), OCL (mean = 0.9, SD = 0.1 vs mean = 1.00, SD = 0.1) and ONB (mean = 3.4, SD = 0.1 vs mean = 2.9, SD = 0.1). After controlling for EDSS and educational level, both CRC and Lublin’s phenotypes predicted the GMLT. Conclusions: Spatial working memory is maximally impaired in cortical MS and varies according to the MS phenotype. Progressive MS is characterised by cognitive impairment in multiple domains. The phenotypic classification of MS may distinguish a group at high risk of cognitive problems earlier during the disease course.

CNS. The identification of specific antibodies directed to aquaporin 4 (AQP4-IgG) led to the distinction from multiple sclerosis (MS). However, up to 25% of the clinically diagnosed NMO patients are seronegative for AQP4-IgG. A subgroup of these patients might be identified by antibodies directed to myelin oligodendrocyte glycoprotein (MOG-IgG). We investigated whether the clinical characteristics of these patients differ. Methods: Using a cell based assay, we analysed 57 AQP4-IgG seronegative patients and 43 AQP4-IgG seropositive patients with clinically NMOSD. Two of the AQP4-IgG seropositive patients were also positive for MOG-IgG and were excluded from statistical analysis. Clinical characteristics of the AQP4-IgG, MOG-IgG seropositive and double seronegative NMOSD patients were compared. Results: 18 of the 57 AQP4-IgG seronegative patients tested MOG-IgG seropositive (32%). MOG-IgG seropositive patients were more frequently males in contrast to AQP4-IgG seropositive patients (56% versus 12%, p = 0.001). They more frequently presented with coincident optic neuritis (ON) and transverse myelitis (TM) (44% versus 15%, p = 0.021) and have a monophasic disease course (72% vs 29%, p = 0.002). AQP4-IgG seropositive patients were 2.5 times more likely to suffer from relapses as compared with MOG-IgG seropositive patients (RR 2.55, 95% CI 1.47 - 5.60). AQP4-IgG seropositive patients with ON had worse visual acuity at nadir (p = 0.023) and higher EDSS levels at last follow-up (p = 0.039). Conclusion: Antibodies directed to MOG identify a subgroup of AQP4-IgG seronegative NMO patients with generally a favourable monophasic disease course. Disclosure E Daniëlle van Pelt: nothing to disclose. Yuyi YM Wong: nothing to disclose. Immy A Ketelslegers: nothing to disclose. Dörte Hamann: nothing to disclose. Rogier Q Hintzen: nothing to disclose.

Disclosure Ariadna Fontes-Villalba: nothing to report. Yi-Ching Lee: nothing to report. Emily Ka Yan Cheung: nothing to report. Adrian J Schembri is full-time employee of Cogstate, the company that provided the tests used in this study. William R McMahon is part-time employee of Cogstate, the company that provided the tests used in this study. John Parratt: nothing to report. P749 Neuromyelitis optica spectrum disorders: comparison of clinical and MRI characteristics of AQP4-IgG versus MOG-IgG seropositive cases in the Netherlands E.D. van Pelt1, Y.Y. Wong1, I.A. Ketelslegers1, D. Hamann2, R.Q. Hintzen1 1Erasmus Medical Centre, Rotterdam, 2Immunopathology and Blood Coagulation, Sanquin Diagnostic Services, Amsterdam, The Netherlands Background: Neuromyelitis optica spectrum disorders (NMOSD) are a group of rare inflammatory demyelinating disorders of the

P750 Seasonal variation of acute exacerbations in neuromyelitis optica spectrum disorder D.W. Bae1, S.-H. Kim2, J.-W. Hyun2, I.H. Jeong2, S.-Y. Huh3, M.-S. Park4, H.J. Kim2, W. Kim1 1The Catholic University of Korea, Seoul, 2Research Institute and Hospital of National Cancer Center, Goyang, 3Kosin University College of Medicine, Busan, 4Yeungnam University College of Medicine, Daegu, Republic of Korea Background: Environmental factors related to season, including ultraviolet radiation, vitamin D, and infective agents, interplay with genetic factors in the development of autoimmune diseases. In multiple sclerosis, several studies have described the seasonality of relapses, which occur more frequently in spring and summer. However, in neuromyelitis optica spectrum disorders (NMOSD), only a few small cohort studies reported no seasonal variation of clinical exacerbations. Objectives: We aimed to determine whether seasonal variation of acute NMOSD exacerbation is observed in a large Korean cohort. Methods: We included 236 consecutive NMOSD patients seropositive for anti-aquaporin-4 antibody from four referral hospitals


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Poster Session 2, 21(S11) in Korea from May 2005 to April 2015. Medical records of demographic and clinical findings, including age, gender, dates of each attack and last follow-up were retrospectively reviewed and only clinically documented exacerbations were considered a definite attack in order to avoid ascertainment and recall bias. Attacks were divided into myelitis, optic neuritis, and brain manifestations with attacks presenting more than one kind of symptom being counted repetitively. Seasons were defined as spring (MarchMay), summer (June-August), autumn (September-November) and winter (December-February). We performed chi-squre tests with a significance level of P < 0.05 to compare the observed numbers of attacks. Results: A total of 1306 attacks from 236 patients (88% female) were identified for a mean follow-up duration of 125 months. The onset of the disease showed no seasonal pattern of variation. Acute exacerbations were most common in winter (355), followed by summer (336), spring (321), and autumn (294) although the differences were not statistically significant. The frequency of exacerbations was highest in January (147) and lowest in October (88). Among the attack symptoms, myelitis was most common (632), followed by optic neuritis (418) and brain symptoms (221). However, their occurrence did not vary markedly with month or season. Conclusions: In Korean cohort of NMOSD, acute attacks appear to occur more commonly in winter, particularly in January, although significant seasonality of attacks was not seen. Larger, nationwide data collection is undergoing. Disclosure W. Kim: nothing to disclose. D.W. Bae: nothing to disclose. S.-H. Kim: nothing to disclose. J.-W. Hyun: nothing to disclose. I.H. Jeong: nothing to disclose. S.-Y. Huh: nothing to disclose. M.-S. Park: nothing to disclose. H.J. Kim has received honoraria for speaking or consulting from Bayer Schering Pharma, Biogen Idec, Genzyme, Merck Serono, and Novartis. P751 Treatment of neuromyelitis optica with rituximab: further insights on efficacy, safety and dosing regimen from 73 Italian patients P. Annovazzi1, M. Capobianco2, L. Moiola3, F. Patti4, J. Frau5, A. Uccelli6, D. Centonze7, P. Perini8, C. Tortorella9, L. Prosperini10, G. Lus11, A. Fuiani12, M. Falcini13, G. Comi3, A. Ghezzi1 1Multiple Sclerosis Study Center, Sant’Antonio Abate Hospital, Gallarate, 2Regional MS Center - University Hosptal S.Luigi Gonzaga, Orbassano, 3Department of Neurology, San Raffaele Scientific Institute, University Vita-Salute San Raffaele, MIlano, 4Multiple Sclerosis Center, University of Catania, Catania, 5Multiple Sclerosis Center, University of Cagliari, Cagliari, 6Department of Neurosciences Ophtalmology and Genetics, University of Genoa, Genova, 7Neurology Clinic, Department of Systems Medicine, University of Tor Vergata, Roma, 8Neurological Department, Azienda Ospedaliera Università di Padova, Padova, 9Department of Medical

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Sciences, Neurosciences and Sense Organs, University of Bari, Bari, 10Department of Neurology and Psychiatry, Sapienza University, Roma, 11Multiple Sclerosis Center Second Division of Neurology, Department of Clinical and Experimental Medicine and Surgery ‘F Magrassi e A Lanzara’, Second University of Naples, Napoli, 12Department of Neurosciences, Multiple Sclerosis Unit - General Hospital ‘OORR’, Foggia, 13Multiple Sclerosis Center, Ospedale Misericordia e Dolce, Prato, Italy Background: Neuromyelitis Optica (NMO) is a severely disabling disease; no treatment is currently approved. Rituximab (RTX) is an anti-CD20 monoclonal antibody whose efficacy in NMO is suggested by few case series, but no consensus exists on optimal dosing strategy. Methods: Data on NMO patients treated with RTX were collected from thirteen Italian Hospitals using a standardized form. Results: 73 patients (64 F), with a mean age of 46,4 +/- 12 years were enlisted. Mean disease duration at RTX start was 9 +/- 7,5 years, median EDSS was 5,5 (range 3,5-7). Mean relapse rate (ARR) one and two years before RTX start was respectively 2,3 +/- 1,3 and 2,6 +/- 1,9. RTX dosage regimens used were either 375 mg/m2/week for 4 weeks (RTX-A: 42/73), or 1000 mg iv twice, two weeks apart (RTX-B: 31/73). Mean follow-up was 35,6 +/- 27 months. All patients completed a 12 months follow-up, 42/73 a 24 months follow-up. RTX was re-administered in 51/73 patients (24/42 on RTX-A; 27/31 on RTX-B). Reasons for re-administration were “on demand” (that is the occurrence of a relapse or a raise in CD19/CD20+ cells) in 31/51 patients, or “pre-planned”, according to a 6 months schedule, in 20/51 patients. ARR 12 and 24 months after RTX was respectively 0,5 +/- 0,8 and 0,6 +/- 1,2. Stratifying for dosage regimen, ARR in the first year of follow-up was 0.8 +/- 0.9, for RTX-A and 0.2 +/- 0.4 for RTX-B (p = 0.01), in the second year was 0.9 +/- 1.5 for RTX-A and 0.4 +/- 0.8 for RTX-B (p = 0.1). 38/73 patients are relapse-free at follow up. Mean EDSS at follow-up was 4,4 +/- 2,1.RTX-B was more effective in delaying the occurrence of a relapse compared to RTX-A (HR 2.2 (1.08-4.53) p = 0.02). A multivariable analysis considering predictors of ARR over the first two years after RTX showed that first dose RTX scheme was the only variable correlated with such outcome (p = 0.009). Neither baseline patients characteristics, nor RTX re-dosing schedule were significantly correlated. Severe adverse events were reported in 19/73 patients (mainly respiratory and infusion reactions). Two severely disabled patients died more than 2 years after RTX last infusion. Conclusions: Even though with the limitations of an observational study, our data give further proof of RTX efficacy and safety in NMO. RTX 1000 mg iv twice, two weeks apart seems to be the preferable dosing regimen, suggesting that a higher RTX first dose is favourable over a lower dose repeated over a longer time period. Disclosure PA declares no disclosures related to this project/manuscript. MC received speaking honoraria and/or consultant fees from Biogen, Merck-Serono, Novartis, Teva, Genzyme and Almirall. LM received speaking honoraria from Sanofi-Aventis, Biogen and Merck Serono. FP declares no disclosures related to this project/manuscript.


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JF declares no disclosures related to this project/manuscript, AU declares no disclosures related to this project/manuscript, DC declares no disclosures related to this project/manuscript PP received speaking honoraria and/or consultant fees from Biogen, Merck Serono, Teva, Novartis, Genzyme. CT received speaking honoraria and/or consultant fees from Biogen, Merck-Serono, Novartis, Teva, Genzyme and Bayer-Shering. LP has received consulting and/or lecture fees and/ot travel grants from Bayer Schering, Biogen Idec, Genzyme, Novartis and Teva. GL declares no disclosures related to this project/manuscript AF received speaking honoraria and/or consultant fees from Biogen, Novartis, Teva. MF received honoraria for speaking and FAD from TEVA; research grants from Novartis. GC has received honorarium in the past 12 months for consulting services and/or speaking activities from Genzyme, Novartis, Teva, Merck Serono, Biogen, Serono Symposia International Foundation, Roche, Almirall, Chugai, Receptos. AG declares no disclosures related to this project/manuscript. P752 Aquaporin-4-autoimmunity and association to systemic lupus erythematosus. A predominantly population-based study N. Asgari1,2, S. Jarius3, H. Laustrup4, S.T. Lillevang5, A. Voss4 1Department of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark, Odense, 2Department of Neurology, Vejle Hospital, Vejle, Denmark, 3Department of Neurology and Molecular Neuroimmunology, University of Heidelberg, Heidelberg, Germany, 4Department of Rheumatology, 5Department of Clinical Immunology, Odense University Hospital, Odense, Denmark Background: Serum immunoglobulin G targeting the astrocyte water channel aquaporin-4 (AQP4) in the central nervous system (CNS) is a biomarker for neuromyelitis optica spectrum disease (NMOSD). The clinical features of NMOSD include inflammation of the optic nerve, the spinal cord and specific brain areas, which coincide with sites of high AQP4 expression. Co-existence between NMOSD and Systemic Lupus Erythematosus (SLE) suggests a general susceptibility to antibody-mediated autoimmune diseases. Objective: To investigate the immunogenetic background for an association of NMOSD and SLE as antibody-mediated autoimmune diseases. Methods: The study included a predominantly population-based retrospective case series with clinical and serological investigations of 208 patients with SLE, followed prospectively since 1995. All patients received immunosuppressive treatment. All patients fulfilled the American College of Rheumatology criteria for SLE. NMOSD was evaluated retrospectively based on the criteria of Wingerchuk (2006). Determination of AQP4-IgG and other autoantibodies was performed blindly as previously described1. Results: Of 208 patients with SLE 45 had a medical history of neuropsychiatric (NP) SLE, and of these 30 predominantly CNS involvement. Serum AQP4-IgG was detected in two of 30 NPSLE patients with CNS involvement. These two patients suffered from NMOSD with signs of transverse myelitis. One of these patients additionally had myasthenia gravis. Investigation of other autoantibodies as well as genetic markers is in progress.

Conclusion: AQP4-IgG autoimmune syndrome seems to occur rarely in SLE patients. However, immunosuppressive treatment may limit autoantibody formation. 1- Asgari N, Nielsen C, et al., HLA, PTPN22 and PD-1 associations as markers of autoimmunity in neuromyelitis optica. Mult Scler 2012; 18:23-30 Disclosure Asgari N: report no disclosures. Jarius S: report no disclosures. Laustrup H: report no disclosures. Lillevang ST: report no disclosures. Voss A: report no disclosures. P753 Adult- versus pediatric-onset acute disseminated encephalomyelitis: is there a difference? A retrospective, multi-center cohort study D.L.H. Koelman1,2, S. Chahin3, S.S. Mar4, A. Venkatesan5, G.M. Hoganson4, A.K. Yeshokumar5, P. Barreras5, B. Majmudar4, T. Chitnis1, F.J. Mateen1,6 1Department of Neurology, Massachusetts General Hospital, Boston, MA, United States, 2Academic Medical Center, Amsterdam, The Netherlands, 3Department of Neurology, University of Pennsylvania, Philadelphia, PA, 4Department of Neurology, Washington University School of Medicine, St. Louis, MO, 5Department of Neurology, John Hopkins University School of Medicine, Baltimore, MD, 6Harvard Medical School, Boston, MA, United States Background: Since acute disseminated encephalomyelitis (ADEM) is usually diagnosed in children, most studies have focused on pediatric-onset ADEM. Little is reported on adultonset ADEM and age-of-onset related differences. Objective: To determine whether there are differences in risk factors, presentation, and outcomes between pediatric (< 18y) and adult-onset cases (⩾18y) initially diagnosed as ADEM at four academic medical centers in the United States. Methods: Demographic, clinical, magnetic resonance imaging, and cerebrospinal fluid (CSF) features at the first clinical presentation, leading to the initial diagnosis, were collected. Patient outcomes were tracked for subsequent events, time to a competing diagnosis, and functional outcomes. Cox proportional hazards models were constructed for time to presentation of a demyelinating disease relapse using the potential associations of age, sex, and encephalopathy. Results: There were 230 patients (123 children, 106 male, mean follow up: 46 months, median age children: 7, median age adults: 37, range: 1-72). In patients who remained monophasic, adultonset was associated with the absence of encephalopathy (57% vs. 74%, p=0.028), fever (26% vs. 60%, p< 0.001), and nausea and/or vomiting (28% vs. 49%, p=0.009); with the presence of sensory abnormalities (43% vs. 14%, p< 0.001); elevated CSF protein (70% vs. 37%, p< 0.001); periventricular lesions (52% vs. 28%, p=0.003); and corpus callosum involvement (39% vs. 10%, p< 0.001). Outcome was less often favorable in adults (modified Rankin scale score ⩽ 2, 68% vs. 92%, p< 0.001). Relapses were seen in similar proportions between adults (22%) and children (25%); however, relapsing disease in adults was more often


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Poster Session 2, 21(S11) diagnosed as multiple sclerosis (67% vs. 26%, p=0.003) and less often diagnosed as multiphasic ADEM (21% vs. 58% p=0.007) compared to relapsing disease in children. Increasing age (HR=0.981, 95% CI 0.965 - 0.998, p=0.025), male sex (HR=0.384, 95% CI 0.212 - 0.698, p=0.002), and presence of encephalopathy at initial presentation (HR=0.351, 95% CI 0.195-0.634, p< 0.001) were independently associated with a longer time to a demyelinating disease relapse. Conclusion: Adult-onset ADEM has clinically distinctive features from pediatric-onset ADEM and may lead to a longer time to relapse, but also a less favorable functional outcome. Age-specific guidelines for the diagnosis and treatment of ADEM may be valuable. Disclosure Diederik L.H. Koelman: nothing to disclose. Salim Chahin: nothing to disclose. Soe S. Mar: nothing to disclose. Arun Venkatesan: nothing to disclose. George M. Hoganson: nothing to disclose. Anusha K. Yeshokumar: nothing to disclose. Paula Barreras: nothing to disclose. Bittu Majmudar: nothing to disclose. Tanuja Chitnis: nothing to disclose. Farrah J. Mateen: nothing to disclose. P754 Prognostic factors in a cohort of neuromyelitis optica and neuromyelitis optica spectrum disorders A. Orviz-García, I. González-Suárez, J. Matías-Guiu, C. OrejaGuevara Neurology, University Hospital San Carlos, Madrid, Spain Introduction: Neuromyelitis optica (NMO) is a rare autoinmune disease of the central nervous system, affecting specially the spinal cord and optic nerves. It usually causes severe neurological disability with permanent secuelae, but not all patients have such a terrible course. Methods: Retrospective study of NMO and NMO spectrum disorders (NMOSD) was performed, from a consecutive sample at our Demielinating Disease Unit between April 2013 and January 2015. We revised demographic, clinical, AQP4 serostatus and MRI features to establish pronostic factors. Results: 26 patients were recruited, mean age at first relapse was 34 years-old. Male:female ratio resulted in 3:7, 80% belonged to caucasic ethnic group and 20% from Latin American. Median disease duration was 64 months and mean current EDSS scored 2.5. 45% presented antibodies antiAQP4 in serum. 61,5% had normal baseline brain MRI, 4/10 of abnormal ones showed specific area postrema lesions. Regarding clinical course, median number of relapses was 3. Time to second relapse was much longer after initial ON, specially bilateral, than after a TM, (21 and 36 months versus 9 months, significant trend: p=0,072). Cases with any abnormal baseline brain lesion trended to recur three times earlier than patients without lesions (6 vs 19 months p=0,055) even inmunosupresive treatment (IST) after first relapses, mainly azatioprine, was initiated on same proportion in both groups. Functional prognosis, measure by EDSS, depended on number of

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previous relapses but not on disease duration. Seropositivity showed no significant influence in time to second relapse or current EDSS, adjusted by number of previous relapses and earlier IS treatment. Conclusions: In our NMO/NMOSD cohort, initial ON and normal baseline brain MRI were associated with longer time to second relapse. The main risk factor for higher EDSS is the number of relapses. Seropositive patients have not worse disease course. Disclosure Aida Orviz-García received honoraria for speaking from Novartis Ines González-Suárez received honoraria for speaking from Biogen and Novartis Jorge Matias-Guiu: nothing to disclosure Celia Oreja-Guevara received honoraria for speaking and/or consultancy from Biogen, Genzyme, Bayer, Merck-Serono, Roche, Teva and Novartis P755 Neuromyelitis optica spectrum disorders: brain lesions in Venezuelans patients I. Soto1, O. Molina1, A. Soto2, E. Armas3, M. Castillo1, F. Hernandez1, E. Mora1, M. Ravelo4, O. Ferrer1, V. Villalobos1, Venezuelan Neuromyelitis Optica Study Group 1Neurology, Hospital Universitario de Maracaibo, Maracaibo, 2Neurology, Hospital Domingo Luciani, 3Neurology, Hospital Universitario de Caracas, 4Neurology, Hospital JM de los Rios, Caracas, Bolivarian Republic of Venezuela Background: Neuromyelitis optica (NMO) inflammatory demyelinating disease of central nervous system (CNS), selectively affects optic nerve and spinal cord. NMO was considered a disease without brain involvement. Since the discovered of NMO IgG /Anti Aquaporin 4 the concept of NMO broarded to NMO Spectro Disease, brain lesions are frequent associated with clinical and Brain Magnetic Resonance Imagen (BMRI), with characteristic configuration and location. Objectives: Demonstrate and describe the presence of brain lesions BMRI in NMOSD patients at Maracaibo University Hospital in Venezuela. Material and methods: A retrospective study was conducted in patients diagnosed with NMOSD at Maracaibo University Hospital to document brain lesions in BRMI . We reviewed files of 120 patients over a two year period in April 2013 - 2015. Results: 120 patients were seen at the Department of Demyelinating diseases in Maracaibo University Hospital in Venezuela. 85 patients with Multiple Sclerosis and 35 with NMOSD. Relative frequency 29%. Of these 35 NMOSD patients, 20 (57%) showed brain lesions, distributed as follows: Nonspecific lesions, punctate or patchy 7 patients, extensive large irregular cerebral hemispheres 8 patients, corpus callosum linear lesions 5 patients, hypothalamus lesions 2 patients, thalamus lesions 3 patients, periventricular lesions 5 patients, III and IV ventricle lesions 8 patients, cerebellum lesions 5 patients, optic lesions 1 patient and pyramidal tracts lesions 2 patients. Conclusion: It is important to recognise brain lesions in NMOSD. In Venezuela we observed a high relative frequency on the


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NMOSD 29%. One of the highest percentages in America. They show brain lesions in 57%. Disclosure Nothing to disclose P756 NMO severity is associated with the presence of AQP4-ab L. Campanella1, M. Alvarenga1, C. Vasconcelos1, L. Leyva2, Ó. Fernández2, R. Alvarenga1 1Clinical Neurology, UNIRIO, Rio de Janeiro, Brazil, 2Hospital Regional Universitario de Málaga, Málaga, Spain Introduction: Neuromyelitis optica (NMO) is a rare and grave syndrome, more frequent in non-white populations and the most recent diagnostic criteria is from 2006. Although there’s been more understanding about NMO, there are still few information about the factors that influence its prognostic. Objective: To analyze the influence of demographic, clinical and laboratorial features in NMO’s morbidity. Methodology: 65 NMO patients attended by our neurology team had their medical registers looked upon for: gender, ethnicity, age of onset, index event (IE), time gap between the IE, disease duration and the presence of AQP4-ab. It was applied a univariate analysis on these data to investigate possible factors involved in morbidity, represented by the outcome paraplegia and bilateral amaurosis. Results: All 65 patients filled the 2006 diagnostic criteria. Demographic and clinical data were harvest from all but one patient. The majority had a relapsing course (n=61). The disease started between the ages of 7 and 67 years old (mean=32.45±14.05; median=31.50). Transverse myelitis was the most frequent IE (n=31), followed by NO (n=23), brainstem syndrome (n=7), encephalopathy (n=2) and TM with NO within 24 hours (n=1). The IE NO was bilateral in 50% of the cases and unilateral in the other 50% and the IE TM was complete in 70% and partial in 30%. The median of the time gap between the IE was 10.0 months, varying from 1 day to 268 months. In the last follow up of these cases, after a mean time of 14.09±8.47 years, the sequelae found were grave visual dysfunction in at least 1 eye (70.8%), bilateral visual damage (44.6%), grave motor dysfunction in at least 1 limb (46.2%), paraplegia and amaurosis 33.8% and 29 patients died. Conclusion: The outcome paraplegia and bilateral amaurosis occurred in approximately one third of the patients. There was no association between gender, ethnicity, age of onset and clinical features. The disease duration was significantly lower in patients that met the outcome. Only the serum positivity of the AQP4-ab was associated with a more severe course of NMO.

P757 Comparison of revised 2014 NMO diagnostic criteria vs. 2006 criteria in a pediatric demyelinating cohort W. Meador1, Y. Harris1, S. Dowdy1, J. Ness2,3 1University of Alabama at Birmingham, 2Dept of Pediatrics, Division of Pediatric Neurology, University of Alabama at Birmingham, 3Childrens of Alabama, Birmingham, AL, United States Neuromyelitis optica (NMO) was initially defined as optic neuritis (ON) and transverse myelitis (TM) in the absence of brain involvement. With discovery of Aquaporin-4 (Aq4) seropositivity in NMO patients, the phenotype broadened to include brain lesions. NMO diagnostic criteria was revised in 2006 to include Aq4 seropositivity, longitudinally extensive TM (LETM) and brain MRI abnormalities. In 2014, NMO spectrum disease (NMOSD) criteria was further revised to incorporate brainstem syndromes plus diencephalic and cerebral syndromes. Objective: Determine the utility of revised 2014 NMO diagnostic criteria in a pediatric MS cohort. Methods: Pediatric demyelinating database from a tertiary children’s hospital with >450 demyelinatng patients followed prospectively since 2000 was queried for patients with ON, TM or brainstem syndromes. Cases were reviewed to determine whether they fulfilled 2006 or 2014 NMO spectrum disease (NMOSD) criteria. Results: NMOSD was diagnosed in 65 patients, with 34 (52%) meeting 2006 criteria requiring both LETM+ON (29% Aq4-Ab positive, n=10) and 31 (48%) meeting 2014 criteria but did not have both LETM + ON (42% Aq4-positive, n=13). Aq4-Ab positive patients were mostly female (87%, 20 of 23) and 74% African-American (17 of 23) with mean onset age12.0 ±4.2 years. In contrast, Aq4-Ab negative patients were significantly younger (9.1±3.6, p < 0.004), more likely to be Caucasian (74%, p< 0.0001) and less predominantly female (62%, p< 0.05). Encephalopathy was present at some point in 48% of Aq4-Ab negative patients (n=20) but only 9% (n-2) seropositive patients (P< 0.002). Brainstem symptoms were present in two-thirds of the entire cohort (n=43), with 8 presenting with area postrema symptoms of vomiting and hiccups (12%). No significant difference was found between patients meeting 2006 vs 2014 criteria with respect to age, race, sex, Aq4-Ab status or presence of brainstem symptoms. Conclusion: Application of revised 2014 NMO criteria enabled NMOSD diagnosis in nearly half of our 65 patients. Baseline demographics did not differ between patients meeting 2006 vs. 2014 critieria. However, Aq4-Ab status was associated with significant differences in age, race, sex and presence of encephalopathy. These findings support application of 2014 NMO diagnostic criteria in a pediatric population and suggest that Aq4-Ab seropositivity may distinguish biologically distinct sub-groups.

Disclosure Luiza Campanella: nothing to disclose Marcos Papais Alvarenga: nothing to disclose Claudia Cristina Vasconcelos: nothing to disclose Laura Leyva: nothing to disclose Óscar Fernández: nothing to disclose Regina Maria Papais Alvarenga: nothing to disclose Funding: Malaga Hospital (Spain) and UNIRIO (Brazil)

Disclosure Ness: Research funding from NIH and NMSS through the US Network of Pediatric MS Centers; study site for Novartis clinical trial Meador: Nothing to disclose Dowdy: Nothing to disclose Harris: Nothing to disclose


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Paediatric MS

Background: Urological symptoms associated with multiple sclerosis (MS) are common in adult patients. No literature is available about the relationship of paediatric MS and bladder function. The objective of this study is to evaluate the prevalence of bladder problems in patients with paediatric MS in the very early phase of their disease. Methods: Eighteen consecutive patients with newly diagnosed paediatric MS were prospectively assessed for bladder and bowel symptoms within the first 18 months after diagnosis. Urological screening included bladder and bowel diaries, uroflowmetry with post voiding residue and questionnaires. Furthermore, neurological characteristics like the Expanded Disease Status Scale (EDSS), and lesions on MRI were analysed. Results: The median age at diagnosis of MS was 13,4 years and the majority of the children were female (78%). Five of the 18 children (28%) showed voiding and bowel problems during assessment. One of these patient did not have voiding complaints. Symptoms of pyramidal syndrome and sensory problems at initial clinical presentation were associated with urinary symptoms (p=0.022 and p=0.036 respectively). No correlation between urological symptoms and specific MRI lesion locations could be found. Patients with bladder problems showed higher EDSS scores at onset (p=0.033), at time of screening (p=0.002) and at last follow-up (p=0.002), even after correction for the bowel/bladder functional score. Conclusion: A high prevalence of bladder symptoms was found in children with recently diagnosed paediatric MS. All patients with paediatric MS should already be assessed for urinary symptoms in an early stage of MS disease in order to initiate appropriate treatment if necessary.

binocular summation, may mitigate the effects of unilateral disease. The magnitude of binocular summation is preserved in pediatric MS compared to adult-onset disease. The mechanism for binocular summation is poorly understood but may represent a post-geniculate neural response. Magnetoencephalography (MEG) detects a gamma-band response in the occipital cortex indicative of neural processing of visual stimuli but has yet to be studied in MS. Aims: To determine whether a gamma-band response can be elicited using high- and low-contrast visual stimuli in pediatric MS and healthy controls and if the presence of the response indicates a greater capacity for binocular summation. Methods: Pediatric MS subjects, with and without a history of optic neuritis (ON), and healthy controls (corrected visual acuity >20/25) were recruited. Whole-head MEG recordings were conducted using a 275 channel system (VSM MedTech). Visual stimuli consisted of vertical, stationary, three cycles per degree, square-wave gratings presented separately at 100% contrast and 10% contrast to lower left and right of fixation (mean luminance background). Monocular and binocular high- and low-contrast (ETDRS and Sloan 1.25%) visual acuity were measured. The magnitude of binocular summation was calculated by subtracting the binocular score from the better eye score. Results: 13 subjects and 8 healthy controls were recruited. Using a high-contrast stimulus, a MEG gamma-band response was present in all control eyes but only 82% of MS non-ON eyes (p=0.07) and 66% of ON eyes (p=0.01). At 10% contrast, 63% of control eyes displayed a visual-gamma response compared to 38% of MS non-ON eyes (p=0.16) and 33% of ON eyes (p=0.21). The presence of a 10% gamma-band response corresponded to a lower magnitude of binocular summation using low-contrast charts, accounting for age, a history of ON, and inter-eye correlations (p=0.005). Conclusions: Cortical responses to high and low contrast visual stimuli can be detected in the eyes of healthy youth but are less commonly detected in children with MS, even without ON. Surprisingly, the presence of visual gamma did not predict a greater magnitude of binocular summation. Further investigation of the cortical thickness and other factors that may influence gamma response are underway.

Disclosure

Disclosure

YYM Wong: nothing to disclose. JR Scheepe: nothing to disclose. ED van Pelt: nothing to disclose. CE Catsman-Berrevoets: nothing to disclose. J van den Hoek: nothing to disclose. RQ Hintzen: nothing to disclose. Dr RF Neuteboom: nothing to disclose.

Amy Waldman: Funding from the National Institutes of Health (USA) and Biogen Idec. I am the site PI for a clinical trial sponsored by Novartis. Amy Lavery: nothing to disclose Laura Balcer: Consulting for Biogen and Gemzyme, clinical trial advisory board for Biogen Grant Liu: nothing to disclose Brenda Banwell: Advisor to Biogen Idec, Serono, and Novartis Tomas Aleman: nothing to disclose William Gaetz: nothing to disclose.

P758 Bladder problems in paediatric patients with multiple sclerosis in the early disease phase Y.Y.M. Wong1, J.R. Scheepe2, E.D. van Pelt1, C.E. CatsmanBerrevoets1, J. van den Hoek2, R.Q. Hintzen1, R.F. Neuteboom1 1MS Centre ErasMS, Neurology, 2Urology, Erasmus Medical Centre, Rotterdam, The Netherlands

P759 Decreased gamma-band oscillations in visual cortex in pediatric MS A.T. Waldman1, A.M. Lavery1, L.J. Balcer2, G.T. Liu1, B.L. Banwell1, T. Aleman1, W. Gaetz3 1Pediatric Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, 2New York University School of Medicine, New York, NY, 3Radiology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States Background: Monocular visual impairment is common in multiple sclerosis (MS) although compensatory mechanisms, such as

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P760 Dissemination in space involving the spinal cord and optic nerves: improving predictors for children with relapsing disease in a high NMO-risk, low MS-risk region T. Thomas1, S.R. Ling1, J. Lin2, C. Chow1, W.K. Liew1, S.K. Tay2, D.W. Chan1 1Neurology Service, Dept of Paediatrics, KK Women’s and Children’s Hospital, 2Division of Neurology, Dept of


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Paediatrics, National University Children’s Hospital, Singapore, Singapore Introduction: Immune demyelinating disorders frequently involve the optic nerves and spinal cord in South East Asian children. Current MRI predictors for relapsing disease focus on dissemination in space (DIS) involving the brain but not the optic nerves (ON) or spinal cord (SC). Methods: 2010 McDonald MRI criteria for DIS and dissemination in time (DIT) and MRI features of ON and SC disease were assessed in a cohort of children presenting with a first acute demyelinating syndrome (ADS) in Singapore from 2003-2014. Results: Seventy-two children with a first ADS were followed for a median of 4.8 (IQR 1.9, 7.0) years. Median age at presentation was 8.9 (IQR 5.1, 11.0) years. Optic nerve or SC involvement was observed in 30% of an acute disseminated encephalomyelitis (ADEM, n=33) and 87% of a non-ADEM (n=39) first ADS. Fifteen (21%) had relapsing disease: 4 with relapsing-remitting multiple sclerosis (MS), 3 had neuromyelitis optica (NMO), 5 with recurrent ADEM-ON and 3 with chronic recurrent inflammatory optic neuritis. Median time to a NMO or MS diagnosis was 3 (IQR 1, 14) months. Forty-nine children had a full set of brain, ON and SC MRI at first ADS. The requirement of either 1 of the 3 following SC/ON DIS items in addition to meeting 2010 McDonald MRI DIS/DIT criteria performed best in improving prediction for relapsing disease: the presence of (1) multiple longitudinally extensive spinal cord lesions (⩾ 3 contiguous vertebral bodies for each lesion, multi-LETM), (2) bilateral optic nerve disease or (3) simultaneous spinal cord and optic nerve disease (sensitivity 77.8 % (95% CI 40.0-97.2%), specificity 97.5 % (86.8-99.9%), positive predictive value 87.5 % (47.499.7%), negative predictive value 95.1% (83.5-99.4%), likelihood ratio 31.1, p< 0.0001). Discrete multifocal spinal cord lesions, optic chiasmal involvement or a unilateral longitudinally extensive optic neuritis (LEON) were not predictive. Conclusions: This preliminary data may suggest the utility of identifying DIS parameters for spinal cord and optic nerve disease to aid prediction for relapsing disease in cohorts at high-risk for NMO and spinal cord/optic nerve demyelination.

improvement, stability) across time. This may be related to baseline sample characteristics and inconsistent length of follow-up. Objectives: To determine the change in performance on the Symbol Digit Modalities Test (SDMT) after 5-year follow-up in pediatric MS. To also identify those baseline factors [parental education and occupation level as measured using the Barratt Simplified Measure of Social Status (BSMSS), age of disease onset, baseline IQ, disease duration at baseline] which may predict change in SDMT performance. Methods: SDMT data were combined from two pediatric MS longitudinal cohorts in Canada and Italy. The total sample comprised of 82 patients (n=55 from Italy, 51 female, mean age of onset=12, mean age=15 and disease duration=3.8 years at baseline) evaluated at baseline, 2-year, and 5-year follow-up. For each patient, slope values were calculated representing the change in SDMT performance across time. Correlational and regression analyses were conducted in order to determine which baseline predictors were significantly associated with slope values. Results: The mean SDMT slope value was 2.05 (SD=4.8) indicating an overall positive trend for improvement of SDMT scores across time. BMSSS score (r=.38, p=.001), age of disease onset (r=.27, p=.015), baseline IQ (r=.48, p< .001), and disease duration at baseline (r=-.26, p=.02) were all significantly correlated with SDMT slope. The Italian cohort demonstrated lower SDMT performance at each time point compared to the Canadian cohort, though this was no longer significant after accounting for betweencohort differences in BSMSS scores. Using stepwise linear regression analysis, baseline IQ (B=.108, p< .001) and disease duration at baseline (B=-.235, p=.066) were the only two variables independently associated with SDMT slope. Conclusions: At the group level, pediatric MS patients show an increase in SDMT performance across 5-years, suggesting the presence of developmental-related increases in processing speed. Higher parental education and occupation level, older age of disease onset, higher baseline IQ, and shorter disease duration are associated with greater improvements in SDMT performance, with baseline IQ and disease duration being the most important predictors. Higher IQ at baseline may thus serve as a protective factor against disease-related cognitive decline. Disclosure

Disclosure All authors report no conflicts of interest. P761 Baseline IQ is a robust predictor of 5-year change in SDMT performance in pediatric MS: results from a combination of Canadian and Italian cohorts N. Akbar1,2, A. Signori3, M.P. Amato4, M.P. Sormani3, E. Portaccio4, C. Niccolai4, B. Goretti4, C. Till5, B. Banwell6 1Neurosciences and Mental Health, The Hospital for Sick Children, 2Institute of Medical Science, University of Toronto, Toronto, ON, Canada, 3Department of Health Sciences (DISSAL), University of Genoa, Genova, 4Department of Neurology, University of Florence, Florence, Italy, 5Psychology, York University, Toronto, ON, Canada, 6Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States Background: In the pediatric MS literature, variability exists with respect to change in cognitive performance (i.e. decline,

This work was funded by a MS International Federation Du Pre Grant for NA. NA has received speaker honoraria from EMD Serono outside of the submitted work. MPA has received research grants and honoraria as a speaker and member of advisory boards by Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Teva, Almirall. MPS reports personal fees from Merck Serono, Biogen Idec, Teva, Actelion, Synthon, Allozyne, outside the submitted work. EP serves on scientific advisory boards for Biogen Idec, Merck Serono, and Bayer Schering and receives research support and honoraria for speaking from Biogen Idec, Merck Serono, Bayer Schering Pharma, Teva Pharmaceutical Industries, Novartis, and Sanofi Aventis. BB serves as an advisor to Biogen Idec, Novartis, Eli Lilly, and Sanofi-Aventis; she does not receive any financial remuneration for her advisory role but is remunerated for work pertaining to centralized imaging analyses by Novartis. BB also serves as a chief editor for Multiple Sclerosis and Related Disorders and is on the editorial board for Neurology. AS, CN, BG, and CT report no disclosures.


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Poster Session 2, 21(S11) P762 Assessing exposure to secondhand smoke in pediatric patients with demyelinating disease A. Lavery1, A.T. Waldman1, A. Bar-Or2, B. Banwell1 1Children’s Hospital of Philadelphia, Philadelphia, PA, United States, 2Montreal Neurological Institute and Hospital, McGill University, Montreal, ON, Canada Background: Smoking has been attributed to an increased risk for adult-onset multiple sclerosis (MS). A single study showed an increased risk for MS in children exposed to secondhand smoke (SHS). Selfreport measures are most often used to categorize exposure to SHS, but biological determination of serum cotinine, a metabolite of nicotine, has proven to be a sensitive measure of a person’s exposure. Objective: To explore serum cotinine concentrations in children with demyelinating disease and to correlate these values with parent reported smoke exposure. Methods: An exploratory analysis of serum cotinine levels in serum samples collected from children enrolled in a prospective study of acute demyelination was performed. Participants were enrolled at one of 23 Canadian centers between 2005-2012, and were evaluated at baseline, 3, 6, and 12 months following symptom onset, and annually thereafter. For this pilot study, samples from 20 participants (10 with monophasic demyelination and 10 diagnosed with multiple sclerosis) whose parents indicated that one or more family member smoked, were selected and correlated with parental self-report assessment of the child’s SHS exposure. Cotinine was assayed using Enzyme-Linked Immunosorbent Assay (ELISA) which has been a validated test for serum cotinine. Statistical differences between MS and monophasic patients were assessed using student T-tests and chi-square tests. Results: All 20 samples had detectable levels of cotinine (median value 1.64ng/mL, range 1.61-50.3). Values above 0.05ng/mL are considered to represent exposure. Cotinine values were not significantly different between MS and monophasic patients (p= 0.30). Values also did not significantly change with increasing self-report measures (increased number of cigarettes, increased number of smokers in home). Cotinine was detected in subjects whose parents indicated that smoking only occurred outside the home. Conclusion: Serum cotinine appears to be a sensitive measure of smoke exposure, and is detectable even in children whose parents claim to smoke outside of the family home. The contribution of smoke exposure to MS risk will require more data on smoke exposure from conception to initial clinical MS attack. Whether children with monophasic demyelination differ from those with MS in terms of smoke exposure will now be explored in our entire cohort of over 400 children. Disclosure Amy Lavery: nothing to disclose. Amy Waldman: funding through NIH, Biogen Idec, and Novartis Pharmaceuticals. Amit Bar-Or: nothing to disclose. Brenda Banwell: nothing to disclose. P763 Low levels of participation in vigorous physical activity in youth with multiple sclerosis and the associations with fatigue and depression

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S.A. Grover1, D. Hopkins-Topp2, C.P. Sawicki1,3, R.W. Motl2, M. Finlayson4, J.E. Schneiderman5,6, C. Till7, B. Banwell8, E.A. Yeh1,3 1Departments of Neurology, Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada, 2Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, IL, United States, 3Faculty of Medicine, University of Toronto, Toronto, 4Faculty of Health Sciences, Queen’s University, Kingston, 5Physiology and Experimental Medicine, The Hospital for Sick Children, 6Faculty of Kinesiology and Physical Education, The University of Toronto, 7Department of Psychology, York University, Toronto, ON, Canada, 8Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States Background: Acquired demyelinating syndromes (ADS) occur in about 1/100,000 children. About 1/5 will eventually receive a diagnosis of multiple sclerosis (MS). Up to 3/4 of children with MS suffer from depression, fatigue, and/or cognitive impairment. Previous studies in healthy adolescents and adults with MS have shown physical activity (PA) to benefit cognition and psychosocial outcomes. Investigating PA may help in the development of non-pharmacologic interventions for symptom management in pediatric MS. Goals: To investigate: (1) PA levels in youth with monophasic ADS (mono-ADS) and MS in comparison to healthy controls (HC); (2) The associations of PA levels in youth with MS wh experience fatigue and depression. Methods: 74 consecutive patients were recruited from the Neuroinflammatory Clinic at the Hospital for Sick Children, Toronto, Canada (25 MS, 49 mono-ADS). 45 HC were recruited by flyers/word of mouth. Accelerometry (7 days), PA (Godin Leisure Time Exercise Questionnaire (GLTEQ)), fatigue (PedsQL MFS) and depression (CES-DC) questionnaires were completed by all participants. SickKids research ethics approval was obtained. Results: MS participants (15.7±1.9 yo) were older than monoADS (13.7±2.6; p=0.001) and HC (14.4±2.4; p=0.03) participants. The proportion of females was not different across groups (p=0.14). Accelerometer data showed lower vigorous PA in the MS group (0.07±1.5 min/d) than in the mono-ADS (3.3±5.6 min/d; p=0.006) and HC (5.6±5.0 min/d; p=0.004) groups. On the GLTEQ, indicated MS patients compared with mono-ADS patients participated in lower levels of strenuous (17±18 vs. 30±21 METs, p=0.01) and total (42±29 vs. 63±32 METs, p=0.02) PA. Results remained after controlling for age. No differences were found in fatigue or depression between the groups. For the MS group, fatigue was correlated with depression (r=0.76) and vigorous PA was negatively correlated with fatigue (r=-0.53) and depression (r=-0.54). Conclusions: Youth with MS participate in less vigorous/strenuous PA than their mono-ADS and HC counterparts. Those who participate in higher levels of vigorous PA report fewer depressive and fatigue symptoms. This study is limited by its crosssectional nature, therefore, directionality of this association is unknown. Future investigations should focus on interventions that will help increase the amount of vigorous/strenuous PA as this may have the potential to ameliorate depression and fatigue in youth with MS.


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Disclosure This study is funded by: The National Multiple Sclerosis Society (Grant #:PP2256) and The Mario Batalli Foundation. S.A. Grover: nothing to disclose. D. Kinnett-Hopkins: nothing to disclose. C.P. Sawicki: nothing to disclose. R.W. Motl has receives funding from Biogen, Acorda, NMSS and CMSS and honoraria from EMD Serono. M. Finlayson: nothing to disclose. J.E. Schneiderman: nothing to disclose. C. Till: nothing to disclose. B. Banwell serves as an advisor to Biogen Idec, Novartis, Eli Lilly, and Sanofi-Aventis; she does not receive any financial remuneration for her advisory role but is remunerated for work pertaining to centralized imaging analyses by Novartis; she also serves as a chief editor for Multiple Sclerosis and Related Disorders and is on the editorial board for Neurology. E.A. Yeh: nothing to disclose. P764 Rituximab in paediatric MS J. Salzer1, R. Wickström2, F. Piehl3, J. Lycke4, A. Svenningsson1 1Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, 2Neuropediatric Unit, Department of Women´s and Children´s Health, 3Department of Clinical Neuroscience, Karolinska Insitutet, Stockholm, 4Department of Clinical Neuroscience and Rehabilitation, Sahlgrenska University Hospital, Gothenburg, Sweden Background: Approximately 3-5% of all multiple sclerosis (MS) patients have their disease onset before 18 years of age. Children with MS have a more pronounced inflammatory phenotype with a 2-3 times higher relapse frequency compared with adults. As of today, there are no published randomized controlled trials (RCTs) on peadiatric MS and no MS therapies are approved for paediatric use. Observational studies (n>600 children) indicate that the effects and side-effects of standard MS drugs (e.g. interferons and natalizumab) are similar in paediatric compared with adult MS. Rituximab (RTX) is a monoclonal depleting antibody directed against B-cells. One randomized study in adult relapsing remitting MS (RRMS) patients (n=104) has been performed, showing promising short term effects on inflammatory activity. However, long term safety and efficacy issues are uncertain, especially in children with MS. Objective: To collect and analyse long term safety and efficacy data for paediatric MS patients treated with RTX in Sweden. Methods: The Swedish MS register (SMSreg) was searched for patients ⩽18 years treated off label with RTX. Data on safety and efficacy were retrieved from SMSreg and medical chart review. Adverse events (AE) were graded according to “Common Terminology Criteria for Adverse Events”, CTCAE, v4.03: June 2010. Results: We identified 13 children (6 girls, 7 boys) with MS treated with RTX between 2009 and 2015. Cases were followed at three specialized MS centres with annual MRI and clinical investigations. A total of 57 doses of RTX (the majority 1000 mg every sixth month) were given. No serious adverse events (SAEs, grade ⩾3) were detected during the study period. One AE (depression CTCAE grade 2, now fully recovered) led to a 2.7 years treatment

hiatus, during this period treated with natalizumab, however returned to RTX due to JCV+. No relapses or gadolinium-enhancing lesion were detected during RTX treatment. Three patients had new T2 lesions on MRI which led to treatment interruption in one case. Drug survival was thus 92% (12/13) at data censure. Data on annualized relapse rates (ARRs) and worsening measured as EDSS before and during RTX treatment will be presented. Conclusions: This case series on RTX for paediatric MS shows a beneficial side effects profile and very low disease activity. RTX may be a safe and effective treatment for paediatric MS. Future MS RCTs on RTX should include persons < 18 years. Disclosure Jonatan Salzer has received lecture honoraria from BiogenIdec, Teva Pharmaceuticals and Genzyme/Sanofi and has received travel support from Biogen Idec. Ronny Wickström has no conflicts of interest Jan Lycke has received travel support and/or lecture honoraria from Biogen, Novartis, Teva and Genzyme/SanofiAventis; has served on scientific advisory boards for Almirall, Teva, Biogen, Novartis and Genzyme/SanofiAventis; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, Novartis and Teva. Fredrik Piehl has received unrestricted academic research grants from BiogenIdec and Novartis, and compensation for lectures and/or participation in advisory boards from Biogen, Merck Serono, Novartis, Sanofi, Roche and Teva, which have been exclusively used for the support of research activities. A. Svenningsson has served on advisory board for SanofiGenzyme and has received travel funding and/or speaker honoraria from Biogen, Sanofi-Genzyme, Novartis and Baxter Medical P765 Higher incidence of lesions involving the cortex detected in pediatric-onset multiple sclerosis using multimodal MRI J. Maranzano1, R. Brown1, C. Till2,3, B. Banwell3,4, D.L. Arnold1, S. Narayanan1 1Neurology and Neurosurgery, McGill University, Montreal, QC, 2York University, 3Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada, 4University of Pennsylvania, Philadelphia, PA, United States Background: Several studies have examined the prevalence of cortical lesions (CLs) on MRI in patients with multiple sclerosis (MS), including three studies in pediatric-onset MS (pMS). Usually, double inversion recovery (DIR) at 1.5T and 3T has been used. However, other MRI sequences (magnetization-prepared rapid gradient echo, phase-sensitive inversion recovery) have demonstrated superior capacity to depict cortical involvement, offering higher tissue contrast and signal-to-noise ratio; such studies have not yet been performed in pMS. Objective: To determine the frequency of CLs in a group of pMS patients using multimodal MRI employing different combinations of MRI contrasts. Methods: 24 pMS patients [mean (range) age at diagnosis: 13.3 (7-19) years; mean age at scan: 18.8 (13-24) years; mean disease duration of 4.97 (0.58-10.91) years] were imaged using a 3T MRI scanner. Images collected were: (1) T1-weighted 3D MPRAGE; (2) 2D proton density-weighted and (3) T2-weighted images; and


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Poster Session 2, 21(S11) (4) 2D FLAIR. Lesions affecting the cortex were segmented following a lesion identification protocol that used all available MRI contrasts. FLAIR, proton density and T2-weighted images were bias field corrected, up-sampled, and linearly registered to the image space of the T1-weighted image. CLs were manually segmented using the interactive software package Display (McConnell Brain Imaging Centre, Montreal Neurological Institute). Classification of CLs into pathological subtypes was not attempted. Only CLs that affected the neocortical grey matter were considered. Results: 391 CLs were identified (mean 16.3, median 7, range: 0-115). CLs were identified in 19 of 24 pMS patients (79%). CL counts correlated positively with disease duration (p=0.05) and age (p=0.02) (negative binomial model). Discussion: CLs occurred in our pMS group with a higher frequency (79%) than the rates of 8%, 12% and 34% previously reported by others, suggesting that the multimodal MRI approach provides more information than DIR alone. However, our cohort was older at the time of imaging and had longer disease duration compared to patients reported in other studies. Application of our multimodal MRI protocol in a younger group of pMS patients, imaged in closer proximity to first attack, will yield further insight into the prevalence of CLs at the earliest stage of MS. Disclosure J. Maranzano: nothing to disclose R. Brown has received personal compensation from NeuroRx Research for consulting services. C. Till: nothing to disclose. B. Banwell serves on advisory boards for Novartis, BiogenIDEC, and Sanofi. She is not remunerated for this effort. Dr. Banwell does received financial compensation for participation as a central MRI reviewer for a clinical trial, and for her role as a Senior Editor of Multiple Sclerosis and Related Disorders. D.L. Arnold reports personal fees from Acorda, Biogen Idec, Genzyne, Hoffman-La Roche, Innate Immunotherapeutics, MedImmune, Mitsubishi Pharma, Novartis, Receptos, Sanofi Aventis and Teva outside the submitted work, and is an employee and stockholder in NeuroRx. S. Narayanan has received personal compensation for consulting activities from NeuroRx Research P766 Alterations in functional and structural connectivity in pediatric-onset multiple sclerosis N. Akbar1,2, A. Giorgio3, C. Till4, J.G. Sled5, S.M. Doesburg1, N. De Stefano3, B. Banwell6 1Neurosciences and Mental Health, The Hospital for Sick Children, 2Institute of Medical Science, University of Toronto, Toronto, ON, Canada, 3Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy, 4Psychology, York University, 5Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada, 6Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States Background: Reduced white matter (WM) integrity is understood to be a fundamental aspect of pediatric multiple sclerosis

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(MS), though relations to resting-state functional MRI (fMRI) connectivity remain unknown. Objective: To relate diffusion-tensor imaging (DTI) measures of WM microstructural integrity to resting-state network (RSN) functional connectivity in pediatric-onset MS. Methods: This study enrolled 19 patients with pediatric-onset MS (mean age=19, range 13-24 years, 14 female, mean disease duration=65 months, mean age of disease onset=13, median EDSS=1.5, range 0-4) and 16 age- and sex-matched healthy controls (HC). All subjects underwent 3.0T anatomical and functional MRI which included DTI and resting-state acquisitions. DTI processing was performed using Tract-Based Spatial Statistics (TBSS). RSNs were identified using Independent Components Analysis, and a dual regression technique was used to detect between-group differences in the functional connectivity of RSNs. Correlations were investigated between DTI measures and RSN connectivity. Results: Lower fractional anisotropy (FA) was observed in the pediatric-onset MS group compared to HC group within the entire WM skeleton, and particularly the corpus callosum, posterior thalamic radiation, corona radiata and sagittal stratum (all p< .01, corrected). Relative to HCs, MS patients showed higher functional connectivity involving the anterior cingulate cortex and right precuneus of the default-mode network (both p< .005, uncorrected), as well as involving the anterior cingulate cortex and left middle frontal gyrus of the frontoparietal network. Higher functional connectivity of the right precuneus within the posterior default-mode network was associated with lower FA of the entire WM skeleton (r=-.525, p=.02), genu of the corpus callosum (r=.553, p=.014), and both left (r=-.467, p=.044) and right (r=-.615, p=.005) sagittal stratum. Conclusions: Loss of WM microstructural integrity is associated with increased resting-state functional connectivity in pediatric MS, which may reflect a more diffuse and potentially compensatory activation early in MS. Such heightened connectivity may have contributed to the large preservation of cognitive abilities in our sample. Further research is required in larger samples with demonstrated cognitive impairment in order to provide insight into possible limits to functional preservation likely underlying loss of intact cognitive functioning in pediatric MS. Disclosure This work was supported by the Scottish Rite Charitable Foundation of Canada (Research Grant 2011-2012). It was also supported by a Studentship from the Multiple Sclerosis Society of Canada (National Bank Financial Group Doctoral Studentship Award 2012-2015), and MS International Federation Du Pre Grant for NA. NA has received speaker honoraria from EMD Serono outside of the submitted work. NDS has received honoraria from Schering, Biogen-Idec, Teva, Novartis, Genzyme, and Merck Serono S.A. for consulting services, speaking and travel support. He serves on advisory boards for Merck Serono S.A. and Novartis. He has received research grant support from the Italian MS Society. BB serves as an advisor to Biogen Idec, Novartis, Eli Lilly, and Sanofi-Aventis; she does not receive any financial remuneration for her advisory role but is remunerated for work pertaining to centralized imaging analyses by Novartis. BB also serves as a chief editor for Multiple Sclerosis and Related Disorders and is on the editorial board for Neurology. AG, CT, JGS, and SMD report no disclosures.


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P767 Decreased quality of life in parents of children with MS irrespective of disease activity J. O’Mahony1,2, B. Banwell3, A. Laporte1, E.A. Yeh2, R.A. Marrie4 1University of Toronto, 2The Hospital for Sick Children, Toronto, ON, Canada, 3Children’s Hospital of Philadelphia, Philadelphia, PA, United States, 4University of Manitoba, Winnipeg, MB, Canada Background: In our prospective national cohort study of 312 Canadian children, acquired demyelinating syndromes (ADS) occurred as the sentinel attack of multiple sclerosis (MS) in 50 (22%) children, while 175 (78%) have experienced a monophasic illness (monoADS). Among the 50 children with MS diagnoses, 19 experienced full recoveries from their incident events and have not experienced additional relapses after 5 (4-7) years follow-up. Among the 175 children with monoADS, 148 experienced full recoveries from their incident events and have been told that they do not meet the diagnosis of MS. Children in these two subgroups differ in that one subgroup have been told that they meet the diagnosis of MS and the other group has not. Objective: The objective of this analysis is to evaluate the impact of the diagnosis of MS, irrespective of clinical relapses and physical deficits, on the health-related quality of life (HRQoL) of children with MS and their families. Methods: In our prospective national cohort study, we assessed children who presented with incident ADS in Canada between September 1, 2004 and June 30, 2013. Children underwent clinical examinations and MRI quarterly in the first year and annually thereafter. HRQoL of the participants and their families was ascertained using the PedsQLTM Inventory and Family Impact Module. Pooled panel analyses were performed taking into account clustering at the individual level. Results: We enrolled 312 eligible children with ADS, of whom 225 children [ 50 (22%) MS and 175 (78%) monoADS; age at onset 10.55 (6.25-13.79); follow-up 5 (4-7) years] and their parents completed HRQoL questionnaires. Analyses revealed lower HRQoL among parents of children with MS compared to parents of children with monoADS (p< 0.001). Additionally, family functioning scores were also decreased in children with MS in comparison to those of children with monoADS (p=0.002). HRQoL of children did not differ between those with MS and those with monoADS. These associations remained statistically significant when controlling for number of clinical relapses and physical deficits. Conclusions: The diagnosis of MS, irrespective of clinical disease activity, decreases HRQoL life of parents of children with MS, impedes familial participation in daily activities, and negatively impacts family relationships. Disclosure Dr Marrie receives research funding from the Canadian Institutes of Health Research, the Multiple Sclerosis Society of Canada, the Multiple Sclerosis Scientific Research Foundation, and the Rx&D Health Research Foundation, and has conducted clinical trials funded by Sanofi-Aventis. Dr. Banwell serves as an advisor to Biogen Idec, Novartis, Eli Lilly, and Sanofi-Aventis; she does not receive any financial remuneration for her advisory role.

Dr Banwell also serves as a chief editor for Multiple Sclerosis and Related Disorders and is on the editorial board for Neurology. P768 The apoptotic markers in adolescents with remitting relapsing multiple sclerosis N. Shatilova1, O. Bykova1, L. Kuzenkova2, L. BaranovaNamazova2, I. Nankina1, T. Batysheva1, A. Boyko3 1Research and Clinical Center of Pediatric Psychoneurology, 2Scientific Center of Children’s Health, 3Russian National Research Medical University named after N.I. Pirogov and the Moscow Multiple Sclerosis Center, Moscow, Russian Federation 122 adolescents with definite RRMS (according to the W. I. McDonald criteria) and different disease duration were tested to the level of serum markers (Fas-L, sAPO-1/Fas, cytochrome C, annexin V and NO) and regulators of an apoptosis (TNF-a). Depending on the RRMS experience children were divided into 4 subgroups: subgroup 1 - included 21 patients with disease duration up to 12 months; subgroup 2 - 34 patients with disease duration from 12 to 24 months; subgroup 3 - 30 patients with disease duration from 24 to 36 months and subgroup 4 - 37 patients with disease duration more than 36 months. The data analysis allowed to conclude that violations of apoptosis in RRMS affected adolescents occur in the first months of the disease and gradually grow as it progresses. This fact was confirmed by the significant increase of sAPO-1/Fas and annexin V levels in the serum of patients with disease duration up to 12 months in comparison with the reference group. In patients with RRMS experience from 2 years and more both paths of the programmed cell death were activated, as it evidenced from significantly elevated (p< 0.05) concentrations of Fas-L, sAPO-1/Fas, annexin V, and cytochrome C. Their maximum values were observed in patients with the largest duration of the disease (more than 3 years), and were significantly higher than the levels of sAPO-1/Fas, annexin V, Fas-L and cytochrome C in the referent group, and in subgroups with less experience of the RRMS (p< 0.05). Disclosure Nothing to disclose

Natural course P769 Latitude significantly predicts an earlier age of disease onset in multiple sclerosis C. Tao, S. Simpson Jr, I. van der Mei, L. Blizzard, B. Taylor, MSBase Investigator Group Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia Background: Age at onset (AAO) of multiple sclerosis may be an important marker of disease severity and may have prognostic significance. Understanding what factors can influence the AAO


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Poster Session 2, 21(S11) may shed light on the aetiology of this complex disease and how age impacts the clinical presentation. Objective: The aim of this work was to evaluate the association of latitudinal gradient and the age of onset in multiple sclerosis population. Methods: The study cohort of 20636 eligible patients from 36 centres in 13 countries worldwide extracted from the MSBase registry. Only clinical definite multiple sclerosis (CDMS) patients aged>16 years were included. Predictors of AOO were evaluated by linear regression. Results: In the univariable analysis, latitude was not a significant negative predictor of onset age, such that each one-unit increase in latitude was associated with a 0.01 year decrease in the age of onset (p=0.53). Evaluating latitude as a categorical term, a threshold association was evident above latitude 40º. On adjustment for relevant covariates, however, particularly sex, MS type and sex and MS type centre ratios, as well as the average population age in the area from whence the centre population was derived, this association became much more dose-dependent (p=4.21x10-12), with those of the highest latitude having nearly a half year earlier age of onset than those of the middle latitudinal increment. There was significant decreased age of onset for MS patients with decreased quartile of ambient UV-radiation (9x10-8). Conclusion: An earlier age of onset in higher latitudinal regions was found in this global MS registry and correlated with variation in latitudinal UVR. These results suggest that environmental factors like ambient UV may significantly influence age of disease onset, in addition to previously demonstrated associations with MS onset and progression. Disclosure Chunrong Tao: nothing to disclose P770 Is it possible to predict benign multiple sclerosis? A. Sartori1, M. Abdoli2, M.S. Freedman2 1Department of Medical, Surgical, and Health Sciences, University of Trieste, Trieste, Italy, 2University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada Background: Benign Multiple Sclerosis (MS) has prognostic and therapeutic implications. Most definitions are retrospective, involving a period of observation of 5-10 years from onset of symptoms with prevalence reported ranging from 6-64%. However, many patients presumed “benign” at 10 years actually progress with time and are no longer benign (NLB). Objectives: To compare clinical and paraclinical characteristics of benign MS patients defined as EDSS score ⩽3, 10 years from disease onset with those who still fulfilled that definition vs. being NLB at 20 years from disease onset. Methods and patients: A retrospective study of patients at the Ottawa Hospital MS Clinic was performed, looking for patients with the following inclusion criteria: clinically definite MS (not CIS); EDSS score ⩽3 at 10 years from onset of first symptoms; disease onset from December 1983 - December 1993; clinical assessments performed at 10±1 and 20±1 years from onset of MS symptoms. Results: We found 175 patients fulfilling the inclusion criteria. 20 years from disease onset, 66.3% of patients still remained benign.

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Considering patients with EDSS score ⩽2 or ⩽1 at 10 years, the percentage remaining benign at 20 years increased to 71.9% and 81.6%, respectively. In a univariate analysis, female sex, EDSS score ⩽1 at 10 years and a pure sensory onset represented the most favourable prognostic factors; EDSS score >2 and a pure motor symptom at onset were associated with the greatest chance of being NLB at 20 years. There were significantly more patients (p=0.033) treated with disease modifying drugs (DMD) in the NLB group. In a logistic regression analysis EDSS ⩽1 at 10 years was able to predict a benign course at 20 years with better than 80% specificity. Discussion and conclusions: We found a higher percentage of benign patients at 20 years compared to previous studies, possibly due to a higher percentage of patients treated with DMD in our population. A multivariate analysis did not find any early clinical variable that could predict a benign course at 20 years. However, EDSS ⩽2 at 10 years had a better predictive value than EDSS score ⩽3 at 10 years, which was neither sensitive nor specific for predicting continuing to be benign at 20 years. Most patients acquiring early disability (>2) before 10 years are very unlikely to remain benign. We propose that a better definition of benign use stricter EDSS cut-offs (⩽2 or even ⩽1) at 10 years, in order to enhance the specificity. Disclosure Arianna Sartori: Receipt of honoraria or consultation fees: Merk Serono, Novartis. Mohammad Abdoli: Receipt of honoraria or consultation fees: EMD Canada, Genzyme Canada, Consortium of Multiple Sclerosis Centers. Mark S. Freedman: Receipt of honoraria or consultation fees: BayerHealthcare, BiogenIdec, Chugai, EMD Canada, Genzyme, Merck Serono, Novartis, Hoffman La-Roche, Sanofi-Aventis, Teva Canada Innovation; member of a company advisory board, board of directors or other similar group: Actelion, BayerHealthcare, BiogenIdec, Hoffman La-Roche, Merck Serono, Novartis, Opexa, Sanofi-Aventis; participation in a company sponsored speaker’s bureau: Genzyme. P771 Time to treatment after acute optic neuritis in patients with neuromyelitis optica and its spectrum disorders predicts visual outcome S. Siritho, V. Sudthikanueng, N. Prayoonwiwat Siriraj Hospital, Mahidol University, Bangkok, Thailand Objective: To evaluate the association between time to treatment and visual recovery, as well as other possible predicting factors, in NMO/NMOSD patients with acute optic neuritis (ON). Methods: Baseline characteristics, investigations and treatment options were retrospectively reviewed. The data of visual acuity were documented at baseline, onset, 1- and 6-month follow-up. Results: There were 32 eligible NMO/NMOSD patients with acute ON during study period. At 1 month, patients receiving early treatment (< 7 days) showed better visual recovery than those without treatment (OR 25, 95% CI 3.39-184.5, p-value 0.001) and those with late treatment (⩾ 7 days) (OR 11.45, 95% CI 2.55-51.59, p-value < 0.001). While at 6 months, group with early treatment also showed better outcome than group without


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treatment (OR 9.2, 95% CI 1.70-49.86, p-value 0.01). Factors predicting good visual outcome at 1-month follow-up were male sex (p-value 0.04), presence of pain on eye movement (p-value 0.011) and presence of AQP4-Ab (p-value 0.043). Presence of underlying disease(s) (p-value 0.03), DM (p-value 0.043) and ANA seropositivity (p-value 0.012) were related to poor outcome at 1 month. At 6-month follow-up, only the presence of ANA (p-value 0.003), anti-SSA (p-value 0.005) and anti-SSB (p-value 0.049) were related to poor visual outcome. Conclusion: Early treatment, especially within 7 days, was related to better visual recovery at 1 month and 6 months. Other factors that predicted outcome were type of diagnosis, sex, presence of underlying disease(s), diabetes, pain on eye movement, ANA, anti-SSA, anti-SSB and AQP4 antibodies. Disclosure

Disclosure Gutemberg Augusto Cruz dos Santos: nothing to disclose. Claudia Cristina Ferreira Vasconcelos: nothing to disclose. Solange Maria das Graças Gomes Camargo: nothing to disclose. Luiz Claudio Santos Thuler: nothing to disclose Regina Maria Papais Alvarenga: nothing to disclose P773 Mortality in a population-based MS cohort K.E. Harding1,2, S. Loveless1,2, M.D. Willis1,2, T.P. Pickersgill2, N.P. Robertson1,2 1Institute of Psychological Medicine and Neurology, Cardiff University, 2Helen Durham Centre for Neuroinflammatory Disease, University Hospital of Wales, Cardiff, United Kingdom

Nothing to disclose P772 Disability in relapsing-remitting multiple sclerosis patients in Rio de Janeiro - Brazil: influence of clinical and demographic factors G.A. Cruz dos Santos1,2, C.C. Ferreira Vasconcelos2, S.M.d.G. Gomes Camargo3, L.C. Santos Thuler2,4, R.M. Papais Alvarenga2,3 1Universidade Estácio de Sá, 2Universidade Federal do Estado do Rio de Janeiro, 3Hospital da Lagoa, 4Instituto Nacional do Cancer, Rio de Janeiro, Brazil Objective: The primary objective of this study was to describe the progression of patients with relapsing-remitting multiple sclerosis (RRMS) in an area of low prevalence and to analyse the clinical and demographic factors that may influence this progression. Methods: In total, 126 patients of the Hospital da Lagoa - Rio de Janeiro with 10 years of disease duration or more were included. Demographic and clinical data were analysed, taking into account disability outcomes (EDSS 2, 3, 6, 7.5 and 8). Results: In total, 79.4% of the analysed population was female. The frequency of patients with African ancestry was 19%. The initially benign form of the disease (EDSS score of 3 or lower after 10 years) was found in 81.7% of the cohort. Disease onset occurred at a mean age of 29.86 years (+/-9.25). The mean duration of the disease was 19.32 years (+/-8.48). In total, 40.5% of patients progressed to secondary-progressive MS over a mean time of 13.4 years (+/-7.7). They achieved EDSS scores of 2, 3, 6, 7.5 and 8 after median durations of 11.3 (+/-9.4), 11.3 (+/-7.7), 12.9 (+/6.8), 18.1 (+/-8.8) and 17.0 (+/-7.0) years, respectively. In the final evaluation, 54% of the patients had EDSS scores up to 3, 12% were between 3 and 6, and 34% were greater than or equal to 6. Conclusions: Factors identified as being associated with the worst prognoses were: African ethnicity, age over 30 years, short interval between the first two outbreaks, incomplete recovery from the first outbreak, the occurrence of two or more outbreaks in the first year and three or more outbreaks in the first five years of progression. Early recognition of the factors that influence increased disability is important for therapeutic decision-making, indications for rehabilitation, changes of lifestyle, adaptation of employment and family clarification regarding the prognosis.

Background: Multiple sclerosis (MS) is a chronic neuroinflammatory disease affecting patients in early to middle adulthood, and evolving over many years. Accurate studies of mortality in MS are therefore difficult, due to the extended followup necessary to evaluate mortality in a disease that may be present for decades. As a result, few studies have previously examined mortality data in population-based cohorts with MS, and in addition there is a lack of studies utilising contemporary data, to reduce the effect of advances in other areas of medicine (particularly cardiovascular disease). We have investigated mortality in a prospective population-based cohort of MS patients, evaluating the association of clinical factors with age at death. Methods: The south Wales MS registry, established in 1985, was interrogated to identify patients who had died. Time to and age at death was measured using Kaplan-Meier survival analysis, for all patients, and age at death was compared by sex, disease course at onset, and EDSS at first presentation to MS services. Cox proportional hazards regression was used to analyse clinical factors associated with age at death in this population. Results: 2145 patients with longitudinal data collected from onset of disease were included, of which 489 had died (of which 19 had had disease-modifying therapy). Median time to death was 40.2 years (39-42.8). Median age at death was 73.1 years (72.1-74.0). There was no difference in age at death in males compared to females (male 71.6, female 73.3, p=0.23). Patients with relapsing onset were younger at death than patients with progressive onset (72.8y versus 76.6y, p=0.006). Median age at death was 84.5y for patients first presenting with EDSS 0-4.5, 82.6y for EDSS 5.06.0, 76.9y for EDSS 6.5-7.5, and 69.1y for EDSS >8.0 (p< 0.0001). Using Cox proportional hazards regression, age at onset (hazard ratio, HR, 0.96 (0.95-0.98), p< 0.0001) and EDSS at first presentation (HR 1.35 (1.22-1.50), p< 0.0001) were associated with age at death, but there was no association for sex or initial disease course. Discussion: The association of age at onset with age at death confirms previous findings of poorer prognosis for patients who are younger at onset of disease. Early fixed disability predicts younger age at death, which may be a reflection of more aggressive disease. These data will be useful to serve as a baseline for the evaluation of long-term outcome in disease-modifying therapies.


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Poster Session 2, 21(S11) Disclosure Katharine Harding: nothing to disclose. Samantha Loveless: nothing to disclose. Mark Willis: nothing to disclose. Trevor Pickersgill: nothing to disclose. Neil Robertson: nothing to disclose. P774 The risk to reach EDSS of 6 and different immunointerventions I. Ilicic, J. Haas Neurology, Jewish Hospital, Berlin, Germany Background: Since 1996 patients (n= 6015) were prospectivly documented in our data base mdoc. The long-time follow-up allows to identify patients with an EDSS 3 and the impact of the immune intervention on the progression of the disease. Objective: Patients with an EDSS 3 are on a high risk for progression. The disability progression to EDSS 6 is independant from the duration of the disease. The recommendation is to start with a higher active treatment to extend the time to reach EDSS 6. The mean time is 5.7 years (due to Rennes data base). The question is, if the different immunotherapies in the last two decades have changed the outcome. Design and methods: Out of 6015 patient documented in our database, we identified 1798 patients with an EDSS of 3. For our analyses age, gender, date of onset and immunotherapy were evaluated with statistical methods. Results: Of the identified patients (n= 1798) were 72 % female and 28% male. The mean duration by reaching EDSS 3 from clinical onset was 121.2 months; females 111.2 months; males 80.0 months. According to the age at clinical onset, the age at onset < 30 years (n=695) reached EDSS 3 in 164.9 months, age at onset 31-40 y (n=524) reached EDSS 3 after 107.3 months and age at onset > 40y (n=447) reached EDSS 3 after 69.2 months. The average time of disease duration from EDSS 3 until EDSS 6 was 7.2 years; without treatment 3.3 years, with first line therapy (Interferon beta 1a and beta 1b) 8.3 years, with Glatirameracetat 6.13 years, with second line therapy (Natalizumab, Fingolimod) 11.1 years. Conclusions: Immunointervention seems to extend the time from EDSS 3 to 6 compared to the Rennes Data. Fingolimod and Natalizumab seem to be more effective compared to the injectibles. This is supporting the therapeutical recommendation to adopt the therapy when reaching an EDSS of 3. Disclosure J. Haas has got compensation by Biogen, Bayer, Teva, Sanofi Aventis, Allergan, Genzyme, CSL Behring, Octapharma. I. Ilicic: nothing to disclose.

Epidemiology P775 The Swiss multiple sclerosis cohort study: a prospective nationwide investigation of disease evolution and the effects of new disease modifying drugs

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G. Disanto1, P. Benkert2, J. Lorscheider3, S. Müller4, J. Vehoff4, C. Zecca1, S. Ramseier5, L. Achtnichts5, O. Findling5, K. Nedeltchev5, E.-W. Radue6, T. Sprenger3, C. Stippich7, T. Derfuss3, J.-F. Louvion8, C. Kamm9, H.P. Mattle9, C. Lotter10, R. Du Pasquier11, M. Schluep11, C. Pot12, P.H. Lalive12, Ö. Yaldizli3, C. Gobbi1, L. Kappos3, J. Kuhle3 1Department of Neurology, Regional Hospital Lugano, Lugano, 2Clinical Trial Unit, University Hospital Basel, 3Neurology, University Hospital Basel, Basel, 4Department of Neurology, Cantonal Hospital St. Gallen, St Gallen, 5Department of Neurology, Cantonal Hospital Aarau, Aarau, 6Medical Image Analysis Centre, University of Basel, 7Neuroradiology, Department of Radiology, University Hospital Basel, Basel, 8RodanoTech, Geneva, 9Department of Neurology, Inselspital Berne, Berne, 10Swiss Multiple Sclerosis Society, Zürich, 11Department of Neurology, University Hospital of Lausanne (CHUV), Lausanne, 12Department of Neurology, University Hospital of Geneva (HUG), Geneva, Switzerland Background: Multiple Sclerosis (MS) is a chronic disease affecting approximately 10,000 patients in Switzerland. Many questions concerning the heterogeneity of the disease, the mechanisms leading to disability and the long term efficacy and safety profiles of the several available disease modifying drugs (DMDs) remain unanswered. The Swiss MS Cohort Study (SMSC) is a longterm prospective multicentre observational study performed across 7 MS centers (Aarau, Basel, Berne, Geneva, Lausanne, Lugano and St. Gallen). Methods: Patients with a diagnosis of relapsing-remitting MS (RRMS), secondary-progressive MS (SPMS), primary-progressive MS (PPMS), clinically isolated syndrome (CIS), radiologically isolated syndrome or neuromyelitis optica are included. Standardized neurological assessments and biological samples are collected every 6-12 months with rigorous quality controls. Expanded Disability Status Scale (EDSS) scores are calculated by certified raters. Cranial MRI are also optionally performed. Results: Between June 2012 and December 2014, 735 patients (5.7% CIS, 84.8% RRMS, 5.7% SPMS and 2.9% PPMS) have been recruited in the SMSC. Median follow-up time was 379 days (interquartile range (IQR) 242-591) for a total of 1,805 visits. The dropout rate was 2.8% (n=21). A total of 1,797 serum, plasma and blood samples and 137 cerebrospinal fluid samples have been collected; 979 brain MRI scans have been performed. EDSS scores at baseline were higher in SPMS (6.0 (4.0-6.5)) and PPMS (6.0 (3.56.0)) than in CIS (1.5 (1.0-2.0)) and RRMS (2.0 (1.5-3.0)). During follow-up 119 relapses have occurred in 106 patients and EDSS scores have increased in PPMS, SPMS and RRMS patients experiencing relapses. At baseline 36.1% of RRMS patients were treated with fingolimod, 25.5% with natalizumab, 14.0% with first line injectable DMDs, 1.5% with other DMDs and 23% were untreated. The mean annualized relapse rate in RRMS patients under treatment with natalizumab was 0.09, with fingolimod 0.20 and first line injectable DMDs 0.47. Discussion: The SMSC is currently collecting high quality clinical information, biological samples and MRI data in a large cohort of MS patients. This cohort will serve as a comprehensive infrastructure available for the realization of a variety of nested research projects and should provide relevant real world information regarding disease course and DMDs effects in the long term.


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Disclosure The Department of Neurology, Regional Hospital Lugano (EOC), Lugano, Switzerland receives financial support from Teva, Merck Serono, Biogen Idec, Bayer Schering, Genzyme and Novartis. The submitted work is not related to these agreements. C. Gobbi, Chiara Zecca and Giulio Disanto receive no other financial support related to the submitted work. J Kuhle has received research support by an ECTRIMS Research Fellowship Programme, University of Basel, Swiss MS Society, Swiss National Research Foundation, Protagen AG, Roche, Genzyme and Novartis. Ö Yaldizli received honoraria for lectures from Teva (2011) and Bayer Schering (2012) both paid to University Hospital Basel. ÖY received research funding from MAGNIMS / ECTRIMS, the University of Basel, the Swiss MS Society and Free Academy Basel, Switzerland. None of these is related to this work. The Department of Radiology, University Hospitals Basel, Switzerland receives financial support from Bayer Healthcare, Bracco and Guerbet and has a research agreement with SIEMENS Medical Solutions. The submitted work is not related to these agreements. C. Stippich receives no other financial support related to the submitted work. HP Mattle has received speaker’s fees by Bayer, Biogen, Covidien, Daiichi Sankyo, Neuravi, Novartis, Sanofi/Genzyme, Serono, Teva and consulting fees by AstraZeneca, Bayer, Biogen, Boehringer Ingelheim, Covidien, Daiichi Sankyo, Genzyme, Merck-Serono, Neuravi, Novartis, Pfizer, Sanofi/Genzyme, Servier, Teva. CP Kamm received honoraria for lectures/consulting and/or grants for studies from Biogen idec, Novartis, Teva, MerckSerono, Genzyme, Bayer Schweiz AG and the Swiss MS society. J Vehoff has received honoraria and travel expenses from Biogen Idec, Bayer, Teva, Novartis, Genzyme (Sanofi Aventis) and Merck. T Sprenger´s institution, the University Hospital Basel, has received payments that were used exclusively for research support for consultation and speaking activities for Mitsubishi Pharma, Eli Lilly, Genzyme, Novartis, ATI, Actelion, Electrocore, Biogen Idec and Allergan. T Sprenger has received grants from the Swiss MS Society, Swiss National Research Foundation, EFICGrünenthal and Novartis Pharmaceuticals Switzerland. PH Lalive received honoraria for speaking from Biogen-Idec, CSL Bering, Merck Serono, Novartis, Sanofi-Aventis, Teva; consulting fees from Biogen-Idec, Geneuro, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, Teva; research grants from Biogen-Idec, Merck Serono, Novartis. T Derfuss serves on scientific advisory boards for Novartis Pharma, Merck Serono, Biogen Idec, Genzyme, Mitsubishi Pharma, TEVA Pharma, GeNeuro, and Bayer Schering Pharma; has received funding for travel and/or speaker honoraria from Biogen Idec, Novartis, Merck Serono, and Bayer Schering Pharma; and receives research support from the Swiss National Research Foundation, Biogen Idec, Novartis Pharma, the European Union, and the Swiss MS Society. J Lorscheider received grant support from Biogen and travel support from Novartis. M Schluep has not received financial support related to this work. S. Mueller received honoraria for travel, honoraria for lectures/ consulting and/or grants for studies from Biogen idec, Novartis, Teva, Merck-Serono, Genzyme and Bayer Schweiz AG.

R Du Pasquier has served on scientific advisory boards for Biogen Idec, Merck Serono, Teva, and Novartis; has received funding for travel or speaker honoraria from Abbvie, Biogen Idec, Teva, Merck Serono, and Bayer Schering Pharma. Ludwig Kappos: institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: steering committee/consulting fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; royalties from Neurostatus Systems GmbH; grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis, Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society, and the Swiss National Research Foundation Remaining authors have nothing to disclose. P776 Sex ratio trends over time in multiple sclerosis patients from Argentina J.I. Rojas1, L. Patrucco1, J. Miguez1, V. Sinay2, F. Pagani Cassara2, F. Caceres3, N. Fernandez Liguori3, M.L. Saladino3, N. Deri4, G. Jaacks4, M. Parada Marcilla5, M.I. Arrigoni6, J. Correale7, M. Fiol7, C. Ysrraelit7, A. Carra8, M.C. Curbelo8, A. Martinez8, J. Steinberg8, S. Bestoso9, J.P. Hryb10, J.L. Di Pace10, M.B. Perassolo10, E. Carnero Contentti11, A. Caride11, P.A. Lopez11, C. Martinez5, E. Reich12, D. Giunta1, E. Cristiano1 1Centro de Esclerosis Múltiple de Buenos Aires, Hospital Italiano de Buenos Aires, 2Instituto de Neurociencias Fundación Favaloro, 3Neurosciences Institute of Buenos Aires, 4Centro de Investigación DIABAID, 5Private Office, Buenos Aires, 6Hospital Italiano de Córdoba, Cordoba, 7Department of Neurology, Institute for Neurological Research Dr. Raúl Carrea, FLENI, 8Hospital Británico Buenos Aires, Buenos Aires, 9Hospital Escuela ‘José F. De San Martín’, Corrientes, 10Hospital General de Agudos Carlos G Durand, 11Hospital Alemán, 12Hospital Julio Mendez, Buenos Aires, Argentina Several studies in multiple sclerosis (MS) suggest a trend of increasing disease frequency in women during the last decades. A direct comparison of sex ratio trends among MS populations from Argentina was not carried out yet. The objective of the study was to compare sex ratio trends, over a 50-year span in MS populations from Argentina. Methods: Multicenter study that included patients from 14 MS Centers of Argentina. Patients with definite MS with birth years ranging from 1940 to 1989 were included. Gender ratios were calculated by five decades based on year of birth and were adjusted for the F/M born-alive ratio derived from the Argentinean national registry of births. The F/M ratios were calculated using a multivariate logistic regression, per five decades by the yob approach. Analyses was performed using Stata 10.1. Results: 1069 patients were included. Sex ratios showed a significant increase from the first to the last decade in the whole MS sample (from 1.8 to 2.7; p value for trend = 0.023). The sex ratio did not showed differences considering MS subtype.


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Poster Session 2, 21(S11) Conclusion: Our study showed a modest increase of the F/M sex ratio (from 1.8 to 2.7) over time among patients affected by MS in Argentina. Disclosure

Disclosure Katsavos Serafeim: nothing to disclose. Davaki Panagiota: nothing to disclose. Stamboulis Eleftherios: nothing to disclose. Anagnostouli Maria: nothing to disclose.

Authors have nothing to disclosure regarding the research study P777 Clinical and neuroimaging characteristics in a sample of patients with familial multiple sclerosis: a Hellenic retrospective cohort study S. Katsavos1, P. Davaki2, E. Stamboulis2, M. Anagnostouli1,2 1Immunogenetics Laboratory, 1st Department of Neurology of Medical School, 21st Department of Neurology of Medical School, Athens National and Kapodistrian University, Athens, Greece Background and goals: Hereditary factors have a well established role in the multifaceted pathophysiology of Multiple Sclerosis (MS). Previous researchers reported that increased genetic burden could be linked with various phenotypic alterations. Aim of this study was το examine characteristics of a sample of patients with familial MS (fMS: at least one relative with MS, 3rd degree or closer), in a cohort of patients who visited the Outpatient Clinic of our Department. Methods: We retrospectively reviewed the files of 345 patients (total sample) with clinically isolated syndrome (CIS) or clinically definite MS. Data collected included demographics (age at onset, gender, family history for MS, personal and family history for other autoimmune disorders), disease-derived variables [subtype, Expanded Disability Status Scale (EDSS) scores, EDSS progression rates, annualized relapse rates (ARRs), and first symptoms], and Magnetic Resonance Imaging (MRI) variables (lesions’ distribution and morphology, whole-brain atrophy measures). Statistical processing included descriptive statistics, univariate and multivariate analyses (level of statistical significance p=0.05). Results: 62 patients out of 345 had fMS (18%). Female gender was predominant (fMS: 67.7 %, total sample: 65.5%). Mean age at onset was 30.2+/-11.5 and 30.7+/-10 years respectively. fMS cases showed trends towards increased co-morbidity with other autoimmune disorders (personal and familial). Statistical significance was reached for Hashimoto’s thyroiditis in relatives of fMS cases (10.2 versus 4.5%, p=0.02). Disease-derived variables showed no correlations with fMS, apart from first symptoms, where diplopia was significantly less often (1.7 versus 18.9% / p=0.002). Lesion distribution did not differ significantly between groups. Interestingly, tumefactive lesions were more frequent in fMS (4.8% versus 0.4%), and whole-brain atrophy measures were more frequently abnormal (p=0.05), irrespectively of disease subtype, duration and treatment (multivariate regression, p=0.01). Conclusions: fMS is probably indicative of a more generalized familial autoimmune predisposition. The observed clinical (diplopia) and neuroimaging correlations (atrophy, tumefactive lesions) may reflect differences in the underlying pathogenic mechanisms of fMS. Further research in larger cohorts is required, in order to clarify these preliminary results.

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P778 Are pregnancies prior to MS onset protective against subsequent disease severity? K. Ribbons1,2, R. Lea1, Z. McPherson3, J. Lechner-Scott1,2 1Hunter Medical Research Institution, 2Neurology, John Hunter Hospital, Newcastle, 3School of Health Sciences, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia Introduction: The protective effect of pregnancies pre-onset of MS on time to the first demyelinating event and later disease progression remains controversial. In the current study we have evaluated if pregnancies prior to disease onset afforded any benefit to long term disease outcomes in a cohort of female MS patients residing in Newcastle, NSW, Australia. Methods: 46 women with a confirmed diagnosis of MS, residing in Newcastle council district in mid 2011 were invited to participate in the study and underwent interviews regarding their pregnancy history, including details of all live births (parity) pre and post MS symptom onset and MS confirmed diagnosis. Disease severity was determined by multiple sclerosis severity scores (MSSS, Roxburgh et al. 2005) using EDSS derived from their most recent clinical evaluation. Parity and age distribution of the same geographical area was determined from data derived from the 2011 national census. Results: In our MS cohort, the number of children born prior to onset of symptoms was positively correlated with MSSS (P=0.048) hence higher parity was associated with a subsequent increased MS severity. However, when we adjusted this model for patient age at the time of diagnosis the significant correlation was no longer apparent (P=0.42) suggesting it was an age-specific effect. When we standardised age the parity in the MS cohort was lower than in the local population (P=0.026)). Conclusions: We conclude that in our Newcastle female MS cohort there was no evidence supporting a protective effect of pregnancies occurring pre-MS onset on subsequent disease severity. In fact, as the MS population is comprised of an older age group of mothers compared to the distribution seen in the general population, higher pregnancy rate and worse disease outcome is likely to be due to their older age at disease onset. However our MS patients did have fewer children compared to that in seen in the age-matched general population. Disclosure K Ribbons, R Lea and Z McPherson have nothing to disclose. Jeannette Lechner-Scott has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment and also clinic support as well as research grants from Bayer Health Care, Biogen Idec, CSL, Genzyme Sanofi, Merck Serono and Novartis.


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P779 Risk of osteoporotic fractures in multiple sclerosis population in southwest Finland J. Åivo1, S. Kurki2, M.-L. Sumelahti3, J. Ruutiainen4, M. SoiluHänninen1 1Division of Clinical Neurosciences, Turku University Hospital, 2Auria Biopank, University of Turku, Turku, 3Department of Neurology, Tampere University Hospital, Tampere, 4Neuroliitto, Turku, Finland Background and purpose: Increased risk of osteoporotic fractures in MS patients compared to general population has been previously reported. There are no previous studies from Finland, where the prevalence of MS is high and vitamin D deficiency is common among MS patients and general population. The purpose of this study was to update the prevalence of MS and the risk of osteoporotic fractures among Finnish MS patients by using hospital administrative data from a large hospital district in southwest Finland. Methods: Patients with MS and comorbid osteoporotic fractures were identified by searching for ICD-10 codes during a period from 2004 to 2012 from hospital administrative data in Turku University Hospital (TYKS) in southwest Finland. Case ascertainment was performed by review of medical records. Osteoporotic fracture was defined as fracture of the pelvis, hip, femur, humerus, ulna/radius, vertebrae or rib. The control population was a 10-fold age- and gender-matched population. The relative risk (RR), confidence intervals (95% CI) and p-values for each diagnosis were calculated using Pearson’s chi-squared test. Statistical analyses were performed using R Statistics version 3.0.2. Results: A total of 1004 MS cases were identified. Validation resulted in exclusion of 10% of MS cases (due to false ICD coding or misclassification), thence, prevalence of MS in a population of 472 139 was 212.6 / 105 (95%,CI, 199.5- 225.8). Of all patients with MS 112 experienced a fracture during sthe study period. 51 of these fractures were osteoporotic and 61 were considered other types of fractures. 8 cases experienced fracture before the date of MS diagnosis and were excluded from the analysis. RR of osteoporotic fractures was significantly increased (3.3. [CI 1.49-7.45]) in patients with MS compared to controls. In particular RR of hip/ femur fractures was elevated in MS patients vs controls (3.46 [CI 2.0-5.8]). Conclusions: We observed a high prevalence of MS in southwest Finland and confirmed increased age-adjusted comorbid risk for osteoporotic fractures. Our study also points at utility of hospital administrative data bases for epidemiological studies.

D.L. Rotstein1,2, K. Tu3, P. Gozdyra3, K. Krysko3, D. Wilton4, J. Kwong4, R. Burnett5, R. Copes6, H. Chen7 1Medicine, Division of Neurology, St. Michael’s Hospital, 2Medicine, Division of Neurology, 3University of Toronto, 4Institute for Clinical Evaluative Sciences, Toronto, 5Health Canada, Ottawa, 6Ontario Agency for Health Protection and Promotion, 7School of Public Health, University of Toronto, Toronto, ON, Canada Background: Recent reports indicate that the incidence and prevalence of MS are increasing, with a disproportionate rise amongst females. Other studies suggest that the previously described latitudinal gradient of MS may be overestimated or disappearing. Objective: To investigate the incidence and prevalence of MS in Ontario, Canada, a region with a large MS population, single payer health care system, high ethnic diversity, and wide range in latitude (40o-55oN). Methods: Incident and prevalent cases of MS from 1996-2011 were identified from administrative data using a validated, previously published algorithm. Incidence, prevalence, and mortality rates of persons with MS were calculated with standardization for age and sex. Standardized rates were also estimated by gender and by geographic location as per census subdivision (CSD). We calculated the correlation of CSD latitude with standardized MS incidence and prevalence respectively. Results: The sex- and age-adjusted prevalence rate of MS increased by 66% from 157/100,000 in 1996 (n=12,157) to 261/100,000 in 2011 (n=27,044), but there was no significant change in the incidence rate (15.8/100,000 in 1996 (n=1,253); 15.9/100,000 in 2011 (n=1,540)). Mortality amongst MS subjects decreased by 35% from 26.7/1,000 in 1996 to 17.4/1,000 in 2011. The incidence of MS from 1996-2011 was higher amongst women (RR 2.15, 95% CI 2.09-2.21). Prevalence of MS was higher amongst women in 1996 (RR 2.36, 95% CI 2.27-2.45) and did not change significantly during the study period. There were weak inverse correlations between standardized MS incidence and CSD latitude from 1996-2011 (r=0.14, p< 0.002) and MS prevalence and CSD latitude (1996-2001: r=-0.18, p< 0.0001; 2002-2006: r=-0.14, p< 0.002; 2007-2011: r=-0.11, p=0.01). Conclusion: In one of the largest population-based cohorts investigated to date, we found evidence of stable incidence and increasing prevalence of MS; the latter is partially explained by declining mortality rates. The gender ratio was essentially constant, in contrast to other recent reports. MS incidence and prevalence were slightly lower with increased latitude, an unexpected finding suggesting that the latitudinal gradient may be disappearing, overestimated, or applicable only at certain latitude ranges.

Disclosure Julia Åivo: nohing to disclose Samu Kurki: nothing to disclose Marja-Liisa Sumelahti: nothing to disclose Juhani Ruutiainen: nothing to disclose Merja Soilu-Hänninen: nothing to disclose

P780 Stable incidence, gender ratio and no direct latitudinal gradient in the incidence and prevalence of MS in Ontario, Canada

Disclosure Dalia Rotstein has served as a a consultant for Novartis and Sanofi. Karen Tu: nothing to disclose. Peter Gozdyra: nothing to disclose. Kristen Krysko: nothing to disclose. Drew Wilton: nothing to disclose. Jeff Kwong: nothing to disclose. Rick Burnett: nothing to disclose. Ray Copes: nothing to disclose. Hong Chen: nothing to disclose.


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Poster Session 2, 21(S11) P781 Prevalence of tumefactive demyelinating lesions in multiple sclerosis R. Totaro1, A. Splendiani2, C. Di Carmine1, S. Torlone2, L. Patriarca2, C. Marini1, A. Carolei1 1Department of Neurology, 2Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, University of L’Aquila, L’Aquila, Italy Objective: The aim of this study was to estimate the prevalence of tumefactive demyelinating lesions (TDLs) in a cohort of patients diagnosed with multiple sclerosis (MS). Materials and methods: We reviewed brain MRI scans of 443 patients referred to our MS center from January 1996 to December 2014 fulfilling McDonald criteria for MS. All patients whose MRI showed at least one TDL were included. TDL was defined by plaque size more than 2 cm, with or without mass effect. TDLs on each MRI scan were analysed for location, size, T2W hypointense rim, contrast enhancement pattern, mass effect, oedema and coexistence of additional T2W lesions. Demographic and clinical data were gathered by electronic medical records review. Results: Out of 443 MS patients, we identified 7 cases (1.5%) who met the inclusion criteria. Five patients were female. Mean age at onset of first TDL was 24±5.06 years. All patients were diagnosed with relapsing-remitting MS prior to the occurrence of a TDL. Three patients were symptomatic at the onset of TDL with sensory (n=3) or sensory-motor (n=2) impairment, and aphasia associated with psychomotor agitation (n=1). In the 7 patients enrolled, we found a total of 8 TDLs. Frontal (n=3), temporal (n=2) and parietal (n=2) regions were more often affected. Mass effect was present in all but one lesion and was graded as mild (sulcal effacement) in 3, moderate (minimal subfalcine or uncal herniation, >1 cm) in 2 and moderate-to-severe (>1cm subfalcine or uncal herniation) in 2 cases, respectively. Perilesional oedema was found in all lesions and was characterized as mild (< 1cm) in 7 lesions and moderate-to-severe in one (>1 cm). T2W hypointense rim surrounding TDLs was found in 3 cases. Contrast enhancement was present in 5 lesions presenting as ring-like (n=2), heterogeneous (n=1), fluffy/cotton-ball (n=1) or concentric (n=1). In 6 cases we found concomitant multiple T2W lesions. One patient presented new TDL at 2-year MRI scan follow-up. Conclusion: TDLs were uncommon in our series and occurred in the course of established RRMS. Disclosure RT received funding for travel or speaker honoraria from Almirall, Bayer, Biogen, Merck Serono, Novartis, Sanofi-Aventis, and TEVA. P782 Upper respiratory infections and MRI activity in relapsing-remitting MS M. Kneider1, V. Lisovskaja2,3, J. Lycke1, C. Malmeström1, J.K. Jakobsen4, O. Nerman2,3, O. Andersen1 1Neuroscience and Physiology, University of Gothenburg, 2Mathematical Sciences, Chalmers Technical University, 3Mathematical Sciences, University of Gothenburg, Gothenburg, Sweden, 4Clinic of Neurology, National Hospital, Copenhagen, Denmark

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Background: While a relationship between systemic infections and MS relapses was suggested from clinical reports, MRI evidence on such relationship was conflicting. Previous MRI studies used fixed intervals between the systemic infection and MRI examinations. Objective: To decide whether MS related MRI activity has any preference to be more intense at any particular time, expressed as days of delay, after an upper respiratory tract infection. Methods: We used data from a randomized clinical trial of an anti-herpes drug in MS. We combined individual data on common infections with data on active lesions in pre-scheduled MRI examinations performed every four weeks for 28 weeks in 69 patients. A 4-week at risk (AR) period started, by definition, one week before the onset of an upper respiratory infection (URTI). The 483 pre-scheduled MRI examinations represented a virtually random matrix of event times in a 4-week period after an URTI. The MRI activity was recorded for each day (0-28 days). We recorded the relationship between the number of active lesions in each MRI with 1) the number of in days AR time in the immediately preceding 4-week period and 2) the number of days passed since the onset of a preceding upper respiratory infection. Results: The average MRI lesions/day showed no difference between the AR (0.0764) and not at risk (NAR)(0.0774) periods. No correlation was found between the number of lesions in each scheduled MRI and the AR proportion of the prior 4-week period (rho=−0.03). The time from URTI onset did not correlate with the number of lesions in the next MRI examination (rho=0.003). Conclusion: Using correlation without a pre-determined theoretical end-point, the onset of an upper respiratory infection in RRMS did not predict increased MRI activity at any particular time point during the following 4-week period. The question of MRI activity in RRMS in relation to infections is still open. Disclosure Maria Kneider: nothing to disclose Jan Lycke has received travel support and/or lecture honoraria from Biogen, Novartis, Teva and Genzyme/SanofiAventis; has served on scientific advisory boards for Almirall, Teva, Biogen, Novartis and Genzyme/SanofiAventis; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, Novartis and Teva. Clas Malmestrom: nothing to disclose. Johannes Jakobsen: nothing to disclose Oluf Andersen: nothing to disclose P783 Reduction of cancer risk in multiple sclerosis, despite use of disease-modifying therapies M. Perie1, X. Moisset1,2, M. Lauxerois1, E. Dumont1, C. Rudelle1, B. Pereira3, P. Clavelou1,2 1Neurology, CHU de Clermont Ferrand, 2Inserm U 1107 NeuroDol, 3Délégation à la Recherche Clinique, CHU de Clermont Ferrand, Clermont Ferrand, France Background: The effect of Multiple Sclerosis (MS) on cancer risk is poorly studied. Moreover, the effect of disease-modifying therapies (DMT) on this risk should also be better investigated.


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Objectives: To investigate the lifetime cumulative cancer incidence prevalence in a large cohort of MS patients and to compare it with those of a contemporary control cohort without MS. To evaluate impact of DMT and evolutive mode on this risk in MS patients. Methods: The association « Réseau SEP Auvergne » includes almost all MS patients in the administrative area surrounding Clermont-Ferrand University Hospital. A written questionnaire was sent to the 1567 members of this association. Data concerning age, gender, MS, potential cancer history and tobacco and alcohol consumption were collected. Control subjects were patients followed in our Neurology department for pathologies other than MS. Propensity score was matched on age, gender, tobacco and alcohol usage. To allow a more reliable comparison between MS patients and controls, a bootstrap method was used to obtain odds ratio (1000 simulations of OR for 1000 samplings). Results: Response rate in MS patients was 69,8% (n=1094). Lifetime cancer incidence was 7.6% (n=83). Breast (n=27), skin (n=13) and uterus cancers (n=12) were the most frequent. Cancer incidence in the control population (n=1516) was 14,0% (n=212). Most frequent were breast (n=39), prostate (n=29) and skin cancers (n=24). Propensity score analysis included 902 MS patients and 903 controls. Thus, cancer incidence was estimated to 8.1% and 16.6% in MS and control patients respectively. MS patients had a significantly lower incidence of cancer (OR=0.61; IC95%: 0.46-0.82; p< 0.001). In MS patients, DMT did not represent a risk factor for cancer. Evolutive mode did not impact cancer risk. Conclusion: MS patients have a lower cancer risk and DMT use does’nt increase this risk. Study supported by: TEVA (AGIR SEP) Disclosure Maud Perie: nothing to disclose Xavier Moisset: received travel expenses from Merk-Serono, Biogen-Idec, Sanofi-Pasteur-MSD and Genzyme and received honoraria from Astellas and Institut UPSA de la douleur. Michel lauxerois: nothing to disclose Emilie Dumont: nothing to disclose Candice Rudelle: nothing to disclose Pierre Clavelou: received honoraria and travel expenses to conferences from and is a consultant to Teva-Pharma, Merck-Serono, Novartis, Biogen-Idec, LFB, Genzyme, Bayer, Almirall and Lundbeck

P784 Systematic assessment and characterization of chronic pain in multiple sclerosis patients: preliminary results D. Ferraro1, D. Plantone2, F. Morselli1, A.M. Simone1, F. Vitetta1, P. Sola1, G. Primiano2, V. Nociti2, M. Mirabella2, C. Vollono2 1Department of Biomedical Metabolic and Neurosciences, University of Modena and Reggio Emilia, Modena, 2Department of Geriatrics, Neurosciences and Orthopedics, Catholic University, Rome, Italy Background: Chronic pain is defined by the International Association for the Study of Pain as constant or intermittent daily pain, persisting for more than 3 months, without apparent biologic

value. Chronic pain is a well-known feature of Multiple Sclerosis (MS). However, no systematic epidemiological data are available in large populations of patients.AIMWe aimed to describe the prevalence and characteristics of chronic pain in a cohort of MS patients. Methods: All consecutive MS patients seen at the Multiple Sclerosis Center of the “Nuovo Ospedale Civile S. Agostino Estense” (Modena, Italy) between February and April 2015 underwent a comprehensive assessment, including a complete neurological examination and documentation of pain history, and were asked to fill out a number of questionnaires including the DN4, the Neuropathic Pain Symptom Inventory, the Brief Pain Inventory, and the McGill Pain Questionnaire. Patients meeting criteria for chronic pain were included in the “Pain Group” (PAIN+). The others were included in the “No-PAIN Group” (PAIN-). We compared demographic and clinical data between the two groups using Mann-Whitney’s test and used Spearman statistics to analyze possible correlations. Results: We assessed 188 patients (age: 44.8±15.4 years, 53 males) with different forms of MS; 157 (83.5%) had relapsingremitting (RR), while 31 (16.5%) had primary (PP) or secondary progressive (SP) MS. The overall prevalence of chronic pain was 57.4% (108/188), most frequently affecting the lower limbs (19,1%). Neuropathic pain was the most frequent type of pain (51/108; 47.2%), with nearly one third of patients presenting constant pain and with 25% of patients taking more than one treatment for neuropathic pain. There were no significant differences in the prevalence of chronic pain the different MS forms or in patients taking different immunomodulatory/suppressant drugs. PAIN+ patients had significantly higher EDSS scores than PAINpatients (2.9 versus 1.8; p=0.002), while the two groups did not differ in terms of age or disease duration. There was a significant correlation between EDSS and DN4 scores (r: 0.27, p=0.005). Conclusions: More than half of MS patients, in our cohort, fulfilled criteria for chronic pain, the most frequent type being neuropathic pain. There was a significant correlation between EDSS and DN4 scores; a high level of disability is an important predictor of neuropathic pain, which, if undetected, may not be adequately treated. Disclosure Diana Ferraro: nothing to discolse Domenico Plantone: nothing to discolse Franca Morselli: nothing to discolse Anna Maria Simone: nothing to discolse Francesca Vittetta: nothing to discolse Patrizia Sola: nothing to discolse Guido Primiano: nothing to discolse Viviana Nociti: nothing to discolse Massimiliano Mirabella: nothing to discolse Catello Vollono: nothing to discolse P785 Social media and recruitment in the NARCOMS registry C. Crowe1, S.S. Cofield1, A.R. Salter1, T. Tyry2, S. McNeal3, G.R. Cutter3, R.J. Fox4, R.A. Marrie5, NARCOMS 1University of Alabama at Birmingham, Birmingham, AL, 2Dignity Health, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, 3Biostatistics, University of Alabama at


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Poster Session 2, 21(S11) Birmingham, Birmingham, AL, 4Neurology, Cleveland Clinc, Cleveland, OH, United States, 5University of Manitoba, Winnipeg, MB, Canada Background: Recent research shows that most of the populations of the US and EU have access to and use the Internet as a primary source of health information. Recent North American Research Committee on MS (NARCOMS) research has shown that 85% of participants have access to the internet, and 59% of participants use the Internet as their primary source of MS-specific health information. With over 1 billion Facebook users and 230 million Twitter users, social media and online advertising are potential recruitment tools for research. Objective: To describe social media and online tools used in NARCOMS recruitment. Methods: NARCOMS is a self-report registry for MS with over 37,000 participants. NARCOMS participants complete an enrollment survey followed by semi-annual surveys. About 70% complete surveys online while the rest mail in paper surveys. NARCOMS began using Google AdWords in August 2012 and Twitter (@NARCOMS) in February 2013, and actively pursued collaborations with other MS and neurology outlets to increase online visibility of the registry. Results: Since August 2012, the Google AdWords has been viewed over 260,000 times with 89% of views on search engines outside of Google; 56% were viewed on smartphones. The most common views or clicks on the ad were from: NARCOMS, multiple sclerosis, MS treatment, and MS symptoms in women. In 2015, 43% of new enrollments reported hearing about NARCOMS from the Internet, Twitter, or Facebook. On Twitter @NARCOMS had high-profile Tweets by well-known researchers, media outlets and celebrities living with MS. In 2011-2012, NARCOMS enrollments averaged 2.3 enrollments/day. Since pursuing an online presence enrollment increased to 2.9/day through 2014. In March 2015, after a National MS Society online article, Tweet (@mssociety; 40,000 followers) and a Facebook post with a direct link to NARCOMS, enrollment increased from 5 to 109 in one day, with enrollment averaging 9/day in the week following. One week after a Tweet by Ann Romney (@ AnnDRomney; 202,000 followers) and Brigham and Women’s (@BrighamWomens; 20,000 followers) on an article in the magazine NARCOMS Now, Google AdWord views increased from 517/day to 1406, and clicks on the ad increased 200%. 2015 enrollment through March 2015 is 4.9/day. Conclusions: Social media approaches to recruitment appear to quickly increase enrollment numbers. It will be important to follow whether individuals who have enrolled after social media efforts continue to participate. Disclosure Dr. Cofield has received support for consulting services from the American Shoulder and Elbow Society, DSMB service from MedImmune, and/or grant support for various entities; no direct conflicts. Dr. Salter has received support for consulting services and grant support; no direct conflicts. Dr. Fox has received support for consulting fees from Actelion, Biogen, MedDay, Novartis, Questcor, Teva, and XenoPort; no direct conflicts.

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Dr. Marrie has conducted clinical trials for sanofi-aventis; no direct conflict. Dr. Tyry has nothing to disclose. Ms. McNeal has nothing to disclose. Ms. Crowe has nothing to disclose. Dr. Cutter has consulting and/or DSMB commitments in Past 12 months. Participation of Data and Safety Monitoring Committees: All of the below organizations are focused on medical research: Apotek, Biogen-Idec, Cleveland Clinic(Vivus), Glaxo Smith Klein Pharmaceuticals, Gilead Pharmaceuticals, Horizon Pharmaceuticals, Modigenetech/Prolor, Merck/Ono Pharmaceuticals, Merck, Merck/ Pfizer, Neuren, Sanofi-Aventis, Teva, NHLBI (Protocol Review Committee), NINDS, NICHD (OPRU oversight committee). Consulting, Speaking fees & Advisory Boards: Consortium of MS Centers (grant), D3 (Drug Discovery and Development), Genzyme, Genentech, Jannsen Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, Novartis, Opexa Therapeutics, Receptos, Roche, EMD Serono, Spiniflex Pharmaceuticals, Somahlution, Teva pharmaceuticals, Transparency Life Sciences. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. Sources of funding: NARCOMS is supported by the CMSC and the Foundation of the CMSC. P786 Recovery from first relapse in the CombiRx trial S.S. Cofield1, S. Krieger2, A.R. Salter1, T. Gustafson2, J.S. Wolinsky3, G.R. Cutter1, F.D. Lublin2, The CombiRx Investigator Group 1Biostatistics, University of Alabama at Birmingham, Birmingham, AL, 2Corinne Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, New York, NY, 3Neurology, University of Texas Health Sciences Center at Houston, Houston, TX, United States Background: The CombiRx trial was a blinded, multi-center randomized trial of 1008 persons with relapsing remitting MS, comparing 50% on interferon beta 1a (IFN) and glatiramer acetate (GA) versus 25% on each single agent arm with matching placebo. Entry criteria required age 18-60 years, ⩾2 relapses in prior 3 years, EDSS ⩽ 5.5, and no prior use of either study medication. Participants were followed for up to 7 years. Objectives: Compare recovery from first relapse as measured by EDSS change by treatment arm and other factors. Methods: On-Study relapse considered the first protocol defined or non-protocol defined exacerbations (PDE, NPDE). PDE required new/worsening symptoms ⩾ 24 hours, no fever, change in EDSS or FS, examined ⩽ 7 days; NPDE as PDE but examined > 7days. Time to recovery was measured as days to return to EDSS score equal to or lower than EDSS measured prior to relapse onset or as days to last EDSS follow up without recovery. Change in EDSS was grouped as an increase of 0.5, 1, 1.5, 2, and 2.5 or more (2.5+). Covariate adjusted logistic regression or Cox Proportional Hazards models were utilized for likelihood of recovery and time to recovery. Results: 453 (44.9%) of participants experienced a PDE or NPDE, with 388 meeting PDE+NPDE by EDSS change. Of these, 309 (79.6%) recovered (median 114 days). The likelihood of


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recovery was not different by age (p=0.53), treatment (p=0.32), or EDSS prior to relapse (p=0.84); females more likely to recover than males (79.1% vs 68.7%, OR 1.8, p=0.034). Those with smaller EDSS changes at time of relapse were more likely to recover: EDSS 2.5+ 55.4%, 2 79.5%, 1.5 67.9%, 1 86.1%, 0.5 80.6% (2 vs 2.5+ OR 3.2, p=0.012, 1 vs 2.5+ OR 5.1, p=0.0001; 0.5 vs 2.5 OR 3.4, p=0.002). Time to recovery was not different by age (p=0.68), treatment (p=0.38), or EDSS prior to relapse (p=0.11), or gender (p=0.06). Those with smaller EDSS changes had a shorter median days to recovery (p=0.001): EDSS 2.5+ 190 days, 2 124, 1.5 137, 1 105, 0.5 106 (2 vs 2.5+ RR 1.7, p=0.025; 1 vs 2.5+ RR 2.2 p=0.0001; 0.5 vs 2.5+ RR 2.2, p=0.0001). Conclusions: Most participants in CombiRx recovered from their first relapse by returning to an EDSS score at or lower than the EDSS prior to relapse. There was no difference in recovery by treatment arm. Males and those experiencing larger EDSS changes were less likely to recover and larger EDSS changes took longer to recover than those with smaller EDSS changes. Disclosure Dr. Cofield has received support for consulting services (American Shoulder and Elbow Society), DSMB service (MedImmune), and/ or grant support; no direct conflicts. Dr. Salter has received support for consulting services and grant support; no direct conflicts. Dr. Wolinsky has received support for consulting services, DSMB service, and/or grant support; no direct conflicts. Dr. Lublin has received support for consulting services, DSMB service, and/or grant support; no direct conflicts. Dr. Krieger Salter has received support for consulting services and grant support; no direct conflicts. Ms. Gustafson has nothing to disclose. Dr. Cutter has consulting and/or DSMB commitments in Past 12 months. Participation of Data and Safety Monitoring Committees: All of the below organizations are focused on medical research: Apotek, Biogen-Idec, Cleveland Clinic(Vivus), Glaxo Smith Klein Pharmaceuticals, Gilead Pharmaceuticals, Horizon Pharmaceuticals, Modigenetech/Prolor, Merck/Ono Pharmaceuticals, Merck, Merck/Pfizer, Neuren, Sanofi-Aventis, Teva, NHLBI (Protocol Review Committee), NINDS, NICHD (OPRU oversight committee). Consulting, Speaking fees & Advisory Boards: Consortium of MS Centers (grant), D3 (Drug Discovery and Development), Genzyme, Genentech, Jannsen Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, Novartis, Opexa Therapeutics, Receptos, Roche, EMD Serono, Spiniflex Pharmaceuticals, Somahlution, Teva pharmaceuticals, Transparency Life Sciences. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. Sources of funding: NIH/NINDS 5-U01-NS045719. Biogen Idec and Teva Neuroscience generously contributed study medications and matched placebo without input into the design, conduct, analysis, or interpretation of results of the trial. P787 Familial forms of multiple sclerosis in Brazilian patients: is HLA-DR2 involved in susceptibility to the disease?

M.S. Bernardes1, R. Papais-Alvarenga1,2, C.L.A. Paiva3, E. Paradela1, F.C. Pereira1, C.F. Vasconcelos1,2, M.P. Alvarenga1,2 1PPGNEURO, Universidade Federal do Estado do Rio de Janeiro, 2Neurologia, Hospital da Lagoa, 3Biologia Molecular e Genética, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, Brazil Background: The occurrence of familial forms of multiple sclerosis (FFMS) -and the evidence of greater risk of the disease among relatives of multiple sclerosis (MS) patients, compared with the general risk for the population, suggest substantial influence of the genetic factor in the etiology of the disease. The haplotype HLA-DR2 (HLA-DRB1*15:01-DQB*06:02-DQA1*01:02) is the major genetic marker of MS susceptibility ever identified. Regarding the miscegenated population from Latin America, information about FFMS is scarce. Objectives: To identify the familial forms of MS, to classify them according to the kinship groups and to describe their clinical and demographic features, as well as to perform a HLA-DR2 survey in the cases comparing the results with healthy controls. Methods: We have searched our database for familial cases, which includes records from 662 MS patients attending a reference center for idiopathic inflammatory demyelinating disease in Rio de Janeiro city (RJ, Brazil). The cases who failed to meet MS diagnostic criteria and the ones who were unavailable for interviews were excluded. We have analyzed demographic (gender, ethnicity, age, foreign ancestry) and clinical [age at onset of MS, disease duration, disability, MS clinical course] variables among the kinship groups (first degree, multiplex and second/third degrees). We performed an intra- and intergenerational analysis of age at onset, disease duration and disability scores. The familial cases were genotyped for HLA, using the Polymerase Chain Reaction Amplification with Sequence-Specific Primers (SSPPCR) technique. Results: The overall FFMS prevalence was 5.0% in MS patients. It was observed a predominance of white subjects (89.2%) and females (78.4%) - female/male ratio = 3.6:1.0. European ancestry was found in 24.3% of cases. The majority of FFMS were included in the first degree group (70.3%), followed respectively for the second/third degrees (21.6%) and multiplex (8.1%) ones. Intergenerational cases exhibited lower age at onset. FFMS showed strong association with HLA-DR2 (P< .001) when compared with healthy controls. It was noticed tendency for PPMS in the HLA-DR2 positive cases,. Conclusions: FFMS was preponderant among Caucasians of European ancestry, in the admixed population of Rio de Janeiro city. It was found a strong association of HLA-DR2 with FFMS cases, thus emphasizing the relevance of genetics contribution to MS etiology. Disclosure Melina S. Bernardes: nothing to declare. Regina Papais-Alvarenga: nothing to declare. Carmen L. A. Paiva: nothing to declare. Eduardo Paradela: nothing to declare. Fernanda C. Pereira: nothing to declare. Claudia F. Vasconcelos: nothing to declare. Marcos P. Alvarenga: nothing to declare.


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Poster Session 2, 21(S11) P788 Increased prevalence of multiple sclerosis (MS) in islands of the Aegean Sea and Crete A.I. Kaliontzoglou1, V.C. Mastorodemos2, C. Mylonakis3, F. Alourda1, G. Amoiridis2,3, I.V. Zaganas2,3 1Neurology, General Hospital of Rhodes, Rhodes, 2Neurology, University Hospital of Heraklion Crete, 3School of Medicine, University of Crete, Heraklion, Greece Background: Greece is traditionally considered a relatively low prevalence region for MS. We previously reported increased MS prevalence (108/105) in the island of Crete. It is uncertain whether increased MS prevalence is also found in adjacent or remote islands of the Aegean Sea. Objective: To update MS prevalence data from Crete and assess MS prevalence rates in neighboring Southeastern Aegean Sea islands, such as Rhodes and Ikaria. Patients and methods: We identified all cases with diagnosis of MS by review of hospital and public insurance records and collaboration with local physicians from Crete, Rhodes and Ikaria. We reviewed clinical and MRI data and confirmed the diagnosis using the criteria of the International Panel on MS. Crude prevalence rates were calculated on the basis of the population of Crete, Ikaria and Rhodes according to the 2011 national census. Results: We identified 819 patients with MS (521 females and 298 males, female/male ratio: 1.75) living on Crete (621,340 total population), which accounts for an overall prevalence rate of 132 per 105 inhabitants. In Rhodes (115,490 total population) and Ikaria (8,423 total population), MS prevalence was even higher (153 per 105 and 154 per105, respectively). Specifically, in Rhodes, 177 MS patients were found (113 females and 64 males, female/male ratio: 1.76), with 15.0 % of the cases being familial. On Ikaria, 13 patients were identified on the island, with most of these patients coming from families with multiple affected members. Conclusions: The increased MS prevalence on the islands of Ikaria and Rhodes and confirmation of previous similar observations in Crete suggest that the Southeastern Aegean islands constitute a high prevalence area for MS. Given the high frequency of familial cases encountered, further studies are warranted to identify probable underlying genetic or environmental factors. Disclosure AK has received travel grants from Biogen Idec and Novartis.VM has received in the past travel grants from Biogen Idec, Novartis, Merck-Serono, Teva and Bayer. IZ has received grants from Genesis Pharma, Novartis and Pfizer. The rest of the authors had nothing to disclose. P789 The diagnosis of multiple sclerosis: pinpointing the concept of “no better explanation” M. Calabrese1, C. Gasperini2, C. Tortorella3, M.P. Sormani4, G. Frisullo5, P. Ragonese6, R. Fantozzi7, L. Prosperini8, P. Annovazzi9, C. Cordioli10, D. Ferraro11, A. Gajofatto1, S. Malucchi12, S. Lo Fermo13, G. De Luca14, M.L. Strimllo15, E. Cocco16, A. Gallo17, D. Paolicelli3, R. Lanzillo18, V. Tomassini19, I. Pesci20, M.E. Rodegher21, C. Solaro22 1Department of Neurological and Movement Sciences, University

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Hospital of Verona, Verona, 2Department of Nerosciences, Az S Camillo Forlanini Roma, Rome, 3Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, 4Biostatistics Unit, Department of Health Sciences, University of Genova, Genova, 5Università Cattolica del Sacro Cuore, Rome, 6UOC Neurologia Policlinico Paolo Giaccone, Palermo, 7Istituto Neurologico Mediterraneo, Pozzilli, 8Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, 9Multiple Sclerosis Study Centre, AO S. Antonio Abate, Gallarate, 10Multiple Sclerosis Center, Ospedale di Montichiari, Spedali Civili di Brescia, Brescia, 11Azienda USL di Modena, Modena, 12AOU San Luigi Gonzaga, Orbassano, 13Multiple Sclerosis Centre A.O.U. PoliclinicoVittorio Emanuele, Catania, 14Ospedale SS Annunziata, Chieti, 15University of Siena, Siena, 16Department Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, 17Department of Medical, Surgical, Neurological, Metabolic and Aging Science, Second University of Naples, 18Dipartimento di Neuroscienze, Scienze Riproduttive e Odontostomatologiche, Università Federico II, Napoli, Italy, 19Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, United Kingdom, 20Centro SM Ospedale di Vaio, Fidenza, 21Ospedale San Camillo Raffaele, Milano, 22Department Head and Neck Neurology, Unit ASL3 Genovese, Genova, Italy Background: Since the first appearance of McDonald’s diagnostic criteria for Multiple Sclerosis (MS), it was clear that a crucial role in the diagnostic work up would have been played by the exclusion of other neurological diseases. Aim of this study is to provide an accurate picture of the main diseases that can mimic MS in the “real world” setting of a large number of MS centres. Methods: This is a prospective, observational clinical and radiological study including all consecutive patients presenting with symptoms suggestive of MS between March and September 2014, in which a further examination was required in order to exclude or confirm MS diagnosis. Each patient after a regular diagnostic workup (including magnetic resonance imaging, visual evoked potentials, blood and cerebrospinal fluid examinations) was included in a 2-year follow up. Results: 642 patients were included in the study. According to McDonald 2010 criteria and after 8 months of follow up, the diagnosis of MS was confirmed in 268 (41.7%) MS patients while in 99 (15.4%) a different diagnosis was made. The remaining 275 (42.8%) patients (including clinical isolated syndromes) entered the 2-year clinical and radiological follow-up in order to clarify the diagnosis. The most frequent alternative diagnoses were vascular encephalopathy (in 21 cases), migraine (in 20 cases), neuromyelitis optica (in 10 cases), recurrent optic neuritis (in 5 cases), and other systemic autoimmune diseases mimicking MS (including Sjogren, neuroBechet, systemic lupus erythematosus and antiphospholipid syndromes, in 11 cases). A higher number of lesions on brain MRI (p< 0.001), demyelination along the central visual pathways (P100 latency, p=0.002) and a higher frequency of IgG oligoclonal bands in the cerebro-spinal fluid (p< 0.001) were found in patients with MS compared to those diagnosing with alternative diseases.


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Discussion: Our preliminary analysis confirms that according to 2010 diagnostic criteria, a defined MS diagnosis can be made at the end of diagnostic work-up in almost 40% of the patients presenting with symptoms suggestive of MS. Migraine, vascular encephalopathy and neuromyelitis optica were by far the most frequent alternative diagnosis, while no infectious diseases have been observed. Results of our study will be helpful to recommend an appropriate diagnostic algorithm based on the most frequent conditions entering the differential diagnosis with MS. Disclosure M. Calabrese has received consulting and/or lecture fees and/ot travel grants from Bayer Schering, Biogen Idec, Genzyme, Novartis and Teva. C. Gasperini received fee as speaker or consultant by Merck Serono, Biogen Idec, Bayer Sheering, Teva, Novartis P Ragonese received received travel expenses or honoraria for consultancy from Merck Serono, Biogen idec, Novartis, TEVA pharma, and Sanophy Genzyme. C. Tortorella received honoraria for consulting from Teva and Bayer Shering and for speaking from Biogen, Teva, Serono, Genzyme and Novartis Salvatore Lo Fermo received honoraria for consultancy from Merck Serono, Biogen idec and Novartis. Cinzia Cordioli has no disclosures L Prosperini has received consulting and/or lecture fees and/ot travel grants from Bayer Schering, Biogen Idec, Genzyme, Novartis and Teva. R Lanzillo received honoraris for public speaking or advisory from Novartis, Merck Serono, Genzyme, Biogen, TEVA. P. Annovazzi received speaking and consulting onoraria from Almirall, Biogen, Genzyme, Novartis and Teva The remaining authors declare no disclosures related to this project/manuscript P790 Prevalence of multiple sclerosis in 2012 from the French health insurance data T. Moreau1, S. Foulon2, M. Debouverie3, A. Weill2 1Neurology, University Hospital of Dijon, Dijon, 2French Public Health Insurance (CNAMTS), Paris, 3Neurology, University Hospital of Nancy, Nancy, France Background: Multiple sclerosis (MS) prevalence is heterogeneous worldwide. In Europe, a North-South prevalence gradient has been described with higher prevalence for North regions. France is located in the middle of Western Europe and considered as a country of medium to high prevalence. In 2004, the MS prevalence was estimated to 94.7 per 100,000 from the Caisse Nationale d’Assurance Maladie des Travailleurs Salariés (CNAMTS) including 87% of the French population with higher rate in north-eastern versus south-west regions without obvious north-south gradient. The national French prevalence using a similar approach has been analysed 8 years later. Objective: To estimate the MS prevalence on December 12, 2012 from the database of the French National information system (SNIIRAM) which covers 98.7% of the French population. Methods and results: From the SNIIRAM, 4 ways of identifying MS cases have been defined: reimbursement of MS disease-modifying

treatment, long-term status for MS, disability pension for MS, hospitalization for MS. The national prevalence was defined as the number of MS cases (at least one of the 4 criteria) divided by the number of people residing in France (January 1, 2013) and standardized by gender and 5 year-age categories on the European 2013 population. On December 31, 2012, 99,123 MS cases were identified for 66,542,916 inhabitants. The sex ratio (F/M) was 2.5 and a mean age of 50.3± 14.2 years. The national French crude prevalence of MS was 151.2 per 100,000 (CI 95%: 150.3-152.2); 210 per 100,000 (208.4-211.5) in women and 88.7 (87.6-89.7) in men. The standardized prevalence on the 2013 European population was 155.6 (154.7156.6). Higher standardized prevalence rates were observed in the North-Eastern regions (eg Lorraine, Picardie, Alsace) approaching 200 per 100,000 compared to South-Western regions (PoitouCharentes, Languedoc-Roussillon, Corse) with approximately 130 per 100,000. Conclusion: Using a national health insurance data and with a prevalence higher than 150 per 100,000; France is a country with a high risk of MS, specially in North and East regions. This prevalence is probably higher than previously described. Disclosure All the authors have nothing to disclose

P791 Anti-JCV antibody levels (index) in the population of Polish patients with multiple sclerosis (multicenter study in patients treated with immunomodulating or immunosuppressive drugs and naïve patients) R. Bonek1, P. Bochniak1, W. Guenter1, A. Karbicka2, R. Jałowiński2, A. Litwin3, K. Kurowska4, W. Wicha4, V. Petit5, K. Rejdak5 1Department of Neurology, Regionalny Szpital Specjalistyczny w Grudziądzu, Grudziądz, 2Department of Neurology, Samodzielny Publiczny Wojewódzki Szpital Zespolony w Szczecinie, Szczecin, 3Department of Neurology, Wojewódzki Szpital Specjalistyczny w Olsztynie, Olsztyn, 4II Department of Neurology, Instytut Psychiatrii i Neurologii w Warszawie, Warszawa, 5Departemnt of Neurology, Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie, Lublin, Poland Background: Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the central nervous system, caused by the John Cunningham virus (JCV). Previous studies have reported the anti-JCV antybodies status may differentiate PML risk. So far in Poland, there were not any studies evaluating the levels of anti-JCV antybodies in patients with MS. Objective: Evaluate the levels of antibodies against JCV in the serum of patients with multiple sclerosis in a Polish population according to demographic data, disease characteristics and treatment (immunosuppressive, immunomodulating or naïve patients). Methods: The presence of anti-JCV antibodies was evaluated in patients from 5 centers with a diagnosis of MS, according with McDonald’s criteria. 610 patients were included into the study, 427 female and 183 male. 227 patients were treated with immunomodulating drugs (IFN, GA), 133 patients with immunosuppressive drugs (mitoxantrone, cyclophosphamide, azathioprine) and 250 naïve patients. Focus Diagnostics’ STRATIFY JCV


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Poster Session 2, 21(S11) DxSelect assay was ussed in the study. That assay is intended for the qualitative detection of antibodies to JC virus in human serum or plasma. All the samples were tested at Unilabs in Denmark. Results: The mean age was 41,7 years, and mean disease duration was 8,7 years, 70,0% was female. The study population was representative for the general MS patients population. The proportion of patients treated with immunosuppressive drugs and immunomodulating drugs was very high, 21,8% and 37,2% respectively. In the study were 67,6% patients with RRMS, 20,9% and 11,5% with SPMS and PPMS respectively. The overall prevalence of anti-JCV antibodies was 69,2%. Index of anti-JCV antybodies was significantly associated with increasing age (p=0,0021), disease duration (p=0,0007), EDSS scale status (p=0,0149), disease course (p=0,0058), and also type of treatment (p=0,0066). Anti-JCV antibody level was significantly lower in patients with RRMS and patients treated with immunomodulating drugs. Anti-JCV antibody index was almost equal for male and female. Conclusion: 1. Patients with higher anti-JCV antibody index were significantly older, they had longer disease duration and higher disability level in EDSS. 2. Lowest anti-JCV antibody index had patients with RRMS and treated with interferon and glatiramer acetate. 3. Anti-JCV antibody index was independent of gender. Disclosure Robert Bonek, MD, PhD - Biogen, Novartis, Merck, Teva, Bayer. Tadeusz Ostrowski, MD - employee of Biogen Poland. Paweł Bochniak, MD - Bayer, Merck, Teva Biogen, Novartis. Wojciech Guenter, MD - Biogen, Novartis, Merck, Teva, Bayer. Anna Karbicka, MD, PhD - Biogen, Novartis, Merck, Teva, Bayer. Robert Jałowiński, MD - Biogen, Novartis, Merck, Teva, Bayer. Anna Litwin, MD - Biogen, Novartis, Merck, Teva, Bayer. Katarzyna Kurowska, MD, PhD - Biogen, Novartis, Merck, Teva, Bayer. Wojciech Wicha, MD, PhD - Biogen, Novartis, Merck, Teva, Bayer. Veronique Petit - Biogen, Novartis, Merck, Teva, Bayer. Konrad Rejdak, MD, PhD - Biogen, Novartis, Merck, Teva, Bayer. P792 Autoimmune hepatitis and multiple sclerosis: an occasional association G. Cação1, E. Santos1, A. Martins Silva1,2 1Neurology, Centro Hospitalar do Porto, 2Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Institute of Biomedical Sciences, University of Porto – UMIB/ ICBAS/UP, Porto, Portugal Background: Autoimmune hepatitis (AIH) is a generally progressive, chronic disease, associated with autoimmune conditions like thyroid disorders, celiac disease and, in a few cases, multiple sclerosis (MS) [1,2,3]. The prevalence of AIH in MS patient is estimated to be 0.17% versus 0.0169% in general population [4]. Case report: We report four cases of MS associated with AIH. A 32 years old man, diagnosed with relapsing-remitting MS (RRMS) in July of 2013, presented an acute hepatitis 3 months

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later, after endovenous corticotherapy for a MS relapse, while off disease modifying therapy (DMT). Liver biopsy revealed lobular lymphoplasmocytic infiltrate compatible with AIH. Treated with steroids hepatitis resolved. In May 2014 started on glatiramer acetate as DMT for MS. A 48 years old woman, diagnosed with RRMS in 1996, unveiled in 2002 a hepatic failure with a cholestasis pattern while still off DMT. A positive smooth muscle antibody (SMA) was disclosed and liver biopsy showed an inflammatory infiltrate with hepatic rosettes, compatible with AIH. Treated with azathioprine and steroids, liver function normalized. Afterward MS and AIH remained stable, but on 2014, developed a fulminant hepatitis requiring liver transplant. Notwithstanding, died 15 days later. A 52 years old woman, diagnosed with RRMS in 1995, treated with interferon beta-1b since 2000. In 2007, presented a cholestasis hepatitis. Interferon was suspended without resolution. A positive SMA, antinuclear and anti-F-actin antibodies were disclosed. Liver biopsy revealed an inflammatory infiltrate compatible with AIH. Treated with steroids and ursodeoxycholic acid, presented cholestasis improvement. Free of DMT remains without MS or AIH relapses. A 28 years old woman, diagnosed with RRMS in 2002, treated with interferon beta-1a 22ug since 2005, followed by interferon beta-1a 44ug and natalizumab 300mg, afterward suspended due to a JC virus >1.5. While off DMT, presented a cholestasis hepatitis with hepatic failure. Liver biopsy revealed lymphoplasmocytic infiltrate compatible with AIH. Treated with steroids and azathioprine, the hepatitis resolved. Continued without MS activity. Conclusion: In our cases, severity of AIH and MS does not seem to correlate, varying from patient to patient. Although rare, the association is clear, as so a liver biopsy should be considered in MS patients with sustained increase of liver enzymes. Disclosure Gonçalo Cação: nothing to disclose Ernestina Santos: nothing to disclose Ana Martins Silva: nothing to disclose P793 Incidence of multiple sclerosis in the Republic of Ireland: an observational population-based study K. O’Connell, M. Hutchinson, N. Tubridy, C. McGuigan Neurology Department, St Vincent’s University Hospital, Dublin, Ireland Background: There is evidence that the incidence of multiple sclerosis (MS) is increasing worldwide, with a disproportionally higher incidence in women and a persistent latitudinal gradient. Ireland is a high prevalence country for MS making it an ideal to further explore this concept. Objectives: The aims of this study were to a) establish the incidence of new cases of MS diagnosed in Ireland over a 12-month period and b) investigate the relationship between incidence rates and latitude. Methods: This was a national prospective population-based observation study designed to record all new cases of MS (McDonald 2010) diagnosed from 1st March 2014 - 28th February 2015 in the Republic of Ireland. Sources of case ascertainment


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included neurologists, MS nurse specialists and MS support services. The Irish census 2011 was used to obtain population statistics and the incidence rate was age-standardized to a European Standardised Population (ESP 2011). Differences in latitude were assessed, by comparing incidence rates between northern and southern counties. Results: 292 patients fulfilled the inclusion criteria yielding an age-standardised incidence (ASI) rate of 5.97/100,000. The female to male sex ratio was 2.7:1. Onset was progressive in 10% of cases. Mean age at diagnosis amongst the RRMS group was 37 years (SD: 9.6) and 55 years (SD: 7.7) in the PPMS group with no difference seen with gender. The ASI rate in the northern counties (mean latitude: 54°32) was 9.6/100,000 {95% CI: 6.9-12.3} compared to an ASI in the southern counties (mean latitude: 52°16) of 5.1/100,000 {95% CI: 3.8-6.3} supporting evidence of a latitudinal gradient. Conclusions: This is the first study to prospectively assess the incidence rate of MS in Ireland. We have demonstrated evidence of an increase in the female:male ratio and we have confirmed the presence of a latitudinal gradient (found in previous prevalence studies in Ireland). Disclosure Dr Karen OĆonnell has received travel grants from Teva, Biogen Idec, Abbvie and Novartis. Professor Michael Hutchinson served on the advisory board [BG00012] for Biogen Idec and is an associate editor of the Multiple Sclerosis Journal. He has received speaker’s honoraria from Biogen Idec, Bayer -Schering, Merck Serono and Novartis and receives research grants from Dystonia Ireland, the Health Research Board of Ireland (CSA-2012/5) and the Irish Institute of Clinical Neuroscience. Dr Christopher McGuigan has received honoraria, participated in advisory boards and/or received research funding from Biogen Idec, Merck Serono, Novartis, Genzyme and Bayer. Professor Niall Tubridy has received, on behalf of the Department of Neurology, St Vincent’s University Hospital, educational and research grants from Novartis, Biogen Idec, Teva and Bayer.

P794 Characterizing sun exposure behaviours in early life using latent variable analyses: the EnvIMS study S. Magalhaes1, A. Ciampi1, K. Bjørnevik2, K.-M. Myhr2, T. Riise2, M. Pugliatti3, C. Wolfson1,4 1Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada, 2University of Bergen, Bergen, Norway, 3University of Ferrara, Ferrara, Italy, 4Research Institute of the McGill University Health Centre, Montreal, QC, Canada Background: Sun exposure is a suggested MS risk factor. Most investigators report estimates for single sun exposure behaviour (SEB) variables (e.g. estimating separate regression models for summer and winter). The large size of the EnvIMS study allows for assessment of interactions with sufficient statistical power. We extend previous analyses and characterize individual SEB using four SEB variables and determine which are associated with higher MS risk.

Methods: EnvIMS in a case-control study conducted in Canada, Italy, Norway Serbia and Sweden; in this analysis we include data from Canada, Italy and Norway. Study participants completed a questionnaire that ascertained history of exposure to selected risk factors, including sun exposure. We used four SEB questions collected in all three countries: sun exposure in summer, in winter, during weekends and use of sun protection. We restricted our analysis to early life (before the age of 15 years). We used latent class analysis (a statistical tool that can be used to identify groups based on similar responses to a set of questions), an efficient alternative to interaction analyses using regression models. We developed a latent class cluster model to group study participants into different SEB groups and used regression to assess if SEB group membership was associated with risk of MS. Results: Our analysis includes 719 cases and 1146 controls from Canada, 724 and 1338 from Italy, and 953 and 1717 from Norway. In each country four SEB groups were identified. Overall these groups described individuals with (group 1) high (e.g. high summer, winter and weekend sun exposure and low sun protection), (group 2) intermediate high and (group 3) intermediate low and (group 4) low levels of sun exposure based on the responses to four SEB variables. In Canada, MS was significantly associated with SEB group in all three age periods (0-5, 6-10 and 11-15 years). In Italy, MS was significantly associated with SEB group in two age periods (0-5 and 6-10 years), but not 11-15. In Norway, MS was not found to be associated with SEB group in any of these age groups. MS cases were more likely to be classified into groups 3 and 4. The relative contribution of each of the four SEB variables to group membership was also examined. Conclusions: We show that MS risk is highest in individuals whose early life SEB is characterized by low levels of sun exposure in summer, winter, during weekends and higher levels of sun protection use. Disclosure The authors have nothing to disclose related to the work presented in the abstract. Funding: Sandra Magalhaes received doctoral studentship funding from the Canadian Institutes of Health Research (2011-2014) and the MS Society of Canada (2014-2016). The EnvIMS study was support by: the University of Bergen, Norway (2007 to T. Riise); the Canadian MS Scientific Research Foundation (20092010 to C. Wolfson); Italian MS Society/Foundation (Fondazione Italiana Sclerosi Multipla, FISM, grants n. 2007/R/14, and n. 2008/R/19 to M. Pugliatti); Sardinian Autonomous Regional Administration, Italy (Regione Autonoma della Sardegna, Assessorato all’Igiene, Sanità e dell’Assistenza Sociale to M. Pugliatt); the Fondazione Banco di Sardegna, Italy; The Western Norway Regional Health Authority (Helse Vest) Norway (grants n. 911421/2008 to M. Pugliatti and n. 911474/2009 to K-M Myhr); and Norwegian MS Society (MS-forbundet i Norge, 2009 to T.Riise); Funds for Clinical Research University Hospital Linköping, Sweden (2010-2011 to A.M. Landtblom). To conduct the full study in Canada the work was supported by the Multiple Sclerosis Society of Canada (2011-2013 to C. Wolfson). P795 The prevalence of John Cunningham virus antibody in the population of Polish patients with multiple sclerosis (multicenter study in patients treated with immunomodulating or immunosuppressive drugs and naïve patients)


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Poster Session 2, 21(S11) R. Bonek1, P. Bochniak1, W. Guenter1, A. Karbicka2, R. Jałowiński2, A. Litwin3, K. Kurowska4, W. Wicha4, V. Petit5, K. Rejdak5 1Department of Neurology, Regionalny Szpital Specjalistyczny w Grudziądzu, Grudziądz, 2Department of Neurology, Samodzielny Publiczny Wojewódzki Szpital Zespolony w Szczecinie, Szczecin, 3Department of Neurology, Wojewódzki Szpital Specjalistyczny w Olsztynie, Olsztyn, 4II Department of Neurology, Instytut Psychiatrii i Neurologii w Warszawie, Warszawa, 5Departemnt of Neurology, Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie, Lublin, Poland

Paweł Bochniak, MD - Bayer, Merck, Teva Biogen, Novartis Wojciech Guenter, MD - Biogen, Novartis, Merck, Teva, Bayer Anna Karbicka, MD, PhD - Biogen, Novartis, Merck, Teva, Bayer Robert Jałowiński, MD - Biogen, Novartis, Merck, Teva, Bayer Anna Litwin, MD - Biogen, Novartis, Merck, Teva, Bayer Katarzyna Kurowska, MD, PhD - Biogen, Novartis, Merck, Teva, Bayer Wojciech Wicha, MD, PhD - Biogen, Novartis, Merck, Teva, Bayer Veronique Petit - Biogen, Novartis, Merck, Teva, Bayer Konrad Rejdak, MD, PhD - Biogen, Novartis, Merck, Teva, Bayer

Background: Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the central nervous system, caused by the John Cunningham virus (JCV). Previous studies have reported the anti-JCV antybodies status may differentiate PML risk. So far in Poland, there were not any studies evaluating the levels of anti-JCV antybodies in patients with MS. Objective: Evaluate the prevalence of antibodies against JCV in the serum of patients with multiple sclerosis in a population of patients in Poland, according to demographic data, disease characteristics and treatment (immunosuppressive and immunomodulating treatment and also). Methods: The presence of anti-JCV antibodies was evaluated in patients from 5 centers with a diagnosis of MS, according with McDonald’s criteria. 610 patients were included into the study, 427 female and 183 male. 227 patients were treated with immunomodulating drugs (IFN, GA), 133 patients with immunosuppressive drugs (mitoxantrone, cyclophosphamide, azathioprine) and 250 were naïve. Focus Diagnostics’ STRATIFY JCV DxSelect assay was used. The assay is intended for the qualitative detection of antibodies to JC virus in human serum or plasma. All the samples were tested at Unilabs in Denmark. Results: The mean age was 41,7 years, and mean disease duration was 8,7 years, 70,0% was female. The study population was representative for the general MS patients population. The proportion of patients treated with immunosuppressive drugs and immunomodulating drugs was very high, 21,8% and 37,2% respectively. In the study there were 67,6% patients with RRMS, 20,9% and 11,5% with SPMS and PPMS respectively. The overall prevalence of anti-JCV antibodies was 69,2%. Seroprevalence was significantly associated with increasing age (p=0,0001), disease duration (p=0,016) and EDSS status scale (p=0,0037). Anti-JCV antibodies prevalence was almost equal for male and female, no significant differences in anti-JCV antibody prevalence were associated with disease course and type of therapy. Conclusion: 1. Patients with anti-JCV antibodies were significantly older compared to patients without antibodies. 2. Duration of disease in patients with anti-JCV antibodies was significantly longer compared to patients without antibodies. 3. Patients with anti-JCV antibodies had significantly higher disability level in EDSS.

P796 Age has an effect on disability independent of age at onset of symptoms and disease duration S. Alla1, J.F. Pearson2, B.V. Taylor3, D.H. Miller4, A. Richardson5, G. Clarke1, D. Abernethy6, E. Willoughby7, C.E. Sabel8, D.F. Mason9 1Medicine, 2Deans, University of Otago, Christchurch, New Zealand, 3Menzies Research Institute, University of Tasmania, Hobart, TAS, Australia, 4Queen Square MS Centre, UCL Institute of Neurology, London, United Kingdom, 5School of Health Sciences, University of Canterbury, Christchurch, 6Neurology, University of Otago, Wellington, 7Neurology, Auckland District Health Board, Auckland, New Zealand, 8School of Geographical Sciences, University of Bristol, Bristol, United Kingdom, 9Neurology, Christchurch Hospital, Christchurch, New Zealand

Disclosure Robert Bonek, MD, PhD - Biogen, Novartis, Merck, Teva, Bayer Tadeusz Ostrowski, MD - employee of Biogen Poland

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Background and objectives: A number of demographic and clinical factors have been shown to be associated with disability progression in multiple sclerosis (MS). However, the association between current age and disability has not been fully investigated. The aim of this study was to quantify the effect of current age on disability status in the New Zealand National Multiple Sclerosis Prevalence (NZNMSP) cohort. Methods: Data were sourced from the 2006 NZNMSP study, a cross-sectional study covering the entire country. The diagnosis of MS was based on the 2005 McDonald criteria. Disability was assessed by a neurologist using the Expanded Disability Status Scale (EDSS) or a telephone EDSS. The relationship of disability with current age, gender, ethnicity, nature of symptoms at onset, disease type at onset and either age at symptom onset or disease duration was explored using multiple linear regression analysis. Results: On census day 2006, New Zealand had 2,917 people with MS (75% female). Those with progressive onset disease were older (mean age 60 vs 52 years p< 0.001), their disease onset was later in life (mean age 42 vs 34 years, p< 0.001) and they had greater disability (mean EDSS 6.3 vs 4.1, p< 0.001) than those with relapsing onset MS. Disease duration was almost identical for both relapsing and progressive onset MS (17.95 vs 17.96, p=0.98). Linear modelling showed that temporal variables (age, age at onset of symptoms, and their interactions) explained 23% of the variation in EDSS while onset type (relapsing or progressive) and onset symptoms explained 11%, with no significant contribution from gender or ethnicity. The models demonstrate that age has a significant effect on disability independent of age at onset of symptoms and disease duration (p< 0.001).


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Conclusions: The clinical and demographic variables explain only 34% of variation in disability status among the MS cohort. Age, age of onset and disease duration were the best indicators of disability status (23% of variation) with nature of first symptoms and progressive or relapsing onset also useful (11%). The remaining 66% is still unexplained .Current age and age at onset, and similarly disease duration, are independent contributors to disability status however their effects interact in contributing to higher disability levels over the course of the disease. Disclosure Source of funding: Health Research Council New Zealand, the National MS Society of NZ, the New Zealand Brain Research Institute and the University of Otago, Christchurch, New Zealand. David Miller: May 2015: I have received honoraria through payments to my employer, UCL Institute of Neurology, for Advisory Committee and/or Consultancy advice in multiple sclerosis studies from Biogen Idec, GlaxoSmithKline, Novartis, Merck, Chugai, Mitsubishi Pharma Europe and Bayer Schering Pharma. I have also received compensation through payments to my employer for performing central MRI analysis of multiple sclerosis trials from GlaxoSmithKline, Biogen Idec, Novartis, Apitope and Merck. The Queen Square MS Centre at UCL Institute of Neurology is supported by the UK MS Society and UCL-UCLH Biomedical Research Centre. Other authors: nothing to disclose P797 Increasing prevalence of multiple sclerosis in tuscany: a study based on validated administrative data D. Bezzini1,2, G. Meucci3, M. Ulivelli4, L. Policardo5, S. Bartalini4, F. Profili5, M.A. Battaglia1,2, P. Francesconi5 1Life Sciences, University of Siena, Siena, 2Fondazione Italiana Sclerosi Multipla, Genova, 3Unit of Neurology, USL 6, Livorno, 4Neuroscience, Neurology and Clinical Neurophysiology Section, University of Siena, Siena, 5Agenzia Regionale di Sanità della Toscana, Firenze, Italy Background: Italy is a high-risk area for Multiple Sclerosis (MS) with a prevalence of around 140-170/100,000 (2005-2009) with with the exception of Sardinia, with about 224 cases per 100,000 (2009). Nowadays, in Italy, prevalence is absolutely higher than the above estimates. Indeed, prevalence is rising due to annual incidence that is higher than annual mortality. In Tuscany a population MS register has been founded but, to date, it’s not yet completed. To monitor disease epidemiology, comorbidities and care pathways, but also to describe the disease burden and to plan its prevention, treatment and management strategies and resource allocation, population-based studies are preferable. Administrative data offer a unique opportunity for population-based prevalence study of chronic diseases such as MS. Goals: To update the prevalence of MS in Tuscany using a validated case-finding algorithm based on administrative data and to demonstrate the progressive increment of prevalence. Methods: The prevalence was calculated using an algorithm based on administrative data: hospitalization, MS drug dispensing, disease-specific exemptions from patient copayment, home and residential long-term care and inhabitant registry. To test

algorithm sensitivity, we used a true-positive reference cohort of 302 MS patients from the Tuscan MS register. To test algorithm specificity, we used a general population cohort of 2,644,094 individuals who were presumably not affected by MS (who had never effectuated either cranial or spinal cord CT scan or MRI and had never received a neurological outpatient visit within the NHS). We calculated prevalence on three consecutive years (2011, 2012, 2013). Results: At prevalence date (31 December), we identified 6,890 cases in 2011, 7,057 in 2012 and 7,330 in 2013 with a rate of 187.9, 191.1 and 195.4/100,000, respectively. The female: male ratio slightly increased from 2.0 in 2011 to 2.1 in 2012-2013. The sensitivity of algorithm was 98% and its specificity was 99.99%. Conclusions: We found a progressive increment of prevalence that confirmed our hypothesis of increasing prevalence. Our algorithm can accurately identify patients and this cohort is suitable to monitor care pathways. Our future aim is to create an integrated dataset with administrative and clinical data from MS register. Disclosure Daiana Bezzini: nothing to disclose. Giuseppe Meucci: nothing to disclose. Monica Ulivelli: nothing to disclose. Laura Policardo: nothing to disclose. Sabina Bartalini: nothing to disclose. Francesco Profili: nothing to disclose. Mario A Battaglia: nothing to disclose. Paolo Francesconi: nothing to disclose. P798 Handling MS patients in the ED: clinical decision making and current practice H. Abboud1,2, K. Mente1, A. Ali1, M. Seay1, M. Willis1 1Cleveland Clinc, Cleveland, OH, United States, 2Alexandria University, Alexandria, Egypt Background: MS patients present to the ED for several reasons. Although the majority of these ED visits are driven by neurological complaints, true MS relapse is rarely the underlying culprit. In addition, not all patients with true relapse require hospital admission and steroid treatment. Aim of the work: We aimed at studying MS patient visits to our ED and evaluate clinical decision making at the time of presentation as well as diagnostic/therapeutic interventions, and the outcome of these visits. Methods: We chart reviewed 42 consecuitive MS visits to the Cleveland Clinic ED in 2014. Results: 6 visits were not related to MS symptoms. in 36 patients (mean age 56 years, mean disease duration 18 years, 32% male) the ED visit was for neurological complaint. Motor symptoms were the most common presentation followed by sensory, visual, coordination, and sphincteric symptoms. New symptoms as opposed to worsening symptoms were present in 47.2% of patients. Infections was found in 61% of patients of which 59% were urinary. New MRI was ordered in 15 (41%) of patients including 5 patients without new symptoms. only 4 MRIs showed new enhancing lesions and one showed new T2 lesions. All but one visits resulted in hospital admission of which 51% was to


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Poster Session 2, 21(S11) neurology. steroids treatment was used in 9 (25%) of patients, 8 of which had either new symptoms or new lesions on MRI. Conclusion: the majority of MS visits to the ED are related to infection causing worsening of pre-existing deficits. a large number of unnecessary MRI´s and hospital admission can be avoided by identifying true MS relapse and evaluating the need for hospitalization and treatment. Disclosure Hesham Abboud received an educational grant unrelated to this research. P799 Vitamin D and the development and evolution of permanent black holes among patients with clinically isolated syndrome K.C. Fitzgerald1, K. Munger1, M.S. Freedman2, H.-P. Hartung3, X. Montalbán4, G. Edan5, F. Barkhof6, R. Sandbrink7, L. Kappos8, G. Suarez9, C. Pohl10, A. Ascherio1 1Harvard T.H. Chan School of Public Health, Boston, MA, United States, 2University of Ottawa and Ottawa Health Research Institute, Ottawa, ON, Canada, 3Department of Neurology, Heinrich-Heine Universität, Duesseldorf, Germany, 4Hospital Universitari Vall d’Hebron, Barcelona, Spain, 5CHUHôpital Pontchaillou, Rennes, France, 6VU University Medical Center Amsterdam, Amsterdam, The Netherlands, 7Bayer Pharma AG, Berlin, Germany, 8University Hospital Basel, University of Basel, Basel, Switzerland, 9Bayer HealthCare Pharmaceuticals, Whippany, NJ, United States, 10University Hospital of Bonn, Bonn, Germany Objective: To assess the relationship between vitamin D [25(OH) D] and irreversible brain tissue damage characterized by the occurrence of persistent T1- hypointensities (permanent black holes-PBHs) in patients with clinically isolated syndrome (CIS) who were followed for 5 years. Methods: BENEFIT was a randomized trial comparing early versus delayed interferon beta-1b (IFNB-1b) treatment in patients with a first event suggestive of MS (CIS). Serum 25(OH)D concentrations were measured at baseline, 6, 12, and 24 months. 433 of the 468 patients had at least one 25(OH)D measurement and had lesion follow-up for at least 1 year. We calculated a seasonadjusted 25(OH)D and estimated the association between the time-dependent cumulative average of 25(OH)D and the number of new PBHs after 6 months. We modeled lesion counts using negative binomial models and logistic regression models to assess the proportion of lesions evolving into PBHs accounting for intrapatient correlation using generalized estimating equations. We also assessed the association between 25(OH)D and number of lesions of a specific type at initial presentation (nodular Gd-enhancement, ring-like Gd-enhancement, T1-isointense T2 lesions or T1-hypointense lesions). Analyses were adjusted for age, sex, treatment, baseline T2 lesions and CIS onset type. Results: A total of 3789 new lesions developed over the 5 year follow-up period with 383 developing into PBHs. Average 25(OH) D levels were significantly inversely correlated with the number of PBHs from the 6-month to five-year MRI; patients with serum 25(OH)D levels ⩾50 nmol/L experienced a 55% lower absolute rate of PBHs (95% CI: 0.29 to 0.71; P=0.006) than those < 50

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nmol/L. We also observed a marginal association between serum 25(OH)D and the proportion of T2 lesions evolving into PBHs (0.71; 95% CI: 0.50 to 1.01; P=0.056, comparing patients with ⩾50 nmol/L vs those < 50 nmol/L). We found generally similar associations between patients with serum 25(OH)D levels ⩾50 nmol/L and the number of each of the 4 lesion types at presentation (for any T1-hypointense lesions: 0.54; 95% CI:0.54-0.91; for T1-isointense lesions: 0.63; 95% CI:0.47-0.85; for nodular Gd+ lesions: 0.67; 95% CI:0.47-0.98; for ring-like-Gd+ lesions: 0.79; 95% CI: 0.47-1.35). Conclusions: Our results that higher levels of 25(OH)D were associated with lesser accumulation of irreversible brain tissue damage support the importance of adequate vitamin D status in delaying MS progression. Disclosure • KC Fitzgerald has no disclosures. • KL Munger has no disclosures. • MS Freedman has received compensation from Bayer HealthCare, Biogen Idec, EMD Canada, Chugai, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, and Teva Canada Innovation for consulting services. He also participates in a Genzyme-sponsored speakers bureau. • H-P Hartung has received honoraria for consulting and speaking at symposia from Bayer Pharma AG, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva, and SanofiAventis, with approval by the rector of Heinrich-Heine University. • X Montalbán has received speaking honoraria and travel expenses for scientific meetings and has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer, Biogen Idec, EMD, Genentech, Genzyme, Merck Serono, Neurotec, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, and Almirall. • G Edan has received honoraria for lectures or consulting from Biogen Idec, Merck Serono, and Sanofi-Aventis, and received personal compensation for serving on the BENEFIT scientific advisory board and for speaking from Bayer Pharma AG. He has also received research support from Serono, (a grant to University Hospital to support a research program on MRI in MS) and from Teva (a grant to support a research program on anti-IBF neutralizing antibodies). • F Barkhof has received compensation for consultancy from Bayer Schering Pharma, Biogen Idec, Synthon BV, Novartis, Sanofi-Aventis, Genzyme, Roche, and Teva, and has received research support from the Dutch Foundation for MS research (an NGO). • R Sandbrink is a salaried employee of Bayer Pharma AG/ Bayer HealthCare Pharmaceuticals. He owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. • L Kappos’ institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof Kappos’ activities as principal investigator and member or chair of planning and steering committees or advisory boards in trials sponsored by Actelion, Addex, Bayer HealthCare Pharmaceuticals, Bayer Schering Pharma, Biogen Idec, CLC Behring, Genentech, GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma,


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Novartis, Octapharma, Praxicon, Roche, Sanofi-Aventis, Santhera, Siemens and Teva and royalties from Neurostatus GmbH. Prof Kappos has received grants from the Swiss MS Society, Swiss National Research Foundation, the European Union, Gianni Rubatto Foundation, and the Novartis and Roche Research foundations. • G Suarez is a salaried employee of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals • C Pohl is a salaried employee of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. He owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. • A Ascherio has received honoraria for participating in advisory boards and speaking at scientific symposia by Almirall, Roche, Sanofi-Aventis, Serono, and Bayer Health Care. P800 Hispanics enriched for non-European derived genetic ancestry are at increased risk of younger age of onset and optic neuritis L. Amezcua1, A. Beecham2, S. Delgado2, M. Burnett1, P. Manrique2, B. Lund1, T. Islam1, A. Levy1, J. Oksenberg3, J. Mc Cauley4 1University of Southern California, Los Angeles, 2Univerisity of Miami, Miami, 3UCSF, San Francisco, CA, 4University of Miami, Miami, FL, United States Background: We have previously reported that Hispanics are at increased risk of presenting with MS at a younger age and twice the risk of presenting with optic neuritis compared to whites. However, the underlying nature of these observations has not been well defined and differences in genetic ancestry have been proposed. Objective: To assess whether Hispanics with low level of European genetic ancestry are at increased risk of presenting with MS at a younger age and optic neuritis involvement compared to those with high level of European ancestry. Methods: The genetic ancestry of 708 self-identified Hispanics with MS living in the United States was estimated by genotyping 12,073 ancestral informative markers (AIMs) using MS chip. The estimate of Asian, African and European ancestral contributions was determined using ADMIXTURE. The study population was categorized by quartiles of European ancestry and clinical presentation of MS was compared between those groups. Results: The genetic ancestry varied considerably among the Hispanic population. The contribution of European ancestry ranged from 13% to 99.99%. A strong inverse correlation was observed between Asian and European ancestry (r=0.87). The contribution of African ancestry was on average less than 10% (mean=8.63%, SD11.31%). The age of disease onset significantly varied by quartiles of European ancestry after controlling for African ancestry, and a younger age of disease onset was associated with lower European ancestry (p-value=0.004). Overall 23.1% of the Hispanics presented with optic neuritis at onset. A significant association was also found between lower European ancestry proportions and optic neuritis (p-value=0.03). From the lowest to highest quartiles of European ancestry the frequency of optic neuritis as the presenting symptom was 31.1%, 22.3%, 17.2%, and 22.2%.

Conclusions: The use of ancestry informative markers may be a way to better understand how genetic factors contribute to clinical aspects of MS in Hispanics. Disclosure Funding in part from to NMSS to J. McCauley and CTSI KL2 to L. Amezcua. L. Amezcua: has consulted for Genzyme, Biogen, Novartis and Acorda. A. Beecham: nothing to disclose. T. Islam: nothing to disclose. S. Delgado: nothing to disclose. P. Manrique: nothing to disclose. M. Burnett: has consulted for Genzyme, Acorda, and Biogen. B. Lund: has research funding from Teva and Novartis. A. Levy: nothing to disclose. J. Oksenberg: nothing to disclose. J. Mc Cauley: nothing to disclose.

P801 Risk of cerebral vascular complications in multiple sclerosis: analysis of the nationwide inpatient sample S.M. Belliston, R.M. Dubinsky, S.G. Lynch Neurology, University of Kansas Medical Center, Kansas City, KS, United States Background: Cerebral ischemia in multiple sclerosis (MS) has been reported to be increased compared to the general population. Possible mechanisms of increased cerebral ischemia include endothelial dysfunction, chronic inflammation, and disease modifying therapies. To date no national study of stroke in MS has been done in the US. Other cerebral vascular complications, including: haemorrhagic stroke, subdural hematoma, subarachnoid haemorrhage, and unruptured aneurysms have not previously been studied. We focused our study on all cerebral vascular diseases in patients with MS in the US. Methods: Retrospective cohort analysis from 1988-2012 of the Nationwide Inpatient Sample (NIS) (AHRQ.gov), a 20% stratified yearly sample of US hospital admissions. Records were identified with a primary diagnosis of ischemic stroke, ICH, SDH, and SAH. Cases with MS were identified by a secondary diagnosis of MS. Indirect adjustment was used to compare the prevalence of MS in this population with that of the USA. We calculated the standerdized prevalence ratio (SPR), adjusted for sex and age, for these events. Results: Of 2,759,232 admissions for cerbrovascular events, 0.18% had MS. When compared with population prevalence, the SPR of MS among patients with ischemic stroke was 1.675 (95% confidence interval [CI] 1.672, 1.678) greater than expected. The SPR for MS among ICH patients was 1.377 (1.370, 1.384). With SDH the SPR of MS was 2.682 (2.657, 2.708). For patients with SAH, the SPR for MS was 1.150 (1.140, 1.160). Finally, the SPR of MS in patients with unruptured aneurysm was 2.807 (2.771, 2.844). Conclusion: In this US hospital cohort, the prevalence of MS in the population with cerebral vascular diseases was over represented, with the largest being in the aneurysm group, three times greater than predicted. This data suggests that cerebrovascular


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Poster Session 2, 21(S11) events are associated with MS. It is possible that more frequent imaging in people with MS led to finding asymptomatic aneurysms. Further research is needed to investigate the increased rate of all cerebral vascular diseases among people with MS to determine if there is an association based upon MS treatment, comorbidities or changes in brain structure. Disclosure Scott M Belliston DO is a clinical multiple sclerosis research fellow with for the National Multiple Sclerosis Society and Biogen Richard M Dubinsky MD is on the scientific advisory board for Allergan and also receives honorarium for speaking and travel Sharon G Lynch MD has received from multicenter clinical trials including: Teva, Biogen, Novartis, Roche, Metamune, Alexian, Acorda, Sunpharm, Vacinex, Opex, Genentec, Genzyme, NIH, NMSS, and Chugi

Disclosure

MS and gender P802 The effect of assisted reproductive techniques on relapse rate in women with multiple sclerosis A. Gullestrup1, A. Thormann2,3, N. Koch-Henriksen3,4, M. Magyari2,3, A. Pinborg5, P. Soelberg Sorensen2 1Department of Neurology, Danish Multiple Sclerosis Center, University of Copenhagen / University Hospital, Rigshopitalet, 2Department of Neurology, Danish Multiple Sclerosis Center, 3The Danish Multiple Sclerosis Registry, Copenhagen University Hospital Rigshospitalet, Copenhagen, 4Department of Epidemiology, Clinical Institute, University of Aarhus, Aarhus, 5Department of Obstetrics and Gynecology, University of Copenhagen / Fertility Clinic, Hvidovre Hospital, Copenhagen, Denmark Background: As fertility decreases with age and women’s age at first pregnancy increases, a growing number of women, including women with multiple sclerosis (MS), seek fertility treatment. The effect on relapse rate in women with MS undergoing advanced reproductive technologie (ART) is unclear. Objectives: To investigate if ART with Gonadotropin-releasing hormone (GnRH) agonist or antagonist affects relapse risk in women with MS. Methods: From the Danish Multiple Sclerosis Treatment Register we retrieved 938 patients, followed at Copenhagen University Hospital Rigshospitalet, and cross-linked them with 83.571 patients in The Danish in vitro fertilisation (IVF) Register by the unique personal identification numbers. Out of 44 identified patients 24 were excluded because of MS onset after ART initiation, insufficient data or other fertility treatments than GnRH agonist or antagonist, leaving 20 women eligible for inclusion. Onset of relapses and dates of initiating ART were obtained from medical records and from The Danish IVF Register. We used Wilcoxon signed rank test to compare the annualized relapse rate (ARR) during the six months preceding initiation and during the six months following initiation of the first cycle of ART. Analyses were carried out on the whole study group (n=20) as well as on subgroups defined by pregnancy (n=8), no-pregnancy (n=12), GnRH agonist (n= 12), and GnRH antagonist (n= 8). Results: Prior to ART initiation, the mean ARR was for: the whole group 0.6 (95% CI: 0.22-1.31); the pregnancy group 1.1

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(0.31-2.92); the no-pregnancy group 0.3 (0.04-1.11); the GnRH agonist group 0.5 (0.10-1.46); the GnRH antagonist group 0.75 (0.16-2.19). After ART initiation, the mean ARR was for: the whole group 1.0 (0.48-1.84); the pregnancy group 1.4 (0.46-3.33); the no-pregnancy group 0.8 (0.25-1.80); the GnRH agonist group 1.3 (0.58-2.63); the GnRH antagonist group 0.5 (0.06-1.81). The analysis showed trends, but no significant increases in ARR after ART initiation in the whole study group (p=0.305), in the no-pregnancy group (p=0.260), as well as in the GnRH agonist group (p=0.059). Conclusions: This study supports previous findings of a tendency to increased ARR after ART initiation. Our results might suggest that some caution and more information should be provided for women with MS seeking fertility treatment. More research is needed on whether GnRH antagonist protocol is preferred over a GnRH agonist protocol in these women.

A. Gullestrup: Nothing to diclose A. Thormann has served on a scientific advisory board for Biogen Idec. She has received support for congress participation from BiogenIdec, Novartis, TEVA, and UCB. N. Koch-Henriksen has received honoraria for lecturing and participation in advisory councils, travel expenses for attending congresses and meetings, and financial support for monitoring the Danish MS Treatment Register from Bayer-Schering, MerckSerono, BiogenIdec, TEVA, Sanofi-Avensis, and Novartis. M. Magyari has served on scientific advisory board for BiogenIdec and TEVA and has received honoraria for lecturing from BiogenIdec, MerckSerono, Novartis, and TEVA. She has received support for congress participation from BiogenIdec, MerckSerono, Novartis, TEVA and Genzyme. A. Pinborg: Nothing to disclose P.S. Sorensen has received personal compensation from Biogen Idec, Merck Serono, Novartis, Genmab, TEVA, GSK, and Sanofi-aventis, Genzyme as member of scientific advisory boards, steering committees or independent data monitoring boards in clinical trials, or as speaker at meetings. His research unit has received research support from Biogen Idec, Bayer Schering, Merck Serono, TEVA, Sanofi-aventis, Novartis, RoFAR, Roche, and Genzyme, the Danish Multiple Sclerosis Society, the Danish Medical Research Council, and the European Union Sixth Framework Programme: Life sciences, Genomics and Biotechnology for health. P803 The impact of age, gender, and geographic region on the prevalence of common comorbidities in patients with MS in a large US administrative claims database from 2006-2012 A.L. Phillips1, N.C. Edwards2, J.C. Locklear1 1EMD Serono, Inc., Rockland, 2Health Services Consulting Corporation, Boxborough, MA, United States Background: Comorbidity is an area of increasing interest in MS as evidence emerges that it may impact diagnosis, disability progression, health-related quality of life, progression of MRI lesion burden, and hospitalization. A recent systematic review of published literature on the incidence and prevalence of comorbidity in


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MS highlighted that it is important to have age- and sex-specific comorbidity rates when evaluating comorbidity. Goals: To evaluate how the prevalence of common comorbidities in patients with MS varied by age, gender, and geographic region in a large US administrative claims database. Methods: This was a retrospective analysis of patients diagnosed with MS in a national, commercial, US managed care database (IMS Life Link) from 2006-2012. Rates of comorbidities in patients with MS were evaluated as exploratory bivariate analyses and compared with national rates for all patients. Results: The most prevalent comorbidities were hypertension (42.8%) and gastrointestinal (GI) disorders (43.2%), followed by thyroid disease (27.3%), arthritis (24.5%), anxiety (23.1%), diabetes (15.4%), and depression (13.0%). Comorbidity rates were generally higher than national rates for all patients. The prevalence of the measured comorbidities decreased for patients diagnosed from 2009-2012, except anxiety, which increased in patients diagnosed after 2009. Anxiety, depression, arthritis, GI disorders, and thyroid disease were more prevalent among female vs. male patients with MS (thyroid disease twice as prevalent, anxiety 1.5 times more prevalent, depression 1.4 times, arthritis and GI 1.2 times). Diabetes and hypertension were more prevalent among males (1.2 times more prevalent). As would be expected, GI disorders, hypertension, thyroid disease, arthritis, and diabetes were more prevalent among older patients. Patients aged 18-44 and 45-64 had higher levels of anxiety and depression compared to patients < 18 and patients 65+. Patients living in the West had consistently lowest levels of all the common comorbidities. Patients in the Northeast had higher levels of thyroid disease, arthritis, anxiety, and diabetes. Patients in the Midwest had higher rates of depression. Patients in the South had higher rates of GI disorders and hypertension. Conclusions: Comorbidity rates varied depending on age, gender, and region. These exploratory bivariate analyses suggest that patient characteristics may be important to consider in evaluating comorbidity in MS. Disclosure ALP and JCL are employees of EMD Serono, Inc., Rockland, MA, USA (a subsidiary of Merck KGaA, Darmstadt, Germany). NCE has received personal compensation as a Health Services Research consultant. Study supported by EMD Serono, Inc., Rockland, MA, USA and Pfizer Inc, New York, NY, USA. P804 Earlier menarche is associated with earlier symptom onset in a clinical cohort of 544 women with MS R. Bove, A. Chua, B. Healy, B. Glanz, T. Chitnis Brigham & Women’s Hospital, Partners MS Center, Harvard Medical School, Brookline, MA, United States Background: Several lines of evidence suggest that the early adolescent period may be a key regulator of multiple sclerosis (MS) risk. Goals: We tested the hypothesis that early menarche is associated with earlier age at first symptoms in a large cohort of women with MS. Methods: The subjects included in this study were patients of the Partners MS Center, aged 18 or above, enrolled in the

Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women’s Hospital (CLIMB). Female subjects were included in this study if they met the diagnostic criteria of relapsing remitting MS (RRMS) by the 2005 McDonald criteria or of clinically isolated syndrome (CIS). A reproductive questionnaire, deployed to all CLIMB women, was analyzed after a 60% response rate was achieved. The variables included in the current analysis were (1) reported age at menarche and (2) response to whether a subject had “been told you were obese” during childhood and/or adolescence. Questionnaire responses were linked to demographic and clinical data from the CLIMB study. Results: Altogether, 544 women were included in the analysis. Mean reported age at menarche was 12.6 (SD:1.4, range 9-17) and mean reported age at first symptoms was 33.6 (SD: 9.6, range 11.5-64.6). Using a linear regression model, a significant association was found between age at menarche and age at first symptom. For every one year decrease in the age at menarche: the mean age at first symptoms was decreased by 0.648 (95%CI:-1.219, -0.078; p=0.026). When we adjusted for latitude at age 15 (north, middle, and south of United States) and obesity (yes/no), in a multivariable linear regression model, for every one year decrease in age at menarche, the mean age at first symptom decreased by 0.652 years (95%CI: -1.228, -0.076); p=0.026). Discussion: This study confirms prior reports of an association between earlier menarche and earlier MS symptom onset. Further prospective studies are required to clarify inflammatory mechanisms for this association. Disclosure R.Bove: nothing to disclose. A.S.Chua: nothing to disclose. B.C.Healy: research support from Merck Serono, Genzyme and Novartis. B.I.Glanz: research support from Merck Serono. T. Chitnis: nothing to disclose. Funding: NMSS (RB, TC) and NIH K12 (RB). P805 Effects of oral hormonal contraceptives on the clinical course of relapsing-remitting multiple sclerosis R. Hernandez Clares1,2, E. Carreón Guarnizo1,2, R. Carrasco Torres1,2, C. Sanchez- Vizcaino Buendia1, M.T. Frutos Alegría3, G. Salgado Cecilia4, J.J. Martín Fernandez5, J.E. Meca Lallana1,2 1Neurology, Multiple Sclerosis Unit, Hospital Universitario Virgen de la Arrixaca, 2Cátedra de Neuroinmunología y EM, Universidad Católica San Antonio, 3Neurology Department. Lorenzo Guirao Hospital, 4Inmunology Department, 5Neurology Department, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain Background: Multiple Sclerosis (MS) is a chronic inflammatory disease of the CNS characterized by demyelination and axonal degeneration. A higher incidence in women, gender-related differences in the clinical course of the disease, immunologic and brain damage


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Poster Session 2, 21(S11) characteristics, along with changes of the disease during pregnancy suggest an effect of sex hormones on MS. Moreover, oestrogens have demonstrated a protective effect in animal models of EAE. Oral hormonal contraceptives (OCs) are an exogenous source of oestrogens and their use in MS patients provides an opportunity to assess their effects in the clinical course of the disease. We present an exploratory retrospective study designed to analyse the association between taking oral contraceptives and the clinical course of MS, considering the annualized relapse rate (ARR), MS severity score (MSSS) and disability progression (EDSS). Methods: Women initially diagnosed with RRMS, who have experienced at least two years of evolution and all of them undergoing treatment for MS. Demographic data have been collected, as well as clinical data about MS and gynaecological and obstetrical data (menarche, contraception taking, age of onset, duration, births and age at first birth). Results: 141 patients (135 RRMS, 6 SPMS): 75 of them not taking OCs (NT) and 66 taking OCs (T), of which 31 were taking before the first appearance of the MS (PreT) and 35 after the first appearance of the disease (PostT). In the three groups, the age (NT: 39.4, PreT: 37.4 and PostT: 36.5) and the evolution time of the disease were similar. EDSS and MSSS scores were significantly lower in the PostT group than in the PreT and the NT groups (1.8/2.4/2.5) and (2.9/4.65/4.85) respectively. No differences were found in the ARR. These differences remain stable when adjusting for age and duration of the MS. Conclusions: Our results suggest that women who take contraceptives after the first symptom of the disease have a less severe disease course (in terms of EDSS and MSSS) than patients who don’t take OHCs or who have taken them before diagnosis. Disclosure Rocío Hernández Clares: nothing to disclose. Ester Carreon Guarnizo: nothing to disclose. Rubén Carrasco Torres: nothing to disclose. Cristina Sánchez Vizcaino: nothing to disclose. M. Teresa Frutos Alegria: nothing to disclose Gemma Salgado Cecilia: nothing to disclose. Jose J. Martín Fernández: nothing to disclose. Jose E. Meca Lallana: nothing to disclose. P806 Pregnancy in women with multiple sclerosis in Portugal results of the national cross-sectional PORT-MS study J. Ferreira1, M. Grilo2, S. Varanda3, R. Samões4, J. Sequeira5, J. Tomás6, P. Abreu2, J. Cerqueira3, R. Pedrosa7, J. Sá1, A.M. Silva8, M.J. Sá2, L. Sousa9, J. Vale10, P. Alegria10, PORT-MS Study Group 1Neurology, Centro Hospitalar de Lisboa Norte - Hospital de Santa Maria, Lisboa, 2Neurology, Centro Hospitalar de São João, Porto, 3Neurology, Hospital de Braga, Braga, 4Neurology, Centro Hospitalar do Porto - Hospital de Santo António, Porto, 5Neurology, Centro Hospitalar de Lisboa Central - Hospital de Santo António dos Capuchos, Lisboa, 6Neurology, Centro Hospitalar Universitário de Coimbra, Coimbra, 7Neurology, Centro Hospitalar de Lisboa Central – Hospital de Santo António dos Capuchos, Lisboa, 8Neurology, Centro Hospitalar

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do Porto – Hospital de Santo António, Porto, 9Neurology, Centro Hospitalar e Universitário de Coimbra, Coimbra, 10Neurology, Hospital Beatriz Angelo, Loures, Portugal Background: In Portugal, there was not a multicentric study on the general characteristics of Multiple Sclerosis (MS) patients and their disease. National data on pregnancy in these patients was also lacking. Objectives: To describe the frequency of gestations and live births in MS patients in Portugal, it’s evolution in time and its relation with other clinical data. Methodology: Patients fulfilling McDonald 2010 criteria in 7 centers were sequentially recruited from May to November 2014. A systematized Case Report Form was applied collecting data on: date and place of residency at birth, at first symptoms and at diagnosis of MS, gender, migrations during life, clinical type of MS, current clinical state, current treatment, education, status of employment, need for a caregiver, involvement in clinical trials, familial MS and pregnancy. These data together constitute the PORT-MS study. Here we focus on the results related to pregnancy. Women were asked about the number of gestations and live births before and after the diagnosis of MS. Results: 561 patients included, of which 397 (70,8%) female. Age at diagnosis of women 34,2±11,5 years-old, age at inclusion 43,6±12,9. 91,7% were in relapsing remitting (RR) form at diagnosis, 83% (of the total) are still in RR at inclusion. All women (independent of age and clinical type): 17,8% had gestations and 15,0% had live births after the diagnosis of MS (the corresponding values for the period before MS are 57% and 53,3%). Women diagnosed in the nineties (n=70) vs those diagnosed in the following decade (n=173): similar age at 1st symptoms, age at diagnosis, proportion of RRMS at diagnosis and level of education; follow-up and current EDSS of the first group are as expected higher; the first group had slightly more gestations (65,2% vs 61,9%) and live births (63% vs 57,6%) before the diagnosis of MS, the second group (despite much shorter follow-up) slightly more gestations (23,1% vs 17,1%) and live births (18,3% vs 17,1%) after the diagnosis, but differences are not significant. There are slightly more miscarriages/abortions in the second decade. Discussion and conclusions: An increase in the number of pregnancies in MS patients in more recent times in Portugal does not seem apparent at first sight but, in view of the shorter follow-up of more recent diagnoses and of the marked decrease of births in the general population in our country lately, we can conclude that in MS the tendency seem to be the opposite of that. Disclosure This research had institucional support from Biogen Idec and the GEEM (Grupo de Estudos de Esclerose Múltipla, the Portuguese medical society for MS. The authors have nothing else to disclose.

P807 Gender effect in the seropositive neuromyelitis optica S.-M. Kim1, E.J. Ju2, S. Cheon1, B. Kim1, D.G. Kim3, S.K. Yeon2, S.W. Kim4, O.H. Kwon5, K.D. Park2, J.-A. Kim6, S. Lee3, K.S. Park3, K.-W. Lee1


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of Neurology, College of Medicine, Seoul National University, 2Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, 3Neurology, Seoul National University Bundang Hospital, Seoungnam, 4Department of Anatomy, College of Medicine, Inha University, Incheon, 5Department of Neurology, College of Medicine, Eul-Ji University, 6Seoul National University, College of Medicine, Seoul, Republic of Korea Background: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that is characterized by high female predominance. However, the effect of gender in patients with NMO has not been fully evaluated. Objective: To determine the gender effect in clinical manifestations and prognosis of patients with seropositive neuromyelitis optica spectrum disorder. Methods: From 473 patients in a Seoul National University Hospital CNS inflammatory demyelinating disease cohort, we identified 109 patients (19 male) having AQP4-Ab (seropositive NMOSD) by fluorescence activated cell sorting (FACS) assay for AQP4-Ab. Dermographics, clinical and radiological characteristics, test results for the eletrophysiological study, and prognosis were assessed. Results: Male gender was associated with a higher tendency of manifesting as isolated myelitis (57.9% vs 29.1%, p = 0.017), less frequent optic neuritis attack per year (0.04 vs 0.25, p = 0.000), and shorter latency of P100 in the visual evoked potential testing (103.8 ± 7.91 vs 113.6 ± 22.8, p = 0.002), compared to females. The age of onset, duration of follow up, test result for the cerebrospinal fluid, EDSS at first attack, maximal contiguous length of myelitis, time to EDSS 6, and mortality didn’t differ between groups. Conclusion: Male gender might be a protective factor against optic neuritis attack among seropositive NMO patients. Further study using experimental NMO model for this phenomenon will be needed, which might be a clue in identifying candidate for a treatment target in NMO. Disclosure All authors: nothing to disclose

MS symptoms P808 Rare symptoms and attack types in the course of multiple sclerosis: a retrospective study in a large population with multiple sclerosis A. Eker1, B. Kaymakamzade1, A. Tuncer2, R. Karabudak2 1Neurology, Near East University, Faculty of Medicine, Nicosia, Cyprus, 2Neurology, Hacettepe University, Faculty of Medicine, Ankara, Turkey Background: Multiple sclerosis (MS) is multifocal, inflammatory and demyelinating disease of the central nervous system. In addition to common symptoms like optic neuritis, sensorial, pyramidal and cerebellar dysfunction there are also a wide range of rare symptoms that have been reported as case reports. In this study we aimed to review the rare presentations and estimate their frequency in a large definite MS population which has never been studied before.

Material and methods: The database of our Neuroimmunology Unit between 1968-2010 was searched for patients presenting with rare symptoms. Results: This study included 557 clinically definite MS patients. We observed 97 rare symptoms in 81 patients in our study population. This group was 14.5% of our total population. The observed rare symptoms have been classified as cranial nerve involvement, brain stem syndromes, seizures, psychiatric disorders, movement disorders, cortical dysfunction, peripheral nerve involvement and encephalopathy. The most frequent rare symptom group was cranial nerve abnormalities. Among these, sixth nerve palsy was the most common presentation of cranial nerve involvements. The other ensuing rare symptoms were respectively brain stem syndromes, seizures, movement disorders and psychiatric disorders. Furthermore, the rare symptoms had appeared as initial symptom in 21 patients. Conclusion: This retrospective study has showed us that a wide range of rare symptoms can be observed in the course of MS due to the extensive involvement of the central nervous system as well as the peripheral nervous system. Disclosure Amber Eker: nothing to disclose Bahar Kaymakamzade: nothing to disclose Aslı Tuncer: nothing to disclose Rana Karabudak: nothing to disclose P809 Gait abnormalities are present in multiple sclerosis even in patients with EDSS 0-1.5 K. Novotna1, J.L. Preiningerova1, L. Sobíšek2, L. Suchá1, D. Horáková1, E. Havrdová1 1Department of Neurology and Centre of Clinical Neuroscience, Charles University in Prague, First School of Medicine and General University Hospital, 2University of Economics in Prague, Faculty of Informatics and Statistics, Department of Statistics and Probability, Prague, Czech Republic Background: Gait impairment represents one of the most common and disabling symptom of multiple sclerosis (MS). The majority of gait studies have been limited to MS patients with mild or severe clinical disability, however there is some evidence to suggest that, even for patients with minimal neurological signs on clinical examination, subtle gait changes may be detected. Objective: To evaluate characteristics of gait in MS patients with no apparent impairment of walking, with EDSS 0-1.5. Methods: This is an observational study of 64 MS patients with EDSS 0-1.5 (16 men, mean age 35 years ± 7,3) enrolled during regular visits at an MS clinic and 47 healthy controls. MS patients were divided into 2 groups according to disease duration from diagnosis (DD): DD < 6 years (N=34, mean DD 5,2 years±0,7) and DD > 6 years (N=30, mean DD 11,8 years±5,2). We measured the timed 25 foot walk test (T25FW), the 2 minute walk test (2MW). The spatio-temporal parameters of gait were obtained by a GAITRite instrument during a self-selected speed of walking and fast walking tests. Results: Both groups of MS patients with EDSS 0-1.5 performed worse in T25FW and 2MW tests than normal controls. Mean walking performance in T25FW in control group was 3,6 seconds


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Poster Session 2, 21(S11) while MS patients with EDSS 0-1,5 have mean test performance 4,3 seconds. In 2MW MS participants covered 190 meters (velocity 1,6 m/s) and mean distance covered in healthy controls was 228 meters (converted to velocity represent 1,9 m/s) .MS patients had prolonged double support phase during the self selected walking speed test and lower cadence and decreased step length during the fast walking speed test in comparison with healthy controls. Both subgroups of MS patients showed described impairment of spatio-temporal parameteres. Conclusion: Gait performance is impaired even in MS patients with no apparent clinical disability with EDSS 0-1.5. The impairment is measurable by spatio-temporal parameters of gait as well as by common clinical tests such as T25FW and 2MW tests. The study was supported by Czech Ministries of Education and Health (NT13237-4/2012, PRVOUK-P26/LF1/4) and Impuls Foundation. Funding for biostatistical support was provided by Novartis Disclosure Funding for biostatistical support was provided by Novartis

Results: 178 RRMS patients were randomized in this study. The intervention did not result in significant differences between fatigue levels of patients using e-training and the waiting group (-1.47 with a 95% CI of [-5.39; 2.44], p=0.4579). However, in a subpopulation of patients with low aerobic capacity (VO2max < 27 l/min/kg) at study onset, a substantial effect of e-training on the primary outcome parameter could be observed. The results of these subgroup analyses indicate an influence of patients´ baseline physical fitness on the effect of sportive e-training. Conclusion: The aim of this study was to evaluate the effect of structured physical e-training vs. no training on fatigue in Fingolimod-treated RRMS patients. In spite of the missing overall effect of the study, we could demonstrate a beneficial effect in a subgroup of patients with low aerobic capacity. Therefore, patients that are less physically fit seem to benefit significantly from structured exercise programs. Aerobic capacity might be a suitable marker for patient selection. Furthermore, this interventional study shows for the first time the safety profile and feasibility of combining individualized physical activity and Fingolimod treatment in RRMS patients Disclosure

P810 A 6-month, multicenter, randomized, controlled study to evaluate the effect of physical training on fatigue in patients with relapsing-remitting multiple sclerosis treated with Fingolimod (Gilenya®) - first results of the PACE study M. Mäurer1, B. Kallmann2, W.E. Hofmann3, E. Schlegel4, S. Seibert5, M. Baier5, K. Schuh5, E. Grünewald6, R. Streber7, C. Hentschke7, A. Tallner7, K. Pfeifer7 1Klinik für Neurologie, Caritas Krankenhaus, Bad Mergentheim, 2Neurologische Praxis mszb im AlphaMed, Bamberg, 3Neurologische Praxis, Aschaffenburg, 4MedCenter GmbH MVZ, Siegen, 5Novartis Pharma GmbH, 6Winicker-Norimed, Nürnberg, 7Institut für Sportwissenschaft und Sport, FriedrichAlexander University Erlangen-Nürnberg (FAU), Erlangen, Germany Aim: Up to 40% of patients with MS report fatigue as the most disabling problem as it affects daily activities and reduces quality of live. So far there is no effective evidence based treatment for this important condition. However, the combination of an effective immunomodulatory treatment and physical activity is considered to be an important clinical concept in controlling fatigue. Therefore, we evaluated the effect of a web- based exercise program on the fatigue level in patients treated with Fingolimod. Methods: This is a 6-month, randomized, controlled, multicenter study in Relapsing-Remitting Multiple Sclerosis (RRMS) patients treated with Fingolimod evaluating effects of structured e-training versus no training on fatigue measured by the modified fatigue impact scale (mFIS) at study onset and after 6 months. Secondary outcome parameters include quality of life, functional performance, muscular strength and aerobic capacity. The e-training intervention employs a web-based application to administer an adaptive and individualized exercise protocol with the focus on endurance and strength training but also balance and core stability exercises. All exercises can be performed at home without the need of further devices.

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MM has received honoraria and travel compensations from following companies: Bayer, Biogen, Boehringer, Genzyme, Merck Serono, Novartis, Roche, Sanofi-Aventis and Teva. BK has received honoraria for serving on advisory boards and as speaker from Biogen, Merck Serono, Novartis, Sanofi/Genzyme and Teva. ES has no disclosures to declare. WEH has received honoraria for serving as speaker from following companies: Bayer, Biogen, Merck Serono, Novartis and Teva. AT has received honoraria for consultancy and lectures including travel compensations from Bayer, Biogen, Novartis and Teva. CH has received honoraria for consultancy and lectures including travel compensations from Novartis. RS has received honoraria for consultancy and lectures including travel compensations from Novartis. KP received research honoraria from Novartis. SS, MB and KS are employees of Novartis Pharma GmbH, Nuremberg. EG is an employee of Winicker-Norimed, Nuremberg. P811 The MS relapse phone as part of a new clinical pathway A. Skår1, R. Haugstad2, L. Bø1, T. Smedal1 1The Norwegian Multiple Sclerosis Competence Centre, 2Haukeland University Hospital, Bergen, Norway Background: Persons with multiple sclerosis (PwMS) are suffering from a wide range of symptoms, and are often unsure whether they are experiencing a new relapse. In a previous clinical survey and in focus group interviews, we found that PwMS expressed a need for better knowledge about relapses and a more consistent and predictable pathway for MS-relapses. We therefore established an MS Relapse Phone as part of a clinical pathway, for patients to call when they experience symptoms that might be a relapse. The phone is operated on regular weekdays by a nurse at the Neurology outpatient clinic, Haukeland University hospital,


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Norway. A standardized relapse-form is filled in by the nurse and given to the neurologist on call, who makes a clinical decision on the need for corticosteroid treatment (by hospitalization or at home) or the need for referral to the GP. Within the hospital referral region there are about 1100 patients with MS. Patients with RRMS received a letter with information about MS relapses and the MS Relapse Phone. They also received a small MS Relapse Card to carry with them, containing the phone number. In addition, we informed the local MS society and the general practitioners about the new service. Aim: We aim to investigate whether the new MS Relapse Phone has resulted in better knowledge and satisfaction among PwMS on what to do if they experience a possible relapse, and a better follow-up of MS relapses. Methods: All PwMS who visited our outpatient clinic in a period of seven months (N=661), were asked to fill in an anonymous survey with questions related to MS relapses. In order to evaluate the effect of implementation of the phone, the same survey will be carried out after two years. It will also be registered if the MS Relapse Phone has been used as intended, and how many of the calling patients who were in need of corticosteroid treatment. Preliminary results: It was necessary with thorough preparations with and information to the medical doctors and nurses involved. The implementation of the MS Relapse Phone then occurred smoothly. During the first 6 months, 70 PwMS called the relapse phone, of whom 56 PwMS were examined by a neurologist and 25 were treated with steroids. We experience that patients are satisfied with this new service. Conclusions: The MS Relapse Phone has been established as part of a new clinical pathway. So far, the experiences are positive and promising, and the effect will be evaluated after two years.

possible. The dataset gathers 464 visits of HP and 70 of MSP. Some people have been assessed several times. There are 33 visits in the group MSPL with the EDSS criterion, and 25 with the DI criterion. Statistical tests (Welch) were performed on the differences and relative differences of the GC measured during the first and last 100m of the test to detect differences between HP and MSPL, and between MSPL and MSPH, as in [ECTRIMS 2012 P755]. Results: Both criteria for defining the groups lead to similar conclusions. For many GC, the distributions of the variations are significantly different between MSPL and MSPH. The largest difference is for the relative difference of speed (p=0.000119 for EDSS and p=0.000021 for DI). In contrast, only the variation of the average lateral distance between the feet, which is related to the size of the base of support (and thus to the balance) shows a very significant difference between HP and MSPL (p=0.000116 for EDSS and p=0.000120 for DI). The balance does not seem to change much from MSPL to MSPH. Besides, we note that the variance decreases slightly from HP to MSPL and increases a lot from MSPL to MSPH. Conclusions: Statistically, from the motor fatigue point of view, it seems that the course of the MS disease is divided in two different stages. In the first one, MSP get more tired than HP because of a deterioration of the balance. Then, in the second one, their fatigue becomes related to a faster decrease of the walking speed. This suggests that physical therapy exercises focused on the balance could be given to MSP in the early stage of the disease. Disclosure The authors have nothing to disclose. We thank the Walloon region of Belgium for partly funding the project GAIMS.

Disclosure The authors report no conflict of interest. P812 Understanding how people with MS get tired while walking S. Piérard1, R. Phan-Ba2, M. Van Droogenbroeck1 1University of Liège, Liège, 2Centre de Revalidation Neurologique de Fraiture en Condroz, Fraiture-en-Condroz, Belgium Background: Walking impairment is frequent, appears early in the disease course of MS patients (MSP), and is perceived as the most disabling symptom. When walking, patients get tired more and differently than healthy people (HP) [Phan-Ba et al PLOS 2012]. This limits their walking perimeter. Understanding this phenomenon is thus important to suggest adequate therapies at the right time. Objective: Our aim is to understand how MSP get tired while walking compared to HP. Two groups of MSP are considered: those with a low disability level (MSPL) and those with a high one (MSPH). We consider two criteria to measure the disability: the EDSS and the deceleration index (DI) [Phan-Ba et al PLOS 2012]. The limit between the groups is set at DI=0.8 and EDSS=3 (inclusive for MSPL). Methods: Many gait characteristics (GC) have been measured with the system GAIMS along a 500m path walked as fast as

P813 High intensity training may reverse the fiber type specific decline in myogenic stem cells in multiple sclerosis patients I. Wens1, J. Farup2, C. Keytsman1, B.O. Eijnde1, U. Dalgas2 1Hasselt University, Diepenbeek, Belgium, 2Aarhus University, Aarhus, Denmark Background: Multiple sclerosis (MS) is associated with loss of skeletal muscle mass and function. The myogenic stem cells (satellite cells - SCs) are instrumental for accretion of additional nuclei to the post-mitotic muscle cells, but remains to be investigated in MS. Objectives: The present study compared the SC and myonuclei content between MS patients (n=23) and age matched healthy controls (HC, n=18). Furthermore, the effects of 12 weeks of high intensity training on SC and myonuclei content were explored in MS. Methods: Muscle biopsies were obtained from m. Vastus Lateralis at baseline (MS+HC) and following 12 weeks of training (MS only). Frozen biopsies were sectioned followed by immunohistochemical analysis for fiber type specific SCs (Pax7+), myonuclei (MN) and central nuclei content and fiber cross-sectional area (fCSA) using ATPase histochemistry. Results: At baseline the SCs/fiber was lower in type II compared to type I fiber in both MS (119%, p< 0.01) and HC (69%, p< 0.05), whereas the SCs/fCSA was lower in type II fibers compared


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Poster Session 2, 21(S11) to type I only in MS (72%, p< 0.05). No differences were observed in MN or central nuclei between MS and HC. Following training the type II fiber SCs per fiber and fCSA in MS patients increased by 165% (p< 0.05) and 135% (p< 0.05), respectively. Furthermore, the type II fiber MN content increased by 35% (p< 0.05) following training. Conclusions: In conclusion, the SC content is lower in type II compared to type I fibers in both MS and HC. Furthermore, high intensity training was observed to selectively increase the SC and myonuclei content in type II fibers in MS patients. Disclosure Inez Wens: nothing to disclose. Jean Farup: nothing to discclose. Charly Keytsman: nothing to disclose. Bert O. Eijnde: nothing to disclose. Ulrik Dalgas has received research support, travel grants and/or teaching honorary from Biogen Idec, Merck Serono and Sanofi Aventis. P814 Prevalence of neuropathic pain in early multiple sclerosis H. Heitmann1, V. Biberacher1, D. Buck1, V. Loleit1, R. Selter1, B. Knier1, M. Mühlau1,2, A. Berthele1, B. Hemmer1,2, M. Ploner1 1Department of Neurology, Technische Universität München, 2Munich Cluster for Systems Neurology (SyNergy), Munich, Germany Pain is considered a frequent symptom in Multiple Sclerosis (MS) with prevalence estimates ranging up to two thirds of patients1. Neuropathic pain is considered the most frequent form of pain in MS1 and is thought to be caused by demyelination-associated hyperexcitability of spinothalamic pathways2. Here, we prospectively reassessed the prevalence of neuropathic pain in patients with early MS and investigated the association of neuropathic pain with other clinical parameters. Data from 377 outpatients with MS participating in a prospective observational study of our department were analysed. The first visit to our MS-Clinic after confirmed diagnosis was chosen for analysis. Mean age was 36 years with mean duration of disease of 4.2 years. The mean EDSS was 1.6. Neuropathic pain was screened for using the painDETECT-questionnaire (PDQ)3. Additionally, depression, fatigue and cognition were assessed using the Beck Depression Inventory (BDI-II), the Fatigue Scale for Motor and Cognitive Functions (FSMC) and the Paced Auditory Serial Addition Test (PASAT). PDQ-scores indicative of neuropathic pain were found in 4.2% of patients. PDQ-scores positively correlated with EDSS, BDI-II and FSMC-scores as well as duration of disease and age (p< 0.001, respectively) but not with PASAT-scores (p>0.05). Our results show that neuropathic pain is less frequent in early MS than expected from previous studies. Our data further indicate that disability, depression and fatigue but not cognitive deficits are significantly associated with neuropathic pain in early MS. 1 Foley et al; Pain. 2013 May;154(5):632-42. doi: 10.1016/j. pain.2012.12.002. Epub 2012 Dec 14. Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis

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OĆonnor et al; Pain. 2008 Jul;137(1):96-111. Epub 2007 Oct 24. Pain associated with multiple sclerosis: systematic review and proposed classification 3 Freynhagen et al; Curr Med Res Opin. 2006 Oct;22(10):191120. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain 2

Disclosure B. Hemmer has served on scientific advisory boards for Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GSK, Chugai Pharmaceuticals, Micromet, Genentech and Genzyme Corporation; serves on the international advisory board of Archives of Neurology and Experimental Neurology; has received speaker honoraria from Bayer Schering, Novartis, Biogen Idec, Merck Serono, Roche, and Teva Pharmaceutical Industries Ltd; and has received research support from Biogen Idec, Bayer Schering, Merck Serono, Five prime, Metanomics, Chugai Pharmaceuticals and Novartis. He has been filed a patent for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and genetic determinants of neutralizing antibodies to interferon-beta. A. Berthele reports grants from Bayer Healthcare, personal fees from Biogen, Merck Serono, Teva, Novartis, and Genzyme, and compensations for clinical trials from Biogen, Novartis, Genzyme, Roche, and Alexion Pharmaceuticals - outside the submitted work. M. Mühlau has received research support from Merck Serono and Novartis; he has received travel expenses for attending meetings from Bayer, and Merck Serono; he has received honoraria for lecturing from Merck Serono; he has received Investigator fees for a Phase III clinical study from Biogen Idec. D. Buck has received compensation for activities with Bayer HealthCare, BiogenIdec, MerckSerono, and Novartis. She is supported by the Abirisk Consortium. V. Biberacher received research support from Merck Serono. M. Ploner, H. Heitmann, B. Knier, R. Selter and V. Loleit: nothing to disclose P815 Changes in configuration of gait temporal joint patterns in PPMS patients: network and random forest analysis D. Gómez-Andrés1, I. Pulido-Valdeolivas1, I. González-Suárez2, J.A. Martín-Gonzalo3, I. Rodríguez-Andonaegui3, A. OrvizGarcía2, C. Oreja-Guevara2, E. Rausell1 1Anatomy, Histology and Neuroscience, Universidad Autonoma de Madrid, 2Neurology, University Hospital San Carlos, 3Physiotherapy School, ONCE-UAM, Madrid, Spain Introduction: Instrumental gait analysis is an emerging technology used increasingly to evaluate motor disorders. Efficient gait relays on the ability of the central nervous system to command a system of sequential muscle synergy chains to manage weight support and translation, by setting gait cycle time-specific joint angle configurations. Gait impairment is the first and the most common symptom in the vast majority of PPMS patients. Objectives: To define which gait parameters swap from normal configuration to a more adaptive one and to assess the system global plasticity using random forest and network analysis respectively.


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Methods: Kinematic and spatial-temporal data were obtained by using a Codamotion system. Seventy -two kinematic/spatiotemporal parameters (36left/36right) of 5 joints were acquired with instrumented gait analysis from 4-5 gait cycles (10 PPMS patients/12 healthy volunteers). Random forests were trained to define classifier parameters for PPMS or healthy condition (goodness-of-fit assessment =1-OOB error rate). The influence of each predictor was estimated by mean percentage of decrease in model accuracy when variable is out-of-the-bag. Two networks were generated (nodes=gait parameters, edge weight = bivariate Spearman’s correlation coefficients between nodes) and their properties and parameter organization (buildingblocks) were assessed after Rubinov and Sporns, 2010. Results: PPMS patients’ walking strategies differ from normal by more flexed knee at initial contact (leading to recurvatum in stance), longer stance time, lower cadence and abnormal minimum hip flexion (goodness-of-fit=95.7%), which reflects a poor distal joint support. PPMS gait system is rearranged to maintain a maximum control of pelvic-femoral joints by setting more distributed relationships with ankle/knee parameters. Conclusions: We found different gait joint configurations in patients with PPMS in comparison with healthy subjects. These new gait joint configurations are provided by plastic adaptation to the constraints imposed by brain damage in PPMS and help to maintain the walking ability and propositive gait in these patients. Disclosure Celia Oreja-Guevara received honoraria for speaking and/or consultancy from Biogen, Genzyme, Bayer, Merck-Serono, Roche, Teva and Novartis. Aida Orviz-García received honoraria for speaking from Novartis. Ines González-Suárez received honoraria for speaking from Biogen D Gómez-Andres: nothing to disclosure. Irene Pulido-Valdeolivas: nothing to disclosure. Juan Andrés Martín-Gonzalo: nothing to disclosure. Irene Rodriguez-Andonaegui: nothing to disclosure. Estrella Rausell: nothing to disclosure. P816 Epilepsy among patients with multiple sclerosis E. Benjaminsen1, K.B. Alstadhaug1,2 1Department of Neurology, Nordland Hospital Bodø, Bodø, 2Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway Introduction: The prevalence of epilepsy (EP) among patients with multiple sclerosis (MS) has been found higher than among the general population. In Norway it has been estimated that 0.7 % of the populations has EP. Methods: Based on a retrospective search in medical records at Nordland Hospital, we identified all patients with MS and comorbid seizures and EP living in Nordland County at January 1, 2010. The diagnoses were set in accordance with the criteria of Poser (1983), McDonalds (2001), and the International League Against Epilepsy (1993). Results: Among 431 patients with MS living in Nordland County at the given time point, we identified 19 (14 women, mean age

53.3 ±16.9, and 5 men, mean age 53.2 ±11.0) with a history of EP, i.e. 4.4 % of the cohort. Fourteen of these (11 women and 3 men), i.e. 3.2 % of the MS population, had active EP defined as use of antiepileptic drugs or seizures within the last 5 years. In 11 with active epilepsy, attack semiology or electroencephalogram (EEG) recordings indicated a focal onset seizures. Four of the 14 patients were diagnosed with primary progressive MS, and the remaining 10 with relapsing remitting MS. Conclusion: The proportion of MS patients with active epilepsy in Nordland is 3.2 %, more than 4 times higher than what is found in the general Norwegian population, and is in accordance with previous studies from other countries. The causal link between MS and epileptic seizures is unclear, but our study supports the idea that focal brain pathology due to the MS is the cause of the comorbid EP. Disclosure Espen Benjaminsen: nothing to disclose Karl B Alstadhaug: nothing to disclose

Clinical assessment tools P817 Defining a score based on gait analysis for the longitudinal follow-up of MS patients S. Azrour, S. Piérard, M. Van Droogenbroeck Montefiore, University of Liège, Liège, Belgium Background: The project GAIMS [ECTRIMS 2013 P800] aims at developing a gait measuring system well suited for the clinical routine, and providing a reference database with the gait characteristics of many MS patients (MSP) and healthy people (HP). As the gait impairments are related to the disease progression, defining an objective and quantitative score based on the gait characteristics would be useful for the longitudinal follow-up. Based on the dataset of GAIMS and machine learning techniques (MLT), a score, well correlated with the Expanded Disability Status Scale (EDSS), can be defined [Azrour et al. ESANN 2014]. Objective: Burggraaff et al. [ECTRIMS 2014 P033] showed that paired comparisons help human raters to better judge the state of the patients. In the same spirit, we aim at predicting the difference of EDSS between two persons or between two visits of a same person, based on clinical gait measures. We show that the pairwise comparison strategy leads to a score (Gait-Score) well correlated with the EDSS and sensitive to small modifications of the gait. Methods: The gait of 162 HP and 72 MSP (44 with EDSS>3) has been recorded and analyzed with GAIMS. The Gait-Score is defined using the MLT of [Geurts et al. 2006]. We can compute the Gait-Score of a person by comparing him to others with known EDSS, and compute the difference of Gait-Score of a same person at two different moments. We measure the merits of the GaitScore by the correlation between the predicted Gait-Score and the EDSS, as well as the ability to detect subtle gait deteriorations among people with ataxia induced by a low dose of alcohol (data of [Piérard et al. ESANN 2014]). Results: The Gait-Score is well correlated with the EDSS (Pearson´s correlation=0.8743). Moreover, it can detect a gait deterioration after a small alcohol intake for 19 persons out of 24 (79% correct) which is much better than what was obtained by


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Poster Session 2, 21(S11) visual inspection of neurologists (62% according to [Piérard et al. ESANN 2014]). Conclusions: Based on the accurate gait measures provided by GAIMS, we are able to derive a Gait-Score, automatically, that is well correlated with the EDSS. Moreover, this score is able to detect subtle deteriorations of the gait caused by a low dose of alcohol. These results reinforce our conviction that the use of an automatic method based on gait analysis is very promising for the longitudinal follow-up of MS patients and the assessment of the impact of new drugs and rehabilitation programs. Disclosure The authors have nothing to disclose. We thank the Walloon region of Belgium for partly funding the project . Samir Azrour has a research fellowship of the Belgian National Fund for Scientific Research (F.R.S.-FNRS) P818 Prediction of expanded disability status scale subscores of motor dysfunction in multiple sclerosis using depth-sensing computer vision M. D’Souza1, J. Burggraaff2, P. Kontschieder3, J. Dorn4, C.P. Kamm5, S. Seinheimer6, P. Tewarie2, C. Morrison3, A. Sellen3, A. Criminisi3, F. Dahlke4, B. Uitdehaag2, L. Kappos1 1Neurology, University Hospital Basel, Basel, Switzerland, 2Neurology, VU University Medical Center, Amsterdam, The Netherlands, 3Microsoft Research, Cambridge, United Kingdom, 4Novartis Pharma AG, Basel, 5Neurology, 6University Hospital Bern, Bern, Switzerland Background: Clinical assessment of impairment and disability in Multiple Sclerosis (MS) remains the most important outcome in therapeutic trials, and is commonly assessed with the Expanded Disability Status Scale (EDSS). However, the EDSS exhibits high inter- and intra-rater variability. The ASSESS MS system is being developed as a non-invasive, more consistent and potentially finer grained tool to measure motor dysfunction in MS, by combining recordings of prescribed neurological movements with machine learning methods to assess motor dysfunction based on EDSS subscores. Objectives: To test the prediction of EDSS subscores from recordings of a depth-sensing video analysed by machine learning algorithms. Methods: Pre-defined movements from the EDSS assessment were recorded in 300 patients and 200 healthy volunteers. Video recordings of patients were scored by four neurologist from 3 sites based on the Neurostatus/EDSS assessment definitions. These scores were used to train a machine learning algorithm to correctly predict motor dysfunction from depth-sensing video recordings, which capture a 3D view of the patient. Results: We report that on movements covering upper extremities and trunk, the machine learning algorithm predicts motor dysfunction of patients with MS with an accuracy similar to neurologists’ intra-rater retest reliability. For example, the agreement of the upper extremity tremor/dysmetria subscore from the finger-tonose test of the algorithm with the neurologists’ assessment is 73% across scores 0, 1, 2 and 3, while the long-term intra-rater

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agreement of the neurologists with their previous assessment is 67% in this challenging-to-assess range. Conclusions: Automated quantification of movement recordings using a depth-sensing camera and image analysis based on a machine-learning algorithm enables an accurate and sensitive quantitative assessment of motor dysfunction in MS patients. ASSESS MS is expected to improve the evaluation of disability progression in clinical studies and clinical practice. Disclosure M. D`Souza received travel support from Bayer AG, Teva and Genzyme and research support from the University of Basel, J. Burggraaff received travel support from Novartis Pharma AG, P. Kontschieder is an employee of Microsoft Research, J. Dorn is an employee of Novartis Pharma AG, Ch. P. Kamm received honoraria for lectures and consulting from Biogen idec, Novartis, Teva, Merck-Serono, Genzyme and Bayer Schweiz AG, S. Steinheimer: nothing to disclose, P. Tewarie received travel support from Novartis Pharma AG, C.Morrison is an employee of Microsoft Research, A. Sellen is an employee of Microsoft Research, B. M. J. Uitdehaag received consultation fees from: Biogen Idec, Novartis, EMD Serono, Teva Pharmaceuticals, Genzyme and Roche. The Multiple Sclerosis Centre Amsterdam has received financial support for research activities from Biogen Idec, Merck Serono, Novartis, and Teva Pharmaceuticals, A. Criminisi is an employee of Microsoft Research, F. Dahlke is an employee of Novartis Pharma AG, Ludwig Kappos’s institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof Kappos’ activities as principal investigator and member or chair of planning and steering committees or advisory boards in trials sponsored by Actelion, Addex, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Biogen Idec, CLC Behring, Genentech, GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Praxicon, Roche, Sanofi-Aventis, Santhera, Siemens and Teva; royalties from Neurostatus GmbH; research grants from the Swiss MS Society, Swiss National Research Foundation, the European Union, Gianni Rubatto Foundation, and the Novartis and Roche Research foundations. P819 Visualizing ubiquitously sensed measures of motor ability in multiple sclerosis for clinical use C. Morrison1, K. Huckvale1, A. Sakar1, P. Kontschieder1, J. Dorn2, S. Steinheimer3, C.P. Kamm3, J. Burggraaff4, M. D’Souza5, F. Dahlke2, L. Kappos5, B. Uitdehaag4, A. Criminisi1, A. Sellen1 1Microsoft Research, Cambridge, United Kingdom, 2Novartis Pharma AG, Basel, 3Neurology, University Hospital Bern, Bern, Switzerland, 4Neurology, VU University Medical Center, Amsterdam, The Netherlands, 5Neurology, University Hospital Basel, Basel, Switzerland Background: Ubiquitous sensor recordings of human movements (e.g. camera or accelerometer) are becoming increasingly


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important for the assessment of motor symptoms in neurological disorders. Many sensed measures rely on machine learning algorithms to quantify motor ability. ASSESS MS, for example, uses camera-based depth-sensing and machine learning to automatically calculate EDSS subscores for prescribed movements. A substantial challenge in moving sensed measures from lab to clinic is presenting results to clinicians in a way that provides enough context to support clinical decision-making. Visualization of the machine learning process is one way to achieve this. Objectives: To explore appropriate data visualisations for the presentation of results in the ASSESS MS system. Methods: Semi-structured interviews were carried out with nine neurologists, which were subsequently transcribed and coded for analysis. The neurologists were asked to discuss approaches for encoding time and patients’ movement properties presented in three visualisations: (1) video of patient outline highlighting the features that most influenced the machine learning algorithm’s assessment; (2) image summarizing key properties of the patient’s movement that may allow estimating the plausibility of the automated assessment; (3) graph of patient performance over multiple visits without additional details about the current visit. Results: The neurologists preferred the static image over video, as it was easier to compare images than video at different time points. The body was not required in interpreting a visualisation, however, the neurologists liked to be able to “see” the movement in the visualisation, even if not the body parts. There was substantial interest in a prognostic view of the data, but clarity was lacking about what made sense given the unpredictable nature of multiple sclerosis. Conclusions: Preliminary results highlight that ubiquitously sensed measures should aim to be static with a clear relation to movement. Numeric and prognostic views require further exploration. Disclosure C.Morrison is an employee of Microsoft Research, K.Huckvale is an employee of Microsoft Research, S.Sakar is an employee of Microsoft Research, P.Kontschieder is an employee of Microsoft Research, J.Dorn is an employee of Novartis Pharma AG, S. Steinheimer nothing to disclose, Ch.P.Kamm received honoraria for lectures and consulting from Biogen idec, Novartis, Teva, Merck-Serono, Genzyme and Bayer Schweiz AG, J.Burggraaff received travel support from Novartis Pharma AG, M. D`Souza received travel support from Bayer AG, Teva and Genzyme and research support from the University of Basel, F.Dahlke is an employee of Novartis Pharma AG, Ludwig Kappos’s institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof Kappos’ activities as principal investigator and member or chair of planning and steering committees or advisory boards in trials sponsored by Actelion, Addex, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Biogen Idec, CLC Behring, Genentech, GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Praxicon, Roche, Sanofi-Aventis, Santhera, Siemens and Teva; royalties from Neurostatus GmbH; research grants from the Swiss MS Society, Swiss National Research Foundation, the European

Union, Gianni Rubatto Foundation, and the Novartis and Roche Research foundations, B.M.J. Uitdehaag received consultation fees from: Biogen Idec, Novartis, EMD Serono, Teva Pharmaceuticals, Genzyme and Roche. The Multiple Sclerosis Centre Amsterdam has received financial support for research activities from Biogen Idec, Merck Serono, Novartis, and Teva Pharmaceuticals, A.Criminisi is an employee of Microsoft Research, A.Sellen is an employee of Microsoft Research. P820 Stability and prognostic utility of patient-derived MS severity score (P-MSSS) among MS clinic patients I. Kister1, T. Bacon2, M. Levinas2, R. Green2, G. Cutter3, E. Chamot3 1Neurology, 2Neurology, New York University School of Medicine, New York, NY, 3Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States Objectives: To determine short-term stability of Patient-derived MS Severity Score (P-MSSS) in MS clinic patients and to explore the utility of the newly-developed P-MSSS-based risk calculator for this population. Background: P-MSSS are duration-adjusted mean ranks of Patient-determined Disability Steps (PDDS) scores in the selfreport North American Research Committee on Multiple Sclerosis (NARCOMS) Registry (Kister et al, Neurology, 80:1018). We have used the NARCOMS data to develop a risk calculator that inputs patient’s baseline P-MSSS, age and gender to estimate probability of ‘severe MS’ (defined as P-MSSS>0.83) at two year follow up. Prognostic utility of P-MSSS risk calculator in MS clinic population has not been investigated. Methods: Consecutive patients at two outpatient MS Centers in the greater New York area were asked to record their PDDS at each routine visit, while their treating neurologist confirmed MS diagnosis and documented disease duration, relapse status and disease-modifying therapy in a standardized fashion. Every MS patient with ⩾2 PDDS scores that were >6 months apart was included unless they had a relapse within 3 months of clinic visit. P-MSSS were obtained using the published reference Table. Risk of severe MS in our patients was calculated using our model developed for the NARCOMS registrants, which had sensitivity of 77% and specificity of 90% at 2-year follow up. Results: The cohort consisted of 823 MS patients. The average age was 46.6 ±13.0 years; disease duration was 12.2 ±8.8 years; 74% were women; 84% were on disease-modifying therapy. Mean PDDS for cohort = 2.1 (median 1, range 0-8), mean baseline P-MSSS was 3.8 ±2.7. Mean duration of follow up was 10.6 (range 6-17) months. P-MSSS change from first to last clinic visit was -0.15, a non-significant difference (p=0.2). Our model correctly predicted severe MS in 71 of 78 patients with severe MS at last follow up and misclassified 74 patients as having severe MS (sensitivity of 91%, specificity of 90%, positive predictive value of 49% and negative predictive value of 99%). Conclusions: P-MSSS scores remain stable in the short term among MS clinic patients without recent relapses. Severe MS at follow-up was observed in 50% of patients with baseline ‘P-MSSS risk score’ predictive of severe MS and ‘missed’ in less than 10% of severe MS cases. P-MSSS risk calculator is quick and easy to


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Poster Session 2, 21(S11) deploy in any clinical setting, and could be a useful adjunct to therapeutic-decision making. Disclosure This Investigator Sponsored Study (ISS) workwas supported by a grant from Genzyme.Ilya Kister served on scientific advisory board for Biogen Idec andreceived research support from GuthyJackson Charitable Foundation, National Multiple Sclerosis Society, Biogen-Idec, Serono, andNavartis. Tamar Bacon: nothing to disclose. Maayan Levinas: nothing to disclose. Rivka Green: nothing to disclose. Gary Cutter: served on scientific advisory boards for sanofiaventis, Cleveland Clinic, Daiichi Sankyo, GlaxoSmithKline, Genmab A/S, Eli Lilly and Company, Medivation, Inc., Modigenetech, Ono Pharmaceutical Co. Ltd., PTC Therapeutics, Inc., Teva Pharmaceutical Industries Ltd., Vivus Inc., University of Penn, the NIH (NHLBI, NINDS, NICHD) and NMSS; serves on the editorial board of Multiple Sclerosis; has received speaker and consulting honoraria from Alexion Pharmaceuticals, Inc., Bayhill Therapeutics, Bayer Schering Pharma, Novartis, Genzyme Corporation, Nuron Biotech, Peptimmune, Somnus Pharmaceuticals, Sandoz, Teva Pharmaceutical Industries Ltd., UT Southwestern, and Visioneering Technologies, Inc.; has received funding for travel and speaker honoraria from Consortium of MS Centers and Bayer Schering Pharma; and has received research support from the NIH (NICHHD, NIDDK, NINDS, NHLBI, NIAIDS), NMSS, the Consortium of MS Centers, and Klein-Buendel Incorporated. Eric Chamot: serves on the NMSS Task Force on Clinical Disability Measures. IK has no conflict of interest to declare. P821 Harnessing real-time patient data to improve clinical outcomes and research: the multiple sclerosis partners advancing technology and healthcare solutions (MS PATHS) initiative E.M. Mowry1, R. Bermel2, L.J. Balcer3, S.D. Cassard1, E. Fisher4, I. Izbudak1, S. Jones2, I. Kister3, G. Krueger5, Y.W. Lui3, J. Perryman2, D. Sickert6, J.R. Williams4, R. Rudick4 1Johns Hopkins University, Baltimore, MD, 2Cleveland Clinic Foundation, Cleveland, OH, 3New York University School of Medicine, New York, NY, 4Biogen, Cambridge, 5Siemens Healthcare, Burlington, MA, United States, 6Siemens Healthcare, Erlangen, Germany Background: Clinical research currently entails costly data collection methods that require resource-intensive involvement of research staff and providers, limiting their deployment to a subset of patients that may not accurately represent all people with MS. Routine care visits of the larger MS population represent opportunities to systematically collect standardized clinical and imaging data for clinical decision-making and research. Goals: 1) To develop a collaborative network of MS Centres linked by technology-based, standardized, routine collection of neuroperformance testing, patient-reported outcomes, and MRI measurements with minimal impact on provider workflow,

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and 2) To establish a centralized, de-identified health information exchange database that functions in real time as a MS learning health system. Methods: A large collaborative network of MS Centres called The Multiple Sclerosis Partners Advancing Technology and Healthcare Solutions (MS PATHS) is being created. At routine clinical visits, patients will self-administer tests analogous to the MS Functional Composite-4 on an iPad. The NeuroQOL and other relevant data will also be collected electronically. Standardized brain MRIs will be acquired on 3T Siemens scanners to enable quantitative image analysis. Participants will optionally enrol in a biobanking sub-study. Results: Three US centres, with Biogen and Siemens, developed a governance structure to empower all collaborating parties. The initial implementation and validation of MS PATHS are underway. Key challenges have included establishing institutional awareness to implement informatics solutions and privacy and consent considerations. Initial enrolment is expected in the fall of 2015; more sites will be added in 2016. Conclusions: The MS PATHS initiative represents a unique partnership that harnesses the independent strengths of MS clinical centres, radiologists, and the pharmaceutical, imaging, and information technology industries to create an integrated, efficient data collection system to improve clinical care and research. Disclosure Project funded by: Biogen & Siemens Healthcare Ellen Mowry: E. Mowry has received research funding from Biogen and received free medication for a clinical trial from Teva Neuroscience. Robert Bermel: R. Bermel has received consulting fees from Biogen, Novartis, Genentech, Genzyme, Mallinkrodt, and is part contributor to the intellectual property used in the MS Performance Test. Laura Balcer: Dr. Balcer has served on a clinical trial advisory board for Biogen and performed consulting for Biogen and Genzyme. Sandra Cassard: S. Cassard received funding by Biogen in the form of contract with her employer, Johns Hopkins University, to support effort on project. Elizabeth Fisher: E. Fisher received consulting fees from Biogen, Genzyme, and Novartis, and funding for research studies from Biogen and Genzyme. She is employed by Biogen as of January 2015. Izlem Izbudak: I. Izbudak received funding by Biogen in the form of contract with her employer, Johns Hopkins University, to support effort on project. Stephen Jones: Dr. Jones received a speaker fee from Monteris. Ilya Kister: Ilya Kister served on scientific advisory board for Biogen Idec and received research support from Guthy-Jackson Charitable Foundation, National Multiple Sclerosis Society, Biogen-Idec, Serono, and Novartis. Gunnar Kreuger: G. Kreuger is an employee of Siemens Healthcare Yvonne Lui: Nothing to disclose. Janet Perryman: Nothing to disclose. Daniel Sickert: D. Sickert is an employee of Siemens Healthcare. James R. Williams: JR Williams is an employee of and stockholder in Biogen. Richard Rudick: R. Rudick is an employee of and stockholder in Biogen.


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P822 Baseline MSSS is not better than EDSS at predicting ambulatory disability R. Gross, C. Farrell, A. Miller, S. Krieger Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States Background: The Multiple Sclerosis Severity Score (MSSS), combining the Expanded Disability Status Scale (EDSS) and disease duration, emerged a decade ago as a cross-sectional measurement of multiple sclerosis (MS) severity. It has been used as a reference tool in multiple MS studies, but its prognostic ability in the individual patient remains uncertain. Impaired walking is assessed in clinical trials and in practice by the Timed 25-Foot Walk (T25FW), wherein worsening is closely tied to disease progression. Goals: We aimed to assess the ability of the initial EDSS and MSSS to predict T25FW outcomes in a long-term cohort. Methods: Records from 123 patients followed for at least 8 years by a single academic MS specialist (AEM) were reviewed. T25FW times were extracted from the last visit where they were recorded. As these visits were prior to the approval of dalfampridine, use of this symptomatic agent did not impact our analyses. We performed simple linear regressions, with last T25FW as the dependent variable and baseline EDSS or MSSS as the explanatory variable. Multivariate linear regression was used to determine impact of these and other clinical variables (sex, type of first relapse, recovery from first relapse, and age at last visit) on most recent T25FW. Stepwise logistic regression was used to determine impact of independent variables on mild, moderate, or severe categories of gait impairment at last visit (T25FW < 5.5, 5.5-7.5, >7.5 seconds, respectively). Results: There were 34 men (27.6%) and 89 women (72.4%). Mean age at disease onset was 31 (range 10-58). Caucasians comprised 92.7%, and 91.1% were on disease modifying therapy at some point during the observation period. They were followed for a mean of 11.7 years (range 8-25). At the first visit, mean EDSS was 2.8 (n=123, range 0-8), and mean MSSS was 4.18 (n=103, range 0.04 to 9.74). In simple linear models, EDSS had a regression coefficient of 2.3, p < 0.001 (r2 =0.20), and baseline MSSS had a regression coefficient of 1.5, p < 0.001 (r2 =0.16). In the multivariate linear model, only baseline EDSS was statistically significant: coefficient 2.4, p = 0.0079. Using stepwise logistic regression, only baseline EDSS remained in the model: OR of longer T25FW times for 1 point increase in baseline EDSS was 2.4 (95% CI 1.8-3.2). Conclusions: Baseline MSSS was not more effective than baseline EDSS alone at predicting walking impairment in this longitudinal cohort. Disclosure R Gross has consulted for MedPage Today. C Farrell has nothing to disclose. A Miller has received research support from Novartis, Genentech, Genzyme, Sanofi-Aventis, BiogenIdec, Roche, and Mallinckrodt (Questcor). He has consulted for Genzyme/Sanofi-Aventis, Biogen Idec, Glaxo Smith Kline, EMD Serono ( Merck Serono), Mallinckrodt (Questcor), Novartis, Acorda, Accordant Health Services, Teva, Roche, Alkermes, Genentech, and Caremark

(Accordant Health Care). He has served on the Speaker´s Bureau for Biogen Idec (unbranded disease awareness programs only). S Krieger has received compensation for consulting and advisory board work with Acorda Therapeutics Inc.; Bayer; Biogen Idec; EMD Serono (Merck & Co., Inc.); Genentech; Genzyme; Novartis; Questcor Pharmaceuticals, Inc; and Teva Pharmaceutical Industries Ltd. and has given non-promotional lectures with Biogen Idec and Genzyme.

P823 Exploratory analysis of multiple sclerosis disability progression unrelated to relapses L. Kappos1, M. Trojano2, H. Butzkueven3,4, H. Wiendl5, T. Spelman3, F. Pellegrini6, Y. Chen6, Q. Dong6, H. Köndgen6, S. Belachew6, on behalf of the TOP Investigators 1University Hospital Basel, Basel, Switzerland, 2University of Bari, Bari, Italy, 3University of Melbourne, Melbourne, 4Monash University, Box Hill, VIC, Australia, 5University of Münster, Münster, Germany, 6Biogen, Cambridge, MA, United States Background: The TYSABRI® (natalizumab) Observational Program (TOP) is an ongoing, global, open-label, 10-year prospective study of natalizumab-treated patients with relapsingremitting multiple sclerosis (RRMS). Objectives: To evaluate different definitions of Expanded Disability Status Scale (EDSS) progression unrelated to relapse as potential metrics to capture development of progressive disease in RRMS patients. Methods: Cumulative probabilities of 24-week confirmed EDSS progression were assessed using a “roving” EDSS reference value and compared with the conventional study baseline reference system. Using a roving EDSS reference value, overall EDSS progression was compared with EDSS progression unrelated to relapse when no concurrent relapse was recorded from ⩽30 days prior to the reference EDSS assessment to ⩽30 days or ⩽12 weeks post progression assessment. The roving EDSS reference value had to be recorded ⩾24 or ⩾48 weeks prior to the date of observed progression. Sensitivity analyses censored progression events recorded based on an EDSS reference other than and lower than study baseline that was not ⩾12-week confirmed. Results: As of 1 May 2014, 5562 of 5623 enrolled patients had baseline EDSS scores (median [range], 3.5 [0.0-9.5]) and were included in the analysis. Using a roving EDSS reference value, at 288 weeks in TOP, the cumulative probability of confirmed EDSS progression between EDSS assessments ⩾24 weeks apart was similar to that between assessments ⩾48 weeks apart, especially for the sensitivity analysis definitions. The more stringent sensitivity analysis definitions identified approximately 70% more progression events unrelated to relapse, and 50% more overall, than definitions using the study baseline as a fixed EDSS reference. Cumulative probabilities based on a roving EDSS reference value confirmed that EDSS progression unrelated to relapse represented approximately 60% of overall progression events for all definitions tested. Conclusions: Cumulative probabilities of 24-week confirmed EDSS progression unrelated to relapse between EDSS assessments ⩾24 or ⩾48 weeks apart appear to be low at ≈5.5 years of natalizumab treatment and represent approximately 60% of


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Poster Session 2, 21(S11) overall progression events. Using a roving EDSS reference rather than a conventional study baseline reference increases the sensitivity of confirmed EDSS progression measures and may more sensitively estimate the onset or rate of progressive MS in a longterm observational study. Disclosure Supported by Biogen. LK: Institution (University Hospital Basel) has received research support from Actelion, Addex, Bayer Health Care, Biogen, Biotica, CSL Behring, Genzyme, Lilly, Merck, Mitsubishi, Neurostatus Systems, Novartis, Ono Pharma, Pfizer, Receptos, Roche, Sanofi, Santhera, Siemens, Teva, UCB, Xenoport, the European Union, the Roche Research Foundation, the Swiss MS Society, the Swiss National Research Foundation. MT: scientific advisory boards for Biogen, Merck Serono, Novartis; speaker honoraria from Biogen, Merck Serono, Novartis, Sanofi, Teva; research grants from Biogen, Merck Serono, Novartis. HB: compensation for consulting from Biogen, Merck Serono, Novartis; research support from Biogen, Merck Serono. HW: honoraria from Bayer, Biogen, Medac, Merck Serono, Novo Nordisk, Sanofi, Schering, Teva; consultant for Bayer Vital/ Schering, Biogen, Medac, Merck Serono, Novartis, Novo Nordisk, Sanofi, Teva; research support from Bayer, Biogen, Medac, Merck Serono, Novo Nordisk, Sanofi, Schering, Teva. TS: honoraria for consultancy and funding for travel from Biogen and Novartis. FP, YC, QD, HK, SB: employees of Biogen. P824 25-foot walking test as predictor of proprioceptive training efficacy in multiple sclerosis patients B. Zakrzewska-Pniewska1, L. Wojciechowski2, M. Nojszewska1, A. Podlecka-Pietowska3, Z. Lewandowski4 1Department of Neurology, Medical University of Warsaw, Warsaw, 2Department of Rehabilitation, District Hospital, Radom, 3Medical University of Warsaw, 4Department of Epidemiology, Medical University of Warsaw, Warsaw, Poland Poor balance and lack of coordination, often found in multiple sclerosis (MS), influence negatively patient’s daily activities. The discovery of the brain plasticity and the introduction of modern diagnostic and therapeutic methods (based on this phenomenon) created a basis for elaboration of novel rehabilitation methods in the therapy of MS patients. Stabilometric platforms are such methods and consisting on interactive training exercises with real-time monitoring of movement for the patients. This form of training leads to the improvement of impaired balance control in MS. The aim of this project was to evaluate the effect of proprioceptive training program with stabilometric platforms on functional state. Functional parameter being used was 25-foot walking test (25WFT). Two randomly assigned groups of patients were analyzed: group A (23 patients) underwent four weeks training on stabilometric platforms, group B (17 patients) - four weeks standard rehabilitation program. In the whole MS group mean EDSS was 3.0 (range:1.5-4.5), mean age - 50.4 years (range: 23-68), mean disease duration - 10 years (range: 1-40). Group A

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and B were matched for the abovementioned parameters. Functional state at baseline and after platform training or standard rehabilitation were evaluated using 25FWT. Four weeks lasting prioproceptive training sessions (performed on stabilometric platforms: ERBE system and LIBRA system) were performed in group A and standard rehabilitation program in group B. Statistically significant improvement in functional test was found after the training program in both (A and B) groups in comparison with the initial assessment but the difference was statistically more evident in group A (P< 0.05). This study proved that 25FWT may be a predictor of proprioceptive training efficacy in MS patients. Disclosure Beata Zakrzewska-Pniewska: nothing to disclose Lukasz Wojciechowski: nothing to disclose Monika Nojszewska: nothing to disclose Aleksandra Podlecka-Pietowska: nothing to disclose Zbigniew Lewandowsk: nothing to disclose P825 The multiple sclerosis Well-Being Map™ - a visual tool to support patient communication with their care team in Korea J. Oh1, O. Kwon2, B.J. Kim3, B. Lee4, B.-J. Kim5 1Konkuk University Medical Center, 2Eulji Geneal Hospital, Eulji University College of Medicine, 3Samsung Medical Center, 4UCB Pharma, 5Korea University Medical Center, Seoul, Republic of Korea Background: A number of clinical scales, both physiciansadministered and patients-reported have been used to examine physical status of patients with multiple sclerosis (MS). However, few translated and validated measures in Korean were available to use in real practice setting. Additionally, it is now increasingly recognized that patients with MS not only suffer from Functional Systems Scores (FSS) based symptoms, but from additional symptoms, such as sleep, pain, social efficacy and well-being. To encourage patients to discuss their condition, the MS Well-Being Map™ (MS WBM) was developed as a visual tool allowing patients to monitor their symptoms over time and to facilitate communication with HCPs. Methods: The MS WBM was developed in consultation with patients and their caregivers and in collaboration with MS experts from the Korean Society of Multiple Sclerosis. After collecting main symptoms that patients reported, a committee composed of 4 MS specialists and 3 non-physician healthcare workers discussed and refined the main symptom list. Each symptom was categorized according to the functional system involved. Patients with MS from 4 university affiliated hospitals were recruited and asked to review the symptom list to test. Correlation analysis of the rating to expanded disability status scale (EDSS) score was performed. Results: The finalized MS WBM was developed following user feedback. It consists of a radar chart with ten radial axes, each representing a functional domain: vision, brain stem, pain/sensory, social well-being, autonomic dysfunction, mood/fatigue, sleep, movement, cognition, and walking/coordination. Each symptom was rated on frequency of occurrence by the patient on


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a scale of 0-4 (Never, Occasionally, Sometimes, Often, Always) across each domain. Scores on the radar chart showed significant correlation to EDSS. Conclusion: The MS WBM provides an ‘at a glance’ visual representation of disease status encompassing a variety of symptoms. The MS WBM could facilitate communication between patients and physicians as well as with caregivers, resulting in focused, in-depth assessment and effective management of symptoms over time.

Conclusions: Our findings provides novel associations between NBV, disability and cognition in patients who received Natalizumab therapy for over 2 years. A longitudinal assessment of NBV changes over two years with comparison with healthy controls will follow.

Disclosure

P827 Functional system involvement and confirmation of EDSS progression in CombiRx S.S. Cofield1, F.D. Lublin2, T. Gustafson2, S. Krieger2, G.R. Cutter1, J.S. Wolinsky3, The CombiRx Investigator Group 1Biostatistics, University of Alabama at Birmingham, Birmingham, AL, 2Corinne Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, New York, NY, 3Neurology, University of Texas Health Sciences Center at Houston, Houston, TX, United States

JeeYoung Oh: nothing to disclose Ohyun Kwon: nothing to disclose Byoung Joon Kim: nothing to disclose Bolam Lee: an employee of UCB Pharma Byung-Jo Kim: nothing to disclose P826 A longitudinal study using whole brain, neocortical and subcortical atrophy rates and patient reported outcomes (PROs). Interim analysis A. Miravalle, J. Honce, E. Alvarez, N. Kavita, V. Brandi, S. Sillau, J. Corboy, T. Vollmer University of Colorado, Aurora, CO, United States Background: Regional brain atrophy and cortical thinning were shown to be reliable measures and important features of MS pathology. Patient reported outcomes (PRO) are useful in demonstrating the impact of a disease from the patient perspective. The PROs proposed in this study are to be used in conjunction with various clinical and MRI measures to assess the impact of a change in brain atrophy rate on the patient’s daily functioning after long term NTZ therapy. Methods: The study is a between group comparison of MS patients and non-MS subjects within a single site. Clinical outcomes include EDSS and MACFIMS. MS patients and controls were administered a panel of PRO scales that included the NeuroQOL scales (which assess physical, emotional, cognitive and social functioning), the Patient Determined Disease Steps (PDDS), (a self-reported measure of physical disability), and employment status. Normalized brain volumes (NBV) were calculated and spearmen correlations were performed for the crosssectional relationship between NBV and each PRO scale, and were adjusted for age, gender and disease duration. Results: This is an interim analysis of baseline characteristics of patients enrolled to date. A total of 35 MS patients who have been taking NTZ for at least 2 years were recruited through the Rocky Mountain MS Center located within the University of Colorado Anschutz Medical Campus in Aurora. Mean age was 41 and 86% were female. When adjusting for age, gender and disease duration normalized brain volume (NBV) was strongly correlated with age (XXX) and was negatively correlated with the PDDS (r=-0.5; p=0.002). PDDS was found to negatively correlate with Right Thalamic Volume (r= -0.4; p=0.04) and various Neuro-QOL scales including Cognition (r=-0.33; p=0.05), Upper extremity disability (r=-0.4; p=0.01), Lower extremity disability (r=-0.6; p=0.001), and Social Score (r=-0.4, p=0.02). PDDS positively correlated with fatigue (r=35; p=0.05).

Disclosure This study was funded by a grant from Biogen Idec.

Background: Progression in clinical trials is generally reported as a confirmed worsening in the Expanded Disability Status Scale (EDSS) with limited discussion on the types and numbers of functional systems (FS) and ambulatory changes involved in the associated EDSS confirmation. Objectives: Describe FS and ambulatory changes associated with 6-month confirmed EDSS progression in CombiRx over 7 years. Methods: The CombiRx trial was a double blind, multi-center randomized clinical trial of relapsing remitting MS, comparing 50% of participants on interferon beta 1a (IFN) and glatiramer acetate (GA) treatment versus 25% on each of the single agent arms with matching placebo. Participants were followed quarterly through month 42 (Core) then every 6 months for up to 7 years (Extension). Confirmed progression was defined as a 1.0 increase in the EDSS from baseline (index visit), when baseline < =5.0; or an increase of 0.5 from baseline, when baseline >=5.5, sustained for 6 months with two successive quarterly Core visits or 1 semi-annual Extension visit, for those participants on study at least 9 months. Results: Of 1008 randomized, 959 (95.1%) were eligible for progression. For the Core, there were 555 FS changes associated with the 229 instances of first progression: 7.6% involved the ambulatory portion of the EDSS but only 1.7% involved ambulatory changes alone. Excluding ambulatory changes, the median number of FS increases was 2 (range 1, 6), with 20.5% involving Sensory, 17.5% Pyramidal, 12.4% Bowel/Bladder, 12.6% Visual, 11.9% Cerebellar, 10.6% Cerebral, 6.8% Brainstem. In the Core, including ambulatory changes: 67.4% of the next quarterly EDSS visit had an increase in the same FS as the index visit. At the confirming 6-month EDSS visit was 65.2%: 88.1% (88.1) ambulatory, 70.1% (63.9) Pyramidal, 70.0% (60.0) Visual, 68.4% (63.2) Brainstem, 66.1% (62.7) Cerebral, 63.8% (60.9) Bowel/Bladder, 63.2% (70.2) Sensory, 59.1% (57.6) Cerebellar. Results were similar for the Extension. Conclusions: The majority of confirmed EDSS changes were confirmed in the same functional system. However, 1/3 of subsequent EDSS visits showed change in a different FS. This difference has definitional, pathophysiologic and prognostic implications.


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Poster Session 2, 21(S11) Disclosure Dr. Cofield has received support for consulting services (American Shoulder and Elbow Society), DSMB service (MedImmune), and/ or grant support; no direct conflicts. Dr. Salter has received support for consulting services and grant support; no direct conflicts. Dr. Wolinsky has received support for consulting services, DSMB service, and/or grant support; no direct conflicts. Dr. Lublin has received support for consulting services, DSMB service, and/or grant support; no direct conflicts. Dr. Krieger has received support for consulting services and grant support; no direct conflicts. Ms. Gustafson has nothing to disclose. Dr. Cutter has consulting and/or DSMB commitments in Past 12 months. Participation of Data and Safety Monitoring Committees: All of the below organizations are focused on medical research: Apotek, Biogen-Idec, Cleveland Clinic(Vivus), Glaxo Smith Klein Pharmaceuticals, Gilead Pharmaceuticals, Horizon Pharmaceuticals, Modigenetech/Prolor, Merck/Ono Pharmaceuticals, Merck, Merck/ Pfizer, Neuren, Sanofi-Aventis, Teva, NHLBI (Protocol Review Committee), NINDS, NICHD (OPRU oversight committee). Consulting, Speaking fees & Advisory Boards: Consortium of MS Centers (grant), D3 (Drug Discovery and Development), Genzyme, Genentech, Jannsen Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, Novartis, Opexa Therapeutics, Receptos, Roche, EMD Serono, Spiniflex Pharmaceuticals, Somahlution, Teva pharmaceuticals, Transparency Life Sciences. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. Sources of funding: NIH/NINDS 5-U01-NS045719. Biogen Idec and Teva Neuroscience generously contributed study medications and matched placebo without input into the design, conduct, analysis, or interpretation of results of the trial. P828 Measures of falls risk in persons with multiple sclerosis: a comparative study of the Timed Up-andGo and Timed Up-and-Go cognitive tests M.A. Ciol1, J.J. Sosnoff2, P.N. Matsuda1, G.H. Kraft1 1Rehabilitation Medicine, University of Washington, Seattle, WA, 2Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, IL, United States Background: The Timed Up-and-Go (TUG) test was developed to assess functional mobility in older adults and identifies those at risk for falls. It is also widely used to assess other patient populations as well. Some versions of TUG have a cognitive task added (TUG-cognitive), such as saying the alphabet backwards (TUGAlpha) or subtracting numbers by 3 (TUG-3s) while doing the test. The TUG and TUG- cognitive have not been studied specifically in people with multiple sclerosis (PwMS). Objectives: 1) To compare performance (in seconds) in the TUG, and TUG-cognitive (TUG-Alpha, and TUG-3s) between PwMS and a control group of similar age and, 2) within each group, to compare TUG and TUG-cognitive (TUG-Alpha, and TUG-3s) for people with and without reported falls in the previous 3 months.

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Design: Comparative study (PwMS versus Control). Methods: 110 community-dwelling participants (53 with MS and 57 controls). TUG measures between MS and control groups were compared via repeated measures analysis of variance. Measures between fallers and non-fallers were compared via non-parametric test for medians. Results: Control participants had lower mean time than PwMS (p=0.009) in all three TUG tests. Both groups had increased mean time from TUG to TUG-Alpha to TUG-3s (p< 0.001), with no interaction between groups and TUG tests. Eleven individuals in the control and 28 in the MS groups reported falls in the previous 3 months. When comparing fallers to non-fallers, there was no difference in TUG times among controls (p= 0.54 to 0.95). For the MS group, TUG-Alpha was not statistically different (p=0.26), but fallers had slower average times than non-fallers for TUG (p=0.005) and TUG-3s (p=0.03). Limitations: Participants were recruited among PwMS and their companions who presented at a clinic, and might not be representative of their respective populations. Falls was collected retrospectively, precluding us from making inferences on fall risk based on the TUG. Conclusions: Persons with MS had slower performance on the TUG, TUG-Alpha, and TUG-3s than controls. All participants slowed down with the addition of the cognitive task. These observations suggest that all three versions of the TUG can be used in PwMS and should be considered as part of a fall risk assessment. Disclosure Marcia A. Ciol: nothing to disclose Jacob J. Sosnoff: was supported in part by funding from the National MS Society, Consortium of MS Centers and Nielsen Foundation. Patricia N. Matsuda: nothing to disclose George H. Kraft: nothing to disclose P829 Brain atrophy in multiple sclerosis patients measured by a web based automated siena version (NeuroResearch) J.L. Ruiz Peña1, M. Alberich Jorda2, P. Sau3, D. Pareto2, F. Damas1, A. Rovira2, G. Izquierdo Ayuso1 1MS Clinic, Department of Neurology, Hospital Virgen Macarena, Sevilla, 2Section of Neuroradiology and MR Unit, Department of Radiology, Vall d’Hebron University Hospital, Barcelona, 3CERCO, Sevilla, Spain Background: SIENA is a free algorithm, part of the FSL toolkit (www.fmrib.ox.ac.uk) that allows the direct quantification of brain atrophy from serial MR images. It has been applied in numerous studies of MS, investigating brain atrophy in people who have experienced a CIS and patients with RRMS, SPMS and PPMS. Purpose: A new web based automated and traditional semi automated methods of Siena are used to measure whole-brain atrophy in multiple sclerosis patients (MS) to know the reliability, sensitivity of the new method. Methods: 41 patients (11 male and 30 female) with Relapsing Remitting MS and a Kurtzke Expanded Disability Scale Score (EDSS) of 0-5.0 were included in a prospective, longitudinal study of Fingolimod in RRMS. All patients were followed up for


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a period of 1 year. Every three months disability was assessed by different neurological scale. Percentage of Brain Volume Change (PBVC) between month 12 and baseline was measured by two methods: semi automated or automated segmentation of Siena (Neuroresearch). Results: The 3D automated method yielded reliable segmentation and was used. Both methods produced data that were highly intercorrelated and indistinguishable by analysis of variance (R2: 0.96, P< 0.0001). Conclusion: This web based automated measure of whole-brain atrophy provided similar and nearly interchangeable data regarding MS. Disclosure JLRP has received speaking honoraria from Novartis Manel Alberich, Pablo Sau, Fatima Damas have nothing to disclose Deborah Pareto has received speaking honoraria from Novartis Alex Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, and has received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Bracco, MerckSerono, Teva Pharmaceutical Industries Ltd, OLEA Medical, Stendhal, Novartis and Biogen Idec. GIA has received honoraria or consultation fees from Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis, Teva, Novartis, Genzyme, and Almirall. P830 Daily activity and its association with gait impairment and fear of falling in patients with multiple sclerosis T. Krüger1, J. Behrens1, K. Otte2, B. Kayser2, S. MansowModel2, A.U. Brandt1,2, T. Schmitz-Hübsch3, F. Paul1,3 1Charité - Universitätsmedizin Berlin, NeuroCure Clinical Research Center, 2Motognosis UG, 3Department of Neurology, Charité - Universitätsmedizin, Berlin, Germany Introduction: Daily activity (DA) is lower in patients with multiple sclerosis (PWMS) and its activity parameters, such as MVPA (moderate-to-vigorous-physical-activity), VPA (vigorous-physical-activity), energy expenditure (EE) and step count, may further be influenced by intra-week differences. The objective of this ongoing study is to assess which parameters and patterns of daily activity are associated with patients’ impairment or fear of falling. Methods: DA will be measured in 30 PWMS and as many healthy controls (HC) using the SenseWear Armband (SWA) during a 7-day period. Gait impairment is assessed with EDSS, Short Maximum Speed Walk (SMSW) using Microsoft’s Kinect and the patient-reported Walk-12. Fear of falling is assessed using the Falls Efficacy Scale International (FES-I) and the number of falls in the last 6 months reported by the PWMS. Results: Preliminary analysis of 22 PWMS and 12 HC showed that compliance of SWA-wearing was better in PWMS than in HC (76% vs. 67% for > 5 and 43% vs. 8% for > 6 days). Lower MVPA-levels and steps which both showed significant intra-week differences (p< .01 and p< .05) correlated with higher EDSS (rho: -.603 and p< .05 and rho: -.653 p=.002) and reduced walking distance (rho: .386 and p< .05 and rho .558 and p=.001).

Higher VPA-levels were associated with lower scores in the FES-I (Spearman’s rho: -.726 and p< .001) and the Walk-12 (rho: -.465 and p< .05), as well as less falls (rho: -.474 and p< .05). Higher VPA and EE correlated both with faster walking performance in SMWS (rho: .665 and p< .001 and rho: .489 and p< .01). Conclusion: Our preliminary analysis suggests that DA is generally well reflected by clinical assessments. But from the activity parameters investigated, VPA showed best correlations with fear of falling while EE was associated with objective gait impairment. Further, our data suggest intra-week differences of mobility, which has to be considered in data comparison from different time intervals. Disclosure TK has nothing to disclose. JB received travel grants from biogen, speaking honoraria from Novartis. TSH has nothing to disclose. AUB reports no conflicts of interest. AUB received consulting fees unrelated to this study from Biogen, Novartis, Teva, Nexus, and Motognosis. AUB received funding unrelated to this study for research from Novartis, Biogen, BMWi and BMBF. BK reports no conflicts of interest. BK is a full-time employee of Motognosis. KO reports no conflicts of interest. KO is a full-time employee of Motognosis. SMM reports no conflicts of interest. SMM is a full-time employee of Motognosis. SMM Holds stocks options in Motognosis as cofounder. FP is supported by the Deutsche Forschungsgemeinschaft, the EU FP7 Framework Program (combims.eu), the Guthy Jackson Charitable Foundation, the Bundesministerium für Bildung und Forschung (Competence Network Multiple Sclerosis and N2 Advisims). FP has received research support, travel reimbursement and personal compensation for activities with Alexion, Bayer, BiogenIdec, Chugai, Teva, Merck Serono, Novartis, Sanofi Genzyme, MedImmune. P831 The effects of different cognitive and motor tasks on the dual task cost of walking in multiple sclerosis: a case-control study C. Leone1,2, F. Patti1, L. Moumdjian2, M. Zappia1, P. Feys2 1Department of Neuroscience GF Ingrassia, University of Catania, Catania, Italy, 2University of Hasselt/REVAL BIOMED, Hasselt, Belgium Background: Dual-task (DT) methodology has increasingly been used to assess the cognitive motor interference while walking in people with Multiple Sclerosis (PwMS). We investigated which DT paradigm has the greatest impact on spatiotemporal gait parameters (DT cost, DTC) and whether we can discriminate PwMS from healthy subjects (HS). Methods: PwMS and sex-matched HS performed 16 DT paradigms, consisting of walking with and without carrying a cup


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Poster Session 2, 21(S11) (WC) during eight different cognitive tasks: subtraction by 3 and 7, digit span (DS) forward and backward, word list generation (WLG) phonemic and semantic, auditory stroop (AS) and clock test (CT). Gait parameters were recorded by wearable sensors. The DTCs of velocity, stride length, cadence, double support and gait cycle were calculated. The Timed Up and Go, Timed-25Foot-Walk, Six-Minute Walk, Nine-hole-Peg Tests, Brief repeatable battery of Rao, Stroop Test, and Trial Making Test (TMT) were collected. Cognitive impairment (CI) was defined when at least three tests were pathologically scored. Results: 40 PwMS (mean age 47±12 yrs, EDSS 3.1±1.8) and 31 HS (mean age 47±14 yrs) were enrolled. Out of 40 PwMS, 10 had CI (25%), whilst none in the HS group. Overall, the DTC of velocity was greater when WC during WLG phonemic (14.2%), DS Backward (13.8%) and WLG semantic (13.4%). The DTC of stride lenght was different between groups (all p< 0.05) when walking alone during subtraction by 7 (5.6% vs 1.9%) and WLG phonemic (6.4% vs 2.4%), and when WC and subtracting by 7 (6.8% vs 2.8%), CT (6.6% vs 2.9%), WLG phonemic (7.4% vs 3.6%) and semantic (7.2% vs 2.9%). The correlation analysis found a r=.38 (p< .05) between stride length DTC of walking during WLG phonemic and TMT in PwMS, and a moderate correlation between EDSS and almost all DTCs calculated (r values from .40 to .60, p< .001) for velocity and stride length. A regression analysis showed that TMT and EDSS accounted for 31% and 29% of the variance in model predicting respectively the DTC of stride length of WC during WLG phonemic and DTC of velocity of WC during DS backward. Conclusion: Overall, walking while performing more difficult cognitive task and a second motor task led to a greater DTC of specific walking parameters. The DT-related decrease in velocity during WC and DS forward and backward and in stride length while WC and WLG phonemic was significantly greater in PwMS. Both cognition (TMT) and motor disability (EDSS) may have a role in the DTC magnitude. Disclosure Carmela Leone: nothing to disclose. Francesco Patti: he as received honoraria for scientific lectures and travel payment from Biogen Idec, Novartis, Teva, Genzyme, Bayer Schering, Merck Serono, Almirall. Lousin Moumdjian: nothing to disclose. Mario Zappia: he has received compensation for consulting services from Boehringer-Ingelheim, Lundbeck, Union Chimique Belge and scientific grants from AIFA- Agenzia Italiana del Farmaco, Novartis, Lundbeck. Peter Feys: he has received honoraria for scientific lectures from Biogen and Novartis. P832 “Function Watch” - a real time, graphical composite representation of MS patients´ health status as a decision support tool in daily clinical practice L. Stawiarz1, E. Hagel2, H. Eriksson3, J. Hillert1 1Department of Clinical Neuroscience (CNS), Karolinska Institutet, 2Department of Learning, Informatics, Management and Ethics (LIME), Karolinska Insitutet, Stockholm, 3Carmona AB, Halmstad, Sweden

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Background: Longitudinally collected, structured clinical data of MS patients have an increasing importance for quality assurance of MS care. However electronic healthcare records have limited ability to extract meaningful data and compare it with matching reference groups. They function largely as archiving tools rather than support tools used in daily clinical practice. Objective: Our aim was to design and implement a tool assembling a composite graphic, based on a set of 12 standardized measurements of functions. Furthermore, we wanted to facilitate a real-time comparisons of individual results with a matching reference group from the Swedish MS registry (SMSreg) applying flexible matching criteria. The tool was to be connected to the SMSreg allowing a direct visualization of data during patient’s visit to a neurologist. Method: A Function Watch was built in SQL and R language, using a collection of R libraries including a powerful web framework - Shiny. Minimum and maximum values for each test were scaled from 0 to 100%, where 100% represented the best performance available. As such, tests of various types became comparable. Results: Individual patient´s data are automatically retrieved from the SMSreg. Last registered results of 12 relevant tests are selected and expressed as a fraction of a defined 100%. Such normalized values are plotted on a spider diagram. Patients exhibiting similar characteristics according to gender, age, disease duration, clinical course and treatment are selected from a pool of 16,500 patients and 100,000 neurological visits registered in SMSreg (flexible matching). Mean/median values for each of 12 tests are then evaluated for the matching group. These values are plotted on the same spider diagram as an area defining the results of a reference group. Individual patient´s values located peripherally represent better performance than the reference group, whereas points positioned inside the area, denote worse performance. Age of each test is shown for quality assurance. The Function Watch is implemented in the web interface of SMSreg. It is used in daily clinical work with MS patients throughout Sweden. Conclusions: A Function Watch representing12 scores is a handy tool for immediate feedback, clearly displaying if a patient performs better or worse than a matching reference. It gives a direct suggestion to the neurologist whether treatment outcome is acceptable and what problems should be addressed during the visit. Disclosure Leszek Stawiarz: nothing to disclose Eva Hagel: nothing to disclose Håkan Eriksson: nothing to disclose Jan Hillert: has received unrestricted research grants or honoraria for lectures or advisory boards from BiogenIdec, Merck-Serono, Novartis, Bayer-Schering, Teva and Sanofi-Aventis. His MS research is funded by the Vetenskapsrådet - Swedish Research Council. P833 Experiences with a self developed accelerometer in multiple sclerosis L. Racz1, C. Ver2, J. Soltesz2, A. Matyas2, L. Csiba2, L. Kardos3, T. Csepany1


418 1Neurology, 2University

Poster Session 2, 21(S11) of Debrecen, 3Kenezy Hospital,

Debrecen, Hungary Objective: Test the usability of a small 3-d acceleration measuring device in mutiple sclerosis (MS). This device was developed at our department and validated for the assessment of the movement-differences between paretic and non-paretic extremities in stroke patients. Background: Multiple sclerosis (MS) is the most common autoimmune neurodegenerative disease of the central nervous system, heterogenous, ranging from well described motor symptoms to non-motor symptoms. Design and methods: We collected data from 55 MS patients and the degree of physical disability was evaluated using Kurtzke’s EDSS, MFSC or non motoric symptoms using SDMT, MSNQ, FIS and Beck depression test. The devices were attached to all the limbs and movements and movement-durations were registered during different types of mobility tests: 9 foot/33 foot walking, tandem walking, Romberg posture, finger to nose tests etc. The data of movement-monitors were compared (STATA version 12) between the groups, according to disability mild (EDSS: 0-2), middle severe (EDSS: 2.5-4.0), severely disabled (EDSS: 4.5-8.0) or cognitive impairment or in subgroups of patients with fatigue vs non fatigue/depressed vs non depressed, also with shorter (0.8 y) vs. longer durations (9-31 y) of disease. Results: The mean age was 37.2±9.4 years; duration of disease: 10 ± 7.5 years; mean EDSS: 3.0 ± 1.8. There was a correlation between the movement-duration and the disability based on EDSS (p< 0.05) in all mobility tests. We found also correlation between the,,movement sample (AUC)” of patients and their disability and disease duration in 9 foot walking test and their disability in 100 m walking, Romberg posture, finger to nose tests (p< 0.05). The presence of depression associated with worse cognitive and mobility functions (p< 0.05). Conclusions: Our device detected some movement-differences between disabled MS patients. Further studies are required to evaluate its usability for the accumulation of disability in relapsing-remitting MS.

Disclosure Nothing to disclose

suboptimal response to treatment with disease modifying therapy (DMT), either due to lack of efficacy or intolerable side effects is to switch to another DMT. Cycling through 1st line DMTs may limit the ability to seize the narrow window of opportunity to alter the disease course early on in RRMS patients. The advantages associated with earlier switching to a 2nd line treatment rather than another 1st line DMT remain to be confirmed. Objective: To compare clinical and economic outcomes among patients with RRMS who switch from 1st line treatment to fingolimod versus those who switch to another 1st line DMT (BRACE) including interferon beta-1a (s.c. and i.m.), interferon beta-1b, or glatiramer acetate. To describe socio-demographic and clinical characteristics of MS patients who switch to fingolimod and other DMTs. To compare persistence, adherence rates, adverse events among RRMS patients who switch to fingolimod versus those who switch to other DMTs. Methods and results: This non-interventional, observational, retrospective multicenter study (SWITCH) study is designed to evaluate patient outcomes following a switch of DMT. Specifically, patients continuing on BRACE will be compared to those switching to fingolimod. The analysis will include patients from Canada and Spain. In this real world setting, two study cohorts will be evaluated: 1) patients who switch from a first-line DMT to fingolimod and 2) patients who switch to another first-line DMT during the reference period. The reference period is between May 1st 2011 and February 28th 2013. Clinical charts will be reviewed for the 12 months period following treatment switch. Data from the 2 cohorts will be compared for relapse rate and disability progression. Economic outcomes including the use of concomitant medication related to MS, number and length of hospitalizations, use of device and aids, caregiver, home alterations and other healthcare resource utilization will also be compared. Patient demographics and results will be presented once available as part of the poster presentation. Conclusions: Gaining a better understanding of the benefits of earlier escalation to a 2nd line treatment may help to optimize the overall management of RRMS, the ultimate goal being delayed disease progression in conjunction with reduced healthcare utilization. GILENYA® is a registered trademark Disclosure

Economic burden P834 Clinical and economic outcomes in MS patients treated with DMTs (SWITCH study): Canadian real-world experience Mark S. Freedman1, Pierre Duquette2,3, Virender Bhan4, Liesly Lee5, Montse Pedros6 Emil Loefroth7 Jennie Medin 7 Robyn Schecter8, Paola Haddad8 1University of Ottawa and The Ottawa Hospital Research Institute, Ottawa, 2Notre Dame Hospital, Montreal, 3Faculté de Médecine, Université de Montréal, Montréal, QC, 4Dalhousie University, Halifax, NS, 5University of Toronto, Sunnybrook Health Sciences Centre, Toronto, ON, 6IMS Health, Toronto, Ontario, Canada,7Novartis AG, Basel, Switzerland, 8Novartis Pharmaceuticals Canada Inc., Dorval, QC, Canada Background: The current recommendation for relapsing remitting multiple sclerosis (RRMS) patients demonstrating

Mark Freedman - Has received honoraria or consultation fees from BayerHealthcare, Biogen-Idec, Chugai, EMD Canada, Genzyme, Novartis, Sanofi-Aventis, Teva Canada Innovation. Dr. Freedman is a member of the following company advisory boards, board of directors or other similar group: BayerHealthcare, Biogen-Idec, Hoffman La-Roche, Merck Serono, Novartis, Opexa, and Sanofi-Aventis. Dr. Freedman is a Participant in the following company sponsored speaker’s bureau: Genzyme. Pierre Duquette - Has received honoraria for advisory boards, for CMEs from Novartis, Biogen-Idec, Genzyme, EMD Serono and Teva Neurosience. Dr Duquette has taken part in Investigatorinitiated trials funded by Novartis, Biogen-Idec, Genzyme and EMD Serono. Dr Duquette has received funding from peerreviewed agencie such as the Canadian Institutes for Health Research (CIHR) and the MS Society of Canada. Virender Bhan - Has received honoraria for speaking, consulting, and advisory board participation from Biogen Idec, EMD Serono, Genzyme, Novartis, Roche and Teva Neuroscience. Dr


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Poster Session 2, 21(S11) Bhan has acted as site principal investigator for clinical trials for the same companies. Liesly Lee - Has conducted clinical trials and has received honoraria for advisory boards from Biogen, EMD Serono, Genzyme Canada, Novartis and Sanofi-Aventis. Montse Pedros is an employee of IMS Health, Canada. Emil Loefroth is an employee of Novartis AG Basel, Switzerland. Jennie Medin is an employee of Novartis AG Basel, Switzerland Paola Haddad - Employee of Novartis Pharmaceuticals Canada Inc. Robyn Schecter - Employee of Novartis Pharmaceuticals Canada Inc. P835 Employment among persons with multiple sclerosis in New Zealand S. Alla1, J.F. Pearson2, G. Clarke1, D.F. Mason3, D.H. Miller4, A. Richardson5, T. Anderson1, D. Abernethy6, E. Willoughby7, C.E. Sabel8, B.V. Taylor9 1Medicine, 2Deans, University of Otago, 3Neurology, Christchurch Hospital, Christchurch, New Zealand, 4Queen Square MS Centre, UCL Institute of Neurology, London, United Kingdom, 5School of Health Sciences, University of Canterbury, Christchurch, 6Neurology, University of Otago, Wellington, 7Neurology, Auckland District Health Board, Auckland, New Zealand, 8School of Geographical Sciences, University of Bristol, Bristol, United Kingdom, 9Menzies Research Institute, University of Tasmania, Hobart, TAS, Australia Background and objectives: A number of demographic and clinical factors including the degree of physical disability have been shown to be associated with reduced work ability among persons with multiple sclerosis (MS). Approximately 56% of New Zealanders with MS were experiencing moderate to severe disability at the time of a national prevalence survey conducted in 2006. The aim of the study was to investigate the demographic and clinical characteristics associated with employment status among the 2006 New Zealand National MS Prevalence (NZNMSP) cohort. Methods: The NZNMSP study included all persons resident in NZ on the census day with a diagnosis of MS based on McDonald Criteria 2005. Demographic and employment information was obtained from a self-administered survey questionnaire. Clinical information was sourced from the medical record. A univariate analysis followed by a bivariate logistic regression analysed the factors associated with employment status among the working age population (25-64 years). Results: A total of 2,917 persons with MS were identified, of which 2073 participants (71.1%) responded to the survey. Over 90% of people with MS in the working age population (n = 1,727) had a work history, however more than 54% were not working in 2006. Loss of work status occurred early in the disease course, before 5 years disease duration, and at low levels of disability (Expanded Disability Status Score of 0 - 2.5) The most frequent self-reported reasons for change in employment status were related to disease factors that included fatigue, lower body motor dysfunction, and impaired cognition. Higher age, progressive types (primary and secondary), longer disease duration, higher

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disability levels and lower education were significantly associated with the loss of work status (all p< 0.001). Conclusions: The findings confirm and extend earlier international work which showed that MS profoundly affects the workforce status of those with MS in the 25-64 year age group. Surprisingly job loss occurs at a young age, early in the disease course and at low levels of disability. These findings indicate a need for improved work place and environmental adjustments to accommodate persons with MS in the work force. Disclosure Source of funding: The National MS Society of NZ, the New Zealand Brain Research Institute and the University of Otago, Christchurch, New Zealand. David Miller: Disclosure May 2015: I have received honoraria through payments to my employer, UCL Institute of Neurology, for Advisory Committee and/or Consultancy advice in multiple sclerosis studies from Biogen Idec, GlaxoSmithKline, Novartis, Merck, Chugai, Mitsubishi Pharma Europe and Bayer Schering Pharma. I have also received compensation through payments to my employer for performing central MRI analysis of multiple sclerosis trials from GlaxoSmithKline, Biogen Idec, Novartis, Apitope and Merck. The Queen Square MS Centre at UCL Institute of Neurology is supported by the UK MS Society and UCL-UCLH Biomedical Research Centre. Other authors: nothing to disclose P836 The rate of retirement due to multiple sclerosis related disability has decreased in Finland since introduction of disease modifying therapy H. Kuusisto1, T. Luukkaala2, K. Mäkinen1, E. Castren1 1Kanta-Häme Central Hospital, Hämeenlinna, 2Science Center, Pirkanmaa Hospital District, Tampere, Finland Introduction: Multiple sclerosis (MS) is the most common cause of non-traumatic neurological disability affecting mainly young adults during their best working years. Previous studies have shown that approximately two-thirds of MS patients are unable to retain employment long term and a significant part of patients retire soon after the diagnosis is made. However, it is not known, how the rate of employment has changed over the decades, especially after the disease modifying treatments (DMTs) have been introduced and what are the possible predictive factors for disability pension. We aimed to evaluate the retention rate of work capacity and the possible risk factors for early retirement in MS in a large community dwelling cohort. Methods: A retrospective survey of all MS patients treated at the Department of Neurology, Kanta-Häme Central Hospital 19782012, was conducted. A computer based search was carried out and all the patients identified as having the diagnosis of MS were included in the analysis. The probability of reaching the end point (starting of disability pension) was assessed by the Kaplan-Meier method. The potential clinical risk factors were collected from the patient files and analyzed by the Cox proportional hazard regression analysis. Results: Altogether 415 patients were identified (119 males and 296 females). The retention rates for remaining able to work were


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estimated for those diagnosed 1966-1994 and for those diagnosed 1995-2012 (after first DMTs were introduced). The median time for reaching disability pension was 6 years in the first cohort and 11 years in the latter, being significantly longer (p‹0.001). Risk factors for disability pension at the time of diagnosis were older age, secondary progressive MS, presence of fatigue and higher EDSS. Conclusions: The probability of remaining able to work despite of MS has nearly doubled during recent years as compared to time before DMTs. The presence of fatigue at the time of diagnosis is one of the significant risk factors leading to disability pension. Disclosure Hanna Kuusisto: nothing to disclose. Tiina Luukkaala: nothing to disclose. Kati Mäkinen: nothing to disclose. Elina Castren: nothing to disclose. P837 Earnings and financial compensation from social security systems correlate strongly with disability for multiple sclerosis patients A. Kavaliunas, M. Wiberg, P. Tinghög, A. Glaser, K. Alexanderson, J. Hillert Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden Background: Multiple sclerosis (MS) is a costly chronic disease often leading to progressive disability. It was previously reported that MS patients of working age in Sweden earn lower incomes and receive higher benefits. However, there is limited knowledge of how this is correlated with MS patients` disability. Objectives: To elucidate sources and levels of income among Swedish MS patients with different disability assessed with the Expanded Disability Status Scale (EDSS). Methods: A cross-sectional study was conducted linking data from Statistics Sweden and the Swedish Multiple Sclerosis Register. A total of 7,929 MS patients aged 21-64 years and living in Sweden in 2010 were identified. Descriptive statistics, logistic and truncated linear regression models were used to estimate the differences between MS patients with different disability regarding the following types of income: earnings, disability pension, sickness absence, disability allowance, unemployment compensation, and social assistance. Results: The average level of earnings was ten times lower and the average level of health related benefits was four times higher when comparing MS patients with severe (EDSS 7−9.5) and mild (EDSS 0−3.5) disability. MS patients with severe disability had on the average 171,615 Swedish Crowns (SEK) less annual income from earnings and 82,804 SEK more income from benefits compared to those with mild disability (p < 0.001) who had earnings and received benefits. The combined average income for MS patients was 35% lower when comparing patients in the mild disability group to those in the severe group. The estimated odds ratio (OR) for having earnings among MS patients with severe disability compared to the patients with mild disability was 0.07 (95% confidence interval [CI] 0.06−0.09), while the estimated OR for having benefits was 89.13 (95% CI 36.73−216.28) when

comparing the same groups. Disability pension was the main source of income for the patients with severe disease disability. Conclusions: Disease progression affects the financial situation of MS patients considerably. Correlations between higher disease disability and patient income were observed (negative for the earnings and positive for the benefits). These results suggest that earnings and benefits could be used as measures of MS progression and proxies of disability in detailed descriptions of the course of MS. Disclosure Study supported by Biogen. Andrius Kavaliunas: nothing to disclose. Michael Wiberg was funded by Biogen. Petter Tinghög was funded by Biogen. Anna Glaser is receiving research support from Biogen. Kristina Alexanderson has recieved project grant from Biogen and several Swedish research councils. Jan Hillert: received honoraria for serving on advisory boards for Biogen and Novartis and speaker’s fees from Biogen, MerckSerono, Bayer-Schering, Teva and Sanofi-Genzyme. He has served as P.I. for projects sponsored by, or received unrestricted research support from, Biogen, Sanofi-Genzyme, Merck-Serono, TEVA, Novartis and Bayer-Schering. His MS research is funded by the Swedish Research Council and the Swedish Brain Foundation. P838 Development of a composite, administrative claims-based measure of disease severity among patients with multiple sclerosis receiving disease-modifying drug therapy J.C. Locklear1, A.L. Phillips1, M. Frean2, J. Menzin2 1EMD Serono, Inc., Rockland, 2Boston Health Economics, Inc., Waltham, MA, United States Background: Beyond relapse, there are limited measures to evaluate disease severity in multiple sclerosis (MS) within medical/ pharmacy claims. Additional claims-based measures may be useful for identifying severe patients requiring intervention. Goals: To develop a composite measure representing MS disease severity, as measured by high costs. Methods: MS patients (age 18-63 yrs; ⩾1 MS diagnosis claim: ICD-9-CM 340.xx) with ⩾1 claim for a disease-modifying drug (DMD; first claim=index) and continuous eligibility 12 months pre- and post-index were identified from a random sample of 5 million lives in the IMS LifeLink Plus database from 1/1/20076/30/2012. A negative binomial regression was estimated to predict all-cause total costs (excluding DMD costs). Covariates included diagnoses, potentially associated with costs, grouped into three domains: MS-related conditions (e.g., disability), Clinical Classification System (CCS) code categories (e.g., cardiovascular) and Charlson-Deyo comorbidities. Additional covariates included demographics and adherence. Coefficients reaching statistical significance (p< 0.05) and increasing costs by ⩾5% were selected for inclusion into two normalized scores (MS-specific and general) then reweighted to a scale of 0 to 100. Validity of the scores to predict costs within the sample was evaluated by comparing the Bayesian information criterion (BIC)


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Poster Session 2, 21(S11) between the fully-specified model and a model predicting costs as a function of the two scores (‘score model’). Results: The analysis included 11,384 patients. Model covariates associated with the most points in the MS-score included rehabilitation services (25.6), altered mental state (15.8), and pain (12.9). Fewer points were associated with malaise/fatigue (4.3) and infections (2.4). Covariates associated with the most points in the general score included myocardial infarction (20.8), metastatic solid tumor (19.0), and any primary malignancy (12.2). Fewer points were associated with rheumatologic (5.4) and genitourinary (5.2) diagnoses. A lower BIC was observed for the score model versus the fully specified model (227340 vs. 227508). This difference of 168 represents higher predictive power for the score model. Conclusions: In this analysis, we developed two claims-based disease severity scores that were predictive of higher healthcare costs. Evaluation of such scores over time may represent a new approach for identifying MS disease progression within administrative claims. Disclosure JCL and ALP are employees of EMD Serono, Inc., Rockland, MA, USA (a subsidiary of Merck KGaA, Darmstadt, Germany). MF and JM are employees of Boston Health Economics which receives funding from the study sponsor, EMD Serono. Study supported by EMD Serono, Inc., Rockland, MA, USA and Pfizer Inc, New York, NY, USA. P839 Cost-effectiveness of 44 mcg subcutaneous interferon beta1a (scIFNβ1a) and 30 mcg intramuscular interferon beta-1a (imIFNβ1a) using clinical endpoints of disease activity A.L. Phillips1, N.C. Edwards2, J.C. Locklear1 1EMD Serono, Inc., Rockland, 2Health Services Consulting Corporation, Boxborough, MA, United States Background: Composite clinical endpoint measures may provide a more comprehensive assessment of disease activity, and the concept of no evidence for disease activity (NEDA) is an emerging treatment goal in MS. A post-hoc analysis of data from the EVIDENCE study, a head-to-head randomized controlled trial (RCT) of 44 mcg subcutaneous interferon beta-1a (scIFNβ1a) and 30 mcg intramuscular interferon beta-1a (imIFNβ1a), evaluated composite endpoints that combine assessment of relapse with measures of disability, worsening, and radiological disease activity. Goals: To evaluate the cost-effectiveness of scIFNβ1a and imIFNβ1a using 2015 costs and various composite clinical endpoint measures from a head-to-head RCT. Methods: A decision model from a US payer perspective was populated with composite clinical outcome data from the EVIDENCE RCT of scIFNβ1a and imIFNβ1a. Clinical activityfree (CAF) status was defined as no relapses and no confirmed 12-week disability worsening. NEDA was defined as no relapses and no confirmed 12-week disability worsening, with no Gd+ lesions and no new or enlarging T2 lesions on the Week 24 MRI scan. At 24 and 48 weeks, a modified definition of NEDA (mNEDA; composite of CAF and no new or enlarging T2 lesions on the MRI scan) was assessed, as only T2 (but not Gd-enhanced

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T1) scans were performed at 48 weeks. Drug cost was based on 2015 wholesale average cost. Medical costs included the costs of monitoring associated with the drugs and the cost of MS relapses. Incremental cost-effectiveness ratios (ICERs) (difference in cost between two interventions divided by difference in effect) were calculated for the different composite measures. Results: For a population of 100 treated patients, treatment with scIFNβ1a would result in 19 additional NEDA patients and 105 additional NEDA months vs. imIFNβ1a. At 48 weeks, scIFNβ1a resulted in 10 additional patients with CAF status, amounting to 111 incremental CAF months. There were 12 additional mNEDA patients at 48 weeks with scIFNβ1a vs. imIFNβ1a, totaling 133 additional mNEDA months. The ICERs for scIFNβ1a vs. imIFNβ1a were $1,756 per additional NEDA-month gained, $3,337 per additional CAF-month gained, and $2,781 per additional mNEDA-month gained. Sensitivity analyses showed the model was robust and most sensitive to drug cost. Conclusions: This analysis showed that 44 mcg scIFNβ1a was a cost-effective treatment relative to imIFNβ1a, using multiple composite clinical outcome measures. Disclosure ALP and JCL are employees of EMD Serono, Inc., Rockland, MA, USA (a subsidiary of Merck KGaA, Darmstadt, Germany). NCE received personal compensation as a Health Services Research consultant. Study supported by EMD Serono, Inc., Rockland, MA, USA and Pfizer Inc, New York, NY, USA. P840 Multiple sclerosis: analysis of predicted medication adherence behavior by morisky medication adherence scale (MMAS-8) and the relationship to patient derived EDSS (PDSS) and multiple sclerosis impact scale (MSIS-29) and quality of life (QoL) M. Gudesblatt1, K. Wissemann1, M. Zarif1, B. Bumstead1, L. Fafard1, S. Thotam1, M. Buhse1,2, D. Golan3,4, S. Becker5, C. Sullivan6,7, J. Wilken6,7, D. Morisky8 1South Shore Neurologic Associates, Patchogue, 2Nursing, State University of New York at Stony Brook, Stony Brook, NY, United States, 3Department of Neurology, Carmel Medical Center, 4Technion Israel Institute of Technology, Haifa, Israel, 5Chicago School of Professional Psychology, 6Neurology, Georgetown University Hospital, Washington, DC, 7Washington Neuropsychology Research Group LLC, Fairfax, VA, 8Fielding School of Public Health, UCLA, Los Angeles, CA, United States Objective: Explore predicted adherence behavior by the Morisky Medication Adherence Scale (MMAS-8) in PwMS as impacted by patient reported outcome (PRO) EDSS (PDSS), disease impact (Multiple Sclerosis Impact - MSIS-29) and Quality of Life (QoL). Background: PwMS have multiple treatment choices for DMT. DMT non-adherence and delay in treatment impact outcomes and costs. Adherence can be measured by patient report, observation and refills. With varied DMT routes and frequency, predicted PwMS adherence behavior during the course of the disease needs exploration. MMAS-8, a validated 8 point questionnaire, is predictive of: medication adherence, pharmacy fill data, and efficacy and economic outcomes. DMT Choice reflects many factors but


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adherence directly impacts therapy efficacy. The long term economic impact of MS demands efficacy, adherence and safety. Methods: Single site cross sectional analysis of PwMS completing MMAS-8, MSIS-29, QoL and PDDS questionnaires on the same day in routine MS care. Results: 686 PwMS, 73% female, average 49+/-11 years, Groups of predicted adherence behavior correlated with different average MSIS-29 scores across all groups (p< 0.001), high adherence (MSIS 49.6), medium adherence (MSIS 57.8) low adherence (68.8). Predicted adherence behavior correlated with PRO QoL (p< 0.001). Increasing disability (PDDS) was associated with reduction in predicted adherence to a lesser degree (p < 0.05). Conclusion: Increasing impact of disease (MSIS-29), worsening QoL, and increased disability (PDDS) all correlate with a reduction of predicted adherence behavior in PwMS. MSIS-29 had the strongest correlation with predicted adherence behavior as PDDS is weighted towards ambulation aspects of disease. Whether increased disability in PwMS is partially from non-adherence or whether greater disease impact results in less adherence is unclear. Suboptimal adherence behavior impacts long term costs of care in PwMS. Adherence profile might be critical in the choice of DMT and adherence might vary during the course of disease. Disclosure Mark Gudesblatt: nothing to disclose. Karl Wissemann: nothing to disclose. Barbara Bumstead: nothing to disclose. Myassar Zarif: nothing to disclose. Lori Fafard: nothing to disclose. Smitha Thotam: nothing to disclose. Marijean Buhse: nothing to disclose. Shenira Becker: nothing to disclose. Cynthia Sullivan: nothing to disclose. Jeff Wilken: nothing to disclose. Donald Morisky: nothing to disclose.

Pathology P841 Clostridium perfringens epsilon toxin induced blood brain barrier permeability: human relevance and molecular mechanisms J.R. Linden, C. Flores, S.V. Shetty, B. Zhao, K.R. Rumah, Y. Ma, T. Vartanian Weill Cornell Medical College, New York, NY, United States Background: The earliest event in formation of an MS lesion is postulated to be breakdown of the blood-brain barrier. Other labs and we have shown that epsilon toxin specifically targets the microvasculature of the central nervous system (CNS). However, three major questions remain; 1) can epsilon toxin cause BBB permeability in human model systems; 2) what are the molecular mechanisms involved in epsilon toxin induced BBB dysfunction; and 3) do the morphology and localization of BBB defects in epsilon toxin treated animals parallel the localization of BBB dysfunction in humans with MS? Goal: The goal of this study was to determine if epsilon toxin could cause BBB permeability in an in vitro model of the human BBB, to identify the molecular mechanism involved in epsilon

toxin induced barrier injury, and to define the neuroanatomic localization of barrier dysfunction in animals treated with epsilon toxin. Methods: Susceptibility of the human brain endothelial cell line HCMEC /d3 to epsilon toxin was evaluated in vitro. To evaluate the role of the myelin and lymphocyte (MAL) protein, the postulated epsilon toxin receptor, wild type mice (WT) and mice deficient in MAL (MAL-/-) were treated with epsilon toxin via tail vein injections. Saline treated mice were used as controls. BBB permeability was evaluated by exclusion of florescent dye from the CNS after toxin treatment and by histopathological examination using markers specific for tight junction proteins and components of the basal lamina. Results: HCMEC /d3 cells are susceptible to epsilon toxin induced cell death. HCMEC /d3 cell death was inhibited by pretreatment with ZVAD, indicating the cell death is caspase dependent. WT mice treated with epsilon toxin exhibited significantly more BBB permeability than control treated WT mice. In addition, WT mice treated with epsilon toxin also demonstrated abnormal tight junction staining compared to control treated WT mice. No differences in permeability or tight junction staining were observed in the epsilon toxin or control treated MAL-/- mice compared to the control WT mice. Conclusions: These results indicate that epsilon toxin is capable of causing BBB permeability in human brain microvasculature endothelial cells. In addition, this process is caspase dependent and requires expression of MAL. Current studies are underway to identify if MAL is involved in signaling the cell death pathway. Disclosure Nothing to disclose. P842 Early disease stage in MOG35-55-induced EAE is associated with induction of the extrinsic apoptotic pathway in neurons J.M. Orian Biochemistry, La Trobe University, Melbourne, VIC, Australia Understanding pathological processes driving axonal and neuronal loss in MS is essential for the generation of neuroprotective approaches. Recent evidence has highlighted the role of mitochondrial damage in irreversible axonal injury, but mechanisms underlying neuronal death are less clear. We investigated mechanisms of neuronal apoptosis from early disease stage in MOG35-55induced EAE in the NOD/Lt mice, which exhibits a relapsing-remitting clinical profile. The long term aim of this study is to map cumulative processes resulting in neuronal death. Neuronal populations were isolated by laser microdissection over a time course in MOG35-55-induced or vehicle-only groups. This was followed by expression profiling for markers of apoptosis. Concurrently, the inflammatory environment was evaluated (a) by laser dissection of grey matter regions and expression profiling for markers of inflammation and (b) by quantitative confocal microscopic evaluation of markers of inflammation, demyelination, glial reactivity and cellular stress. To confirm the relationship between inflammation and observed changes, experiments were repeated in the presence of the immunomodulatory drug FTY720. Profiling of markers of inflammation in grey matter demonstrated a highly elevated inflammatory environment from the pre-clinical


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Poster Session 2, 21(S11) stage, reaching maximum levels by the peak of the first attack. This was confirmed by quantitative confocal microscopic data showing significant neuronal stress. Profiling of markers of apoptosis revealed that both pro-and anti-apoptotic pathways were simultaneously upregulated in neurons at the peak of disease. The pro-apoptotic pathway that was upregulated was the extrinsic pathway, whilst markers of the intrinsic pathway showed no change relative to the vehicle-only group. Treatment with FTY720 almost completely abolished inflammation and was associated with reduction of both pro and anti-apoptotic markers. Neuronal counts showed no significant difference between vehicle-only and FTY720-treated groups showing that drug treatment is associated with preservation of neuronal numbers. Thus in early disease stage a pronounced inflammatory environment in grey matter is associated with neuronal stress and expression of the extrinsic apoptotic pathway in contrast with proposed mechanisms of axonal damage. Reduction of levels of inflammation with the immunomodulatory drug FTY720 appears to be neuroprotective. Disclosure Jacqueline Orian has received grants and travel funds from Novartis Pharmaceuticals Australia P843 Novel in vivo immunoglobulin G-driven model of multiple sclerosis K.R. Blauth, J. Soltys, A.M. Matschulat, A.M. Ritchie, J.L. Bennett, G.P. Owens Neurology, University of Colorado School of Medicine, Aurora, CO, United States Background: B cells drive MS immunopathology, but their precise role is subject to debate. Intrathecal IgG synthesis and oligoclonal bands (OCBs) are biochemical hallmarks of disease and are hypothesized to represent a pathologically relevant targeted B cell response. We have generated monoclonal recombinant antibodies (rAbs) that reproduce the in vivo specificities of the expanded MS cerebrospinal fluid (CSF) plasma cell clones producing OCBs. We have previously demonstrated that these rAbs mediate demyelination and astrocyte activation in an ex vivo spinal cord slice culture model. Their ability to drive demyelination in an intact animal model remains unexplored. Methods: To understand the potential roles of MS CSF antibodies in CNS tissue injury, we microinjected MS and neuroinflammatory control rAbs into the brains of wildtype and PLP-eGFP mice in the presence or absence of human complement. Mice were perfused with 4% paraformaldehyde (PFA) at days 1, 2, 3, 7, and 14, and the brains removed, cryoprotected, and sectioned for histologic analyses. Myelin integrity, oligodendroglial death, neuronal injury, astrocyte activation, immune cell influx, and complement activation were assayed by immunofluorescence microscopy. Results: Injection of MS rAbs, but not neuroinflammatory control rAbs, led to the focal demyelination (loss of myelin oligodendrocyte glycoprotein [MOG]) and astrocytic activation (enhanced glial fibrillary acidic protein [GFAP] immunoreactivity). Affected tissue showed denuded axons, Iba1+ macrophages/microglia containing MOG+ debris, and deposition of terminal complement

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complexes. Myelin loss increased over time and was dependent upon the MS rAb injected. Conclusions: Recombinant antibodies derived from MS CSF plasma cell clones cause CNS demyelinating lesions when injected with human complement into murine brains. The pathology bears hallmarks of human MS lesions including denuded axons, microglial activation, and astrogliosis. MS rAbs may vary in pathogenic capacity due to distinct antigenic and cellular targets. Intracerebral microinjection provides a novel IgG-driven model of MS pathology that may aid in our understanding of disease mechanisms and serve as a platform to test reparative therapies. Supported by the NEI, NINDS, and the Guthy-Jackson Charitable Foundation. Disclosure K.R. Blauth is an employee of UC Denver and has nothing to disclose. J. Soltys is a student in the UC Denver Medical Scientist Training Program and has nothing to disclose. A.M. Matschulat is an employee of UC Denver and has nothing to disclose. A.M. Ritchie is an employee of UC Denver and has nothing to disclose. J.L. Bennett is on the editorial board for Journal of Neuroophthalmology, Multiple Sclerosis, Neurology: Neuroimmunology & Neuroinflammation, holds patents for compositions and methods for the treatment of neuromyeltis optica, novel blocking monoclonal therapy for neuromyelitis optica, has consulted for EMD-Serono, Questcor Pharmaceuticals, Alnaylam Pharmaceuticals, Medimmune, Abbvie, Novartis Pharmaceuticals, Chugai Pharmaceuticals, Genzyme, Genentech, received research support from Questcor Pharmaceuticals, Novartis Pharmaceuticals, NIH, Guth-Jackson Foundation, holds stock in Apsara Therapeutics, receives license fee and royalty payments from Aquaporumab. G.P. Owens receives agency funding from the Pablove Foundation and the National Institutes of Health. He holds a patent on Aquaporumab. P844 Cortical atrophy predicts neuronal loss in MS: a post mortem study using unbiased sampling D. Carassiti1, B. Pakkenberg2, F. Scaravilli3, K. Schmierer3 1Blizard Institute, Queen Mary University, London, United Kingdom, 2Research Laboratory for Stereology and Neuroscience, Bispebjerg Hospital, Copenhagen University, Copenhagen, Denmark, 3Queen Mary University of London, Barts and The London School of Medicine, London, United Kingdom Indices of brain volume change are used to measure outcome in trials for people with MS (pwMS). Brain volume loss (BVL) is associated with accrual of disability. BVL may be due to a number of histological changes encompassing MS pathology. We investigated the extent of cortical volume loss (CVL), the presence of cortical demyelination and the loss of neurons using unbiased sampling techniques.


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Objective: To investigate association between CVL, demyelination and neuronal loss across the entire neocortex in MS. Formalin fixed brain hemispheres of nine pwMS (6 women, 3 men, age= 68±5 years, disease duration= 27±5 years) and seven controls (3 women, 4 men, age= 75±7 years) were studied. Lobar topography was marked on the surface before dissection into 1.1 cm-thick coronal slabs. Slabs were embedded for processing in paraffin and sections stained for Giemsa/40µm and myelin basic protein (MBP)/10µm. Neurons were identified on Giemsa-stained sections using a microscope equipped with a stage controlled by Stereo Investigator. Areas of interest (AOI) were outlined to include the entire cortex on each section; disectors were placed using systematic random sampling. The total number of neocortical neurons (TNNN) was calculated as the sum of NV x VREF in each slab, where NV= neurons counted/volume of disectors quantified and VREF(cortical volume)= AOI x slab thickness (t), multiplied by 2. The area of grey matter demyelination was measured on MBP immuno-stained sections adjacent to Giemsa sections. CVL across the whole brain was mild (18%; p= n.s.), but more pronounced in the motor cortex (38%, p=0.01) where neuronal loss was 57% (p=0.003). The TNNN was 14.9 ± 1.9bn in MS and 24.4 ± 2.4bn in controls (p= 0.007), equivalent to a neuronal loss of 38% overall. Neuronal density was significantly decreased by 26% (p=0.01), 25% (p=0.03), 32% (p< 0.0001) and 25% (p=0.003) in the frontal, motor, parietal/temporal and occipital cortices, respectively. Strong correlation was detected between TNNN and cortical volume (r= 0.85, p= 0.0082). No significant correlation was observed between cortical demyelination and (i) TNNN (r=-0.049, p=0.71) and (ii) neuronal density in each tissue block (r=0.15, p=0.26). Strong association between CVL and TNNN suggests cortical atrophy is a useful predictor of TNNN. Demyelination appears to have limited impact on TNNN in the chronic MS brain. The pronounced involvement of the motor cortex warrants further research. Disclosure Daniele Carassiti: nothing to disclose. Bente Pakkenberg: nothing to disclose. Francesco Scaravilli: nothing to disclose. Klaus Schmierer has received speaking honoraria from, and/or served on advisory boards for Novartis, Biogen, Teva, MerckSerono and Merck Inc, and has received support for attending an international conference from Genzyme. KS is a PI on studies sponsored by Novartis, Roche and Teva, has been supported by a Higher Education Funding Council for England Clinical Senior Lectureship and received support for research from Novartis, The Royal College of Radiologists, The National MS Society (US), The MS Society of Great Britain & Northern Ireland, and Barts Charity. P845 The influence of HLA-DRB1*15 on motor cortical neurodegeneration in multiple sclerosis R.L. Yates, M.M. Esiri, J. Palace, G.C. DeLuca Oxford University, Oxford, United Kingdom Background: Multiple Sclerosis (MS) is a common and heterogeneous inflammatory demyelinating disease of the central nervous

system. Evidence suggests that the HLA-DRB1 locus influences clinical outcome, but the influence of this allele on the neuropathology of the disease is relatively unexplored. We have previously shown that HLA-DRB1*15+ MS cases have more severe demyelination and inflammation in the motor cortex. The mechanisms underlying these associations, and their impact on local neurodegeneration, are unknown. Experimental animal work has suggested that fibrinogen extravasation from CNS vasculature activates resident microglia and leads to downstream axonal injury in EAE. The aim of this study was to investigate whether similar mechanisms are operative in human MS and are influenced by HLA-DRB1*15 status. Methods: A post-mortem cohort of pathologically confirmed age- and sex-matched MS (n= 47) and non-neurologic control (n=10) cases was used. Adjacent sections of motor cortex were stained for myelin (PLP), fibrinogen, microglia (Iba1 and CD68) and neurons (NeuN). The extent of BBB disruption and the influence of HLA-DRB1*15 status on relationships between BBB disruption, microglia inflammation and neuronal density was evaluated. Results: In our cohort, evidence of cortical fibrinogen deposition was common (occurring in 46/47 MS cases), being observed in significantly greater quantity in MS than in controls (p< 0.05). Cortical parenchymal fibrinogen negatively associated with neuronal density in HLA-DRB1*15+ MS cases only (15+: r=-0.563, p< 0.05; 15-: r=-0.324, p=0.114). Whilst no relationship between fibrinogen deposition and microglia inflammation was observed, HLA-DRB1*15 status influenced relationships between innate inflammation and degeneration. In HLA-DRB1*15- MS cases, microglia inflammation positively correlated with neuronal density (r=0.734, p< 0.001), a relationship not observed in HLADRB1*15+ MS cases (r=0.198, p=0.402). Conclusions: We provide unequivocal evidence for the deposition of fibrinogen in the MS motor cortex. Furthermore, we show that relationships between cortical parenchymal fibrinogen, microglia inflammation and neuronal density are related to genetic variation at the HLA-DRB1 locus. Future work aimed at discovering the mechanisms by which HLA-DRB1*15 influences the extent of neurodegeneration in MS will be necessary to identify therapeutic targets that may impact long-term outcome. Disclosure RL Yates: RLY is supported by a Medical Research Council PhD studentship (University of Oxford). MM Esiri: nothing to disclose J Palace: JP serves on the scientific advisory board for the Charcot Foundation and has performed advisory work for Biogen Idec, Merck Serono Ltd, Bayer Schering Pharma, Novartis Pharmaceuticals UK Ltd, Teva Pharmaceutical Industries Ltd, Gilenya, Ono Pharmaceutical Co Ltd, Primary i-research, Chugai Pharma Europe and CI Consulting and receives research support from the MS Society, QIDIS, Merck Serono Ltd and Bayer Schering Pharma, and has received conference expenses from Novartis and Merck Serono Ltd. GC DeLuca: GCD is supported a Goodger Scholarship (University of Oxford) and the NIHR Biomedical Research Centre, Oxford and has received honoraria and travel expenses as an invited speaker for Bayer Schering and travel expenses from Biogen Idec, Genzyme, and Novartis.


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Inflammation and tissue damage P846 Distinct energy utilization properties of human oligodendrocytes and oligodendrocyte progenitor cells (OPCs) as determinants of their susceptibility to injury in multiple sclerosis M. Rone1, Q.-L. Cui1, M. Bedard1, H. McBride1, J. Zhang2, V. Rao1, G. Almazan3, T. Kennedy1, S. Ludwin1, J. Antel1 1Montreal Neurological Institute, McGill University, 2Alan Edwards Centre for Research on Pain, 3Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada Objective: Determine the relationship between the bio-energetic properties of oligodendocytes (OLs) and their progenitors (OPCs) and their susceptibility to injury induced by metabolic stresses that mimic the multiple sclerosis (MS) lesion micro-environment. Background: MS lesions feature demyelination with limited remyelination. OLs are required for myelin maintenance while OPCs are considered essential for remyelination. A feature of “sub-lethally” injured OLs in experimental toxic demyelination models (Ludwin 1981), and in selected MS lesions, is withdrawal of their terminal processes ie dying back oligodendrogliopathy. Previous studies indicate relatively greater loss of OPCs versus OLs in acute MS Lesions (Cui et al 2013). Metabolic stresses in MS lesions reflect disturbed micro-circulation with associated ischemia and/or production of toxic metabolites that disturb mitochondrial energy metabolism (Lassmann 2003). Methods: We used OLs and OPCs (A2B5+ cells) isolated from adult human brain specimens to examine their injury responses (survival, process extension) to reduced trophic factor, low glucose, and hypoxia conditions and compared these with OL lineage cells derived from post-natal rat CNS. We examined the underlying bio-energetic properties of all these cell types using a Seahorse XF96 extracellular flux analyzer. Results: Human OLs grown under the above stress conditions for 48 hours showed only a marginal increase in % of TUNEL+ cells but a significant decrease in process area per cell. The latter response was more apparent in human OPCs. In contrast, rodent OLs and OPCs show significant cell death by 24 hours under these conditions. Seahorse results showed that both oxygen consumption rates (OCR) and extracellular acidification rate (ECAR), the measure of glycolytic metabolism, were lower in human compared to rodent OLs and OPCs. For both species, OPCs have increased OCR and ECAR compared to OLs. Human OLs and OPCs show relatively greater use of glycolytic pathways to produce ATP compared to the rodent cells. Conclusions: We link the relative resistance of human OL lineage cells to their distinct energy utilization properties that include reduced basal rates of oxidative and glycolytic metabolism with greater dependence on the glycolytic pathway compared to rat OPCs and OLs. Targeting the molecular mechanisms that contribute to such resistance provides a means to protect cell survival and enhance myelin repair prior to lethal injury. Disclosure Rone M: Nothing to disclose, Cui QL:Nothing to disclose, Bedard M:Nothing to disclose McBride H:Nothing to disclose,

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Zhang J: Nothing to disclose, Rao VTS:Nothing to disclose, Almazan G:Nothing to disclose, Kennedy TE:Nothing to disclose Ludwin SK: Nothing to disclose, Antel JP: Has received compensation for serving on advisory and/ or safety monitoring boards for Novartis, Biogen IDEC, EMD Serono, Sanofi Aventis, and MedDay Pharmaceuticals and as editor of the Americas of the Multiple Sclerosis Journal. Source of funding - Fellowship (MR) and operating grant (JA) from the MS Society of Canada P847 High HDL levels suppress blood brain barrier injury following the first demyelinating event K. Fellows1, T. Uher2, R.W. Browne3, B. Weinstock-Guttman4, D. Horakova2, H. Posova5, M. Vaneckova6, Z. Seidl6, J. Krasensky6, M. Tyblova2, E. Havrdova2, R. Zivadinov4, M. Ramanathan1,4 1Pharmaceutical Sciences, State University of New York, Buffalo, NY, United States, 2Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, Prague, Czech Republic, 3Department of Biotechnical and Clinical Laboratory Sciences, State University of New York, Buffalo, 4Department of Neurology, State University of New York, Buffalo, NY, United States, 5Institute of Immunology and Microbiology, 6Department of Radiology, Charles University in Prague, Prague, Czech Republic Objectives: To investigate the associations of serum cholesterol and apolipoproteins with measures of blood brain barrier (BBB) permeability and central nervous system (CNS) inflammation following the first clinical demyelinating event. Methods: This study included 154 patients (67% female, age: 29.5 ± SD 8.2 years) enrolled in a multi-center study of interferon beta-1a (IFN) treatment following the first demyelinating event suggestive of multiple sclerosis (MS). Blood and cerebrospinal fluid (CSF) were obtained at screening prior to corticosteroid or IFN treatment. A comprehensive serum lipid profile including cholesterol and apolipoprotein levels was obtained. Multiple surrogate markers of BBB breakdown and CNS immune activity in CSF were obtained including: total protein, albumin, IgG, IgM and CSF-restricted oligoclonal bands. The frequencies of CD80+, CD80+CD19+, CD4+, CCR5+ and CXCR3+ cell subsets in CSF were obtained by flow cytometry. Regression analyses were used to assess the associations between the lipid profile variables and CSF BBB breakdown and immune activity measures. Results: Higher serum high density lipoprotein cholesterol (HDLC) levels were associated with lower CSF total protein level, CSF albumin level, albumin quotient and CSF IgG level. Higher apolipoprotein A1, the characteristic apolipoprotein of HDL, was also associated with lower BBB permeability. CSF CD80+ and CD80+CD19+ cell frequencies were negatively associated with HDL-C levels. Conclusions: Higher serum HDL is associated with lower levels of BBB injury and decreased CD80+ cell extravasation into the CSF. HDL may potentially inhibit the initiation and/or maintenance of pathogenic BBB injury following the first demyelinating event.


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Disclosure Kelly Fellows has nothing to disclose. Tomas Uher has received speaker honoraria from Novartis and compensation for conference travel from Biogen Idec and Genzyme. Dr. Dana Horakova received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck Serono, Teva and Bayer Schering and financial support for research activities from Biogen Idec. Dr. Eva Havrdova received honoraria and consulting fees from Genzyme, Biogen Idec, Sanofi-Aventis, Merck Serono, Roche, Teva and Novartis for consulting services, speaking and serving on a scientific advisory boards Dr. Robert Zivadinov has received speaker honoraria and consultant fees from Teva Pharmaceuticals, Biogen Idec, Genzyme-Sanofi, Novartis, Claret Medical and EMD Serono. He has received research support from the National Multiple Sclerosis Society, Department of Defense, Biogen Idec, Teva Neuroscience, Teva Pharmaceuticals, EMD Serono, Genzyme-Sanofi, Claret Medical and Novartis. Dr. Michaela Tyblova has received compensation for conference travel from Biogen Idec, Teva, Novartis and Genzyme. She received financial support for research activities from Biogen Idec. Drs. Zdenek Seidl and Jan Krasensky received financial support for research activities from Biogen Idec. Dr. Helena Posova received speaker honoraria from Novartis. Dr. Manuela Vaneckova received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck Serono, and Teva, as well as support for research activities from Biogen Idec. Dr. Bianca Weinstock-Guttman received honoraria for serving in advisory boards and educational programs from Teva Pharmaceuticals, Biogen Idec, Novartis, Accorda EMD Serono, Pfizer, Novartis, Genzyme and Sanofi. She also received support for research activities from the National Institutes of Health, National Multiple Sclerosis Society, National Science Foundation, Department of Defense, EMD Serono, Biogen Idec, Teva Neuroscience, Cyberonics, Novartis, Acorda and the Jog for the Jake Foundation. Dr. Murali Ramanathan received research funding the National Multiple Sclerosis Society and the Department of Defense. He received compensation for serving as an Editor from the American Association of Pharmaceutical Scientists. These are unrelated to the research presented in this report. P848 Astrocyte injury and secondary demyelination induced by intracerebral injection of AQP4IgG and complement in mouse brain Y. Takai1, T. Misu2, Y. Abe3, K. Kurosawa1, T. Takahashi4, H. Kuroda1, I. Nakashima1, S. Nishiyama1, D. Sato2, M. Yasui3, K. Fujihara2, M. Aoki1 1Department of Neurology, Tohoku University School of Medicine, 2Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, 3Department of Pharmacology, Keio University School of Medicine, Tokyo, 4Department of Neurology, National Yonezawa Hospital, Yonezawa, Japan Background: Neuromyelitis optica (NMO) is an inflammatory disease of the CNS characterized by severe optic neuritis and longitudinally extended myelitis. After the discovery of anti-aquaporin4 (AQP4) antibody, there has been increasing evidence that

astrocyte injury is the primary pathology of NMO and demyelination occur secondarily. However, the pathomechanism of demyelination in NMO has not been well elucidated. Purpose: To examine whether demyelination is associated with astrocyte dysfunction or tissue inflammation in NMO. Material and methods: We created an NMO mouse model in which destruction of astrocytes and secondary demyelination are induced by directly injecting anti-mouseAQP4 monoclonal antibody and human complement into the mouse brain. We evaluated the expression of markers of astrocytes (AQP4/ Glial fibrillary acidic protein (GFAP)/ Excitatory amino-acid transporter 2 (EAAT2)/ connexin 43 (Cx43)), myelins (Myelin basic protein (MBP) and Kluver-Barrera´s stain), and inflammatory cells (CD3/ CD68) at lesion sites by immunohistochemistry. Results: In acute stage (day1), the areas with loss of AQP4 and GFAP also lacked EAAT2 and Cx43. These lesions did not have demyelination or inflammatory cell infiltration. In subacute stage (day4), demyelination was observed at the center of the lesion with astrocyte loss. In chronic stage (day 7), the demyelinating lesions were covered with reactive astrogliosis positive for GFAP. The size of demyelinating lesions correlated with the degree of infiltrated macrophages (n=14). Moreover, when recombinant C5a,a chemotactic factor, was injected with AQP4 antibody and complement, more macrophages were infiltrated and the areas of demyelination were enlarged (n=5). On the other hand, in the absence of inflammation, demyelination did not expand at the periphery of the lesions with loss of EAAT2 and Cx43 (n=18). Conclusion: Inflammation causing astrocyte injury rather than impaired astrocytic functions may be associated with the development of demyelination in NMO. Disclosure Dr. Takai has received Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan. Dr.Misu: nothing to disclose Dr.Abe: nothing to disclose Dr.Kurosawa: nothing to disclose Dr.Takahashi: nothing to disclose Dr.Kuroda: nothing to disclose Dr.Nakashima: nothing to disclose Dr.Nishiyama: nothing to disclose Dr.Sato: nothing to disclose Dr.Yasui: nothing to disclose Dr.Fujihara: nothing to disclose Dr.Aoki: nothing to disclose P849 Increased production of pro-inflammatory cytokines and chemokines in the cerebral leptomeninges of MS cases with more severe cortical pathology C. Cruciani1,2,3, E. Browne1, R. Schalks1, L. Fuentes1, R. James1, R. Magliozzi1,2,3, A. Bradley1, O. Howell1,4, M. Calabrese2, R. Reynolds1 1Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom, 2Dept Neurological & Movement Sciences, University Hospital Verona, Verona, 3Dept Cell Biology & Neuroscience, Istituto Superiore di Sanita,


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Poster Session 2, 21(S11) Rome, Italy, 4Neurology & Molecular Neuroscience, Insitute of Life Science, Swansea University, Swansea, United Kingdom Background: Imaging and post-mortem tissue studies show that the accumulation of cortical pathology in MS is closely associated with increasing clinical progression. Previous work in this laboratory has shown that the presence of tertiary lymphoid organ-like (TLO) immune cell infiltrates in the cerebral leptomeninges is associated with a greater extent of cortical demyelination, increased neuronal loss and microglial activation and exacerbated clinical progression. Objectives: It is suggested that cytokines/chemokines produced in the meninges can diffuse into the underlying cortical grey matter, through a damaged glia limitans, to cause both direct and indirect cytotoxicity. We aimed to identify the nature of these inflammatory mediators produced in the meninges. Methods: Meningeal tissues were dissected from snap frozen cortical tissue blocks obtained from MS cases exhibiting high levels of meningeal infiltrates and TLO-like structures (F+SPMS), cases with only diffuse meningeal inflammation (F-SPMS) and nonneurological controls (n=10 for each group). RNA was extracted and analysed using PCR cytokine/chemokine arrays and individual QPCR. Results: Gene expression for the proinflammatory cytokines tumour necrosis factor (TNF), interferon-gamma (IFNg) and lymphotoxin-alpha (LTa) was significantly elevated in the MS meninges, with TNF and IFNg highest in F+SPMS cases. Expression levels of the chemokines CXCL9 and CXCL13 were strikingly elevated only in the MS meninges from F+SPMS cases. Protein analysis of the post-mortem CSF revealed significantly increased levels of TNF and CXCL13 only in the F+SPMS cases. Immunohistochemistry on sections from the same cases used for RNA extraction demonstrated the presence of cells expressing TNF and IFNg in the meningeal infiltrates with a monocyte/macrophage and lymphocytic morphology respectively. Cells expressing CXCR3 and CXCR5, the receptors for CXCL9 and CXCL13 respectively, were also present in the lymphocytic infiltrates. Conclusions: Our data suggests that the cortical grey matter in the MS brain is bathed in a pro-inflammatory milieu, the extent of which is determined by the level of organisation of immune cell infiltrates in the meninges. The presence of lymphoidogenic chemokines indicates an environment that will support the development and maintenance of TLOs in the F+SPMS cases and identifies some novel therapeutic targets for inhibiting progression. Disclosure Carolina Cruciani: nothing to disclose. Eleanor Browne: nothing to disclose. Renee Schalks: nothing to disclose. Laura Fuentes: nothing to disclose. Rachel James: nothing to disclose. Roberta Magliozzi: nothing to disclose. Amy Bradle: nothing to disclose. Owain Howell: nothing to disclose. R Reynolds: has received honoraria for speaking from Novartis, Biogen Idec and EMD Serono. M Calabrese: has received consultancy fees from Biogen Idec, Genzyme, Novartis and Teva.

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P850 Elevated levels of S100B impair oligodendrogenesis G. Santos1, A. Barateiro1, D. Brites1,2, A. Fernandes1,2 1Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 2Department of Biochemistry and Human Biology, Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal We recently detected high S100B levels in the cerebrospinal fluid, serum and brain samples of Multiple Sclerosis patients, while its inhibition in an ex vivo demyelination model prevented demyelination and glia reactivity. Though S100B is increasingly expressed by oligodendrocyte precursor cells (OPC) and essential for oligodendrocytes (OL) development, high levels released upon brain injury may be toxic. Here, we assessed the role of S100B on oligodendrogenesis. Primary OPC were incubated with 10 and 1,000 nM S100B, to mimic the physiological or toxic effects of S100B, for 24 h just after isolation or in the first 24 h of differentiation. After 7 days in vitro cells were evaluated for OL differentiation/maturation and expression of differentiation-related Olig1/Olig2/MBP. To study the role of S100B on OPC migration, cells incubated with S100B or S100B plus FGF were allowed to migrate to 20 ng/mL FGF for 24h for chemotaxis or chemokinesis, respectively, using the Boyden chamber. Exposure of OPC to 1,000 nM of S100B during proliferation significantly reduced MBP+ cells (0.7-fold, P< 0.05) increasing NG2+ cells (1.6-fold, P< 0.05), while treatment during initial differentiation induced a less pronounced effect (MBP+, 0.8-fold). OL morphologic maturation can be scored as: 1) MBP+ cells poorly branched, 2) cells with complex branched processes and 3) cells with complex branched processes that partially form membranes. Exposure to 1,000 nM S100B during proliferation reduced maturation by increasing the number of OL in stage 1 (1.6-fold, P< 0.05) and decreasing in stages 2 and 3 (0.9-fold and 0.4-fold, respectively). This effect was enhanced during differentiation (1.9-fold for stage 1, p< 0.01; 0.8-fold for stage 2 and 0.1-fold for stage 3, p< 0.05). Treatment with 10 nM S100B increased Olig1 (1.7-fold, p< 0.01), while 1,000 nM S100B reduced Olig1 and MBP expression (0.6-fold and 0.5-fold, p< 0.05 and p< 0.01) and increased Olig2 (1.5-fold, p< 0.05), corroborating the reduced OPC differentiation upon treatment with high S100B levels. In addition, 1,000 nM S100B markedly impaired chemotaxis (0.5fold, p< 0.01) and chemokinesis (0.4-fold, p< 0.001). These results points to a negative role of elevated S100B in oligodendrogenesis, suggesting that S100 modulation may be a good therapeutic strategy to reduce damage in inflammatory-related myelin disorders. Supported by Medal of Honor L’Oréal for Women in Science and Innovation grant Ordem dos Farmacêuticos to AF. Disclosure G Santos, A Barateiro, D Brites and A Fernandes: nothing to disclose.

P851 Increased cortical lesion load and CSF cytokines in oligoclonal band positive MS patients


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G. Farina1,2, R. Magliozzi1,3, A. Gajofatto1, M. Zanoni1, O. Howell4, M.D. Benedetti1, R. Reynolds5, S. Monaco1, M. Calabrese1 1Neurology Section, Dept. of Neurological and Movement Sciences, University of Verona, Verona, 2Unit of Neurology, Dept. of Clinical and Experimental Medicine, University of Sassari, Sassari, 3Istituto Superiore di Sanità, Cell Biology and Neuroscience, Rome, Italy, 4Swansea University, Swansea, 5Faculty of Medicine, Imperial College London, Division of Brain Sciences, London, United Kingdom

A. Gajofatto: nothing to disclose. M. Zanoni: nothing to disclose. O. Howell: nothing to disclose. M. D. Benedetti: nothing to disclose. R. Reynolds has received honoraria for lectures from Novartis, Biogen Idec and EMS Serono. S. Monaco: nothing to disclose. M. Calabrese has received consulting and/or lecture fees and/or travel grants from Bayer Schering, Biogen Idec, Genzyme, Novartis and Teva.

Background: Although IgG oligoclonal bands (OCB) are a wellrecognized marker of Multiple Sclerosis (MS) and of worse clinical outcome, their pathogenesis and relationship with cortical lesions (CLs) have not been clarified yet. Inflammatory infiltrates and lymphoid-like structures consistently observed in the meninges above extensive subpial demyelination, in a subgroup of MS patients, represents the most likely source of both OCB and of soluble factors having a pathogenic role in cortical demyelination. Objective: We aimed at evaluating difference in number of CLs and cytokine expression in CSF between OCB+ and OCB- MS patients, in order to find a closer connection between biomarkers and cortical pathology and to define a possible role of meningeal inflammation in causing both processes. Methods: We enrolled 40 consecutive OCB-negative patients and 50 OCB-positive age-, sex- and disease duration-matched patients and 6 controls without inflammatory neurological conditions. The number of CLs was evaluated by 2 experienced observers blinded to clinical data, on Double Inversion Recovery imaging. 56 patients underwent 1.5T MRI while 34 underwent a 3T MRI. The cytokine expression in the CSF was evaluated in 13 patients and in 6 controls by using the BioPlex protein-assay platform. Results: CL number in OCB+ patients was almost double (mean=4.50±4.55) that in OCB- patients (mean= 2.03±2.52; p=0.003), whereas no difference in the number of white matter lesions (WMLs) was observed. These data were confirmed both at 1.5T and at 3T MRI. OCB+ patients group had significantly higher levels of IFNα-2, IFN-β, IFN-γ, IFN-λ1, IFN-λ2, IL-10, IL-19, IL-22, IL-27, BAFF, sCD30, sIL6α, gp130, sTNFR1, sTNFR2 compared to the OCB- patient group who had a mean overexpression of IL-8, IL-34 and TNFSF14 compared to the OCB+ group. Moreover, OCB+ patients showed a higher disability (median EDSS=2.75) compared to OCB- (median EDSS=1.5, p< 0.001). Conclusions: OCB+ patients showed almost double CLs than OCB- patients despite no difference in WMLs. Difference in cytokine expression between the two groups suggest higher levels of B-lymphocyte-linked, antiviral, and innate immunity molecules in the OCB+ group. These data strongly support the crucial role played by B-lymphocytes in the pathogenesis of CLs and OCB. The combination of CSF data with cortical MRI activity might be helpful in defining the individual pathological profile and in choosing the most appropriate treatment.

P852 Reduced tissue perfusion in MS lesions evident at time of acute inflammatory activity Y. Kang, E. Monohan, A. Kuceyeski, S. Vallabhajosula, P.D. Mozley, J. Babich, N. Nealon, J. Perumal, Y. Wang, T. Vartanian, S.A. Gauthier Weill Cornell Medical College, New York, NY, United States

Disclosure G. Farina has received travel grants from Biogen Idec, Genzyme, Novartis and Teva. R. Magliozzi: nothing to disclose.

Background: Pathological studies of multiple sclerosis (MS) lesions have suggested vascular damage occurs as a result of the inflammatory event, however we lack an understanding of the onset and extent of this damage within lesions. Objectives: The objective of this study is to utilize [11C]PK11195 PET, which is known to bind to activated microglia and macrophages, to study tissue perfusion and innate immune activity in acute gadolinium enhancing lesions as compared to older lesions. Methods: Fourteen MS patients (age= 39±12.4, EDSS=3±1.9, disease duration 12±9.1 years) and 5 age-matched healthy controls (HC) had a 3T MRI brain and dynamic [11C]-PK11195 PET imaging. White matter (WM) MRI segmentation and a semi-automated T2 lesion algorithm created normal appearing white matter (NAWM) and WM T2 lesion masks. A subset of gadolinium positive (Gd+, n= 16) and gadolinium negative (Gd-, n=31) lesions were identified. Time activity curves (TAC), representing tissue uptake and clearance of [11C]-PK11195, were extracted from WM and lesions. Tissue influx rate (K1) and distribution volume (Vt), related to binding of [11C]-PK11195, were calculated. For lesions, K1 and Vt values were calculated as a ratio to the individual patient’s NAWM. Results: WM [11C]-PK11195 tissue kinetics, as measured by TAC, revealed a small difference between WM of HC and NAWM of patients (p=0.018), however the K1 and Vt values were similar (p=0.528, p=0.299, respectively). The TAC’s for NAWM and WM lesion masks revealed a more apparent deviation in tissue kinetics (p=0.002), with a lower K1 within lesions as a whole (0.24) as compared to NAWM (0.37), p=0.046, yet Vt was similar (p= 0.982). Both individual lesion subtypes demonstrate lower tissue influx compared to NAWM, however K1_ratio for Gd+ (0.69±0.25) was higher than and Gd- (0.54±0.19), p=0.021. Vt_ ratio was higher in Gd+ lesions (1.22± 0.24) as compared to Gd(1.00±0.12) lesions, p=0.003. Conclusions: Tissue influx rate, a parameter directly dependent on vascular perfusion, is impaired within acute MS lesions as compared to NAWM. The change in vascular perfusion persists from acute Gd+ lesions to chronic Gd- lesions. We postulate that the microenvironment within acute inflammatory demyelinating lesions results in a permanently altered microvasculature.


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Poster Session 2, 21(S11) Importantly, this damage, which occurs at the early inflammatory stage, as measured by Gd+ positivity and high [11C]PK11195 binding, may influence tissue recovery. Disclosure Yeona Kang has nothing to disclose. Elizabeth Monohan has nothing to disclose. Amy Kuceyeski has nothing to disclose. Shankar Vallabhajosula has nothing to disclose. Paul D. Mozley has nothing to disclose. John Babich has nothing to disclose. Nancy Nealon has nothing to disclose. Jai Perumal, MD is a speaker for Biogen Idec, Teva Neuroscience, Genzyme, and Acorda and has consulted for Biogen Idec and Genzyme. Yi Wang has nothing to disclose. Timothy Vartanian is a speaker for Teva Neuroscience, has received honoraria for advising Genzyme, and has received grant support from the National Multiple Sclerosis Society, Biogen Idec, and Mallinckrodt Pharmaceuticals. Susan A. Gauthier has received honoraria for advising Genzyme and Teva Neuroscience and has received grant support from the National Multiple Sclerosis Society, Biogen Idec, Novartis Pharmaceuticals, Mallinckrodt Pharmaceuticals, Genzyme, and EMD Serono. P853 The role of temperature deregulation in neurodegeneration in multiple sclerosis A.G. Barsukova-Bell1, D. Bourdette1,2 1Neurology, Oregon Health & Science University, 2Neurology Service VA Medical Center, Portland, OR, United States Background: Iinflammation and oxidative stress are recognized as critical pathological components leading to neuronal death in multiple sclerosis (MS) (Thanan R et al., 2014; Fakhoury M. 2015). The brain temperature (T) imbalance is also recognized in MS: a proton magnetic resonance spectroscopy showed a significantly elevated T in the active MS lesions (Pietroboni A et al., 2013). Our study in primary neurons shows that inflammatory cytokines and oxidative stress alter intra-neuronal T. The main hypothesis of this exploratory research is that inflammatory cytokines and oxidative stress result in a significant sustained neuronal T change leading to neuronal injury. Objective: To determine intra-neuronal T response to inflammatory cytokines and oxidative stress in individual adult neurons and their axons in vitro. Methods: Using temperature-reporting nanocrystals (Han et al., 2009) and real-time imaging we investigated T response in primary neurons from adult C57BL/6 mice. Nanocrystals were loaded into neurons and reported T within the cytoplasm. Imaging bugger T was set at 37C. Results: Significant adult neuronal loss occurred in response to 38C and 39C at 120 hours. Intra-neuronal T was only transiently elevated in response to a physiologic cytoplasmic Ca2+ increase triggered by ATP. Intra-neuronal T showed a sustained increase to 38.5C in response to TNF-α. Intra-neuronal T showed a sustained decrease to 35.8 C in response to interferon-γ and to hydrogen peroxide to 35.1 C.

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Conclusions: Sustained T elevation of 1-2C in adult neurons leads to their loss. Neurons can have independent T level from the extracellular environment T during physiological activity or in response to stress. Oxidative stress and inflammatory cytokines implicated in MS lead to a sustained intra-neuronal temperature change. Understanding intra-neuronal temperature alterations in response to stress and finding molecular targets to prevent pathologic temperature can provide powerful neuroprotective tools for MS. Support: Race to Erase MS Foundation top A.B.; grants from the National Institutes of Health to D.B; the St. Laurent Foundation of Vancouver Disclosure Anna Barsukova-Bell: nothing to disclose Dennis Bourdette: nothing to disclose

Experimental models P854 RNA-induced silencing complex (RISC) determined miRNA abnormalities in autoimmune demyelination P. Lewkowicz, H. Cwiklinska, M. Mycko, M. Cichalewska, M. Domowicz, N. Lewkowicz, A. Jurewicz, K. Selmaj Department of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, Lodz, Poland Mammalian micro RNAs (miRNAs) associate with Argonaute (Ago) and glycine-tryptophan (GW182) proteins and form RNAinduced silencing complex (RISC) that interacts with partially complementary sequences in the 3’ untranslated region (UTR) of specific target mRNA leading to degradation of mRNA or inhibition of its translation. Thus, RISC represents a critical checkpoint in regulation and bioavailability of miRNA. Recent studies have suggested dysregulation of miRNAs in experimental autoimmune encephalomyelitis (EAE), and multiple sclerosis (MS). However, the function of RISC proteins in EAE and MS is largely unknown. We have examined the expression of Ago, GW182 and fragile X mental retardation-related protein 1 (FXR1) in the CNS tissue, oligodendrocytes (OLs), brain-infiltrating T lymphocytes and CD3+ splenocytes (SCs) of EAE mice, and found that global RISC protein levels were significantly dysregulated. Specifically, Ago2 and FXR1 levels were decreased in OLs and brain-infiltrating T cells. Accordingly, assemble of Ago2/GW182/FXR1 complexes in EAE brain tissues was disturbed as confirmed by immunoprecipitation experiments. Parallel to disturbed RISC assembly in OLs, we have found dysregulation of miRNA synthesis and down regulation of miRNAs essential for differentiation and survival of OLs and myelin synthesis. In infiltrating T cells aberrant RISC formation contributed to miRNA dependent proinflammatory Th cell polarization. In CD3+ SCs, contrary to OLs and brain infiltrating T cells, we have found increased expression of both Ago2 and FXR1 in EAE compared to non-immunized mice. Thus, our results demonstrate gradient expression of miRNA between primarily activated T cells in periphery and polarized CNS-infiltrating T cells. These results suggest that in polarized autoreactive effector T cells miRNA synthesis is inhibited in co-operation with dysregulated RISC assembly allowing them to maintain highly specific proinflammatory program. Thus, our findings explain the mechanism leading to miRNA dysregulation in EAE/MS and contribute significantly to better understanding of pathogenesis of EAE and MS.


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Disclosure

Disclosure

Conflict of interest: The authors: Przemysław Lewkowicz, Hanna Cwiklińska, Marcin P. Mycko, Maria Cichalewska, Małgorzata Domowicz, Natalia Lewkowicz, Anna Jurewicz and Krzysztof W. Selmaj declare no competing financial interests. This work was supported by grants from the National Science Centre: 2014/13/B/NZ6/00235 to P.L., 2013/11/B/NZ6/02055 to H.C., 2011/01/N/NZ6/01849 to M.C., UMO-2012/04/A/ NZ6/00423 to K.S., and National Center for Research and Development ERA.NET-RUS/04/2012 to M.M.

Rachel James: work funded by the MS Society UK Eleanor Browne: nothing to disclose Nicholas Mazarakis: nothing to disclose Richard Reynolds: have received honoraria for lectures for Biogen Idec, Novartis and EMD Serono

P855 Chronic meningeal production of TNF and interferon-γ can drive cortical grey matter pathology R.E. James, E. Browne, N. Mazarakis, R. Reynolds Medicine, Division of Brain Sciences, Imperial College London, London, United Kingdom Background: The secondary progressive phase of multiple sclerosis is characterised by accumulating axonal loss and cortical grey matter (GM) pathology. The presence of tertiary lymphoidlike structures in the meninges is associated with greater cortical demyelination, shorter disease duration and neuronal loss that is greatest in superficial layers. Analysis of RNA extracted from meninges of MS cases with lymphoid-like infiltrates has demonstrated increased gene expression for major pro-inflammatory cytokines, tumour necrosis factor (TNF) and interferon-γ (IFNγ). Objectives: We aimed to test the hypothesis that the cytokines, TNF and IFNγ, produced in the meningeal compartment can diffuse to underlying GM and drive pathology. Methods: We have established a new experimental model using a HIV-1 based lentiviral transfer vector stereotactically injected into the sagittal sulcus (SS) of DA rats to deliver continuous transgene expression for chronic periods. A bicistronic construct was designed consisting of both human TNF and IFNγ genes linked by a T2A sequence, allowing cleavage through ribosomal skipping during translation resulting in equimolar protein production. Results: The bicistronic construct had a VSV-g envelope that produced efficient transduction of meningeal cells resulting in cytokine expression for up to 3 months confirmed by ELISA, PCR and western blot. Injection of the vector into the SS induced the formation of large immune cell aggregates by 7dpi, which remained at 3 months, containing CD4+ and CD8+ T-cells, CD79a+ B-cells and Iba1+ macrophages. These aggregates extended the length of the SS and across the surface of the cortex, many millimetres from the injection site. Subpial demyelination accompanied by microglial activation was observed underlying the cellular aggregates. TNF can act through TNFR1 receptors to initiate cell death by activating necroptosis pathways. RT-PCR on cortical RNA from bicistronic injected animals at 7 dpi showed an increase in expression of TNFR1 and downstream necroptotic genes RIP3 and MLKL compared to eGFP vector control animals. RIP3+ and MLKL+ immunopositive cells with the morphology of neurons were present in bicistronic injected animals. Conclusions: Our results suggest that TNF and IFNγ are potent inducers of meningeal inflammation and can activate TNF signalling pathways in cortical cells leading to neuronal death and subpial demyelination and thus may contribute to clinical progression in MS.

P856 Interleukin 5 mediates disease protection associated with parasite infestation in EAE S. Hodgkinson1,2, G. Tran2,3, L. Dent4, C. Robinson2,3, P. Wilcox5, B.M. Hall3 1University of New South Wales, Strathfield, 2Liverpool Hospital, Liverpool, 3Medicine, University of New South Wales, Kensington, 4University of Adelaide, Adelaide, 5University of Sydney, Sydney, NSW, Australia MS patients with eosinophilia from parasitic infestation have no or few relapses of MS and reduced new lesions on MRI and this protection is eliminated if parasites are eradicated. Parasitic infestations induce Th2 responses that produce IL-4, IL-5 and IL-13. Eosinophilia is induced by IL-5. We have examined the induction of antigen specific T regulatory cells by Th2 cytokines, and have shown that the antigen specific CD4+CD25+Treg activated by IL-4, express specific receptor for IL-5 (IL-5Ra) and can be further activated by IL-5. We hypothesized that the Th2 response produces excess IL-5 that results in eosinophilia and may promote expansion of antigen specific IL-4 activated Treg. We tested if the beneficial effects of parasitic infection on EAE induced by MBP/CFA in Lewis rats were due to induction of Th2 responses; specifically IL-5. Nippostrongylus brasiliensis infestation delayed onset and reduced the severity of EAE in Lewis rats with peak disease at 2.6+0.8 at 17d vs control EAE peak of 3.3+ 0.7 at 16d. Parasite infested has less severe EAE at 11-16d (p< 0.05). Blocked IL-5 with an anti-IL-5 monoclonal antibody ablated the beneficial effect of parasitic infestation as did depletion of CD25+ cells and blocking IL-4. Parasite infested animals with EAE had more CD4+CD25+Treg than controls with EAE and those from parasite infested animal expressed more IL-5Ra and IRF4, than controls, consistent with induction of Ts2 or Th2-like Treg. These results suggest that cytokines from Th2 cells activated by the parasite, promote induction of antigen specific Treg and that IL-5 is a key mediator of the protective effects of parasites. These results are consistent with IL-4 and antigen activating antigen specific naïve CD4+CD25+FOXP3+Treg to Ts2 cells that express IL-Ra and are expanded further by IL-5 produced by the anti-parasitic Th2 response. This suggests that IL-5 may be a potential treatment to induce Treg and control MS. Disclosure Suzanne J. Hodgkinson: nothing to disclose Giang T. Tran: nothing to disclose Lindsey Dent: nothing to disclose Catherine M Robinson: nothing to disclose Paul L Wilcox: nothing to disclose Bruce M Hall: nothing to disclose


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Poster Session 2, 21(S11) P857 The development of a novel demyelination zebrafish model to be used for high-throughput drug screening of pro-myelinating compounds in multiple sclerosis A. McGown, B. Sharrack, T. Ramesh Neuroscience, University of Sheffield, Sheffield, United Kingdom Background: Current animal models of multiple sclerosis (MS) focus on inducing neuroinflammation or causing focal demyelination. Lysolecithin is a commonly used toxin which induces focal demyelination in rodent models. However, such models are expensive and have low throughput in therapeutic testing. There is a need to identify new models which have high throughput to improve therapeutic discovery in MS. Zebrafish are emerging as an excellent tool to help developing a better understanding of various neurodegenerative disorders. The rapid development, characterised central nervous system, transgenic models and large numbers of offspring lend themselves well to drug discovery. Zebrafish models currently exist for many neurodegenerative disorders such as Parkinson’s disease and amyotrophic lateral sclerosis. Objective: Here we describe the development of a rapid demyelination/remyelination zebrafish model, which has the potential to be used in the high-throughput screening of therapeutic compounds which promote remyelination. Methods: Oligodendrocytes are the key myelinating cell in the zebrafish central nervous system. Demyelination was induced by injection of a lysolecithin solution directly into the CNS of the zebrafish at day 4. Results: Oligodendrocyte cell processes were vastly reduced 24 hours after toxin exposure and continue to be significantly reduced for 4 days. This was not due to oligodendrocyte toxicity as no decrease in cell body number was seen after lysolecithin treatment. Myelination was significant reduced in the optic tectum 48 hours post injection. Neuroinflammation, a key pathogenic pathway in MS, was detectable 3 days post injection, with a significant increase in leukocytes seen within the white matter tracts. Neuroinflammation is a continuing process that continues throughout the remyelination process. Recovery of oligodendrocyte processes was seen by 4 days post injection, and myelin returned to control levels by 6 days post injection highlighting the usefulness of this model as a rapid tool for investigating the pathways involved in demyelination/remyelination. Conclusion: We describe a robust, rapid and reproducible model of demyelination and remyelination that models two of the key pathological characteristics of MS (neuroinflammation and demyelination). Future work on this model is underway to optimise and validate it as a screen tool for assesing pro myelinating therapeutic compounds.

1Department

of Neurology, Medical University of Lodz, Lodz, Institute Polish Academy of Science, Warsaw, Poland, 3Alexander Flemming Institute, Athens, Greece 2Nencki

Heat shock protein (HSP) are conservative proteins involved in proper protein folding and stress-induced cell responses. It was also shown that one of HSP, HSP70, might be involved in antigen presentation and is highly expressed in MS lesion. However its role in demyelination is largely unknown. We assessed the role of HSP70 overexpression in oligodendrocytes in myelin-directed responses in vivo in transgenic mice with enhanced HSP70 expression in oligodendrocytes (Hsp70Tg). Hsp70Tg were sensitized for EAE with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55. EAE course was assessed by clinical score and CNS inflammation by histopathological staining. Autoimmune response to MOG peptide was assessed by lymphocyte proliferation and cytokine production and oligodendrocytes susceptibility to pro-inflammatory cytokine was assessed by annexin and PI staining and flow cytometry analysis. The remyelination processes were assessed with toluidin blue staining after demyelination induced with lysolecithine (LL) in thoracic spinal. The Hsp70Tg mice showed enhance EAE symptoms in compare to control mice (2,5 v. 1,5, respectively). Similarly, in LL model we observed enhanced tissue damaged and almost complete lack of remyelination in Hsp70Tg mice compared to control mice (remyelination rank: 2,5 v. 7,8, respectively). The lymphocytes isolated from EAE Hsp70Tg mice showed enhance response to myelin antigen in compare to control mice (SI: 5,6 v. 2,2, respectively). The hsp70 overexpression in oligodendrocytes enhanced inflammatory responses and EAE symptoms and inhibited remyelination in LL model of demyelination. Disclosure Anna Jurewicz: nothing to disclose, Grazyna Galazka: nothing to disclose, Malgorzta Zawadzka: nothing to disclose, Malgorzata Domowicz: nothing to disclose, Alicja Ewiak: nothing to disclose, George Kollias: nothing to disclose, Krzysztof Selmaj: nothing to disclose P859 Effects of in vivo chronic fingolimod on impaired presynaptic functions in experimental autoimmune encephalomyelitis EAE mice at different stages of disease A. Pittaluga1,2, T. Bonfiglio1, S. Di Prisco1, E. Merega1, M. Vergassola1 1DIFAR, School of Medical and Pharmaceutical Sciences, University of Genova, 2Centre of Excellence for Biomedical Research, University of Genova, Genova, Italy

Disclosure Alexander McGown: Nothing to disclose

P858 HSP70 overexpression in oligodendrocytes exacerbate demyelination and inhibits remyelination A. Jurewicz1, G. Galazka1, M. Zawadzka2, M. Domowicz1, A. Ewiak-Paszynska1, G. Kollias3, K. Selmaj1

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Background: It has been recently demonstrated that glutamate exocytosis was reduced in the cortex of mice suffering from the experimental autoimmune encephalomyelitis (EAE) starting from 13 days post immunization (d.p.i.) and did not recover during disease progression, while increased release was detected in spinal cord at the acute stage (21 d.p.i.) of the disease. Reduced glutamate exocytosis in the cortex and increased release in spinal cord could be relevant to the onset of early cognitive impairments and


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acute neuroinflammation in MS, respectively. In these mice, in the hippocampus, glutamate release from nerve terminals (synaptosomes) was unmodified until 35 d.p.i., after which it dramatically declined. Gamma-aminobutyric acid (GABA) outflow was unmodified from both cortical and hippocampal synaptosomes, but it was significantly increased in spinal cord synaptosomes. Objective: To study whether in vivo administration of fingolimod in EAE mice could restore glutamate and GABA exocytosis to physiological level in these CNS regions. Methods: Control (non-immunized) and EAE mice were administered fingolimod (0.3-0.03 mg/Kg) through the drinking water starting from 7 d.p.i. for 14 days. Results: In fingolimod (0.3 mg/Kg)-treated EAE animals, the onset of clinical signs was delayed and the maximal score was halved when compared to untreated EAE mice. Fingolimod (0.3 mg/Kg) almost completely restored glutamate exocytosis from EAE mouse cortical and spinal cord synaptosomes. Spinal cord GABA exocytosis also recovered to physiological level. In vivo chronic (14 days) lower dose (0.03 mg/Kg) of fingolimod significantly recovered glutamate exocytosis from cortical synaptosomes in EAE mice at 21 d.p.i., but failed to affect glutamate exocytosis in spinal cord synaptosome. Finally, in chronic (14 days) administered fingolimod (0.3 mg/Kg) mice (from 21 d.p.i. to 35 d.p.i), a significant reduction of the clinical score was observed starting from 23 d.p.i. until 36 d.p.i. that was paralleled by an almost complete restoration of glutamate exocytosis from both cortical and hippocampal, but not in spinal cord, synaptosomes. Conclusion: It is concluded that fingolimod administration has beneficial effects on central glutamate homeostasis in the CNS of EAE mice and therefore could represent a useful therapeutics to control cognitive impairments and mood disorders that often are observed in MS patients.

range of anti-inflammatory actions, able to improve experimental autoimmune encephalomyelitis (EAE), the animal model of MS. Mesenchymal stem cells (MSC) have important immunoregulatory and regenerative properties shown in various disease models. Both CBD and MSC are potential therapies for MS. Neither CBD nor MSC, have been tested in the passive variety of EAE. Objectives: To compare CBD and MSC efficacy as therapies for adoptively transferred EAE. Methods: Mouse MSC (mMSC) were isolated from bone marrow of C57BL/6J mice, expanded and characterized. Encephalitogenic T cells were obtained from lymph nodes and spleens of C57BL/6J mice inoculated with MOG35-55, primed with MOG35-55 and IL-12 and transferred intraperitoneally (i.p) to naïve mice. Three groups of 5-7 transferred mice were established: EAE+vehicle; EAE+CBD 50mg/kg/d; and EAE+0.5 x106 mMSC (intravenously twice a week for 3 weeks). Animals were examined for neurological signs up to day 28. MRI (7T) was performed after 15 days. Images were acquired using T1-, T2- and T2*-weighted sequences. Results: Compared to control EAE mice, CBD induced a highly significant suppression of clinical signs without untoward effects. MMSC treatment had a mild but significant effectiveness in clinical evolution. On MRI, control mice had inflammatory brain lesions that were less frequent in mMSC treated mice and absent in the CBD treated group. Conclusions: Adoptively induced EAE allows for a better delineation of the effector role of encephalitogenic cells, on the bloodbrain barrier and the CNS, avoiding possible interferences that inflamed lymph nodes and spleen might have on MSC circulation. MMSC effectively suppressed EAE on clinical and imaging grounds, but to a lesser extent compared to the CBD treated group. CBD might be a suitable agent for MS considering its efficacy and the lack of psychoactive effects.

Disclosure

Disclosure

Finding Source: This study was funded by Novartis CO28-39000006436) Anna Pittaluga declares no conflict of interest concerning grant support, consultancy, membership on advisory Tommaso Bonfiglio declares declares no conflict of interest concerning grant support, consultancy, membership on advisory Silvia Di Prisco declares declares no conflict of interest concerning grant support, consultancy, membership on advisory Elisa Merega declares declares no conflict of interest concerning grant support, consultancy, membership on advisory Matteo Vergassola declares declares no conflict of interest concerning grant support, consultancy, membership on advisory

Coral González-García: nothing to disclose Antonio J. Sánchez-López: nothing to disclose Lucía Campos-Ruíz: nothing to disclose Irene Moreno-Torres: nothing to disclose María José Coronado: nothing to disclose J. Antonio García-Merino: nothing to disclose

P860 Evaluation of cannabidiol and mesenchymal stem cells in adoptively transferred experimental autoimmune encephalomyelitis. A comparative study C. González-García1, A.J. Sánchez-López1, L. Campos-Ruíz1, I.P. Moreno-Torres1, M.J. Coronado2, J.A. García-Merino1 1Neuroimmunology, 2Confocal Microscopy, University Hospital Puerta de Hierro Research Institute, Majadahonda / Madrid, Spain Background: Cannabidiol (CBD) is a cannabinoid compound independent of CB1 or CB2 receptor stimulation, with a wide

P861 Neuromyelitis optica IgG in the cerebrospinal fluid induces astrocytopathy in optic nerve K.K. Soelberg1,2,3, S. Lillevang4, M.T. Mørch3, R. Khorooshi3, C.T. Berg3, B.P. Morgan5, N. Asgari1,3, T. Owens3,6 1Department of Neurology, Vejle Hospital, Vejle, 2Department of Ophthalmology, Odense University Hospital, 3Deparment of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark, 4Department of Clinical Immunology, Odense University Hospital, Odense, Denmark, 5Systems Immunity University Research Institute, Cardiff University, Cardiff, United Kingdom, 6TO and NA Share Last Authorship, ., Denmark Background: Serum immunoglobulin G targeting the astrocyte water channel aquaporin-4 (AQP4) in the central nervous system (CNS) is a biomarker for neuromyelitis optica spectrum disease


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Poster Session 2, 21(S11) (NMOSD). Optic neuritis (ON) is believed to be immune-mediated and is associated with AQP4-IgG in NMOSD-ON. The predilection of the optic nerve in NMOSD may partly be explained by the dense expression of AQP4 in the optic nerve. We previously reported that AQP4-IgG in cerebrospinal fluid (CSF) becomes widely distributed in the brain and causes complement-dependent astrocyte injury in periventricular areas and brain parenchyma. Objective: To examine the pathogenicity of CSF AQP4-IgG on the optic nerve. Materials and methods: Purified AQP4-IgG from an NMOSD patient was given to naïve mice as a single intrathecal injection into CSF at the cisterna magna with human complement (C) +/anti- regulatory protein CD59a antibody (anti-CD59a). A total of five mice received AQP4-IgG + C + anti-CD59a, four mice received normal-IgG + C + anti-CD59a, four mice received AQP4-IgG+ C and one normal-IgG + C. Mice were killed four days later. The optic nerves were isolated and fixed in paraformaldehyde. Paraffin embedded optic nerves were cut into sections of 6µm, and immunostaining was performed1. Histological changes were scored semiquantitatively 0-31. Results: Intrathecal injection of AQP4-IgG + C induced focal astrocyte pathology with loss of AQP4 and glial fibrillary acidic protein (GFAP) in optic nerves from all mice, which was coincident with deposition of complement. Histopathological lesions were markedly enhanced with extensive/long-segment astrocytopathy of optic nerve and optic chiasm involvement in AQP4IgG+ C + anti-CD59a treated mice. Such pathology was not seen in mice receiving normal human IgG, C and anti-CD59a. Conclusion: We describe the induction of ON in an animal model for NMOSD, utilizing the intrathecal route for antibody administration, which mimics a physiological approach for the presence of antibody in the CSF.

Reference: 1- Asgari N, Khorooshi R, Lillevang ST, Owens T. Complementdependent pathogenicity of brain-specific antibodies in cerebrospinal fluid. Journal of neuroimmunology 2013;254:76–82. Disclosure KK. Soelberg: nothing to disclose. ST. Lillevang: nothing to disclose. M. Mørch: nothing to disclose. R Khorooshi: nothing to disclose. CT. Berg: nothing to disclose. BP. Morgan: nothing to disclose. N. Asgari: nothing to disclose. T. Owens: nothing to disclose.

P862 Human herpesvirus 6 accelerates clinical and radiological disease in a nonhuman primate model of multiple sclerosis E. Leibovitch1,2, B. Caruso1, P. Sati1, B.J. Billioux1, J. Guy1, X. Li1, J. Lefeuvre1, M. Schindler1, A. Silva3, D. Reich4, S. Jacobson1 1NINDS, National Institutes of Health, Bethesda, MD, 2The George Washington University, Washington, DC, 3NINDS, National Institute of Health (NIH), 4National Institutes of Health, Bethesda, MD, United States

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Viruses, particularly human herpesviruses, have long been suggested to be an environmental risk factor in the pathogenesis of Multiple Sclerosis (MS). Human herpesviruses HHV6A and HHV6B are associated with MS and several other inflammatory conditions affecting the central nervous system (CNS). Since HHV6 may act as a trigger in MS, we investigated whether small non-human primates (marmosets) previously exposed to HHV6 exhibit an altered disease course of experimental autoimmune encephalomyelitis (EAE) compared to naïve animals. EAE is a well-accepted model of CNS inflammatory demyelination that when induced in nonhuman primates, accurately reflects clinical and radiologic features of MS. To represent a physiologically relevant route of viral exposure, marmosets were inoculated intranasally with HHV6A (n=6), HHV6B (n=4) or uninfected control material (n=6) monthly for four months. Six months after the last viral inoculation, all animals were immunized with white matter homogenate to induce EAE. All animals underwent frequent neurologic exams, in vivo brain MRI, blood and saliva collection. At necropsy, the CNS and other tissues were collected for viral distribution and immunohistochemical studies. Marmosets previously inoculated with HHV6A or HHV6B (HHV6+EAE) exhibited accelerated clinical and radiologic disease compared to previously naïve marmosets (EAE alone). Specifically, HHV6+EAE marmosets had significantly shorter survival times (p=0.01) associated with significantly earlier MRI-detectable brain lesions (p=0.04). HHV6+EAE marmosets exhibited an earlier and heightened induction of myelin-specific antibodies and several inflammatory, angiogenic and vascular injury factors, including vascular endothelial growth factor (VEGF) and its soluble receptor fms related tyrosine kinase 1 (Flt1). These factors have been reported to be elevated in MS patient sera. Analyses of the longitudinally and terminally collected samples are ongoing. Data on viral distribution and cellular immune responses to myelin and viral antigens will be presented. We hypothesize that the mechanism of accelerated disease will reflect inflammatory-mediated blood brain barrier breakdown, which may also involve a marmoset homolog of Epstein Barr virus (EBV). Combining models of a virus and an inflammatory demyelinating disease may enable mechanistic insights into the interplay of viral and autoimmune components, which are believed to be involved in the complex pathophysiology of MS. Disclosure Emily Leibovitch: nothing to disclose. Breanna Caruso: nothing to disclose. Pascal Sati: nothing to disclose. Jeanne Billioux: nothing to disclose. Joseph Guy: nothing to disclose. Xiaozhen Li: nothing to disclose. Jennifer Lefeuvre: nothing to disclose. Matthew Schindler: nothing to disclose. Afonso Silva: nothing to disclose. Daniel Reich: nothing to disclose. Steven Jacobson: nothing to disclose. P863 Amantadine ameliorates gait deficits and disease severity in an animal model of multiple sclerosis J. Nguyen1, E. Brigham1, J. Oksman2, T. Ahtoniemi2, B. Sava3, B. Buisson3


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1Adamas

Pharmaceuticals, Emeryville, CA, United States, River Discovery Services, Kuopio, Finland, 3Neuroservice, Aix-en-Provence, France 2Charles

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). MS is characterized by the impairment of axonal transmission and the reduction in nerve conduction velocity, resulting neurological and motor deficits. Fampridine is approved as a treatment to improve walking in MS. It is thought that fampridine improves walking in MS patients by blocking potassium channels, thereby improving nerve impulses across regions of demyelination in axons. In a mouse model of MS, fampridine has been shown to ameliorate gait deficits but did not alter the disease course1. Amantadine HCl is an NMDA receptor (NMDAr) antagonist approved for the treatment of influenza infection and Parkinson’s disease. In addition to its glutaminergic activity, amantadine has also been shown to modulate other neurotransmitter systems, inhibit microglial activation, and elevate levels of brain-derived neurotrophic factor (BDNF). Amantadine has been shown in clinical trials to reduce fatigue in MS, but its effects on gait and walking have not been evaluated. Here, we characterize the in vitro effects of amantadine on potassium channel activity and the efficacy of amantadine in a mouse model of MS. First, we compared the effects of amantadine to fampridine on the blockade of potassium currents in rat coronal brain slices. Both amantadine and fampridine blocked potassium leak currents and delayed rectifying currents in a concentration-dependent fashion, but potassium current blockade occurred at 10-100 fold lower concentration with amantadine compared to fampridine. Next, we assessed the effects of amantadine in experimental autoimmune encephalomyelitis (EAE), a mouse chronic model of MS. EAE was induced in female C57BL/6 mice by subcutaneous injection of myelin oligodendrocyte glycoprotein (MOG35-55), and disease severity and gait parameters were measured over 28 days. We found that chronic administration of clinically relevant doses of amantadine reduced the severity of clinical disease, improved gross motor function and improved walking following EAE in mice. Together, the data suggest that amantadine may have clinical utility as treatment in MS, and provide a framework for further clinical evaluation.

References 1. Gobel et al. (2013) 4-Aminopyridine ameliorates mobility but not disease course in an animal model of multiple sclerosis, Experimental Neurology, 248: 62. Disclosure This study was funded by Adamas Pharmaceuticals. Jack Nguyen: employee and stock holder of Adamas Pharmaceuticals Elizabeth Brigham: employee and stock holder of Adamas Pharmaceuticals Juho Oksman: received funding from Adamas Pharmaceuticals Toni Ahtoniemi: received funding from Adamas Pharmaceuticals Bogdan Sava: received funding from Adamas Pharmaceuticals Bruno Buisson: received funding from Adamas Pharmaceuticals

P864 Oleanolic acid protects against optic nerve degeneration and retinal ganglion cells loss in an experimental model of multiple sclerosis C. Cordova1, S. Jimenez1, B. Gutierrez1, R. Martin1, M. Hernandez1, N. Tellez2, C. Martinez3, M.L. Nieto1 1Unidad de Inmunidad Innata e Inflamación, IBGM-CSIC/ UVa, 2Servicio de Neurología, Hospital Clínico Universitario de Valladolid, 3Departamento de Biología Celular, Histología y Farmacología, Universidad de Valladolid, Valladolid, Spain Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that currently lacks neuroprotective treatments. In many patients optic neuritis (ON) is the first clinically symptom. Experimental autoimmune encephalomyelitis (EAE), an animal model of MS, affects spinal cord, brain and optic nerves causing ON, among others disabilities. ON occurs as a result of inflammation, oxidative stress, demyelination, axonal damage in the optic nerve followed by retinal ganglion cell (RGC) loss. Our goal was to determine the usefulness of the triterpene, oleanolic acid (OA) in preventing ON with a focus on neuroprotection. Methods: OA (50 mg/kg/day) was i.p. administered to MOG35-55 immunized-C57/BL6 mice from immunization to day 45. Eyeballs were cut through the pupillary-optic nerve plane and optic nerve was cut longitudinally. Sections were stained with hematoxylin and eosin (inflammation), luxol fast blue (demyelination), toluidine blue (RGC counts), tunel (apoptosis) and Fluoro-Jade® B (axonal degeneration). RGC were counted on 3 standard areas. Glutamate concentration was determined with a Glutamate Assay Kit. Results: Histopathological analysis of optic nerves showed presence of cell infiltration, myelin loss as well as swollen and distorted axons in untreated-EAE mice, whereas these effects were not detectable in sections from healthy or OA-treated EAE mice. We found that the number of apoptotic cells and degenerated axons (Fluoro-Jade® B+) were lower in optic nerve sections from OA treated-EAE mice than in the untreated-EAE group. Apoptotic cells in untreated-EAE mice were enhanced over 3-4 fold compared to healthy mice (p< 0.001), while in samples from OA-treated EAE mice the apoptotic cells only increased 1.6 fold (p< 0.001). At the same time, glutamate levels in optic nerve decreased from 16.6 ± 2.8 mM, in untreated EAE mice, to 3.5 ± 0.2 mM in OA-treated EAE mice (p< 0.001), with the concentration in controls being 0.7 ± 0.3 mM. In addition, EAE caused a significant loss of cells by an average of 39.35% (p< 0.001) in the RGC layer, which was eliminated in OA-treated EAE mice. Conclusion: OA suppresses inflammation, reduces demyelination, axonal injury, and promotes RGC survival during experimental optic neuritis. This study provides new findings regarding the neuroprotective activity of OA in EAE. Disclosure Nothing to disclose P865 Transforming growth factor-β1-producing B-cells limit the severity of autoimmune neuroinflammation by exerting regulatory functions


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Poster Session 2, 21(S11) N. Molnarfi1,2, K. Bjarnadóttir1, M. Benkhoucha1, G. Schneiter1, P.H. Lalive1,2 1Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 2Department of Clinical Neurosciences, Division of Neurology, Unit of Neuroimmunology and Multiple Sclerosis, University Hospital of Geneva, Geneva, Switzerland Objective: The efficacy of B-cell depletion in Multiple Sclerosis (MS) has renewed interest in the role of B cells in this disease. We evaluated the importance of B cell-derived transforming growth factor (TGF)-β1 in two related mouse models of central nervous system (CNS) autoimmunity. Background: B cells are thought to contribute to the pathogenesis of MS in several ways: as a source for differentiation of CNSreactive antibody-secreting plasma cells, as antigen-presenting cells (APCs) for T cells specific for CNS autoantigens, and as immunoregulatory cells (Bregs) that produce suppressive cytokines and/or influence regulatory T cell activity. While data indicate a role for TGF-β1 expression in Breg functions, this mechanism has not yet been tested in CNS autoimmunity. Design and methods: Transgenic mice that cannot express TGFβ1 in B cells (B-TGF-β1-/-) were tested in experimental autoimmune encephalomyelitis (EAE) induced by either recombinant mouse myelin oligodendrocyte glycoprotein (rmMOG), a model in which B cells are considered to contribute pathogenically, or MOG peptide (p)35-55, a model of CNS inflammation that is considered less dependent upon B cells. Results: Irrespective of the EAE model used, B-TGF-β1-/- mice developed clinically a significantly more severe EAE than control mice with early onset and rapid progression. Exacerbated EAE susceptibility in B-TGF-β1-/- mice was associated with augmented autoimmune Th17 responses in the peripheral immune compartment and the CNS. Importantly, the frequencies of regulatory T cells (Tregs) were unaltered in B-TGF-β1-/- mice, discounting a role of TGF-β1-producing B cells in Treg generation and/or expansion. In contrast, selective B cell TGF-β1 deficiency increased the frequencies of activated dendritic cells, the most potent professional APCs, suggesting that B cell-derived TGF-β1 can constrain Th17 responses through inhibition of APC activity. Conclusion and relevance: Collectively our data suggest that B cells can down-regulate encephalitogenic Th17 responses by provision of TGF-β1, findings which may be relevant to B cell-targeted therapies. Disclosure N. Molnarfi: nothing to disclose. K. Bjarnadóttir: nothing to disclose. M. Benkhoucha: nothing to disclose. G. Schneiter: nothing to disclose. P.H. Lalive: nothing to disclose.

P866 Human aquaporin 4 auto-antibody alters blood brain barrier permeability A. Cobo-Calvo1,2, A. Ruiz2, A. Babikian2, S. Blondel2, S. Cavagna2, S. Vukusic3, J.F. Gershi-Egea2, P. Giraudon2, N. Strazielle2, R. Marignier2,3

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1Hospital

Universitari de Bellvitge - IDIBELL, Multiple Sclerosis Unit, Barcelona, Spain, 2Lyon’s Neuroscience Research Center, U 1028 Inserm, UMR 5292 Cnrs, Team Oncoflam, 3Service de Neurologie A, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France Background: Breakdown of the blood brain barrier is considered as a key step in the development of neuromyelitis optica (NMO) lesion formation. However little is known about the molecular mechanisms responsible of BBB alteration. We hypothesized that aquaporin 4 (AQP4)- antibody (Ab) (AQP4-Ab) could be directly involved. Aim: To evaluate, by in vivo and in vitro dedicated NMO models, the effect of human AQP4-Ab on blood-brain barrier properties. Methods: First we exposed brain isolated microvessels from OFA rats to purified immunoglobulins from AQP4-Ab positive NMO patients at different time points (nine and 24 hours incubation). We analyzed, by Western Blotting (WB), the expression of different tight junction proteins, claudin-5, occludin and ZO-1. In parallel, we investigated by WB and immunohistochemistry (IHC) the expression of these tight junction proteins in our animal model of NMO (ratNMO), based on chronic infusion (7 days) of purified patient AQP4-Ab in the brain ventricle. Functional alteration of barrier properties was also assessed in rat-NMO by analyzing extravasation of circulating rat immunoglobulins from luminal side of blood vessels into the brain parenchyma by WB. In all experimentations immunoglobulins purified from healthy donors were used as control. Results: In brain isolated microvesssels, human AQP4-Ab reduced by up to 24% claudin-5 levels after 24hours incubation. A slight decrease up to 5% was observed in occludin expression at this time point. No decrease was observed after exposure to control immunoglobulins. These findings were confirmed in vivo with a decreased claudin-5 expression in vessels from periventricular areas, as assessed by IHC. Finally, we observed extravasation of circulating rat IgG into the brain parenchyma only in rats infused with AQP4-Ab. Conclusions: Human AQP4-Ab induce claudin-5 and occludin downregulation, suggesting that AQP4-Ab, by itself, could modulate BBB permeability and facilitate and amplify the CNS entry of pathogenic immune factors. Disclosure Nothing to disclose

Genetics/Epigenetics and Pharmacogenetics P867 Genetic load in eleven distantly related individuals from an MS high risk area K. Imrell1, T. Masterman1, B. Brynedal1, I. Lima1, J. Hillert1, I. Kockum1, A.-M. Landtblom2 1Karolinska Institutet, Stockholm, 2Akademiska Sjukhuset, Uppsala, Sweden A previous study of MS prevalence in Sweden revealed a cluster of individuals with MS in the parish Lysvik, located in the northern part of Värmland, Sweden. Genealogists helped us to trace 26 MS patients to a common ancestral couple, who immigrated to


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Lysvik at the end of the 16th century. The couple belonged to a group of burn-beating farmers who left Savolax in the southeastern part of Finland to settle in the sparsely inhabited parish of Lysvik. The Finnish immigrants seem to have married within their own group for a number of generations. Lysvik later experienced periods of rapid expansion followed by a period of extensive emigration at the end of the 19th century. We applied an affected-only strategy, and by using a method that identifies genetic segments shared identical-by-descent we took advantage of their shared ancestry. We ran a whole genome single nucleotide polymorphism (SNP) array on eleven individuals. They showed a mean genetic distance of eleven meioses from the common ancestor, except a mother and her two children that was also included among those eleven. Pairwise identical by descent sharing was identified among nine distantly related individuals. If at least four of nine distantly related individuals carried an allelic match overlapping segment, that was considered a “hit” (p=2 × 10-6). The additional two individuals (the sibs) where used to narrow down the “hits”. Hit regions were: 6p21.32 (covering HLA-DRB1 and 7 more genes) and 6p21.33-p22.1 (HLA class I), four within a locus at chromosome 22q12.3-13.32, one at 10q22.1 (covering 7 genes, e.g. the gene for perforin with already existing evidence for genetic and functional implications in MS), one on chromosome 1p2.11, and one at 17q11.2-12 targeting one gene: ACCN1 which has previously been associated to MS in the Sardinian population. It encodes acid-sensing ion 2 who’s partner ASIC1 has had some attention among MS researchers. These channels mediate acidosis-induced neurotoxicity by enhancing intracellular calcium-influx. Hence, we here propose a method for investigating genetic risk in complex diseases by taking advantage of distantly shared ancestry; under the hypothesis of enrichment for genetic disease-risk factors in a parish in Sweden with dramatic demographic history and high prevalence of MS. Disclosure Kerstin Imrell: nothing to disclose. Thomas Masterman: nothing to disclose. Boel Brynedal: nothing to disclose Izaura Lima: nothing to disclose Dr Hillert received honoraria for serving on advisory boards for Biogen and Novartis and speaker’s fees from Biogen, MerckSerono, Bayer-Schering, Teva and Sanofi-Genzyme. He has served as P.I. for projects sponsored by, or received unrestricted research support from, Biogen, Sanofi-Genzyme, Merck-Serono, TEVA, Novartis and Bayer-Schering. Dr Kockum has received speaker’s fees from Merck-Serono. She is involved in a project sponsored by Biogen. Anne-Marie Landtblom has received support from Teva, Biogen Idec, SAnofi, Genzyme. The research-project was funded by the Swedish Research Council, the Swedish Brain Foundation and Neuroförbundet. P868 NOX genes - genetic markers for severe multiple sclerosis? A. Gyllenberg1, L.M. Olsson2, B. Acharjee1, M. Khademi1, F. Piehl1, L. Alfredsson3,4, J. Hillert1, R. Holmdahl2, T. Olsson1, I. Kockum1

1Clinical

Neuroscience, 2Medical Biochemistry and Biophysics, Medicine, Karolinska Institutet, 4Stockholm Center for Public Health, Stockholm County Council, Stockholm, Sweden 3Environmental

NEURINOX is a collaborative project between research groups in several EU countries with the aim of finding new therapeutic targets for neurological inflammatory diseases, among them Multiple Sclerosis (MS). The focus is on analyzing how NADPH oxidases, or NOX enzymes, essential for the formation of reactive oxygen species (ROS), govern neuroinflammation. ROS have a variety of functions, including combating pathogens and regulation of the immune response. Reduced ROS levels increase susceptibility to autoimmunity, however, high levels of ROS can lead to tissue damage and neurodegeneration, and variation in NOX activity may affect the formation of chronic neuroinflammation. Our aim was to identify severity variables for MS and investigate genetic association between NOX related genes and MS progress in relation to NOX enzyme activity.Using genotypes from a custom made Illumina chip from 7701 MS patients and 6637 healthy controls; we analyzed 1733 Single Nucleotide Polymorphisms (SNPs) in 34 NOX-related genes. In the analysis, we compared both MS patients versus healthy controls, but also created variables based on severity or progress of disease. We also measured oxidative burst in peripheral blood mononuclear cells (PBMC) from 156 patients with MS or other neurological disease.We identified several SNP markers in NOX related genes associated to severity phenotypes of MS. SNPs in the FPR3 gene was associated in MS patients with second line treatment compared to other patients (p=0.0002, OR:0.84 CI: 0.77-0.92). SNPs in the VAV3 gene (p=0.0004, OR 0.79 CI 0.69-0.90) and SSTR3 gene (p=0.0008, OR 1.39 CI 1.15-1.69) were associated with primary progressive MS compared to other types of MS. In the NOD1 (p=0.0009, OR1.18 CI: 1.07-1.31) and NCF4 (p=0.003, OR 0.75 CI: 0.61-0.91) genes, SNPs were associated in patients with high MS severity scores (MSSS) compared to individuals with low scores (quartiles).In addition, phagoburst activity was associated with several of the genes that also were associated with severity variables (VAV3 p=0.00009, SSTR3 p=0.0005, NCF4 p=0, 0006). Our results provide preliminary evidence for the involvement of NOX related genes in severity and progress of MS disease, possibly through the mechanisms of oxidative burst. However, several genes were implicated suggesting a complex genetic influence. Importantly, these results do not reach formal criteria for genome wide significance and need confirmation in independent cohorts. Disclosure A. Gyllenberg, L M. Olsson, B. Acharjee, M. Khademi and R. Holmdahl have no financial, personal or professional conflict of interest to declare. A. Gyllenberg have received funding from the Swedish NEURO foundation. Dr. Piehl has received unrestricted academic research grants from BiogenIdec and Novartis, and compensation for lectures and/or participation in advisory boards from Biogen, Merck Serono, Novartis, Sanofi and Teva, which have been exclusively used for the support of research activities.


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Poster Session 2, 21(S11) Dr. Alfredsson receives research support from the Swedish Medical Research Council (K2013-69X-14973-10-4 and 8252012-5168) and Swedish Council for Health, Working Life and Welfare (Dnr 2012-0325). Dr. Hillert received honoraria for serving on advisory boards for Biogen and Novartis and speaker’s fees from Biogen, MerckSerono, Bayer-Schering, Teva and Sanofi-Genzyme. He has served as P.I. for projects sponsored by, or received unrestricted research support from, Biogen, Sanofi-Genzyme, Merck-Serono, TEVA, Novartis and Bayer-Schering. His MS research is funded by the Swedish Research Council and the Swedish Brain Foundation. Dr. Olsson has received unrestricted MS research grants from Biogen, Novartis, Genzyme and Astra Zeneca. Avdisory board compensations from Biogen, Genzyme and Novartis. Research grants from the Swedish research council, the AFA foundation, the Swedish Brain fouandation, Maragareta af Ugglas fouundation, Knut adn Alice Wallenberg foundation. Dr. Kockum has received speaker’s fees from Merck-Serono. and is involved in a project sponsored by Biogen. We acknowledge the International Multiple Sclerosis Genetics Consortium (IMSGC) for the genotyping. This specific project have support from EU fp7, Neurinox. P869 A weighted genetic risk score distinguish MS patients from healthy individuals but does not correlate with MS disease activity H. Bach Søndergaard1, E.R. Petersen1, M. Magyari1,2, F. Sellebjerg1, A. Bang Oturai1 1Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark, 2Neuroscience Centre, The Danish Multiple Sclerosis Registry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Background: In multiple sclerosis (MS) 110 non-HLA genetic risk variants have been established but their impact on disease activity has not previously been investigated. Objective: The aim of the present study was to investigate if disease activity correlates with a weighted genetic risk score (wGRS) in more than 500 interferon (IFN)-beta treated patients. Methods: A wGRS was calculated in 647 healthy Danish controls and 873 Danish MS patients, all genotyped with the Immunochip conducted by the International MS Genetics Consortium. The wGRS was based on 109 risk gene variants out of the 110 established non-HLA MS-risk gene variants. The weight for each genetic variant was the allelic odds ratio (OR) as determined in the Immunochip study. The clinical disease activity measures, relapses 2 years prior to treatment and number of relapses after treatment start, were available from a total of 512 IFN-beta treated MS patients. The discriminatory effect of wGRS between healthy controls and MS patients was analysed with or without the human leukocyte antigen (HLA) contribution. Relapses 2 years prior treatment and relapses after treatment start were investigated by Poisson regression analysis for association with the non-HLA wGRS and the wGRS, containing the contribution from HLA-DRB1*15 and HLA-A*02, adjusting for age and gender in the analysis. Only

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patients without neutralizing antibodies against beta-IFN were analysed. Results: Both the non-HLA and the wGRS including HLA were significantly higher in MS patients than in controls (p=10-40 and p=10-82, respectively). Among patients no significant association was observed between number of relapses 2 years prior treatment and the non-HLA wGRS (OR=0.90;p=0.21) or the wGRS including HLA (OR=1.02;p=0.78). Likewise, relapses during treatment with IFN-beta were not associated with the non-HLA wGRS (OR=1.06;p=0.53) or the wGRS including HLA (OR=1.04;p=0.57), respectively. As expected, relapses before and after IFN-treatment were significantly correlated (rho=0.29; p=10-11). Conclusions: This study confirms a highly significant difference between both the non-HLA and the HLA-included wGRS in Danish MS patients and healthy controls. However, a wGRS calculated from 109 MS risk gene variants was not associated with disease activity in Danish MS patients, even with the HLA effect included. Disclosure Helle Bach Søndergaard has nothing to disclose. Eva Rosa Petersen has received support for congress participation from Teva. M. Magyari has served on scientific advisory board for Biogen and TEVA and has received honoraria for lecturing from Biogen, MerckSerono, Novartis, and Teva. She has received support for congress participation from Biogen, MerckSerono, Novartis, TEVA and Genzyme. Finn Sellebjerg has served on scientific advisory boards for Biogen Idec, Genzyme, Merck Serono, Novartis and Teva, served as consultant for Biogen Idec and Lundbeck; has received support for congress participation from Biogen Idec, Novartis and Teva; has received speaker honoraria from Biogen Idec, Genzyme, Merck Serono and Novartis. His laboratory has received research support from Biogen Idec and Novartis. Annette Bang Oturai has served on scientific advisory boards for Biogen Idec and Novartis; has received research support from Novartis and Biogen Idec; has received speaker honoraria from Biogen Idec, Novartis and TEVA; and has received support for congress participation from, Merck Serono, Biogen, Novartis and Genzyme.

P870 Exome sequencing in multiple sclerosis patients with benign and aggressive disease courses N. Fissolo1, J.C. Triviño2, G. Marco2, L. Negrotto3, S. Malhotra3, À. Vidal-Jordana3, X. Montalban3, M. Comabella3 1Multiple Sclerosis Centre of Catalonia/Neuroimmunology Department, Vall d’Hebron University Hospital & VHIR, Barcelona, 2Bioinformatics Department, Sistemas Genómicos, Valencia, 3Multiple Sclerosis Centre of Catalonia/ Neuroimmunology Department, Vall d’Hebron University Hospital & VHIR, Barcelona, Spain Background: Great progress has been made in the identification of genes that influence the risk of developing multiple sclerosis (MS). However, genetic modifiers that may help in the distinction between MS patients with benign and aggressive disease courses


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are still lacking. Here, we aimed to identify genes associated with MS disease course by exome sequencing. Methods: Patients with relapse-onset MS were classified according to their disease course into benign (n=10) and aggressive (n=10) phenotypes. Patients with benign phenotypes had EDSS scores equal or lower than 3.0 after 15 or more years from disease onset and never received MS therapies. Patients with aggressive disease courses reached an EDSS score equal or higher than 6.0 within the first 5 years after disease onset, regardless of treatment. Exome sequencing was performed in DNA samples from patients with benign and aggressive phenotypes and was based on an Illumina HiSeq2000 sequencing platform and Agilent’s SureSelect Target Enrichment System for 51Mb. For the variant calling process different algorithms were applied including GATK and VarScan. The annotation was based in Ensembl and NCBI databases. For the selection of significant variants, a Fisher exact test was applied for the benign and aggressive phenotypes and a p-value threshold of 0.05. Results: In the global analysis of all samples, a total of 186.706 variants were detected, of which 915 reached the threshold for statistical significance. For prioritization and selection of the most interesting variants, different filters were applied based on odds ratios, phenotype prevalence, number of statistically significant variants per gene, and type and variant effects on the predicted protein. A total of 32 variants belonging to 28 genes were selected after applying these criteria, and will be genotyped in an independent cohort of MS patients classified into benign and aggressive phenotypes according to the same criteria, in order to validate the exome sequencing findings. Conclusions: Genes related with the selected variants may become attractive disease activity biomarkers to identify MS patients with diverging disease courses, and they may help to better understand the molecular mechanisms underlying MS pathogenesis. Disclosure N Fissolo, JC Triviño, G Marco, L Negrotto, S Malhotra, and A Vidal-Jordana report no disclosures. X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall and Roche. M Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, and Novartis. P871 Estrogen receptor alpha role in multiple sclerosis patients: trying to identify a new biomarker of disease activity M. Clerico, S. Cutrupi, S.F. De Mercanti, E. Virgilio, A. Iannello, M. De Bortoli, L. Durelli University of Torino, Torino, Italy Background: The role of estrogen in the immunomodulation is well known. High level of estrogen during third trimester of pregnancy correlates with a reduction of relapse rate among woman

with multiple sclerosis ( MS). The molecular mechanisms by which Estrogen Receptor-alpha (ERa) acts are unknown. Several data suggest that ERa may regulate the differenziation of T cell subtypes. The epigenetic reprogramming is linked to cell differentiation, therefore our hypothesis is that ERa binding on specific genomic regions may regulate epigenome acting on T cell subtypes, in particular in the balance between Treg and Th17. Objectives: To evaluate ERa binding and epigenetic remodeling of Treg and Th17 cells of MS patients during pregnancy. To identify the epigenetic remodeling of Treg and Th17 cells during pregnancy as a potential biomarker in different phases of the disease in different patients´ population. Material and methods: Peripheral blood mononuclear cells (PBMC) from 4 pregnant MS patients have been collected respectively at the 1st, 2nd and 3rd trimester of pregnancy. Using Jaspar tool we have identified ERE sites (estrogen response elements) in the promoter regions upstream to FoxP3 and RORc, transcription factor master regulators of Treg and Th17 differentiation. Epigenetic modifications and ERa binding enrichment are evaluated by chromatin immunoprecipitation assay. Results: We have found that ERa binds on RORC promoter, gene encoding for master transcription factor, key player for Th17 diffentiation, and ERa binds on the FoxP3 promoter, master transcription factor, key player for Treg differentiation. In Treg H3K4me3 on FoxP3, active gene mark, is enriched higher respect to H3K27me3, silence gene mark, in third trimester. This balance H3K4me3/ H3K27me3 changes in the post-partum. 3rd trimester: Treg are higher with increase binding of ERalpha at the Foxp3 promoter region, but no signal is detected for RORc on PBMC. Increased signal of both H3K4me3 on Foxp3 and H3K27me3 on RORc. Post partum: ERalpha binding increases on RORC promoter in Th17 and H3K27me3, silencing marker, increases on this genomic regions. Conclusion: ERa binds on the regulatory regions of Foxp3 and RORC, important in the regulation of Treg/Th17 balance, is found in SM patients during third trimester of pregnancy. Our future direction is to confirm these preliminary data in a bigger patients population and to identify in our findings a potential marker of disease activity. Disclosure M. Clerico: nothing to disclose. S. Cutrupi: nothing to disclose. S.F. De Mercanti: nothing to disclose. E. Virgilio: nothing to disclose. A. Iannello: nothing to disclose. M. De Bortoli: nothing to disclose. L. Durelli: nothing to disclose. P872 Search of causal variants in risk genes for multiple sclerosis by means of DNA-sequencing E. Gil1, N. Spataro2, S. Malhotra1, A. Navarro2,3,4, E. Bosch2, X. Montalban1, M. Comabella1 1Multiple Sclerosis Centre of Catalonia/Neuroimmunology Dept & Epidemiology Dept, Vall d’Hebron University Hospital & VHIR, 2Department of Experimental and Health Sciences, 3Proteomics Unit (CRG), University Pompeu Fabra (UPF), 4ICREA, Barcelona, Spain


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Poster Session 2, 21(S11) Background: Multiple sclerosis (MS) is a disease of complex pathogenesis. Both genetic and environmental factors are known to influence disease phenotype. Over the last years, several genome-wide association studies have significantly contributed to the characterization of the MS genetic component. However, for the majority of genes associated with MS, the causal variants remain unknown. Here, we aimed to identify the causal variants for the following MS risk genes by DNA-sequencing: FCRL1, RGS1, TIMMDC1, HHEX, CXCR5, LTBR, TSFM, GALC, TRAF3, STAT3, TNFSF14, IFI30, CD40, and CYP24A1. Methods: All exons and regulatory regions of the selected 14 MS risk genes (~140kb) were sequenced using the Illumina Hiseq technology after enrichment with a Nimblegen array in a total of 750 DNA samples, 375 from patients with relapse-onset MS and 375 from healthy donors. Raw reads were first mapped to the human reference genome (hg19) using the BWA aligner and then subsequently processed using the GATK pipeline. Structural variants were explored using the XHMM software. Variant discovery and functional annotation were performed with the Unified Genotyper tool of GATK and ANNOVAR, respectively. Variants with minor allele frequencies (MAF>1%) were tested for association using Fisher’s exact test, under an additive model and calculating asymptotic p-values. Enrichment for rare variants in the two cohorts was assessed with different collapsing statistical association methods using the Variant Tools package. Results: We identified a total of 1,472 SNPs and 163 indels, which included 98 non-synonymous SNPs (70 predicted as damaging) and 2 frameshifts, and 1 stop-gain. Read-depth analysis suggested two deletions of ~10 kb in the FCRL1 and LTRB genes. Up to 30 common variants within genes FCRL1, RGS1, CXCR5, TSFM, GALC, TRAF3, STAT3, IFI30, CD40 and CYP24A1 were found associated with MS, with one variant surviving strict Bonferroni correction. The variant is an intronic variant in the GALC gene presenting a MAF of 6% in cases and 13% in controls. Several collapsing tests showed enrichment of rare variants in MS cases for RGS1 (when considering all variants) and for CD40 (when considering non-synonymous variants). Conclusions: The greater frequency in controls than in MS cases of the common variant found in GALC suggests a protective role. The enrichment of rare genetics variants of CD40 and RGS1 in MS points to genic and allelic heterogeneity in the genetic etiology of the disease. Disclosure E Gil, A Navarro, N Spataro, E Bosch and S Malhotra report no disclosures. X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall and Roche. M Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, and Novartis. P873 Global methylation in multiple sclerosis patients. Correlation with pathogenesis and therapeutic response to IFNbeta

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M.J. Pinto-Medel1, J.A. Sánchez2, C. Marin-Bañasco1, B. OliverMartos1, M. Suardiaz1, J. Ortega-Pinazo1, V. Reyes2, L. Leyva1, Ó. Fernández2 1Research Laboratory, Institute of Clinical Neurosciences, HRU de Málaga, 2Department of Neurology, Institute of Clinical Neurosciences, HRU de Málaga, IBIMA (Instituto de Investigación Biomédica de Málaga), Hospital Regional Universitario, Universidad de Málaga, Málaga, Spain Background: IFN beta (IFNb) is one of the most important firstline treatments in multiple sclerosis (MS). Clinical trials demonstrate the beneficial effects of IFNb. However, individual response is highly heterogeneous and 30-50% of patients are considered non-responders or suboptimal responders to this treatment. So far, there is not consensus to classify IFNb responder status, and the factors that determine the response to this drug in individual patients have not been fully elucidated. Presently, it is known that epigenetic mechanisms play a key role in gene regulation and alterations in the global methylation status have been related to various autoimmune diseases. Aim: To investigate possible changes in the global DNA methylation in MS and to analyze its relation with the response to treatment with IFNb. Methods: This study included 58 untreated MS patients, 39 IFNb treated MS patients and 18 healthy controls. The response to treatment was established by clinical criteria: occurrence of 1 relapse and/or an increase of 1 point in the EDSS after one year of treatment compared with the year prior to IFN-b therapy. Analysis of global DNA methylation was performed by bisulfite method, assessing the methylation status of LINE-1 (long interspersed nucleotide element-1) elements. Results: The percentage of methylation of the CpG islands 3 and 6 was significantly higher in untreated patients compared to controls. Non-responder MS patients showed a significantly higher percentage of global methylation compared to responder patients. Conclusions: Epigenetic alterations have been involved in the pathogenesis of various autoimmune diseases. Our results suggest that DNA hypermethylation might play a pathogenic role in MS, probably by the induction of a deregulation of gene expression. Moreover, the higher degree of global DNA methylation found in suboptimal responder MS patients could be associated with a lower expression profile of genes related to response to IFNb. Disclosure Pinto-Medel MJ: nothing to disclose Sánchez JA: nothing to disclose Marin-Bañasco C: nothing to disclose Oliver-Martos B: nothing to disclose Suardiaz M: nothing to disclose Ortega-Pinazo J: nothing to disclose Reyes V: nothing to disclose Leyva L: nothing to disclose Fernández O: has received honoraria as consultant in advisory boards, and as chairman or lecturer in meetings, and has also participated in clinical trials and other research projects promoted by Biogen-Idec, Bayer-Schering; Merck-Serono, Teva, Novartis, Almirall and Allergan


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P874 A genetic variant associates with intrathecal immunoglobulin status and multiple sclerosis susceptibility F. Matesanz1, A. Alcina1, M. Delgado-García2, M. Fedetz1, M.I. García-Sánchez2, J.L. Ruiz-Peña2, O. Fernández3, M.J. Pinto Medel3, L. Leyva3, C. Arnal4, C. Delgado5, L.M. Villar6, J.C. Álvarez-Cermeño6, C. Picón6, R. Arroyo7, J. Varadé8, E. Urcelay8, M. Lucas9, G. Izquierdo2 1Instituto de Parasitología y Biomedicina López Neyra (IPBLN), CSIC, Granada, 2Unidad de Esclerosis Múltiple, Hospital Universitario Virgen Macarena, Sevilla, 3Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Málaga, 4Servicio de Neurología, Hospital Virgen de las Nieves, 5Centro Regional de Transfusión Sanguínea Granada-Almería, Granada, 6Departments of Immunology and Neurology, Hospital Ramon y Cajal, 7Multiple Sclerosis Unit, 8Immunology Department, Hospital Clínico San Carlos, Madrid, 9Facultad de Medicina, Hospital Universitario Virgen Macarena, Sevilla, Spain An elevation of intrathecal IgG synthesis and the presence of oligoclonal IgG bands (OCBs) is a characteristic of Multiple Sclerosis (MS). Also, the intrathecal IgM synthesis predicts a worse disease course in the first stages of MS. Recent findings have shown association of intrathecal IgG index with several variants at the immunoglobulin heavy chain (IGHC) locus but they were not associated with the disease. In this study, the rs11621145 variant, located at the IGHC locus, was genotyped in three independent cohorts consisting in total of 2,726 MS patients and 2,133 healthy controls, showing a statistical significance of association with disease at GWAS level. In addition, this variant was also associated with the intrathecal IgG index as analyzed by linear regression analysis in samples from 541 MS patients, in agreement with previous reports. Furthermore, this variant was inversely correlated with IgM index and it marks a decreased likelihood of presenting IgM OCB. Therefore, the most frequent allele of the rs11621145 variant was associated with higher MS risk, higher IgM index and lower IgG index, suggesting that it could alter the switching of the immunoglobulin isotype in B-cells. Disclosure Mercedes Delgado-García: nothing to disclose, Fuencisla Matesanz: nothing to disclose, Antonio Alcina: nothing to disclose, Maria Fedetz: nothing to disclose, María Isabel García-Sánchez: nothing to disclose, Juan Luis Ruiz-Peña: nothing to disclose, Oscar Fernández: nothing to disclose, María Jesús Pinto Medel: nothing to disclose, Laura Leyva: nothing to disclose, Carmen Arnal: nothing to disclose, Concepción Delgado: nothing to disclose, Luisa María Villar: nothing to disclose, José Carlos Álvarez-Cermeño: nothing to disclose, Carmen Picón: nothing to disclose, Rafael Arroyo: nothing to disclose, Jezabel Varadé: nothing to disclose, Elena Urcelay: nothing to disclose, Guillermo Izquierdo: nothing to disclose, Miguel Lucas: nothing to disclose.

P875 GWAS on relapse outcomes in CombiRx trial H. Tiwari1, A. Patki1, S.S. Cofield1, T. Gustafson2, D. Duggan3, S. Jacobson4, J.S. Wolinsky5, F.D. Lublin2, G.R. Cutter1, The CombiRx Investigator Group 1Biostatistics, University of Alabama at Birmingham, Birmingham, AL, 2Corinne Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, New York, NY, 3TGen, Phoenix, AZ, 4National Institute of Health (NIH), Bethesda, MD, 5Neurology, University of Texas Health Sciences Center at Houston, Houston, TX, United States Background: The CombiRx trial was a double blind, multi-center randomized clinical trial of relapsing remitting MS, comparing 50% of participants on interferon beta 1a (IFN) and glatiramer acetate (GA) treatment versus 25% on each of the single agent arms with matching placebo. Subject entry criteria include: EDSS ⩽ 5.5, RRMS diagnosed by Poser or McDonald criteria. Participants were followed for up to 7 years with an ancillary genetic study (CombiRx Biomarker). Objectives: To assess baseline genetic association with clinical relapses in Relapsing Remitting MS patients using GWAS. Methods: On-Study relapse defined as a protocol defined or non-protocol defined exacerbations (PDE, NPDE). PDE required new/worsening symptoms ⩾ 24 hours, no fever, change in EDSS or FS, examined ⩽ 7 days; NPDE as PDE but examined > 7days. For participants consented to the CombiRx Biomarker ancillary trial, samples were taken at Baseline, Months 6, 12, 36 and 48. DNA was obtained at baseline and a GWAS was conducted using an Illumina 1 million SNP chip on any relapse outcomes. Quality control (QC) and association analyses of the GWAS data were conducted using the PLINK software with individual exclusion for the analyses based on outlier criteria, specifically based on four characteristics, namely, population stratification, genotype call rate, relatedness, and gender misclassification. Additive models; adjusted for age, sex, and duration (years) of MS symptoms; were used to test the effects of SNPs, with a multiple testing adjustment of p< 5x10E-8 threshold for significant association. Results: 608 Caucasian samples were used in the analyses after QC; of whom 72% were females with similar mean age of males and females. The analyses identified the regions on chromosomes 3 and 11 with p-value < 1.0E-6. The SNP rs7130553 (p-value=7.35E-08) was significantly associated with relapse outcomes and had the smallest p-value observed in the GWAS. Conclusions: The rs7130553 is an intronic SNP located within a NELL1 gene. NELL1 encodes a cytoplasmic protein that contains epidermal growth factor-like repeats, which contain signal peptides at the N-terminals. NELL1 is known gene as a novel IBD disease gene, an autoimmune disorder (Franke et al., 2007). The determination of genomic markers of disease course and severity is key to the understanding of the underlying pathophysiology. Disclosure Dr. Cofield has received support for consulting services (American Shoulder and Elbow Society), DSMB service (MedImmune), and/ or grant support; no direct conflicts. Dr. Wolinsky has received support for consulting services, DSMB service, and/or grant support; no direct conflicts.


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Poster Session 2, 21(S11) Dr. Lublin has received support for consulting services, DSMB service, and/or grant support; no direct conflicts. Ms. Gustafson has nothing to disclose. Dr. Cutter has consulting and/or DSMB commitments in Past 12 months. Participation of Data and Safety Monitoring Committees: All of the below organizations are focused on medical research: Apotek, Biogen-Idec, Cleveland Clinic(Vivus), Glaxo Smith Klein Pharmaceuticals, Gilead Pharmaceuticals, Horizon Pharmaceuticals, Modigenetech/Prolor, Merck/Ono Pharmaceuticals, Merck, Merck/ Pfizer, Neuren, Sanofi-Aventis, Teva, NHLBI (Protocol Review Committee), NINDS, NICHD (OPRU oversight committee). Consulting, Speaking fees & Advisory Boards: Consortium of MS Centers (grant), D3 (Drug Discovery and Development), Genzyme, Genentech, Jannsen Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, Novartis, Opexa Therapeutics, Receptos, Roche, EMD Serono, Spiniflex Pharmaceuticals, Somahlution, Teva pharmaceuticals, Transparency Life Sciences. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. Dr. Jacobson is an employee of NIH. Dr. Dugan is an employee of TGen has no disclosures or conflicts to declare; this work was performed as part of a contract from NINDS/NIH. Dr. Tiwari has nothing to disclose. Mr. Patki has nothing to disclose. Sources of funding: NIH/NINDS 5-U01-NS045719. Biogen Idec and Teva Neuroscience generously contributed study medications and matched placebo without input into the design, conduct, analysis, or interpretation of results of the trial. P876 Association of genetic variants to multiple sclerosis by performing whole exome sequencing in a high prevalence family G. Mattei1, R. Mechelli1, V.A.G. Ricigliano2, M.C. Buscarinu1, M. Frontali3, G. Ristori1, M. Salvetti1 1NESMOS, Sapienza University of Rome, 2IRCSS SDN Foundation, 3National Research Council, Rome, Italy Our research aims to shed light on the role of genetic component in Multiple Sclerosis etiology by identifying rare or new gene variants, by whole exome sequencing (WES) in a high prevalence family (HPF). Infact, the high prevalence of the disease in the family, seems to suggest that the genetic component plays a major role in MS onset. We started selecting from this HPF three patients (a father and two sons) and then we performed the WES. Reads obtained were aligned to reference genome hg19 by BWA aligner, then, GATK tool kit has been used for quality score recalibration near indels regions and to perform variant calling. The study of raw data, executed by Ingenuity Variant Analysis permitted to select those shared between donors and then to filter rare variants with a global Minor Allele Frequency< 5% and those predicted deleterious by SIFT and PolyPhen2. We found 1483 variants on 856 genes. Then we selected all the variants that potentially result as alteration of gene function and probably induce a phenotypic manifestation: homozygous variants, compound heterozygous variants, hemizygous variants and haploinsufficient variants. 832 variants on 288 genes were been found. Starting from this list of genes, we executed further analysis. We firstly focused on variants that may alter

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pathways or physiologic mechanisms supposed to be related to MS. We found 331 deleterious variants laid on 102 genes involved in the regulation of the immune response and it results that 29 pathways, regulating immune processes (p-value ⩽ 0.05, Fisher’s exact test), could be potentially altered. Moreover, we identified variants affecting genes that interact with environmental risk factors. By comparing the starting list of 288 genes with most recent Virus Mentha database, we identified 11 variants affecting 10 genes that interact with EBV. Then, by an analysis performed through String, we found one gene affected by deleterious and homozygous variants interacting with VDR that potentially could alter Vitamin D pathway. Finally, by comparing a list of damaging and likely damaging variants shared by patients we found variants on 4 genes already related to MS by former GWAS studies: 2 genes, affected respectively by 3 and 2 deleterious variants and 2 genes, affected by non-deleterious variants. By this analysis, we found altered mechanisms potentially involved in MS, contributing to identification of new targets that could be studied to enlighten MS etiology. Disclosure Mattei G.: nothing to disclose Mechelli R.: nothing to disclose Ricigliano VAG.: nothing to disclose Buscarinu MC.: nothing to disclose Annibali.: nothing to disclose Frontali M.:nothing to disclose Ristori G.: nothing to disclose Salvetti M.: received lecture fees from Biogen-Dompé,research support from Bayer-Schering, Biogen-Dompé, Merck-Serono, Sanofi-Aventis

Immunology P877 Increased neutralization capacity of TNF-α in sera of relapsing remitting multiple sclerosis patients is not related to soluble TNF-α receptors or anti-TNF-α autoantibody levels K. Mausner-Fainberg1, Y. Feurman2, K. Regev2, H. Kolb2, A. Karni3 1Neurology, 2Tel Aviv Sourasky Medical Center, 3Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel The increased TNF-α levels in active lesions and CSF of multiple sclerosis (MS) patients and the beneficial effect of TNF-α blockade in animal models of MS led to the therapeutic usage of TNF-α antagonists in MS patients. However, systemic TNF-α blockade exacerbated MS activity and was associated with new-onset MS when implemented for treating other autoimmune disorders. We employed a TNF-α neutralization bioassay that induced apoptosis of L929 cells, and demonstrated that the capacity of sera from untreated (n=21) and IFN-β-treated (n=21) relapsing remitting MS patients to neutralize TNF-α is significantly higher than that of matched healthy controls (n=20) as was calculated in percentages of neutralization: 61.3 ± 2.9 % in the Untx group vs. 43.8% ± 3.2% in the HC group at a two-fold dilution, p=0.0002. No significant differences were found between the untreated group and the IFN-β-treated patients (57.3 ± 3.8%). Examination


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of the levels of the serum TNF-α neutralizing factors, i.e. sTNFRI (full-length isoform) (1611.1 ± 109.8 pg/ml in the HCs, 1530.6 ± 111.1 pg/ml in the untreated patients and 1695.8 pg/ml ± 102.2 in the IFN-β-Treated patients, p=NS), sTNFRII (3118.3 ± 174.1 pg/ ml for the Untx patients and 3519.6 ± 244.2 pg/ml for the HCs, p=NS). Unexpectedly, a decreased in sera levels of anti-TNF-α Abs in untreated patients (11.8%) and the IFN-β-treated patients (11.1%) as compared to the HCs (p=0.004 and p=0.03, respectively). Therefore, the TNF-α neutralization capacity was not related to the levels of sTNFRs or anti-TNF-α Abs. These findings may support the notion that qualitative rather quantitative differences in the endogenous TNF-α blockers such as the reported sTNFR1 isoform lacking exon 6 (Δ6-TNFRI), may account for the increased TNF-α neutralization capacity in RR-MS. We present an unreported aspect of TNF-α neutralization in RR-MS which may shed light on an aspect of the disease mechanism. Disclosure The study was partialy suported by Medison. P878 Expanded T-cell clonotype sequences showed specificity relatedness in the peripheral blood of MS patients by phylogenetic tree analysis A. De Paula Alves Sousa1, K.R. Jonhson1, R. Nicholas2, S. Darko3, D. Price4, D. Douek3, P. Muraro2, S. Jacobson1 1National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States, 2Imperial College London, London, United Kingdom, 3National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, United States, 4Cardiff University, Cardiff, United Kingdom Immunological studies have demonstrated that peripheral inflammatory T cells infiltrating the central nervous system play a fundamental role in the development of multiple sclerosis (MS). However, the clonal composition profile of circulating T-cells in MS patients, that may reflect perturbations of the adaptive immune response has been poorly characterized. High throughput sequencing (HTS) technology of T-cell receptors and bioinformatics analysis were applied in this study in order to evaluate the frequency of T-cell clones in MS patients and their clonotype antigen relatedness across these patients. We have used an unbiased molecular approach called 5’rapid amplification of cDNA ends to amplify the V-D-J genes of unsorted T-cells obtained from PB of 5 patients with MS who were out of any form of therapy and 5 controls classified as non-inflammatory neurological disease (NIND), and evaluated the TCR repertoire by HTS Illumina system platform. A total of 80 million reads covering the TCR hypervariable regions were analyzed using a bioinformatics program that align and match the human TCR beta-chain nucleotide sequences through IMGT database and the specificity clonal relatedness was investigated by phylogenetic tree analysis. We observed a higher number of unique TCR clonotypes and diversity in the peripheral blood of MS patients compared with that in NIND controls. When we looked at the degree of clonally expanded T-cells, differences between MS patients and controls was clearly displayed by the frequencies of each individual clonotype. In addition, we investigated the presence of public TCR repertoires, here defined as the

shared clones across all subjects. A total of 94 shared clones was identified in this study. Interestingly, we identified approximately 200 clonotypes that were specifically related to either MS or NIND control. By phylogenetic tree analysis we observed a cluster of 26 groups of clones showing similarities of their CDR3 amino acid sequence in MS patients. Analysis of the amino acid conservative position of CDR3 region suggested a motif sequence that could distinguish MS from NIND. These findings demonstrated that a comprehensive deep sequencing analysis of biased T-cell repertoire was observed in MS patients. Disclosure The authors have no conflict of interest. P879 The Gut-Brain CD39+ T regulatory cell Axis: role of the microbiota and gut associated lymphoid tissue in regulating inflammatory CNS demyelination J. Ochoa-Reparaz1, E. Kasper1, C. Kircher1, Y. Wang1, K. Telesford1, S. Haque-Begum1, A. Pant1, L.H. Kasper2 1Dartmouth College, 2Microbiology/Immunology, Dartmouth College, Hanover, NH, United States Recent evidence shows that the gut microbiota is essential for the normal development and function of the immune system. Germfree mice cannot develop experimental inflammatory disease such as EAE. Gut microbiome alterations due to both environmental and genetic factors can be associated with experimental autoimmunity, including CNS inflammatory demyelination. We have investigated the role of gut derived functionally distinct regulatory T cells (Tregs) in response to alteration of the microbiome. Others have shown that circulating CD39+Tregs are reduced in both number and capacity to suppress IL-17 by CD4+ T cells in those with relapsing MS. CD39 is an ecto-enzyme that dephosphorylates ATP to adenosine. We have reported that the polysaccharide-A (PSA), a symbiont factor produced by the human commensal B. fragilis, protects against murine EAE. Oral treatment with PSA induces IL-10-producing CD39+ FoxP3+Tregs that accumulate in the CNS of EAE mice and functionally suppress the inflammatory response. The increase of CD39+Tregs can persist for months after the last treatment with PSA. In vitro human studies show PSA can convert and amplify CD39+ expression by naïve human CD4+ T cells. We demonstrate herein that some of the approved oral and infused IMD therapies for relapsing MS promote an enhanced frequency of GALT derived CD39+Tregs. Teriflunomide (20mg/kg) (Aubagio) when delivered by oral gavage to mice reduces both frequencies and numbers of certain immune compartments in the gut associated lymphoid tissue (GALT e.g. Peyer’s patches) whereas there is a concomitant, significant increase in the frequencies of CD39+Tregs among total leukocyte population. Teriflunomide-induced GALT derived Tregs suppress the proliferation of MOG-specific auto-reactive T cells in vitro. Similarly s.c. administration of murine anti-CD52 in EAE mice promotes a phenotypic rise in GALT derived CD39+Tregs. Of interest, our previously reported preliminary human data suggests that infused anti-CD52 (Lemtrada) enhances a population of circulating CD39+Tregs amongst the residual CD4+ T cells at 4-6 months post infusion. Our data and those of


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Poster Session 2, 21(S11) others evaluating CD39+ Tregs in response to fingolimod lead us to hypothesize that GALT derived CD39+Tregs are a key immunoregulatory factor that IMD therapies promote in the gut, and constitute a common mechanism of action for the protective effects of both oral and infusion based therapies currently approved to treat MS. Disclosure J. Ochoa-Reparaz: nothing to disclose, E. Kasper: nothing to disclose, C. Kircher: nothing to disclose, Y. Wang: nothing to disclose, K. Telesford: nothing to disclose, S. Haque-Begum received grant support from Genzyme and Teva Neuroscience, APant: nothing to disclose, D. Kasper: nothing to disclose, L.H. Kasper:received grant support from GZ, Teva Neuroscience and Symbiotix Biotherapies P880 Antiviral B-cells can activate demyelinating T-cells N.S.R. Sanderson, M. Zimmermann, A. Sylvain, R.L.P. Lindberg, L. Kappos, T. Derfuss University of Basel and University Hospital Basel, Basel, Switzerland Background: The success of B cell depleting therapies in multiple sclerosis implies that B cells contribute to pathology. A possible mechanism is the activation of inflammatory T cells by presentation of T cell cognate antigen. However, according to the current view, activation of autoreactive T cells requires the presence of active, autoantigen-specific B cells, because B cells have minimal ability to present antigens other than those captured by their own B cell receptor (BCR). We propose instead that in the case of antigens expressed on the surfaces of epithelial cells (e.g., viral proteins during infection), antigen capture by viral-specific B cells involves co-capture of small amounts of other membrane components, including self proteins, and that co-presentation of these self antigens with viral antigens can activate autoantigenspecific T cells. We examined the ability of B cells to capture and present membrane-expressed cognate antigens versus coexpressed non-cognate antigens, and the ability of T cells exposed to such B cells to induce demyelinating experimental autoimmune encephalomyelitis (EAE) in mice. Methods: We exposed transgenic B cells with BCRs specific for either influenza haemagglutinin (FluBI B cells), or myelin oligodendrocyte glycoprotein (MOG)(Th B cells) to epithelial cells expressing various combinations of antigens and then co-cultured the antigen-loaded B cells with MOG-specific 2D2 T cells and examined proliferation and phenotype of T cells and B cells by flow cytometry. We visualised B cell - T cell interactions by live cell microscopy, and adoptively co-transferred both cell types into lymphocyte-deficient RAG2 -/- mice and followed them for signs of demyelination. Results: Th B cells loaded with MOG from cell membranes were potent antigen presenters, inducing robust T cell proliferation and causing EAE in 70-90% of recipient mice when cotransferred with 2D2 T cells. FluBI B cells also induced 2D2 T

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cell proliferation after exposure to cells expressing both MOG and haemagglutinin, but not if either antigen was omitted. Experiments assessing the ability of FluBI B cells to induce EAE after co-capture of haemagglutinin and MOG are currently underway. Conclusion: In the context of viral infection, it is likely that viralspecific B cells can capture and present non-cognate self antigens, leading to the activation of autoreactive T cells if such T cells are present. Disclosure N. Sanderson, M. Zimmermann and A. Sylvain have nothing to disclose. L. Kappos received institutional research support from Acorda, Actelion, Allozyne, BaroFold, Bayer HealthCare, Bayer Schering, Bayhill, Biogen Idec, Boehringer Ingelheim, Elan, Genmab, Glenmark, GlaxoSmithKline, Merck Serono, MediciNova, Novartis, sanofi-aventis, Santhera, Shire, Roche, Teva, UCB, Wyeth, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, the Novartis and Roche Research Foundation. T. Derfuss serves on scientific advisory boards for Novartis Pharma, Merck Serono, Biogen Idec, Genzyme, Mitsubishi Pharma, TEVA Pharma, GeNeuro, and Bayer Schering Pharma; has received funding for travel and/or speaker honoraria from Biogen Idec, Novartis, Merck Serono, and Bayer Schering Pharma; and receives research support from the Swiss National Research Foundation, Biogen Idec, Novartis Pharma, the European Union, and the Swiss MS Society. P881 Proinflammatory ALCAM+ B-cells migrate faster across blood meningeal barrier L. Michel1, J. Alvarez1, M.-A. Lécuyer1, L. Bourbonnière1, P. Duquette1, J. Gommerman2, A. Bar-Or3, A. Prat1 1Neurosciences, CRCHUM, Montréal, QC, 2University of Toronto, Toronto, ON, 3McGill University, Montréal, QC, Canada Background: Multiple Sclerosis (MS) is classically considered as a T lymphocyte-mediated autoimmune disease. However, the efficacy of therapies targeting B cells and the presence of lymphoid follicles within the meninges of some patients, plead for an important role of B lymphocytes in MS physiopathology. Objective: To analyze the interactions of B cells with endothelial cells (ECs) derived from distinct central nervous system (CNS) barriers. Methods: Transmigration of B lymphocytes from Healthy Volunteers (HV) was assessed in primary cultures of parenchymal and meningeal ECs that replicate in vitro the Blood Brain Barrier (BBB) and Blood Meningeal Barrier (BMB). The phenotype of migrated B cells was analyzed and compared to those of non migrated cells by flow cytometry. Blocking experiments were also performed using an anti ALCAM (Activated Leukocyte Cell Adhesion Molecule) antibody. Results: Trans-endothelial migration assays revealed that BBB is significantly less permissive to B cell migration when compare to the BMB (10.1% (BMB) vs. 4.9% (BBB)) (n=14 HVs). Migrated


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B cells across BBB and BMB present a proinflammatory profile with a significantly higher secretion of TNFα and GMCSF and a higher expression of CD80 and ALCAM. Interestingly, it has been demonstrated by our team that this molecule is implicated in leucocytes migration across BBB. In our assays, the use of antiALCAM blocking antibody induced a significant 25% reduction in the number of migrated B lymphocytes across the BMB (n=4 HVs). These ALCAM+ B lymphocytes contain significantly more CD19+CD27+/CD24hiCD38- memory B lymphocytes. They are also significantly enriched in markers of activation (such as CD80, CD86 and CD95), and secrete significantly more proinflammatory cytokine (IL-6, TNFα and GM CSF) as compared to ALCAMneg B cells. After 2 days of activation, ALCAM is also significantly upregulated (from 32% to 87%, n=6 HVs) (Flow cytometry and immunocytofluorescence). Conclusion: The BMB is more permissive to proinflammatory B cell transmigration as compared to the BBB and ALCAM is likely playing an important role in this process. Our future work aims to bring out proinflammatory B cells inside the CNS of MS patients, but also to identify additional pathways implicated in their transmigration across distinct CNS vascular beds. Disclosure Laure Michel: nothing to disclose. Jorge Alvarez: nothing to disclose. Marc-André Lécuyer: nothing to disclose. Lyne Bourbonnière: nothing to disclose. Pierre Duquette: nothing to disclose. Amit Bar-Or: nothing to disclose. Jennifer Gommerman: nothing to disclose. Alexandre Prat: nothing to disclose. P882 Placental mesenchymal stem cells (pMSCs) modulate the differentiation and functions of macrophages in multiple sclerosis patients M. Al Jumah1, S. Kojan1, A. Al Khathaami2, N. Al Otaibi2, A. Jawhary3, F.M. Abomaray3, A.M. Alsubayyi3, M.H. Abumaree4 1Division of Neurology, KAMC, King Abdulaziz Medical City, King Abdullah International Medical Research Center, King Saud Ben Abdulaziz University for Health Sciences, and National Guard Health Affairs, 2Division of Neurology, KAMC, King Abdulaziz Medical City, 3King Abdullah International Medical Research Center, King Abdulaziz Medical City, 4College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, National Guard Health Affairs, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia Objectives: Multiple sclerosis (MS) is a chronic, progressive inflammatory disorder of the central nervous system (CNS) that results from a destruction of myelin sheath covering axons by autoreactive T cells. Remyelination and restoration of neuronal functions in MS can be achieved via stimulating endogenous neuronal repair mechanism or by transplanting myelinating cells. However, maintaining neuron functions for long term, it requires the regulation of the immunopathogenic process. Mesenchymal stem cells (MSCs) can reduce the encephalitogenic manifestation

of MS by inhibiting autoreactive T cell functions. Here, we demonstrated that placental MSCs (pMSCs) can alter the differentiation and functions of macrophages from MS patients. Methods: Monocytes isolated from peripheral blood of MS patients were spontaneously differentiated into macrophages and then co-cultured with pMSCs in the early stages of macrophage differentiation. We then evaluated the effect on differentiation by microscopic examination, flow cytometry and ELISA. Results: The co-culture of pMSCs with monocytes spontaneously differentiated into macrophages shifted macrophage differentiation from inflammatory M1 macrophages into anti-inflammatory M2 macrophages. This was confirmed by morphological changes typical of M2 macrophages, and by changes in cell surface marker expression including CD14, CD163, CD206 and B7-H4, which are distinctive of M2 macrophages. In addition, pMSCs reduced the expression of the costimulatory molecules (CD40, CD80 and CD86), increased the expression of co-inhibitory molecules (CD273, CD274 and B7-H4) and MHC-II molecules. Furthermore, IL-10 secretion was increased while the secretion of IL-1β, IL-12 (p70) and MIP-1α was decreased; a profile typical of M2 macrophages. Conclusions: We have shown that pMSCs can change macrophages from an inflammatory M1 into an anti-inflammatory M2 phenotype. This result demonstrates that pMSCs have the potential to modulate the immunostimulatory process in MS, Therefore, pMSCs may have a therapeutic application in treating MS through M2 macrophages, which can suppress autoreactive T cell functions. Disclosure Dr. M Al Jumah: nothing to disclose. Dr. S Kojan: nothing to disclose. Dr. A Al Khathaami: nothing to disclose. Dr. N Al Otiabi: nothing to disclose. Dr. A Jawhary: nothing to disclose. Dr. FM Abomaray: nothing to disclose. Dr. AM Alsubayyil: nothing to disclose. Dr. MH. Abumaree: nothing to disclose. P883 The association between IgM and IgG antibodies against cardiolipin, β2-glycoprotein I and Domain I of β2-glycoprotein I with disease profile in patients with multiple sclerosis N. Filippidou1, G. Krashias2, C. Pericleous3, A. Rahman3, I. Giles3, Y. Ioannou3, A. Anatolitou1, C. Christodoulou2, M. Pantzaris1, A. Lambrianides1 1Neurology Clinic C, 2Department of Virology, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus, 3Centre for Rheumatology, University College London, London, United Kingdom Background: Autoantibodies occur frequently in autoimmune neurological diseases such as multiple sclerosis (MS). There have been a number of studies reporting that patients with MS have elevated levels of aPL; nonetheless their exact prevalence and pathogenic role remain unclear. The strongest evidence for pathogenicity of aPL in autoimmune diseases such as the antiphospholipid syndrome, is against β2-glycoprotein I (β2GPI); noteworthy clinical significance points specifically to antibodies against


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Poster Session 2, 21(S11) domain I (DI) of β2GPI as being important. Our objective was to assess the frequency of aPL in a large well-defined cohort of patients with MS. We pursued an approach to explore the potential relevance of antibodies against DI in patients with MS. Methods: Serum samples from a cohort of 132 patients with MS [91 relapse-remitting MS patients (RRMS), 13 primary-progressive MS patients (PPMS) and 29 secondary progressive (SPMS)] and 89 controls, matched for age and gender, were tested by standard ELISA for IgM and IgG antibodies against cardiolipin (CL), β2GPI and DI. Cut-offs for positivity in the assays are defined by mean+2SD of the activity of controls. Analysis was performed with Chi-squared test using the Fisher´s exact results where a variable had an expected frequency of five or less. Results: Higher levels of IgM and IgG anti-CL were found in patients with MS (28.1% and 23.8% respectively), compared to controls (4% and 2.7%, p< 0.01). Interestingly, anti-DI (both IgM and IgG) were associated with MS subjects, with 22.8% and 17.3% being positive for anti-DI IgM and IgG, respectively, compared to controls, 8.3% and 3.3% (p< 0.01). The frequency of IgM and IgG anti-β2GPI did not differ significantly between patients with MS and controls. Levels of IgM and IgG anti-CL were elevated in SPMS compared to PPMS and RRMS. There was a trend suggesting that IgM anti-DI are associated with RRMS patients while IgG anti-DI were elevated for SPMS patients. Levels of IgG anti-CL were significantly less in patients that received interferon-β treatment (94.7% being negative, p< 0.01) compared to those that did not receive interferon-β. Conclusion: Although we have confirmed that IgM and IgG antiCL antibodies occur in patients with MS, this is the first study that has identified anti-DI antibodies in MS. This new finding may prove valuable and future studies are required to evaluate its role as a potential risk factor of arterial and venous thromboembolic phenomena in MS. Disclosure Natalia Filippidou: nothing to disclose. George Krashias: nothing to disclose. Charis Pericleous: nothing to disclose. Anisur Rahman: nothing to disclose. Ian Giles: nothing to disclose. Yiannis Ioannou: nothing to disclose. Afrodite Anatolitou: nothing to disclose. Christina Christodoulou: nothing to disclose. Marios Pantzaris: nothing to disclose. Anastasia Lambrianides: nothing to disclose. P884 Clinical and histopathological amieloration of experimental autoimmune encephalomyelitis by AAV vectors expressing soluble IL23 receptor C. Espejo1, M. Miralles2, H. Eixarch1, M. Puig2, C. Costa1, M. Tejero2, K. Hirota3, R. Castaño4, G. Stockinger3, X. Montalban1, A. Bosch2, M. Chillon2,5,6 1Multiple Sclerosis Centre of Catalonia/Neuroimmunology Dept, Vall d’Hebron University Hospital & VHIR, Barcelona, 2Center of Animal Biotechnology and Gene Therapy (CATEG), Dept Bioquímica i Biologia Molecular, Universitat Autònoma Barcelona, Bellaterra, Spain, 3MRC, National Institute for Medical Research, London, United Kingdom, 4IBB, Dept

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Bioquímica i Biologia Molecular, Universitat Autònoma Barcelona, Bellaterra, 5ICREA, Barcelona, 6Vector Production Unit (UPV), Universitat Autònoma Barcelona, Bellaterra, Spain Background: The role of the Th17 pathway has been proven in the pathogenesis of multiple sclerosis (MS), where IL23 has a key role in maintaining Th17 response. Recent therapeutical strategies based on blocking the IL23:IL23 receptor (IL23R) interaction have been developed to regulate the Th17 response. Objectives: To investigate whether the use of soluble IL23R (sIL23R) to selectively block the IL23:IL23R interaction has a clinical positive effect in the MOG-induced EAE model. Methods: Adeno-associated vectors (AAV8) containing the soluble subunit p19 of IL23R or null sequences were produced. A dose of 5x1011vg of AAV8-sIL23R or AAV8-null was administered intravenously to mice. After 18 days, experimental autoimmune encephalomyelitis (EAE) was induced by immunizing mice with MOG45-55. Mice were daily assessed for neurological signs. Histo- and immunohistopathological and immunological studies were also performed. Results: Mice treated with sIL23R showed a significant improvement of the EAE clinical signs with respect to those treated with the null vector. Clinical improvement was stable and sustained in time until the end of the experiment, with a mean clinical score on the last day of 4.69±0.84 in the control group and of 2.71±1.70 in the sIL23R group (p=0.012). In addition, the cumulative mean clinical score was 39.8±28.2 for sIL23R-treated animals compared to 84.4±12.9 for control mice (p=0.003). No differences were observed when polyclonal (PHA) or antigen-specific proliferation of splenocytes was assessed. However, sIL23-treated mice produced a higher amount of IFNγ than control mice (5,691.30±2,639.28 pg/ml vs. 1,765.89±1,146.08 pg/ml, p=0.016). In addition, sIL23R-treated mice showed much more discreet inflammatory infiltrate and no demyelination, while control mice showed demyelination and abundant inflammatory infiltration in the spinal cord. Microglial and astroglial activation in sIL23R-treated mice were significantly lower than in control mice (mean integrated fluorescence intensity, control: 1.58x1012±9.34x1011; sIL23R: 0.29x1012±2.54x1011; p< 0.05 for microglia and control: 7.43x1011±1.81x1011; sIL23R: 2.11x1011±7.75x1010; p=0,0002 for astroglia). Conclusions: Blocking the IL23:IL23R interaction with AAV vectors carrying sIL23R may be a new therapeutic strategy for MS treatment that could take advantage from those in which monoclonal antibodies were used, avoiding the formation of neutralizing antibodies with consequent loss of efficiency. Disclosure The sources of funding for the research submitted in the abstract are: - The Instituto de Salud Carlos III (ISC-III PI10-00561) - “Agència de Gestió d’Ajuts Universitaris i de Recerca” (AGAUR) of the Generalitat de Catalunya in Spain SGR2009-1300; SGR2014-1354 - Carmen Espejo is partially supported by the “Miguel Servet” programme (CP07/00146; CP13/00028) of the Fondo de Investigación Sanitaria, the Instituto de Salud Carlos III, the Ministry of Economy and Competitiveness of Spain. - Marta Miralles has been recipient of a FPU-Ministerio de Educación fellowship.


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- Herena Eixarch declares no competing financial interests. - Meritxell Puig declares no competing financial interests. - Carme Costa declares no competing financial interests. - Marcos Tejero declares no competing financial interests. - Keiji Hirota declares no competing financial interests. - Raul Castaño declares no competing financial interests. - Gitta Stockinger declares no competing financial interests. - Xavier Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall. - Assumpció Bosch declares no competing financial interests. - Miguel Chillon declares no competing financial interests. P885 Characterization of local T-cell responses in multiple sclerosis patients G.P. van Nierop1,2, J.G. Mitterreiter1,3, M. Janssen2, G.M. Verjans1,3, R.Q. Hintzen2 1Department of Viroscience, 2MS Center ErasMS at the Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands, 3Research Center for Emerging Infections and Zoonosis, University of Veterinary Medicine, Hannover, Germany MS develops in genetically susceptible individuals in response to environmental factors, potentially Epstein-Barr virus (EBV) infection. MS pathology is potentially mediated by local T-cell responses directed to autoantigens and/or foreign antigens like EBV. We determined the frequency, phenotype and antigens recognized by T-cells recovered from cerebrospinal fluid (CSF) of early MS patients and controls and from brain tissue of deceased end-stage MS patients. T-cell lines (TCL) were generated by mitogenic stimulation of (1) surplus CSF obtained from early MS patients and patients with other neurological disease (OND) and (2) paired CSF and brain tissues [both macroscopic lesion and normal appearing white matter (NAWM)] of deceased end-stage MS patients. Brain tissues were used for in situ analysis and ex vivo T-cell phenotyping using flow cytometry. CSF- and brain-derived TCL were analysed for T-cell clonality and antigen specificity. From paired blood, EBV-transformed B-cells (BLCL) were generated and used as antigen presenting cell (APC) to enumerate and phenotype EBV-specific T-cells in the TCL generated. Additionally, BLCL were transduced to accomplish endogenous expression of eight different human MS-associated antigens (MSAg) as APC for the detection of autoreactive T-cells in TCL: MBP, MAG, MOG, PLP, KIR4.1, S100B, CNTN2 and NFASC. Early MS patients showed an elevated oligoclonal BLCL-specific CD4 and CD8 T-cells response in CSF directed to lytic EBV antigens. No T-cell reactivity to MSAg was detected. In situ analysis of end stage MS lesions revealed extravasated T-cells, mainly CD8 that express Ki67 and granzyme B, indicating local proliferation of antigen-experienced T-cells. Flow cytometric analyses

showed that T-cells in paired NAWM and MS lesions expressed a similar, mainly effector memory T-cell phenotype; but with a distinct oligoclonal T-cell receptor Vß repertoire. Notably, BLCL reactive T-cells were selectively detected in lesions of 2 of 7 endstage MS patients. Enhanced intrathecal BLCL-specific T-cell reactivity, selectively directed towards lytic EBV proteins in CSF-TCL, suggest a local T-cell response to EBV early in MS. The inability to detect T-cells specific for multiple human MSAg questions their role as prominent target antigens in MS. Finally, the selective retention of CD8 T-cells in MS lesions directed to BLCL but not MSAg suggest involvement of EBV-specific T-cells in diseased brain tissue of end-stage MS patients. Disclosure This work was partially funded by the Dutch MS Research foundation (project #09-670 to GPvN) and the NiedersachsenResearch Network on Neuroinfectiology, of the Ministry of Science onad Culture of Lower Saxony, Germany (to JGM and GMGMV) Gijsbert P van Nierop: nothing to disclose Johanna G Mitterreiter: nothing to disclose Malou Janssen: nothing to disclose Georges M.G.M. Verjans: nothing to disclose Rogier Q. Hintzen: nothing to disclose

P886 Adhesion molecule dynamics after natalizumab withdrawal in T-lymphocytes subpopulations A. Cobo-Calvo1, A. Figueras2, L. Bau1, E. Matas1, M.A. Mañé1,3, L. Romero Pinel1, S. Martínez Yélamos1 1Hospital Universitari de Bellvitge - IDIBELL, Multiple Sclerosis Unit, 2Laboratori de Recerca Translacional ICO-IDIBELL, 3Hospital Juan XXIII de Tarragona, Barcelona, Spain Background: Natalizumab (NTZ) is a monoclonal antibody that binds to the α4 integrin (CD49d) leading to an inhibition of immune cells migration into the central nervous system (CNS). Although adhesion molecules (AM) expression in leucocytes have been already studied during NTZ introduction in Multiple Sclerosis (MS) patients, their temporal dynamics after NTZ withdrawal (NTZ-W) has not been described. Aim: To evaluate the changes in the expression levels of cell trafficking AM involved in T cell migration after NTZ-W. Methods: Peripheral blood samples from 22 MS patients treated with NTZ (NTZ duration range, 2.56 - 7.87 years) were prospectively collected at one, two, three and six months after last NTZ infusion. Fingolimod was initiated between month two and three from last NTZ infusion. Eighteen samples were collected in nine treatment- naive MS patients[a1] (TN-MS) without active clinical activity. CNS-addressing integrins (CD49d and CD29a) and AM (L-Selectine and CD11a) expression on CD45+CD4+ and CD45+CD8+ T cells were determined by flow cytometry. Patients were evaluated clinically every month and a brain Magnetic Resonance Imaging (MRI) was performed at the start of the study and after 6 months. Results: We observe a continuous significant increase of CD49d, CD29a and CD11a expression in both


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Poster Session 2, 21(S11) T cells subsets after two months of last NTZ infusion (p< 0.001). Expression of these molecules reached a significant higher expression than TN-MS patients at the end of the study. Cd49d levels at moth six correlated to NTZ treatment duration in CD45+CD4 (r=0.66, p=0.008) and CD45+CD8 (r=0.59, p=0.030) T cells. There was no association between other AM and clinical or MRI data. Conclusions: Ms patients showed a progressive increase of CD49d, CD29a and CD11a during the six month period after NTZW. Apart from the CD49d/CD29a integrins, CD11a could be involved in T cell transmigration into the CNS during NTZ treatment. MS patients with longer NTZ treatment period experienced a higher Cd49d surface expression after six months from NTZ-W. Disclosure Nothing to disclose P887 Natural killer cell redistribution during short-term treatment with fingolimod in multiple sclerosis A. Harrer1, G. Pilz1, K. Oppermann1, S. Afazel1, E. HaschkeBecher2, J. Kraus1,3, E. Trinka1, J. Sellner1, P. Wipfler1 1Department of Neurology, Paracelsus Medical University Salzburg, 2Department of Laboratory Medicine, Paracelsus Medical University Salzburg, Salzburg, 3Department of Neurology, Public Hospital Zell am See, Zell am See, Austria Background: A role of innate lymphoid cells (ILC), in particular natural killer (NK) cell subsets in relapsing-remitting multiple sclerosis (MS) is increasingly recognized. Fingolimod treatment induces peripheral lymphocytopenia mainly of T cells, B cells, and a minority population of CD56bright (br) natural killer (NK) cells whereas relative proportions of NK and NKT cells are increased. Results: On total NK cells in the circulation, however, are inconclusive. We, therefore, compared changes in absolute numbers and relative proportions of NK cells in response to short-term fingolimod treatment. Methods: Percentages of T cells (CD3), B cells (CD19), NK cells (CD56CD3-, CD56brCD3-) and NKT cells (CD56CD3+) of peripheral blood mononuclear cells (PBMC, enriched by density centrifugation) from 11 MS patients were analyzed before initiation of treatment (baseline; T0) and on short-term fingolimod treatment (T1; median 3.4 months, range 2.8-7.0) by flow cytometry. Absolute numbers of lymphocyte subsets were determined by relating percentages of lymphocyte subsets to the absolute lymphocyte counts assessed from whole blood by an automated hematology analyzer. Results Absolute lymphocyte counts dropped from median 2.2x109 G/L (interquartile range (IQR) 2.02.5) to 0.5 (IQR 0.4-0.5) in response to short-term fingolimod treatment. This involved a pronounced decrease of absolute numbers and percentages of T and B cells and a similar trend in CD56br cells. Contrary, percentages of NK and NKT cells increased from median 13% (IQR 8.0-18.0) to 47% (IQR 30-54) and 4% (IQR 3-5) to 13% (IQR 8-18), respectively, whereas cell numbers remained largely unaltered (NK: median 0.23x109 G/L (IQR 0.19-0.37) and 0.17 (IQR 0.13-0.26), p=0.108; NKT: median 0.08x109 G/L (IQR 0.05-0.1) and 0.07 (IQR 0.03-0.09), p=0.103).

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In detail, percentages of NK cell were 2-10 fold increased in all whereas absolute NK numbers were decreased in 7, unchanged in 2, and increased in 3 of the 11 patients in response to fingolimod. Discussion: The fingolimod-induced redistribution of lymphocytes favors NK cells as predominant subset in the circulation. The role of NK cells is unclear but the pronounced interindividual differences in absolute NK cell numbers during fingolimod, however, are a possible source for different therapy efficacy. Disclosure AH received travel support from Merck Serono, Genzyme, Novartis, Teva; KO received travel support from Bayer, Biogen-Idec, Genzyme, Merck Serono, Sanofi-Aventis; GP received travel support from Biogen-Idec, Bayer, Merck Serono, and Teva-Ratiopharm; EHB received financial support for research activities from Abbott Diagnostics, Roche Molecular Diagnostics SA has nothing to disclose JK received financial support for research activities from Almirall, Bayer, Biogen-Idec, Genzyme, Medtronic, Merck-Serono, Novartis, Sanofi-Aventis,TEVA ratiopharm. ET received financial support for research activities from Eisai, Ever-Neuropharma, Medtronics, Pfizer, Sunovion, New Bridge, Gerot-Lanacher, Biogen-Idec, Sanovi, Bial, Cyberonics, Novartis, Actavis, UCB Pharma JS received personal compensations for consulting services from Biogen-Idec, Terumo, Merck-Serono, Genzyme, Novartis, Teva-Ratiopharm. PW received travel support and speaker’s honoraria from Merck Serono, Biogen-Idec, Bayer, Novartis; P888 The novel role of integrin alpha8 in mediating CD4+ T lymphocyte migration across the CNS vasculature in multiple sclerosis E.M. Gowing1, S. Gendron1, M.-A. Lecuyer1, B. Broux1,2, S. Terouz1, L. Bourbonniere1, M. Charabati1, S. Larouche1, C. Pittet1, P. Duquette3, A. Prat1,3 1Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada, 2Hasselt University, Diepenbeek, Belgium, 3Multiple Sclerosis Clinic, Department of Neurology, CHUM Notre-Dame Hospital, Montreal, QC, Canada Introduction: Active migration of peripheral blood (PB) leukocytes across the central nervous system (CNS) barriers into the parenchyma is a critical process in multiple sclerosis (MS) pathogenesis. These barriers include the tightly regulated blood-brain barrier (BBB) and blood-meningeal barrier (BMB). Integrins, which are heterodimeric alpha/beta transmembrane proteins, facilitate this transmigration by mediating cell-cell or cell-extracellular matrix protein interactions. Beta1 integrin heterodimers are associated with the migration of PB lymphocytes across CNS barriers, as supported by the clinical efficacy of Natalizumab, a monoclonal antibody targeting integrin alpha4beta1. However, due to widespread expression of alpha4beta1 on most leukocyte subsets, Natalizumab treatment is associated with impaired


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immune surveillance and susceptibility to lethal viral infections. Therefore, our goal is to characterize the role of novel beta1 integrin partners in the specific migration of pathogenic T lymphocytes across the CNS vasculature. Methods and results: Whole cell lysate proteomic analysis reveals that polarized TH17 cells express integrin alpha8beta1. Here we show through qPCR, western blot and immunocytochemistry that alpha8 is specifically expressed by activated CD4+CD45RO+ T lymphocytes and is upregulated in pro-inflammatory conditions in healthy controls and MS patients. Immunofluorescence reveals that alpha8 is expressed on CD4+ T cell infiltrates in MS and mouse experimental autoimmune encephalomyelitis (EAE) brains. Furthermore, we demonstrate via RT-PCR, western blot and immunofluorescence that both BBB endothelial cells (ECs) and BMB-ECs express the main ligand of alpha8, nephronectin (NPNT). Blockade of alpha8 binding using an RGD-blocking peptide results in decreased TH1 and TH17 lymphocyte migration across a monolayer of BBB-ECs in an in vitro migration assay. Moreover, preliminary in vivo data suggest that therapeutic i.p. injections of alpha8 blocking peptide is sufficient to reduce disease severity as compared to control peptide or HBSS injections in MOG35-55 - induced EAE mice. Conclusions: These data highlight an important role for alpha8 in mediating pro-inflammatory T lymphocyte migration across blood-CNS barriers, and suggest that targeting this integrin may be an effective therapeutic intervention for preventing pathologic neuroinflammation and relapses in MS.

related to CD4+ T cells, macrophages and type-1 interferon (IFN) response, respectively. Expression of CD8, IFN-γ, granzyme A, interleukin-15, CXCL10 and matrix metalloproteinase-9 genes was significantly lower in meningeal B-cell follicles than in the less organized meningeal infiltrates; only IFN-α receptor 1 was more expressed in the ectopic follicles. Using digital PCR and EBV DNA polymerase as target gene, viral DNA load was accurately assessed in the meningeal infiltrates of 8 MS cases. Although at different levels, 7 of 8 meningeal laser cut samples analyzed displayed a positive signal for EBV DNA. We are currently examining a larger number of immune-related genes and will extend the analysis of cellular genes and EBV DNA load to perivascular immune infiltrates from the white matter. The information gathered from these experiments will help clarify the involvement of specific immune cell types and molecular pathways in different brain compartments and lesion stages and will advance our understanding of EBV-immune system interactions in the MS brain. Disclosure This study is funded by Italian Multiple Sclerosis Foundation (grant 2013/R/22 to BS) and Italian Ministry of Health (grant RF 2011-02347228 to FA). Caterina Veroni: nothing to disclose Barbara Rosicarelli: nothing to disclose Barbara Serafini: nothing to disclose Francesca Aloisi: nothing to disclose

Disclosure

P889 Gene expression analysis of immune infiltrates isolated by laser microdissection from the multiple sclerosis brain C. Veroni, B. Rosicarelli, B. Serafini, F. Aloisi Istituto Superiore di Sanità, Rome, Italy

P890 CD8+CD45RClow regulatory T-cells are functionally altered in multiple sclerosis B. Nicol1,2, S. Bézie1,2, A. Garcia1,3, S. Wiertlewski4,5, S. Brouard1,3, C. Guillonneau1,3, D.A. Laplaud1,4,5 1INSERM, UMR 1064, 2Université de Nantes, Faculté de Médecine, 3CHU de Nantes, ITUN, 4CHU de Nantes, Département de Neurologie, 5INSERM 015, Centre d’investigation Clinique, Nantes, France

This study was designed to test the hypothesis that brain damage in multiple sclerosis (MS) is the result of the host’s immune system attempt to eradicate a persistent intracerebral infection with Epstein-Barr virus (EBV), this virus gaining access to the central nervous system through its preferred cellular reservoir, the B cell. To this end, we have used post-mortem brain tissue form 12 cases with secondary progressive MS (obtained from the UK MS Tissue Bank) and combined immunohistochemical techniques, laser capture microdissection and advanced polymerase chain reaction (PCR) methods to analyze cellular gene expression and EBV DNA load in well characterized immune infiltrates isolated from the white matter and the meninges (including ectopic B-cell follicles), and to search for possible correlations among cellular transcript levels, EBV infection, localization/cellular composition/ organization of the microdissected immune infiltrates, and tissue pathology. To date, we have examined expression of 40 immunerelated genes in 37 meningeal infiltrates using preamplification real time reverse transcription PCR. Significant correlations were found among genes involved in viral nucleic acid recognition, CD8+ T-cell and NK-cell recruitment and cytotoxicity, and genes

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system, probably of autoimmune origin. To date, the role of CD8+ regulatory T cells (Tregs) in MS remains largely unexplored. Recently, we have described a new subset of CD8+ Tregs included in CD45RClow subpopulation and able to produce IFNγ, with a great efficiency in regulating graft-versus-host disease (GVHD) and skin transplantation in humanized mice (Guillonneau et al., JCI, 2007; Picarda et al., JCI, 2014; Bezie et al., JCI, in revision). Recent findings in our team showed two distinct subsets in CD8+CD45RClow, called CD8+CD45RCint and RCneg, with distinct phenotypes and functions. The aim of our study is to analyze the frequency and function of CD8+CD45RClow and its two subpopulations in the blood of MS patients as compared to healthy volunteers (HV). First, twenty-two patients with an untreated relapsing-remitting MS were compared to 24 age- and gendermatched HV. The frequency of CD8+CD45RCint tend to decrease in the blood of MS patients as compared to HV (p=0.06). Then, we tested the ability of CD8+CD45RClow cells to suppress CD4+ T cell proliferation in a Mixed Lymphocyte Reaction. Our

E.M.G., S.G., M.A.L., B.B., S.T., L.B., M.C., S.L., C.P., P.D. and A.P. have nothing to disclose.


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Poster Session 2, 21(S11) preliminary results showed a profound reduction (about 75%) of the suppressive capacity of CD8+CD45RClow in MS patients as compared to HV. Finally, the frequency of IFNγ-, IL-2 and IL-10/ IFNγ-secreting CD8+CD45RCint was decreased in the blood of MS patients as compared to HV (p=0,0066; p=0,06 and p=0,0173 respectively). These preliminary results suggest an impairment of the function of CD8+ Tregs in MS patients and will be strengthen by next functional experiments, including transfer to NOD scid gamma mice to prevent GVHD. If confirmed, these results would suggest that CD8+CD45RClow, especially its subsets, may be potential therapeutic tools in MS patients. Disclosure B.Nicol: nothing to disclose S.Bézie: nothing to disclose A.Garcia: nothing to disclose S.Wiertlewski: nothing to disclose S.Brouard: nothing to disclose C.Guillonneau: nothing to disclose DA.Laplaud: nothing to disclose P891 TCF-1 regulates T-cell response in multiple sclerosis M.A. Mazzola1, R. Raheja1, H. Rajabi2, R. Griffin1, L. Aly1, B. Patel1, H. Weiner1, R. Gandhi1 1Harvard Medical School, Brigham and Women’s Hospital, 2Dana Faber Cancer Institute, Boston, MA, United States Objective: We investigated the association of T cell Factor-1 (TCF-1) on T cells activation in Multiple Sclerosis (MS).  Background: Multiple Sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS), driven by autoreactive lymphocytes resulting into an inflammatory cascade and subsequent damage of myelin and axons that lead to neurodegeneration. TCF-1 is a transcription factor that plays an important role in T cell development and differentiation. Polymorphism of TCF-1 has been associated with autoimmune disease such as Multiple Sclerosis and Type-1 Diabetes. FTY720, the first oral treatment approved for MS, is sphingosine-1-phosphate agonist that induces rapid and reversible sequestration of lymphocytes into secondary lymphoid organs. Method: Gene expression profiling in T cells from control and MS patients was measured with nanostring and qPCR. T cells were cultured in vitro with and without FTY720 and cytokines production was measured using luminex assay. The expression of TCF-1 was knocked down in primary CD4 naïve T cells by lentivirus vector carrying shRNA against TCF-1. Chromatin immune precipitation was performed to assess the TCF-1 binding to promoter regions. Results: We found that T cells from Relapsing Remitting Multiple Sclerosis (MS) patients have decreased expression of TCF-1 compared to healthy controls. We investigated the molecular mechanism of TCF1 mediated regulation of T cell differentiation. We found that TCF-1 down-regulates IFN-γ and Granzyme B (GZMB) expression by direct binding to their promoter or enhancer region. The knock down of TCF-1 using lentivirus increased the cytokine expression and induced a more inflammatory T cell phenotype. T

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cells activated with FTY720 have higher expression of TCF-1 and reduced expression of IFN-γ and GZMB. FTY720 regulates TCF-1 expression through crosstalk of sphingosine pathway with Wnt signaling. Conclusion: TCF-1 regulates differentiation of inflammatory T cell, development of autoimmunity and its upregulation, upon FTY720 treatment, induces a less inflammatory T cell phenotype. Disclosure Maria Antonietta Mazzola: nothing to disclose Radhika Raheja: nothing to disclose Hasan Rajabi: nothing to disclose Russell Griffin: nothing to disclose Lili Aly: nothing to disclose Bonny Patel: nothing to disclose Howard Weiner: I have research support from Serono, Biogen, Therapix, Novartis, Genzyme and Teva. Roopali Gandhi: I have research support from Serono, Biogen and Novartis. P892 Increase in JC virus antibody levels during pregnancy in MS patients S. Atula1, K. Hedman2, L. Jouhi3, A. Jalkanen4, L. Airas4 1Clinical Neurosciences, Neurology, 2Department of Virology, 3Otorhinolaryngology - Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, 4Division of Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, Finland Background: Cell-mediated immunity is moderately impaired during pregnancy and, probably related to this, cell-mediated (Th1-type) autoimmune diseases, such as multiple sclerosis (MS), tend to ameliorate during pregnancy. Sometimes the mother may suffer from such aggressive MS, that efficient treatment is warranted also during pregnancy. An important element of JC virus (JCV) immunity is cell-mediated, i.e. the surveillance of JCV may be weakened during pregnancy. Hence, pregnant MS patients might be at increased risk of natalizumab-related progressive multifocal leucoenkefalopathy (PML). JCV antibody (Ab) levels are linked to PML immunity, with high Ab levels reflecting increased PML risk. The purpose of this study was to assess whether JCV Ab levels in MS patients change during pregnancy and postpartum. Materials and methods: Six serial serum samples were prospectively collected from MS patients (n=60) during and after pregnancy in 2003-2005. A control group consisted of 60 healthy pregnant women with corresponding pregnancy serum samples. Anti-JCV-Ab-index was determined by the second-generation ELISA (STRATIFY JCVTM DxSelectTM) assay. Total-Ig and Ig-subclass levels were measured for comparison. SPSS version 20.0 was used for statistical analysis of the data. Results: The mean JCV Ab levels increased significantly during pregnancy in MS patients: during the 1st trimester (early pregnancy) the mean index was 0.79 (SEM 0.19) and during the 3rd trimester (late pregnancy) 1.35 (SEM 0.39, p=0.03). No such increase was observed in the total Ig levels or in Ig subclasses. Conclusions: Cell-mediated immunity is generally weakened during pregnancy, which predisposes the mother to infections


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caused by intracellular pathogens. JCV-IgG levels in MS patients increased significantly during pregnancy. The observed increase in JCV-IgG levels is possibly related to the general weakening of cell-mediated immunity during pregnancy. Caution is warranted when prescribing natalizumab to JCV-positive MS patients during pregnancy. Disclosure Dr. Sari Atula has received speaker honoraria from Biogen Idec,Merck Serono, Novartis and Genzyme and has got travel grants from Novartis and Genzyme. Dr. Laura Airas has received speaker honoraria from Biogen Idec, Sanofi-Aventis, Merck Serono, Novartis and Genzyme, and has received research support from Biogen Idec, Novartis, GE and Merck Serono. Dr. Anna Jalkanen has nothing to disclose. Dr Lauri Jouhi has nothing to disclose. Dr Hedman has nothing to disclose. P893 The role of norepinephrine in regulating interactions of the immune and nervous system in multiple sclerosis M. Melnikov1, V. Murugin2, M. Pashenkov2, A. Boyko1 1Russian National Research Medical University, 2Institute of Immunology, Moscow, Russian Federation Introduction: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), which is caused presumably by an autoimmune attack against the CNS. Norepinephrine may participate in MS pathogenesis by modulating immune cell activity and cytokine production. Objective: To study the relationship between neuropsychological impairment, norepinephrine concentration in the serum, quantitative and qualitative characteristics of Тh17-cells, and to clarify the influence of dopamine on the function of Th17 cells. Materials and methods: Data from 53 patients with relapsingremitting MS and 20 healthy controls were included. The presence of depression was evaluated using the Beck’s scale. The norepinephrine concentration in the serum was measured by ELISA. Circulating Th17-cells were determined by flow cytometry (CD4+CD26+CD161+CD196+). The levels of IL-17 were studied by ELISA in supernatants of peripheral blood mononuclear cells stimulated with anti-CD3/anti-CD28 antibodies in the absence and in the presence of norepinephrine at a concentration of 10^-4M. Results: The concentration of norepinephrine was not different between the groups. The percentage of Th17-cells in MS patients in exacerbation was higher than in remission or in the control group (p< 0,01). In patients with depression, the percentage of Th17 cells was also higher than in the control group (p< 0,05), while in patients without depression, the percentage of Th17 cells was not different from the control group. Production of IL-17 in MS patients in exacerbation was higher than in remission (p< 0,05). Production of IL-17 in patients with depression was higher than in the group without depression (p< 0,05). Norepinephrine suppressed IL-17 production in all groups (p< 0,01). Conclusion: Effects of norepinephrine on IL-17 production could be proposed as an additional factor of immunoregulation in MS.

Disclosure Nothing to disclose.

P894 Study of intracellular cytokine production in CSF of MS patients classified according to oligoclonal IgM band status C. Picón1, L. Costa-Frossard1, I. Toboso1, S. Sainz de la Maza1, E. Rodriguez-Martin1, A. Tejeda1, R. Alenda1, Y. Aladro2, J.C. Alvarez-Cermeño1, L.M. Villar Guimerans1 1Ramon y Cajal University Hospital, Institute Ramon y Cajal for Biomedical Research, 2Hospital Universitario de Getafe, Madrid, Spain Background: Intrathecal synthesis of lipid specific oligoclonal IgM Bands (LS-OCMB) is related to an aggressive multiple sclerosis (MS) course. Our aim was to elucidate the immune mechanisms associated between with the presence of these antibodies in MS patients. Material and methods: 87 consecutive patients diagnosed with MS were included in this study. CSF and serum samples were collected. We analyzed oligoclonal IgG and IgM in the CSF by isoelectrofocusing and immunoblotting and studied different leukocyte subsets in CSF by flow cytometry. We studied both percentages and total cell counts of every subpopulation. We analyzed the following subsets: CD4, CD8, activated CD4 (HLA-DR+), regulatory T cells, B cells (CD19+5+. CD19+5-), monocytes (CD14hiCD16-, CD14hiCD16+, CD14loCD16+) and intracellular production of cytokines (IFN-gamma, TNF-alpha, IL-17, IL-22) in CD4 and CD8 cells. Results: 28 (32.2%) patients had LS-OCMB+ restricted to CSF and the remaining 59 were LS-OCMB-. When analyzing cell percentages in CSF we found that LS-OCMB+ patients showed increased values of CD19 cells (p=0.0028), especially of the CD19+5+ subset (p=0.0002) as previously reported. Conversely, LS-OCMB- patients showed increased percentages of monocytes were elevated in LS- (p=0.0003). This increase was mainly due to CD14hiCD16-(p=0.002) and CD14hi, CD16+ (p=0.002) subsets. When studied absolute cell counts, we observed that LS-OCMB+ patients showed increased values in total B (p=0.002), CD4 (p=0.02), CD8 (p=0.03) populations. Differences were higher when exploring DR+ CD4+T cells (p=0.003) and CD4 cells showing intracellular production of IFN-gamma (p< 0.0001), TNF-alpha (p< 0.0001), IL22(p< 0.0001), or IL-17(p< 0.0001). This association was also observed in CD8 cells. Conclusions: The presence of LS-OCM bands in MS is related to a high number of T cells producing inflammatory cytokines in CSF. The absence of these antibodies associates with a lower number of B cells and an increased percentage of monocytes. These results suggest both groups of patients may have different disease mechanisms. Disclosure Carmen Picón: nothing to disclose. Lucienne Costa-Frossard received payment for speaking, research, travel expenses or grants from Merck Serono, Biogen, Genzyme, Teva, Novartis. Immaculada Toboso: nothing to disclose.


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Poster Session 2, 21(S11) Susana Sainz de la Maza received payment for speaking, research, travel expenses or grants from Merck Serono, Biogen, Genzyme, Teva, Novartis. Eulalia Rodriguez-Martin: nothing to disclose. Amalia Tejeda: nothing to disclose. Raquel Alenda: nothing to disclose. Yolanda Aladro received payment for speaking, research, travel expenses or grants from Merck Serono, Biogen, Genzyme, Teva, Novartis. Jose Carlos Alvarez-Cermeño eceived payment for speaking, research, travel expenses or grants from Merck Serono, Biogen, Genzyme, Teva, Novartis. Luisa Maria Villar received payment for speaking, research, travel expenses or grants from Merck Serono, Biogen, Genzyme, Teva, Novartis. P895 Blood coagulation factor XII drives adaptive immunity during neuroinflammation via modulation of dendritic cells K. Göbel1, S. Pankratz1, A.M. Herrmann1, H. Wiendl1, T. Chavakis2, C. Kleinschnitz3, S.G. Meuth1,4 1Department of Neurology, University of Münster, Münster, 2Department of Clinical Pathobiochemistry, Department of Medicine and Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technical University of Dresden, Dresden, 3Department of Neurology, University Hospital Würzburg, Würzburg, 4Institute of Physiology - Neuropathophysiology, University of Münster, Münster, Germany Multiple sclerosis (MS) is the most frequent inflammatory demyelinating disease of the central nervous system (CNS). Although the pathogenesis of MS is still not completely understood, but it is widely accepted that it is an immune mediated disease. However, it becomes more and more apparent that a crosstalk between coagulation and immunity might contribute to and amplify inflammatory response in MS. Growing evidence indicate a role of the extrinsic coagulation system in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Even so, the function of the intrinsic coagulation system remains unknown in this context. Here, we investigate the role of coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein-kinin system, in autoimmunity and the potential underlying mechanisms of action. This study shows that high levels of FXII activity are present in the plasma of MS patients. To challenge the relevance of FXII activity under pathophysiological conditions in vivo, EAE was used. Thereby, we demonstrate that deficiency or pharmacologic blockade of FXII renders mice less susceptible to autoimmune CNS inflammation. Reduced numbers of interleukin-(IL)17A-producing T helper cells (TH17) as determined via intracellular cytokine staining accompanies this amelioration. We found that FXII-dependent immune modulation is mediated by dendritic cells (DC). Thereby, FXII can directly act on DC and impacts their cytokine response to inflammatory signals yielding a typical TH17 cytokine network by boosting IL-6 production. Furthermore, histologic analysis disclosed that FXII is in close contact with DC in brain tissue from MS patients.

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Overall, our findings introduce a member of the plasmatic coagulation cascade as a completely novel and unexpected key regulator of DC-mediated immune cell modulation, and thus, indicate that FXII inhibition may offer a novel strategy to combat MS and other immune-related disorders. Disclosure K.G. holds a patent to treat neuroinflammatory disorders with FXIIa inhibitors. C.K. holds a patent to treat neuroinflammatory disorders with FXIIa inhibitors. S.G.M. holds a patent to treat neuroinflammatory disorders with FXIIa inhibitors. T.C.: nothing to disclose. A.M.H.: nothing to disclose. S.P.: nothing to disclose. H.W.: nothing to disclose.

P896 EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) gene expression is downregulated in multiple sclerosis patients S. Malhotra, M. Tintoré, J. Castilló, X. Montalban, M. Comabella Multiple Sclerosis Centre of Catalonia/Neuroimmunology Department, Vall d’Hebron University Hospital & VHIR, Barcelona, Spain Background: EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) is a histone methyltransferase with putative roles in cell adhesion and migration via methylation of talin, a key regulatory molecule in cell migration. Recently in the animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), it was shown that mice deficient for Ezh2 had attenuated EAE disease progression due to the inability of Ezh2-deficient cells, particularly neutrophils and dendritic cells, to reach the site of inflammation. Here, we aimed to investigate the role of EZH2 in MS by measuring gene expression levels for this molecule in patients with different clinical forms of the disease. Methods: mRNA expression levels for EZH2 were measured by real time PCR in peripheral blood mononuclear cells (PBMC) from 24 healthy controls and 57 untreated MS patients. The MS group included 20 patients with relapsing-remitting MS - RRMS, 20 patients with secondary progressive MS - SPMS, and 17 patients with primary progressive MS - PPMS. Differences in gene expression between groups were analyzed using the 2-ΔΔCT method. Results: EZH2 expression was significantly decreased in PBMC from the whole MS group compared with the healthy control group (p=0.008). Further stratification of the MS group revealed significant reductions in EZH2 mRNA expression levels in patients with RRMS (p=0.03), SPMS (p=0.04), and PPMS (p=0.02) compared with healthy controls. Conclusions: This unforeseen down-regulation of EZH2 expression observed in MS patients may suggest either potential EZH2 post-translational modifications, or additional roles of EZH2 beyond cell migration in MS patients. Studies at the protein level


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are currently underway to further investigate the involvement of EZH2 in the disease. Disclosure S Malhotra and J Castilló report no disclosures. M Tintoré has received compensation for consulting services and speaking from Bayer-Schering, Merk-Serono, Biogen-Idec, Teva, Sanofi-Aventis, and Novartis. X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall and Roche. M Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, and Novartis.

P897 NLRP3 (Nod-like receptor family, pyrin domain containing 3) inflammasome is increased in patients with primary progressive multiple sclerosis S. Malhotra, J. Sastre-Garriga, J. Castilló, X. Montalban, M. Comabella Multiple Sclerosis Centre of Catalonia/Neuroimmunology Department, Vall d’Hebron University Hospital & VHIR, Barcelona, Spain Background: NLRP3 (Nod-like receptor family, pyrin domain containing 3), the most fully characterized inflammasome, regulates the maturation of cytokines such as interleukin (IL)-1beta and IL-18 and has recently been involved in the response to interferon-beta in patients with multiple sclerosis (MS). Considering the potential regulation of NLRP3 expression by the pro-inflammatory transcription factor nuclear factor kappa B, in the present study we aimed to investigate the role of NLRP3 in MS disease course and activity. Methods: NLRP3 mRNA expression levels were determined in peripheral blood mononuclear cells (PBMC) from 67 untreated MS patients and 26 healthy controls by real time PCR. The MS group included 20 patients with primary progressive MS - PPMS, 20 patients with secondary progressive MS - SPMS, and 27 patients with relapsing-remitting MS - RRMS (21 patients during clinical remission and 6 patients in whom blood was collected at the time of a clinical exacerbation). The 2-DDCT method was used to analyze differences in NLRP3 gene expression between healthy controls and patients with different clinical forms of MS. Results: A trend for higher NLRP3 mRNA expression levels was observed in PBMC from the whole MS group compared with the healthy control group (p=0.059). Within the MS group, mRNA expression levels for NLRP3 were highest in PPMS patients, and differences reached statistical significance when compared with RRMS patients in clinical remission (p=2x10-5), SPMS patients (p=1x10-3), and controls (p=1x10-5). NLRP3 expression levels were significantly up-regulated in RRMS patients during relapse compared with RRMS patients during clinical remission (p=0.04).

Conclusions: These findings suggest a role of the NLRP3 inflammasome in MS disease course and activity, particularly in patients with PPMS and patients with RRMS during relapse. They also underscore the pleiotropic actions of NLRP3 in the disease. Disclosure J Sastre-Garriga has received compensation for consulting services and speaking honoraria from Merck-Serono, Biogen-Idec, Teva, Genzyme and Novartis. X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall and Roche. M Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, and Novartis. P898 Interleukin-24, produced by both TH lymphocytes and astrocytes, decreases blood brain barrier function B. Broux1,2, C. Peter3, L. Bourbonnière2, C. Pittet2, P. Duquette2, T. Korn3, A. Prat2 1Hasselt University, Diepenbeek, Belgium, 2CRCHUM, Montreal, QC, Canada, 3Technische Universität München, Department of Neurology, Munchen, Germany It is well established that TH1 and TH17 lymphocytes, as well as the cytokines they produce, are crucial in the pathogenesis of multiple sclerosis (MS). In this study, we evaluate the unexplored role of IL-24 in the pathogenesis of MS. We show that both IL-24 mRNA and protein are predominantly expressed by TH1 cells, but also by TH17 cells, of both healthy donors and MS patients, as assessed by quantitative PCR and ELISA. Furthermore, we detected IL-24 in serum, but not in cerebrospinal fluid (CSF), of both healthy donors and MS patients by ELISA. In our cohort of patients, immunomodulatory treatment reduced the concentration of IL-24 in the serum of these patients. In active MS lesions, we did not find IL-24 expressing TH lymphocytes by immunohistofluorescence and confocal microscopy. However, reactive astrocytes within these lesions highly expressed IL-24, compared to normal appearing white matter. Indeed, when we inflamed astrocytes in vitro, they upregulated the expression of IL-24, as studied by immunocytofluorescence and confocal microscopy. Finally, we found that recombinant human IL-24 decreased transendothelial electrical resistance (TEER) of blood brain barrier endothelial cells (BBB-ECs), as measured using the ECIS system. These results suggest a functional mechanism of astrocyte-induced breakdown of the BBB through IL-24 in an inflammatory environment such as MS. Disclosure Bieke Broux: FWO postdoctoral fellow Christian Peter: nothing to disclose Lyne Bourbonnière: nothing to disclose


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Poster Session 2, 21(S11) Pierre Duquette: nothing to disclose Thomas Korn: nothing to disclose Alexandre Prat: nothing to disclose

P899 The effect of IL-27 signaling on miRNA expression in myeloid dendritic cells in multiple sclerosis R. Raheja, F. von Glehn, G. Murugaiyan, C. Kuhn, K. Regev, M.A. Mazzola, S. Jangi, A. Paul, H. Weiner, R. Gandhi Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, United States Background: Dendritic cells (DCs) contribute to multiple sclerosis (MS) by promoting the entry, activation and differentiation of pathogenic T cells into the central nervous system (CNS). On the other hand, myeloid DCs (mDCs) primed with interleukin 27 (IL27) can induce T cell tolerance, thereby reducing the differentiation of pro-inflammatory Th1 and Th17 cells and the development of CNS autoimmunity in an EAE mouse model. In order to understand tolerogenic mDCs in disease progression, we identified differences in microRNA (miRNA) expression in IL-27 primed mDCs from healthy controls (HCs) and relapsing-remitting MS (RRMS) patients. The role of miRNAs in mDCs and how they might contribute to IL-27 mediated tolerogenicity of mDCs in MS remains to be studied. Objective: To determine the role of miRNAs in IL27-mediated tolerance in mDCs from HCs and RRMS patients. Methods: mDCs were purified from HCs and RRMS patients (n=6) by flow cytometry. The mDCs were either activated with LPS only or LPS with IL-27 (IL-27 primed mDCs). Total RNA was isolated and analyzed using PCR-based microRNA array. The findings were validated by Taqman RT-PCR. LUMINEX was used to detect cytokine expression in the supernatant from coculture assays. Results: In our microRNA array from HCs, we detected 7 miRNAs that were significantly downregulated and 3 that were upregulated in IL-27 primed mDCs compared to those treated with LPS only. Upon validation by Taqman RT-PCR, only miR27a was significantly decreased in IL-27 primed mDCs compared to mDCs treated with LPS alone (p< 0.05). On the other hand in RRMS patients, 6 miRNAs were significantly downregulated and 4 were upregulated in IL-27 primed mDCs compared to mDCs treated with LPS only. Interestingly, however, miR27a was not significantly reduced in IL-27 primed mDCs from RRMS patients by microarray analysis or Taqman RT-PCR (p=0.126). Further, we detected an increased expression of the anti-inflammatory cytokine IL-10 in the supernatant from IL-27 primed mDCs cocultured with T cells from HCs. Conclusions: IL-27 mediated decrease in miR27a expression in mDCs from HCs generates an anti-inflammatory response that could consequently limit the differentiation of Th1 and Th17 cells. This effect might be deregulated in RRMS patients. Further studies to validate gene targets will enable us to assess the significance of miR27a expression in mDCs and how it might contribute to disease pathogenesis. Disclosure Radhika Raheja: Nothing to disclose

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P900 Broad screening for anti-neuronal and anti-glial autoantibodies in patients with pathologically classified multiple sclerosis S. Jarius1, I. Metz2, F. König2, K. Ruprecht3, F. Paul4, W. Brück2, B. Wildemann1 1Department of Neurology, University of Heidelberg, Heidelberg, 2Department of Neuropathology, University Medical Center Göttingen, Göttingen, 3Department of Neurology, Charité - Universitätsmedizin Berlin, 4NeuroCure Clinical Research Center, Charité - Universitätsmedizin, Berlin, Germany Background: Histopathological studies have revealed four different immunopathological patterns of lesion pathology in early multiple sclerosis (MS). Pattern II MS lesions are characterized by immunoglobulin and complement deposition in addition to T cell and macrophage infiltration. Patients with pattern II MS are also more likely to respond to plasma exchange therapy. This suggests a possible contribution of autoantibodies to lesion pathology. Inflammatory demyelinating CNS conditions associated with myelin oligodendrocyte glycoprotein (MOG) or aquaporin-4 (AQP4) antibodies show a significant clinical overlap with MS. These two conditions, although targeting different CNS antigens, are histopathologically characterized by antibody and complement deposits as well. Recently, antibodies to N-methyl-Daspartate receptors (NMDAR) have been reported in patients with demyelinating diseases. Objective: To assess the frequency of anti-MOG, anti-M1-AQP4, anti-M23-AQP4, anti-NMDAR, and twenty-three other anti-neural antibodies among patients with MS. Patients and methods: Thirty-nine serum samples from patients with MS who had undergone brain biopsy (n=24; including 13 patients with pattern II MS) and from histologically non-classified MS patients (n=15) were tested for 27 anti-neural IgG antibodies previously implicated in CNS inflammation including antibodies to full-length MOG, M1-AQP4, M23-AQP4, NMDAR, AMPAR, GABABR, the VGKC complex proteins LGI1 and CASPR2, DPPX, Tr/DNER, Hu, Yo, Ri, Ma1, Ma2, CV2/CRMP5, GAD, amphiphysin, Ca/ARHGAP26, Sj/ITPR1, Homer3, CARPVIII, mGluR1, and mGluR5 as well as for AGNA, PCA2 and myelin antibodies using commercial cell-based assays and tissue-based assays. Results: In total, 780 individual antibody tests were performed. A single pattern II MS patient was positive for MOG-IgG. Myelin antibodies of unknown specificity as detected by immunohistochemistry were present in 25/39 (64%) of all MS patients and occurred irrespective of pathological patterns. None of the 39 patients was positive for any of the remaining 25 anti-neuronal and anti-glial antibody reactivities assessed. Conclusions: Our study suggests that MOG-IgG may play a role in rare patients classified as pattern II MS and argues against a major role of AQP4-IgG, NMDAR-IgG, or any of the other tested antibodies in MS. Future studies on pattern II MS should focus on antibodies other than those investigated here. Disclosure Brigitte Wildemann has received honoraria for speaking/consultation and travel grants from Bayer Healthcare, Biogen Idec, Merck Serono, Genzyme, a Sanofi Company, Novartis Pharmaceuticals, and Teva Pharma GmbH and research grants from Biogen Idec,


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Biotest, Merck Serono, Novartis Pharamceuricals, Teva Pharma GmbH, the German Ministry of Education and Research, and the Dietmar Hopp Foundation. Sven Jarius has nothing to disclose. Wolfgang Brück has received honoraria for lectures by Bayer Vital, Biogen Idec, Merck Serono, Teva Pharma, Genzyme, Sanofi-Aventis and Novartis. Wolfgang Brück is a member of scientific advisory boards for Teva Pharma, Biogen Idec, Novartis and Genzyme. Wolfgang Brück receives research support fromTeva Pharma, Biogen Idec, Genzyme and Novartis. Wolfgang Brück serves on the editorial boards of Neuropathology and Applied Neurobiology, Multiple Sclerosis International and Therapeutic Advances in Neurological Disorders. Klemens Ruprecht has received research support from Novartis as well as speaking fees and travel grants from Guthy Jackson Charitable Foundation, Bayer Healthcare, Biogen Idec, Merck Serono, sanofi-aventis/Genzyme, Teva Pharmaceuticals, and Novartis; and is supported by the German Ministry of Education and Research (BMBF/KKNMS, Competence Network Multiple Sclerosis). Imke Metz reports grants from German Ministry for Education and Research (BMBF, ‘’German Competence Network Multiple Sclerosis’’ (KKNMS), Pattern MS/NMO), during the conduct of the study; personal fees from Biogen, Bayer Healthcare, TEVA, Serono, grants from BiogenIdec, outside the submitted work. Friedemann Paul is supported by the Deutsche Forschungsgemeinschaft, the EU FP7 Framework Program (combims.eu), the Guthy Jackson Charitable Foundation, the Bundesministerium für Bildung und Forschung (Competence Network Multiple Sclerosis and N2 Advisims). Friedemann Paul has received research support, travel reimbursement and personal compensation for activities with Alexion, Bayer, BiogenIdec, Chugai, Teva, MerckSerono, Novartis, SanofiGenzyme, MedImmune. Fatima König has nothing to disclose.

evaluate the crosstalk between gut microbiome and adaptive immune responses in MS. Methods: We performed 16S sequencing of bacterial DNA from fecal samples of 55 control subjects and 51 MS patients that were not actively undergoing treatment. Next, we investigated how differentially abundant bacteria altered the adaptive immune response. We stimulated human peripheral blood mononuclear cells using bacterial peptides from strains that were significantly different between patients and controls and analyzed the subsequent proliferation and differentiation of T lymphocytes into Th1, Th2, Th17 and regulatory T cell (Treg) subtypes using flow cytometry. We also investigated differences in serum antibody binding of bacteria of MS patients and controls. Results: No significant differences were found in alpha diversity nor Unifrac distance-based clustering between MS patients and healthy controls. However, significant differences were observed at the level of several individual microbial genera. Stimulation of T cells with MS-increased Acinetobacter calcoaceticus resulted in a significant reduction of CD3+CD4+CD25+FoxP3+ Tregs, but an increase of CD3+CD4+IL4+ Th2 cells. Simulation with control-increased Parabacteroides distasonis augmented cells with CD3+CD4+CD25+ phenotype. Furthermore, we found that a larger proportion of gut bacteria of MS patients compared to controls were bound by serum IgG, suggesting the possibility that a larger proportion of bacteria might escape the gut lumen into the circulation and elicit an (auto)immune response in MS patients. Conclusion: Gut microbiota of MS patients and healthy controls differ significantly at genus level. We show here that certain differentially abundant bacterial species can elicit different adaptive immune responses. Further research on this topic may lead to a better insight in MS pathogenesis and eventually to microbiomebased MS therapeutics. Disclosure

P901 The influence of microbiota on the adaptive immune response in MS E. Cekanaviciute1, T.F. Runia1,2, J.W. Debelius3, S.K. Mazmanian4, R. Knight3, I. Katz Sand5, B.A.C. Cree1, P. Casaccia5, S.E. Baranzini1 1Neurology, UCSF, San Francisco, CA, United States, 2Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands, 3Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, CO, 4Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 5Icahn School of Medicine, Mount Sinai Medical Center, New York, NY, United States

T.F. Runia: nothing to disclose. E. Cekanaviciute: nothing to disclose. J.W. Debelius: nothing to disclose. S.K. Mazmanian: nothing to disclose. R. Knight: nothing to disclose. I. Katz-Sand: nothing to disclose. B.A.C. Cree has received personal compensation for activities with Abbvie, Biogen Idec, EMD Serono, Genzyme, Medimmune, Novartis, Sanofi Aventis, and Teva Neuroscience. Dr. Cree has received research support from Acorda, Avanir, Hoffman La Roche, and Novartis. P. Casaccia: nothing to disclose. S.E. Baranzini is a consultant for Novartis, TEVA, Genzyme, EMD-Serono and Biogen.

Background: Commensal gut microbes interact intimately with our immune system, and have been recently related to the development of CNS-specific autoimmunity. We hypothesize that alterations in the gut microbiota induce specific changes in the immune response, thus contributing to the environmental component in the pathogenesis of multiple sclerosis (MS). To date no studies have systematically compared gut bacterial contents between MS patients and controls or univocally demonstrated the effect of gut dysbiosis on immune responses in this disease. Here, we aimed to

P902 Intrathecal transplantation of neural stem/progenitor cells modulates the CNS-confined autoimmune response of experimental autoimmune encephalomyelitis D. De Feo1, A. Merlini1, E. Brambilla1, C. Laterza2, C. Farina1, F. Ruffini1, G. Comi1, G. Martino1 1Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy, 2Division of Neurology Lund University, Lund, Sweden


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Poster Session 2, 21(S11) Background: In central nervous system (CNS) autoimmunity, disease development and manteinace depend on the reactivation of auto-reactive T cells by local antigen-presenting cells (APC) in the perivascular (subarachnoid) space. Reactivated T cells secrete inflammatory mediators that recruit subsequent waves of leukocytes leading to the progressive tissue damage. Systemic and local transplantation of neural stem/progenitor cells (NPCs) promotes neuroprotection in experimental multiple sclerosis (MS) through strong but partially understood immunomodulatory effect. Objectives: The aim of this work was to investigate if and how the intrathecal (ic) transplantation of NPCs might modulate the CNS-compartmentalized immune response of the effector phase of the experimental autoimmune encephalomyelitis (EAE), as pre-clinical model of MS. Methods: We injected ic 10^6 of GFP-labeled subventricular (SVZ)- NPCs in myelin oligodendrocyte glycoprotein (MOG)3555-immunized C57BL/6 EAE mice at the peak of disease severity. Cytofluorimetric analysis of the CNS-inflammatory infiltrate were performed at 7 days post-transplantation (dpt). Behavioral and histopathological outcomes were collected up to 60 dpt. Results: Early after treatment, we found a significant reduction of infiltrating monocyte-derived DCs and pathogenic TH1 and TH17 cells in the CNS of NPC-treated, compared to sham-treated control mice. Consistently, NPC-treated mice showed a significant and persistent amelioration of clinical disability and tissue damage at the end of the follow-up. Transplanted NPCs localized in perivascular spaces, in close contact with CNS-myeloid DCs, where they reactivate myelin-specific T cells. In fact, in vitro, NPC-conditioned medium (NCM) inhibited the functional maturation and the capability of DCs to activate and polarize myelin-specific T cells towards a pathogenic phenotype. These findings correlated with impaired activation of RelB canonical NF-kB pathway in NCM-treated DCs. Conclusions: Our work confirms the efficacy of the ic NPC transplantation, in ameliorating EAE disease severity, even if transplanted after the clinical onset of the disease. The ex-vivo and in-vitro findings suggests that NPC soluble mediators might interfere with the antigen recall and the terminal polarization of encephalitogenic TH cells within the CNS by inhibiting NF-kB pathway in DCs, thus, preventing the accumulation of infiltrating myeloid cells, which are responsible for the EAE progression. Disclosure Donatella De Feo: noting to disclose. Arianna Merlini: noting to disclose. Elena Brambilla: noting to disclose. Cecilia Laterza: noting to disclose. Cinthia Farina: noting to disclose. Francesca Ruffini: noting to disclose. Giancarlo Comi: noting to disclose. Gianvito Martino: noting to disclose.

MS and infections P903 EBV genotypes and response to high-dose interferon-beta in multiple sclerosis R. Mechelli1, M.C. Buscarinu1, G. Coarelli1, G. Mattei1, M. Ruggieri2, A. Uccelli3, G. Matarese4,5, D. Centonze6,7, G.

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Ristori1, M. Salvetti1, on behalf of the MSRUN Network 1Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, 2Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, Bari, 3Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, 4Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, Salerno, 5IRCCS MultiMedica, Milano, 6MS Clinical and Research Center, Tor Vergata University and Hospital, Rome, 7IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli, Italy Background: Our recent studies unveiled an association between Epstein-Barr virus (EBV) genomic variants and multiple sclerosis (MS), reinforcing the idea that EBV contributes to disease development (Mechelli et al. Neurology, 2015). In an analysis of a region of the viral DNA coding for Epstein-Barr nuclear antigen 2 (EBNA2) protein in peripheral blood of persons with relapsingremitting MS and control subjects, we showed that MS risk significantly correlated with an excess of 1.2 allele and under-representation of 1.3B allele. We found no correlation between EBV genotypes and clinical characteristics of patients at the time of blood sampling, except for a trend toward lower disease duration in subjects bearing the 1.2 allele. Objectives: Based on these findings, we are now investigating whether there is an association between polymorphisms found in the EBNA2 gene and different responses to IFN-b therapy. Methods and results: EBNA2 genotyping was conducted in patients (N = 53) who were naive to disease-modifying therapies. Of these 53 patients,16 had started high-dose interferon-β (IFN-b) therapy (either Rebif 44, IFN-b-1a 44mcg three times a week s.c, or Betaferon, IFN-b-1b 250mcg three times a week s.c). Within this group, the initial distribution of EBNA2 alleles was representative of the original, untreated population (32% 1.3B; 6% 1.3A; 12% GD1, 50% 1.2). In a follow-up ranging between 2 and 5 years, our preliminary data showed that only one of 6 patients still receiving IFN-b treatment had the 1.2 EBNA2 allele. Conversely, 7 of the remaining 10 patients that shifted to secondline therapies (Tysabri or Fingolimod) were 1.2 EBNA2-positive at the beginning of the study. Conclusions: Our initial results suggest an association between EBV genotypes and response to high-dose IFN-b therapy. This observation should be confirmed in a larger study population. Disclosure Rosella Mechelli: nothing to disclose Maria Chiara Buscarinu: nothing to disclose Giulia Coarelli: nothing to disclose Gianluca Mattei: nothing to disclose Maddalena Ruggieri: nothing to disclose Antonio Uccelli has received consulting honoraria and/or speaker fees and a basic science study grant to support part of the work submitted from Biogen; consulting honoraria and/or speaker fees from Genentech, Roche, Allergan, Sanofi-Aventis, BiogenDompé, and Novartis; consulting honoraria and/or speaker fees and a basic science study grant from Merck-Serono. Giuseppe Matarese: nothing to disclose Diego Centonze acted as an Advisory Board member of MerckSerono, Teva, Bayer Schering, Biogen Idec, Novartis, and


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received funding for traveling and honoraria for speaking or consultation fees from Merck Serono, Teva, Novartis, Bayer Schering, Sanofi-aventis, Biogen Idec. He is the principal investigator in clinical trials for Novartis, Merck Serono, Teva, Bayer Schering, Sanofi-aventis, Biogen Idec, Roche Giovanni Ristori: nothing to disclose Marco Salvetti received lecture fees from Biogen-Dompé,research support from Bayer-Schering, Biogen-Dompé, Merck-Serono, Sanofi-Aventis P904 Search of biomarkers for PML risk in multiple sclerosis patients receiving natalizumab M. Comabella1, N. Fissolo1, C. Matute1, J.C. Triviño2, B. Pignolet3, Ó. Rodríguez2, À. Vidal-Jordana1, J. Río1, X. Montalban1, D. Brassat3 1Multiple Sclerosis Centre of Catalonia/Neuroimmunology Department, Vall d’Hebron University Hospital & VHIR, Barcelona, 2Bioinformatics Department, Sistemas Genómicos, Valencia, Spain, 3Pole des Neurosciences et INSERM UMR 1043, Université de Toulouse, Toulouse, France Background: Natalizumab is a highly effective disease modifying therapy for patients with relapsing forms of multiple sclerosis (MS). However, a major concern related with natalizumab is the increased risk for progressive multifocal leukoencephalopathy (PML). Here, we pursued the identification of biomarkers associated with the development of PML in MS patients treated with natalizumab. Methods: Relapsing-remitting MS patients who developed PML under natalizumab therapy (n=5) and non-PML natalizumabtreated patients (n=8) were included in the study. Peripheral blood mononuclear cells (PBMC) were collected from these patients at baseline, at one- and two-year treated time points, and during PML. RNA-sequencing was performed in PBMC using the Illumina technology. Reads were mapped using Tophat algorithm. Subsequently, low quality mapped reads were removed using Picard Tools. After selecting the reads with the highest mapping quality values, assembly, gene identification and differential expression was performed using Bayesian inference methods with Cufflinks v2.2.0. Results: Among top differentially expressed genes between PML and non-PML cases (adjusted p-values < 0.05), there was a high representation of molecules belonging to the following categories: cytokines, chemokines, plasminogen- and coagulation-related molecules, and pro-angiogenic factors. A total of 14 candidates were selected from the RNA-sequencing analysis for quantification of serum protein levels by means of a Luminex multiplex bead assay. Significant differences remained for the two pro-angiogenic molecules that were selected, and serum levels for these proteins were significantly lower at baseline in MS patients who developed PML compared to non-PML cases and remained unchanged during natalizumab treatment, whereas in patients who did not develop PML levels for the two pro-angiogenic factors were significantly down-regulated by treatment. These results are being validated in additional serum samples from PML and nonPML patients. Conclusions: The results from this study suggest that pro-angiogenic factors may play a role as biomarkers associated with the development of PML in MS patients treated with natalizumab.

Disclosure N Fissolo, C Matute, JC Triviño, B Pignolet, O Rodriguez, and A Vidal-Jordana report no disclosures. M Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, and Novartis. X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall and Roche. D Brassat has received speaking honoraria and travel expenses for scientific meetings in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genzyme, Novartis, SanofiAventis, Teva Phramaceuticals

P905 Antigen-selective reduction of intrathecal synthesis of antiviral antibodies during natalizumab treatment of MS patients F. Largey, I. Jelcic, M. Sospedra, R. Martin, I. Jelcic Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital of Zurich, Zurich, Switzerland Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab treatment (NAT) in multiple sclerosis (MS) patients and is caused by JC virus (JCV). NAT is thought to facilitate PML development by inhibiting entry of JCV-specific T cells into the brain. It may further influence intrathecal antibody production, as previous studies showed a reduction of oligoclonal bands (OCB) or total IgG and IgM levels in cerebrospinal fluid (CSF) during NAT. Moreover, intrathecal production of JCVspecific antibodies was found in 55% of MS patients with freshly diagnosed PML, but not in MS patients during NAT therapy. Here, we characterized the influence of NAT on general and antiviral intrathecal B cell immunity systematically, including JCV-specific antibodies. We collected paired serum and CSF samples from 15 MS patients before NAT (V0) and after 12 (V12) and 24 months (V24) of NAT. We analysed OCB, quantified total IgG, IgM and IgA, and used ELISAs in order to analyse sample-specific antibody reactivity against measles, rubella, mumps, influenza viruses, enteroviruses, varicella zoster virus, herpes simplex virus 1 and 2, cytomegalovirus, Epstein-Barr virus and human polyomaviruses, JC, BK, KI and WU virus, as well as bacterial antigens. The virus-specific CSF/serum IgG antibody index (CAI) was calculated in paired serum and CSF samples, and a CAI⩾1.5 indicated intrathecal synthesis of virus-specific antibodies. Intrathecal production of antibodies against JCV and BKV was detected in 20% of MS patients before NAT (V0), but disappeared during NAT (V12 and V24). The intrathecal antibody synthesis against all other tested antigens was either unchanged or tended to decrease slightly (by 0-7%) from V0 to V12. CSF-derived antibodies against JCV were not cross-reactive to BKV and vice versa. Prevalence of OCB in CSF decreased from 93% to 87% without correlation to loss of intrathecal antigen-specific antibody


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Poster Session 2, 21(S11) production. NAT reduced intrathecal IgG and IgM production significantly. In summary, NAT induces a quantitative reduction of intrathecally produced IgG and IgM and selective disappearance of intrathecally produced JCV- and BKV-specific IgG, whereas intrathecal production of OCB and antibodies against a broad spectrum of other viral antigens is not or less modified. The deletion of intrathecal JCV-reactive antibody production in a minor fraction of MS patients might add to increased PML susceptibility. Disclosure Neuroimmunology and MS Research receives unrestricted grant support from Biogen and Novartis, seminar support from Genzyme/Sanofi Aventis, Novartis, Biogen, Merck, Teva. F. Largey has nothing to disclose. IV. Jelcic has nothing to disclose. M. Sospedra has nothing to disclose. R. Martin has received personal compensation (advisory function) from Novartis, Biogen, Merck, Bionamics, CellProtect, Genzyme/ Sanofi Aventis. IL. Jelcic has received unrestricted grants from Biogen Idec and Novartis, and speaker honoraria from Novartis. P906 Formation of JCV- and BKV-cross-reactive antibodies during natalizumab-associated progressive multifocal leukoencephalopathy F. Largey, I. Jelcic, M. Sospedra, R. Martin, I. Jelcic Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital of Zurich, Zurich, Switzerland Natalizumab (NAT) treatment in multiple sclerosis (MS) patients increases the risk for contracting progressive multifocal leukoencephalopathy (PML), a severe infectious brain disease caused by JC virus (JCV) and promoted by NAT-induced reduction of lymphocyte transmigration from blood into brain. Washing out NAT by plasma exchange leads to PML-immune reconstitution inflammatory syndrome (PML-IRIS), an acute neurological deterioration due to invasion of JCV-specific immune cells into PML lesions. This inflammatory reaction might finally resolve cerebral JCV infection. 55% of NAT-treated MS patients with newly diagnosed PML (NAT-PML) were found to produce JCV-reactive antibodies intrathecally as opposed to none of NAT-treated MS patients without PML (0%). We here investigated changes in intrathecal antibody responses to various viral antigens in correlation to JCV-specific antibody responses during PML, IRIS and after IRIS. Paired serum and CSF samples from 16 Swiss NAT-PML cases were collected at PML diagnosis (PML), onset of PML-IRIS and/or after PML-IRIS. Samples were tested in capture ELISAs using antigens from measles, rubella, mumps, influenza, entero-, herpesviruses and polyomaviruses (JC, BK, KI, and WU viruses), with BKV being the nearest polomaviral homologue (70% sequence identity). Virus-specific CSF/serum antibody index (CAI) was calculated for paired serum and CSF samples, and CAI⩾1.5 indicated intrathecal synthesis of virus-specific antibodies.

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The prevalence of cases with intrathecally produced JCV-reactive antibodies increased from PML (25%) to IRIS (88%) and after IRIS (100%), paralleled by increase in intrathecally produced BKV-reactive antibodies (20% of PML, 60% of IRIS cases and 80% after IRIS). In contrast, prevalence of intrathecal antibody production against all other viral antigens rather decreased between PML and IRIS, followed by increase after IRIS. BKVreactive antibodies mainly cross-recognized JCV in serum and CSF, whereas a minor fraction of JCV-reactive antibodies crossrecognized BKV at onset of IRIS and after IRIS. In conclusion, intrathecal antibody responses to JCV and BKV are increasing specifically during course of NAT-PML and PMLIRIS. Cross-recognition of BKV indicates broadening of the antigen spectrum recognized by JCV-reactive antibodies during natural PML course. The role of such broadly recognizing JCVreactive antibodies in resolution of PML needs to be clarified in future studies. Disclosure Neuroimmunology and MS Research receives unrestricted grant support from Biogen and Novartis, seminar support from Genzyme/Sanofi Aventis, Novartis, Biogen, Merck, Teva. F. Largey has nothing to disclose. IV. Jelcic has nothing to disclose. M. Sospedra has nothing to disclose. R. Martin has received personal compensation (advisory function) from Novartis, Biogen, Merck, Bionamics, CellProtect, Genzyme/ Sanofi Aventis. IL. Jelcic has received unrestricted grants from Biogen Idec and Novartis, and speaker honoraria from Novartis. P907 The association between human endogenous retroviruses and multiple sclerosis: a systematic review and meta-analysis E. Morandi1, R. Tanasescu1, C. Tench1, W. Zhang2, B. Gran1 1Division of Clinical Neuroscience, 2Division of Rheumatology, Orthopaedics and Dermatology, University of Nottingham, School of Medicine, Nottingham, United Kingdom Background: The interaction between genetic and environmental factors is crucial to multiple sclerosis (MS) pathogenesis. Human Endogenous Retroviruses (HERVs) are endogenous viral elements of the human genome that can preserve some functions of exogenous retroviruses and are potential contributors towards autoimmunity. Increased expression of different HERV families is associated with MS, but the extent of this association is not known. Objective: To perform a meta-analysis and assess qualitative and quantitative evidence on the expression of HERV families in MS patients. Methods: Medline, Embase and the Cochrane Library were searched for published studies on the association of HERVs and MS for the different retroviral families, viral proteins and RNA expression, in different tissues and at different stages of the disease compared with a group of healthy controls (HC). Metaanalysis was performed on family-specific studies if they used similar techniques and studied similar protein/nucleic acid. Odds Ratios (OR) using the Mantel-Haenszel test, standard error and confidence intervals were calculated for each study included in


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the meta-analysis. Total OR, the p-value of Fixed effects (inverse variance) and of Random effects (DerSimonian-Laird) were calculated using STATA. Results: 44 reports were extracted (27 related to HERV-W, 9 to HERV-H, 5 to HERV-K, 3 to HRES-1 and1 to HER-15 family). Due to the low number of publications and the variability of techniques, only studies on the HERV-W family were included in the meta-analysis (10 papers including 420 MS patients and 330 controls). Of these, 4 studies investigated MSRVenv (multiple sclerosis related virus envelope protein) mRNA expression detected by RT-PCR in PBMC; 6 studied MSRVpol (multiple sclerosis related virus polymerase) mRNA expression detected by RT-PCR in serum or plasma of MS patients and HC. The analysis showed a strong association between all HERV families and MS, in particular for the HERV-W (OR 31.99; 95% CI 8.58 to 119.28 for MSRVenv, and 44.11; 95% CI 12.95 to 150.30 for MSRVpol). Conclusions: This systematic review and meta-analysis shows a very robust association of HERVs expression proteins with MS. This strong association indicates that further studies are needed to address the role of HERVs in MS pathogenesis. Disclosure Elena Morandi: nothing to disclose. Chris Tench: nothing to disclose. Weiya Zhang: nothing to disclose. Radu Tanasescu: has received support to attend scientific conferences from Genzyme and Novartis. Bruno Gran: has received unrestricted grants to conduct MS-related research and to attend scientific conferences from Merck Serono, Teva UK, Biogen, Novartis, Bayer Schering, Novartis and Genzyme. He has been an advisor to Merck Serono, Teva UK, and Roche.

innumber of packs/year, duration of smoking). The patients were divided into three groups: never smokers, former smokers and current smokers. Clinical data concerning the history of NMO were obtained from patients’ clinical records. Results: There were 74 (53.2%) never smokers, 35 (25.2%) former smokers and 30 (21.6%) current smokers. The numbers of relapses was significantly higher in currents smokers than in the other two groups (p< 0.01). The number of patients with severe relapses was significantly higher in current smokers than in never smokers (p< 0.01). The Expanded Disability Status Scale (EDSS) score was positively correlated with the number of packs/year (correlation coefficient = 0.4; IC95% [0.1, 0.6]; p< 0.01) and with the duration of smoking (correlation coefficient = 0.3; IC95% [0.05; 0.5]; p< 0.05). No correlation was found between the number of packs/year or the duration of smoking and the number of relapses. Conclusions: This is the first study evaluating the impact of tobacco smoking in NMO, and our results suggest that in our population of patient with NMO, tobacco smoking can adversely affect disease progression and severity, as has also been demonstrated in some other autoimmune diseases and especially in multiple sclerosis. Disclosure Laurent Kremer: nothing to disclose. Nasrin Asgari: nothing to disclose. Maureen Mealy: nothing to disclose. Kerry Mutch: nothing to disclose. Michael Lewy: nothing to disclose. Anu Jacob: nothing to disclose. Nicolas Collongues: nothing to disclose. Jérôme De Seze: :nothing to disclose.

Environmental risk factors P908 Tobacco smoking and severity of neuromyelitis optica L. Kremer1, N. Asgari2, M. Mealy3, K. Mutch4, M. Lewy3, A. Jacob4, N. Collongues1, J. De Seze1 1Hopitaux Universitaires de Strasbourg - Service de Neurologie - Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, UMR_S INSERM U 1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France, 2Vejle Hospital - Service de Neurologie, Vejle, Denmark, 3Baltimore Hospital - Service de Neurologie, Baltimore, MD, United States, 4The Walton Center - Service de Neurologie, Liverpool, United Kingdom Objective: To evaluate the impact of tobacco smoking on disease progression and severity in a cohort of patient with neuromyelitis optica (NMO). Methods: We performed a multicenter study in 4 centers (Strasbourg, France; Odense, Denmark; Baltimore, United States and Liverpool, United Kingdom) of 139 patients with NMO or NMO spectrum disorder (NMOSD), diagnosed according to the 2006 Wingerchuk criteria. We evaluated records prospectively, with a standardized questionnaire in all centers, in an in- or outpatient setting or by telephone interviews, and obtained details of patients’ habits regarding tobacco smoking (quantity of smoking

P909 Commensal gut flora in MS: spatial organization and composition K. Baum1, R. Rejmus1, Y. Dörffel2 1Neurologische Abteilung, Klinik Hennigsdorf, Hennigsdorf, 2Medizinische Klinik und Poliklinik, Charité Universitätsmedizin Berlin, Berlin, Germany Background: The mucosal immune system is important for regulation of autoimmunity. Changes of fecal microbiota may result in an increase of autoimmune diseases which has been shown for rheumatoid arthritis, inflammatory bowel diseases, diabetes mellitus type 1 and allergic diseases. The role of commensal gut flora is not known in an immune-mediated, Th1dependent disease as MS. Objectives: To determine biostructure of fecal flora in MS, compared to a control group. Methods: 4 µm slices of fecal cylinders were investigated by rRNA-based oligonucleotide probes (coupled with fluorescence dyes) in an in situ-hybridization. Identification and quantification of bacterial populations were performed by fluorescence microscopy. The selection of bacteriae (Atopobium, Bacteroidaceae, Bifidobacteriae, Enterobacteriaceae, Eubacterium rectale, Faecalibacterium prausnitzii) was according to results in EAE. 54 MS patients of the Hennigsdorf MS Centre were compared


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Poster Session 2, 21(S11) with an equal control group of the Charité, healthy for CNS and bowels. Results: Compared to controls, the MS patients showed significantly higher concentrations of Atopobium (5.31±2.94x109/ml vs 1.82±1.65x109/ml; p=0.000) and Bifidobacteriae (5.26±3.76x109/ ml vs 1.09±1.20x109/ml; p=0.000). Bacteroidaceae had significantly lower concentrations in MS (8.16±3.76x109/ml vs 11.16±3.87x109/ml; p=0.000). The results were independent from clinical phenotype, disease activity, EDSS, immune therapy and place of residence (country side or urban). However, a longer duration of disease was associated with higher concentrations of Bifidobacteriae and a shorter duration with higher concentrations of Eubacterium rectale. Interestingly, there were less leucocytes and a broader thickness of mucus in MS patients. Conclusion: There are changes in commensal gut flora in MS patients. Dysbiotic changes with an increase of Atopobium and a decrease of Bacteroidaceae seem to be a reproducible pattern in autoimmune diseases. The meaning of these results for the development and outcome of MS has to be investigated. Disclosure PD Dr. Baum has received personal speaking and consulting fees from Almirall, Bayer Schering, Biogen Idec, Merck-Serono, Novartis, Sanofi Genzyme, TEVA. Dr. Rejmus has nothing to declare. Prof. Dr. Dörffel has nothing to declare. P910 Adiponectin and not leptin is associated with genetic susceptibility to multiple sclerosis E. Kantorová1, D. Čierny2, P. Petrova3, P. Slezak4, T. Adam3, J. Michalik1, S. Sivák1, V. Nosáľ1, E. Kurča1 1Neurology Clinic, 2Biochemistry Department, Jessenius Faculty of Medicine, Comenius University Bratislava, Martin, Slovakia, 3Biochemistry Department, Palacky University, Olomouc, Czech Republic, 4Department of Simulation and Virtual Medical Education, Comenius University Bratislava, Bratislava, Slovakia Introduction: Multiple sclerosis (MS) as a most common chronic disabling inflammatory-autoimmune demyelinating disease of the CNS affects genetically susceptible individuals. Genetic susceptibility interacts with lifestyle and environmental factors in determining the risk of developing autoimmunity. The high rate of overweight and obesity in a population have awakened the interest of understanding a role of adipose tissue and adipokines as environmental factors of MS. Methods: We investigated a potential relationship between adipokines (leptin and adiponectin), excess of adipose tissue and human leukocyte antigen genotype. A presence HLA antigen DRB1 together with single nucleotide polymorphism rs 3135388, specific markers of genetic susceptibility of MS, were analyzed. Total of 74 patients MS (60 female, 14 male) completed the study. Patients with both relapsing-remitting and secondary progressive courses were included. The mean age in the group was 40,8 ± 10,5, disease duration 11,1 ± 4,8. The rate of disability was 3,7 ± 1,4 (range 0-10), measured by Kurtzke “expanded disability status scale” (EDSS). Adipose tissue mass was assessed by body mass index (BMI), a mean value was 25,3 ± 5,6. BMI presented at the

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disease onset was obtained from patient´s documentation. Leptin and adiponectin were tested by ELISA method (Biovendor). Statistical analysis included nonparametric Kendall-tau b test and multivariant regression analysis. Results: We found significant association of increased leptin with EDSS (r = 0,22, p = 0,006), and decreased adiponectin with higher EDSS (r = - 0,17, p = 0,036). In multivariant regression analysis both leptin (parcial correlation 0,28, p = 0.017) and adiponectin (parcial correlation -0.19, p = 0.012) were found to be good BMIdependent predictors of progression of disability. However, adiponectin, and not leptin, correlated with carrying of HLADRB1 and rs 3135388 A (r = 0,16, p = 0,053) in MS patients. Conclusion: Adipokines, released from an excessive adipose tissue, are potent modulators of inflammatory activity in MS. Adiponectin is associated with genetic susceptibility of multiple sclerosis. A precise role of adipokines in immune processes contributing into MS pathogenesis requires future studies. Disclosure Ema Kantorova MD, Ph.D, Štefan Sivák MD, Ph.D and Vladimír Nosáľ MD, Ph.D have been supported by Project ESF ITMS kód: 26110230067. Ema Kantorova received financial support for conference travel from Genzyme Corporation and consultant fees from Merck Serono. Daniel Čierny MD, Ph.D, Pavla Petrova MD, Slezák Peter MgR Ph.D (4), Tomáš Adam RNDr, Doc; Jozef Michalik MD, Egon Kurča MD, Ph.D, Prof reported no disclosures P911 Is there any relation between Gilbert syndrome and multiple sclerosis? M. Sharifian Dorche1,2, A. Nikseresht1, M. Moini3, A. Setare Aseman2, A. Hamidian Jahromi4, N. Hasanabadi2, P. Ghadiri2, M. Nomovi5 1Shiraz University of Medical Sciences, 2Student Research Committee, 3Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Islamic Republic of Iran, 4Department of Surgery, Louisiana State University Health Sciences Center, Shreveport, LA, United States, 5Department of Internal Medicine, Shiraz University of Medical Sciences, Shiraz, Islamic Republic of Iran Introduction: Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS) which predominantly affects white matter. It has been shown that oxidative stress plays a major role in the pathogenesis of MS. Gilbert Syndrome (GS) is a common mild liver condition associated with un-conjugated hyperbilirubinemia. As bilirubin is a potent antioxidant, hyperbilirubinemia in the GS could in theory have a protective effect on development of MS. Patients and methods: This Institutional Review Board (IRB) and Ethics Committee approved retrospective study included all patients with a definite diagnosis of MS (according to McDonald criteria) who were referred to the only referral neurology clinic in our region between April 2004 and April 2012 .(all patients with newly diagnosed MS are referred to and followed at this specialty clinic and received expedited treatment). Diagnostic criteria of GS were; consistently mild un-conjugated hyperbilirubinemia (Serum


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bilirubin level=1.2-5.3 mg/dL) during 18 months follow up period in the presence of a normal blood count, reticulocyte count and liver enzymes and absence of other liver diseases and hemolytic blood disorders (normal hemoglobin and reticulocyte counts) . the prevalence of GS was calculated in these patients. The prevalence of GS in the regional population was compared with the prevalence of GS in the MS patients and descriptive statistics, student T test and chi-squared test were used for statistical analysis. P-value < 0.05 was considered as statistically significant. Results: We found that only 41 (5.3%) of the MS patients had the criteria of GS during the follow up period .In this group of patients, there were 11 (26.8%) males and 30 (73.2%) females. So, 7.3% of males and 4.8% of females had GS in MS patient population. Comparing to the prevalence of GS in normal population of our region (19.1 %) prevalence of GS among the MS population was significantly lower. (P-value < 0.05). Conclusion: Prevalence of GS in the MS patients was significantly lower than general population, so, there is a possibility that GS (due to hyperbilirubinemia) could have some protective impact on development of MS in the patients. Large cohort studies with a prospective design are required to further assess such a relationship between MS and GS . Disclosure No conflict of interest P912 Set-up of a smoking cessation program for MS patients: results after 1 year S. Otero-Romero1, S. Sánchez1, J.M. Sánchez2, I. Galán1, G. Vila2, J. Río1, J. Sastre-Garriga1, À. Vidal-Jordana1, G. Arrambide1, M. Tintoré1, M. Campins2, X. Montalban1 1Multiple Sclerosis Centre of Catalonia/Neuroimmunology Dept & Epidemiology Dept, Vall d’Hebron University Hospital & VHIR, 2Preventive Medicine & Epidemiology Dept, Vall d’Hebron University Hospital, Barcelona, Spain Background: Smoking increases the risk of relapses, disability progression and MRI activity in MS patients and cessation has a positive impact on prognosis. Smoking cessation programs improve the patients’ chances of quitting. We evaluated the implementation of a smoking cessation program for MS patients attending the Neurorehabilitation Unit at Cemcat. Methods: The program was implemented in two phases: 1) Awareness and education (January 2014) 2) Recruitment and referral to the Smoking Cessation Unit SCU - (February 2014-ongoing). Patients were systematically screened for smoking status and encouraged by their physician to attend the SCU. The intervention consisted of a first face-to-face counseling session (assessment of tobacco use, dependence and motivation, cessation plan and pharmacotherapy) with posterior follow-up monitoring visits. Demographics and MS clinical Information was collected for all patients approached and information related to smoking habits only for those attending the SCU. Results: From February 2014 to March 2015, 289 patients were screened and 47 were current smokers (prevalence: 16.3% IC 95% 12-21%). Of these, 31 patients (65.9%) accepted participation in

the program, and 14 finally attended the first counseling session (participation rate 28.8%). Patients who rejected to participate were more disabled compared to those who accepted (EDSS 6.6 vs 5.4 p=0.009) with no significant differences in other demographic or clinical variables (gender, age, disease duration, disease phenotype or disease modifying therapy). Patients who attended the SCU were predominantly women (79%), mean age 45.8 (SD 8.9) with a mean score of 4.3 (SD 2.2) in the Fagestrom nicotine-dependence test and 7 (SD 1.8) in the Richmond motivation test. Tobacco cessation pharmacotherapy was prescribed in 88.5% of patients. Conclusions: Patients enrolled in the program where mostly women with moderate nicotine dependence and high motivation. Participation rate was low and more disabled patients seemed to be less likely to engage. Strategies to increase involvement are needed. Disclosure Authors have nothing to disclose P913 Delayed onset and reduced disease severity of spontaneous CNS autoimmunity by conjugated linoleic acid-rich diet S. Hucke1, M. Herold1, M. Hartwig1, I. Kuzmanov1, B. Grützke1, M. Eveslage2, T. Kuhlmann3, H. Wiendl1, L. Klotz1 1Department of Neurology, 2Institute of Biostatistics and Clinical Research, 3Department of Neuropathology, University of Münster, Münster, Germany Background: Despite great advances in therapeutic options for treatment of multiple sclerosis (MS), intrinsic protective immuneregulatory pathways and their potential for therapeutic interventions are still poorly understood. This is especially appealing as an enforcement of such intrinsic regulatory pathways may be employed complementary to conventional therapies. In several models of autoimmunity, oral application of conjugated linoleic acid (CLA), a fatty acid that can be found in meat and dairy products, ameliorated autoimmune inflammation. Objectives: The effects of CLA supplementation on central nervous system (CNS) autoimmunity are less clear. We therefore investigated the effects of dietary CLA intake on clinical features and immunological alterations in a spontaneous mouse model of CNS autoimmunity in mice harboring MOG specific T and B cells. Methods: Effects of CLA supplementation on the clinical severity and CNS immune cell infiltration were analyzed in a spontaneous mouse model of CNS autoimmunity. Furthermore, the effects of CLA on murine and human effector T cell responses were investigated in vitro. Results: Continuous supplementation of CLA via the chow suppresses CNS autoimmunity, as CLA-treated mice exhibited a significantly delayed disease onset as well as a significantly ameliorated disease course. This decrease in clinical disease severity was accompanied by profoundly reduced CNS inflammation as assessed by histology as well as flow cytometry of different CNS regions. Furthermore, oral application of CLA via the diet rendered MOG-specific CD4+ T cells less susceptible towards antigen-specific activation without impacting T cell survival. Importantly, addition of CLA restricted not only newly differentiated effector T


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Poster Session 2, 21(S11) cell responses from healthy donors and MS patients, but was capable of inhibiting established T cell responses during restimulation experiments. Conclusions: Together, these data illustrate the therapeutic potential of dietary fatty acid supplementation as novel complementary strategy to improve CNS autoimmunity. Disclosure Stephanie Hucke:SH received speaker honoraria from Novartis. Martin Herold, Marvin Hartwig, Ivan Kuzmanov, Berit Grützke and Maria Eveslage: nothing to disclose Tanja Kuhlmann: TK received speaker honoraria from Novartis, Biogen Idec Canada,and Teva; she received compensation as a consultant from Genzyme. Heinz Wiendl: HW received compensation for serving on Scientific Advisory Boards/Steering Committees for Bayer Healthcare, Biogen Idec, Genzyme, Merck Serono, Novartis and Sanofi Aventis; he received speaker honoraria and travel support from Bayer Vital GmbH, Bayer Schering AG, Biogen Idec, CSL Behring, Fresenius Medical Care, Genzyme, Glaxo Smith Kline, GW Pharmaceuticals, Lundbeck, Merck Serono, Omniamed, Novartis and Sanofi Aventis; he received compensation as a consultant from Biogen Idec, Merck Serono, Novartis and Sanofi Aventis, has received research support from Bayer Vital, Biogen Idec, Genzyme Merck Serono, Novartis, Sanofi Aventis Germany, Sanofi US. Luisa Klotz: LK received compensation for serving on Scientific Advisory Boards for Genzyme and Novartis; she received speaker honoraria and travel support from Novartis, Merck Serono and CSL Behring; she receives research support from Novartis and Biogen Idec. P914 Sodium chloride promotes pro-inflammatory macrophage polarization thereby aggravating CNS autoimmunity S. Hucke1, M. Herold1, M. Eschborn1, M. Liebmann1, T. Kuhlmann2, H. Wiendl1, L. Klotz1 1Department of Neurology, 2Department of Neuropathology, University of Münster, Münster, Germany Background: It has long been debated whether environmental factors such as nutrition may have an influence on Multiple Sclerosis (MS) incidence and severity. Recently it was shown that a sodium chloride (NaCl)-rich diet influences T cell responses during autoimmunity of the central nervous system (CNS) in the animal model of MS, i.e. experimental autoimmune encephalomyelitis (EAE). Objectives: As the influence of NaCl on macrophages is largely unclear, we wanted to evaluate the influence of NaCl on proinflammatory macrophage responses in the context of CNS autoimmunity. Methods: Murine and human macrophage responses were investigated in vitro and in vivo under homeostatic conditions, upon stimulation as well as during MOG-induced EAE. Furthermore, the impact of transferred NaCl-treated macrophages on EAE disease severity was assessed. Results: Murine NaCl-treated macrophages exhibited a strong pro-inflammatory phenotype upon stimulation characterized by significantly higher production of TNFa and IL-12, increased

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expression of immune-stimulatory molecules such as MHC-II and CD40, and the capacity to boost T cell proliferation in an antigenindependent manner. Mice receiving an NaCl-high diet showed significant aggravation in clinical EAE severity compared to mice receiving normal diet accompanied by a strongly activated phenotype of CNS macrophages at the peak of EAE. Transfer of NaClconditioned macrophages into EAE-diseased animals resulted in a significant aggravation of disease severity when compared to transfer of untreated macrophages, thus underlining the pathophysiological relevance of NaCl for macrophage activation in the context of EAE. Importantly, also in human monocytes, NaCl promoted a pro-inflammatory phenotype that was characterized by increased production of cytokines, enhanced expression of surface markers, and an antigen-independent boost of T cell proliferation. Conclusions: NaCl-high diet promotes a pro-inflammatory phenotype in macrophages that aggravates CNS autoimmunity. Further studies are warranted to determine the relevance of increased dietary NaCl uptake in humans for MS disease incidence and disease severity. Disclosure Stephanie Hucke: SH received speaker honoraria from Novartis. Melanie Eschborn, Marie Liebmann and Martin Herold: nothing to disclose. Tanja Kuhlmann: TK received speaker honoraria from Novartis, Biogen Idec Canada,and Teva; she received compensation as a consultant from Genzyme. Heinz Wiendl: HW received compensation for serving on Scientific Advisory Boards/Steering Committees for Bayer Healthcare, Biogen Idec, Genzyme, Merck Serono, Novartis and Sanofi Aventis; he received speaker honoraria and travel support from Bayer Vital GmbH, Bayer Schering AG, Biogen Idec, CSL Behring, Fresenius Medical Care, Genzyme, Glaxo Smith Kline, GW Pharmaceuticals, Lundbeck, Merck Serono, Omniamed, Novartis and Sanofi Aventis; he received compensation as a consultant from Biogen Idec, Merck Serono, Novartis and Sanofi Aventis, has received research support from Bayer Vital, Biogen Idec, Genzyme Merck Serono, Novartis, Sanofi Aventis Germany, Sanofi US. Luisa Klotz: LK received compensation for serving on Scientific Advisory Boards for Genzyme and Novartis; she received speaker honoraria and travel support from Novartis, Merck Serono and CSL Behring; she receives research support from Novartis and Biogen Idec. P915 Sunshine, sea, and season of birth: MS incidence in Wales L.C. Balbuena, R.M. Middleton, K.E. Williams, K. Tuite-Dalton, H. Lockhart-Jones, J. Peng, D.V. Ford College of Medicine, Swansea University, Swansea, United Kingdom Background: Exposure to sunlight, proximity to coastal areas, and season of birth have been reported as factors associated with multiple sclerosis (MS). Sunlight exposure in gestation and development is necessary for vitamin D synthesis, and living near the sea is a proxy for access to vitamin D in seafood. This study examines whether geographical factors are related to MS incidence in Wales.


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Method: Our main data source was a central MS diagnosis registry of hospital admissions between 2002 and 2013. Geographical information was available, including the lower super output area (LSOA) level of residence. For the 1,909 LSOAs, coastal status, population, longitude/latitude, and average hours of sunlight were obtained. MS incidence was calculated separately for males and females. Poisson regression was used to model MS counts with the geographical characteristics as predictors. Month of birth was compared with the distribution of births in Wales. Results: There were 3,769 new MS cases between 2002 and 2013, with an incidence of 8.4 (95% CI: 7.95-8.85) among males and 13.32 (12.79-13.85) among females. The Poisson model showed that MS incidence varied directly with latitude, with more northern areas having more cases, and inversely with sunlight, fewer cases with more sunlight hours. There was a significant interaction between coastal status and longitude indicating that proximity to the coast was important only for more eastern areas. MS patients were more likely to be born in the months of April, May and September as compared to the Welsh population. Discussion: The study supports previous findings regarding the beneficial effect of sunlight in relation to MS. Higher cases of MS in more northern latitudes may suggest other factors in addition to sunlight such as ethnicity. The Coast × Longitude interaction suggests that coastal status is critical in the east, where occupations are more likely to be indoors. Disclosure Balbuena: nothing to disclose. Middleton: nothing to disclose. Williams: nothing to disclose. Tuite-Dalton: nothing to disclose. Lockhart-Jones: nothing to disclose. Ford: nothing to disclose. P916 Ambient air pollution boosts multiple sclerosis activity through up-regulation of adhesion molecules and chemokine receptors on circulating lymphocytes A. Cortese1, L. Lova2,3, S. Villa1, S. La Salvia1, G. Nosari1, A. Romani1, D. Franciotta1, F. Gigli Berzolari4, P. Borrelli4, C. Cereda1, R. Bergamaschi1 1National Neurological Institute Mondino, Pavia, 2BD Biosciences Italia, MIlan, 3University of Pavia, 4Department of Public Health, Experimental and Forensic Medicine, Unit of Biostatistics and Clininal Epidemiology, University of Pavia, Pavia, Italy Background: Incidence of multiple sclerosis (MS) varies greatly with geographical location being higher in western countries. Environmental air pollution has been associated with increased incidence and exacerbation of numerous respiratory, cardiovascular and rheumatologic diseases, however, little is known about the impact of air pollution on MS course. Objective: Aims of this study are: 1. to investigate the relationship between air pollution, namely particulate matter 10 (PM10), and MS disease activity as defined by the presence of contrast-enhancing (CE) lesions on brain MRI 2. to assess the potential in vivo correlation between mean and peak PM10 levels in the previous month, and expression on

peripheral blood lymphocytes of inflammatory markers and adhesion molecules in relapsing remitting MS (RRMS) patients and healthy controls (HC) . Methods: 1) Brain MRI performed on RRMS patients at C. Mondino Neurological Institute from 2003 to 2010 2) mean and peak PM10 ambient air levels of 60 days prior MRI (mg/m3) available from ARPA-Lombardia Environmental Protection Office 3) Expression levels (mean fluorescence intensity) of activation markers (CD69, CD38, HLA-DR), chemokine receptors (CCR6, CXCR3) and adhesion molecules (LFA1, VLA4,CD44, PSGL1) on CD4 and CD8 T cells measured on fresh blood by FACS on a prospective independent cohort of RRMS, who underwent brain MRI scan, and HC. Results: 226 brain MRI, of which 79 (36%) showing CE lesions, of 51 patients were considered. The mean PM10 level in 60 days prior MRI was significantly higher in patients with CE lesions compared with subjects without CE lesions (54.93±2.73; 47.46±2.06, p=0.001), independently from time of the year and treatments. In an independent cohort of 56 prospectively enrolled RRMS patients but not on 19 matched HC, we observed a positive association between CCR6 expression on CD4+ T cells and mean PM10 (p=0.003) and peak PM10 (p=0.01), PSGL1 on CD8+ T cells and mean (p=0.02) and peak (p=0.03) PM10, LFA1 on CD4+ T cells and mean PM10 (p=0.08). Conclusion: Our results show in RRMS patients a positive association of ambient air pollution with disease activity as well as the expression of adhesion molecules and chemokine receptors on circulating lymphocytes. We speculate that PM10 exposure in the lung may lead to MS exacerbation by boosting the migratory capacity of auto-reactive lymphocytes and, eventually, by increasing their ability to cross the blood-brain-barrier. Disclosure Andrea Cortese: nothing to disclose. Luca Lova: nothing to disclose. Silvia Villa: nothing to disclose. Sabrina La Salvia: nothing to disclose. Guido Nosari: nothing to disclose. Diego Franciotta: nothing to disclose. Alfredo Romani: nothing to disclose. Francesca Gigli Berzolari: nothing to disclose. Paola Borrelli: nothing to disclose. Cristina Cereda: nothing to disclose. Roberto Bergamaschi has served on scientific advisory boards for Biogen Idec and Almirall; has received funding for travel and speaker honoraria from Sanofi-Aventis, Genzyme, Biogen Idec, Bayer Schering, Teva Neurosciences, Merck Serono, Almirall, and Novartis; received research support from Merck Serono, Biogen Idec, Teva Neurosciences, Bayer Schering, Novartis, Sanofi-Aventis. Andrea Cortese and Luca Lova equally contributed to this work.

Progressive MS P917 Role of B-cells in primary progressive multiple sclerosis: elevated intrathecal IgG production at disease onset predicts aggressive disease course


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Poster Session 2, 21(S11) A. Abdelhak1, C. Mayer2, T. Fangerau1, H. Tumani1 Department, University Hospital Ulm, Ulm, 2Neurology Department, University Hospital Frankfurt, Frankfurt, Germany

1Neurology

Introduction: B cells play an important pathogenic role in some subgroups of Multiple sclerosis (MS) which could be mediated via antibody (Ab)-synthesis, cytokines release or antigen presentation (Cross & Waubant, 2011). B-cell depletion was effective in a group of primary progressive multiple sclerosis (PPMS) patients (Hawker et al., 2009). Markers of B cells activation like the intrathecal IgG production could help to better understand the involvement of B-cells in PPMS. Methods: We retrospectively evaluated cerebrospinal fluid (CSF) data obtained by lumbar puncture (LP) from PPMS patients (McDonald criteria 2010 (Polman et al., 2011)) seen between 2009 and 2014. The intrathecal IgG fraction by IgG-index (IgGI) according to Link&Tibbling (1977) and the concentration of intrathecal IgG by IgGloc (in mg/l) according to Reiber&Felgenhauer (1987) were analyzed in correlation with the EDSS at time of first LP (EDSSLP) and at follow-up (EDSSFU) as well as with the progression rate. Results: A total of 40 patients were included. Median values for IgGI and IgGloc were 0.64 and 0.5 mg/l. Median EDSSLP and EDSSFU were 3.0 and 4.2, respectively. Pathologically elevated IgGI was found in 36.7%, while elevated IgGloc in 51.7%. In patients with elevated IgGI the EDSSLP was lower (2.5 vs 4.0, p=0.7) while EDSSFU was higher (4.7 vs 4.0, p=0.6) compared to normal IgGI. Similarly, the progression rate was higher (1.4 vs 0.6, p=0.2) in patients with elevated IgGI. Likewise, the EDSSFU was higher in patients with elevated IgGloc compared to those with normal IgGloc (5.0 vs 4.0, p=0.6) while the EDSSLP didn’t differ (4.0 in both groups). Furthermore, the progression rate was higher in the elevated IgGloc group (1.1 vs 0.65, p= 0.2). Discussion: We report a trend towards lower EDSSLP with elevated IgG index. However, this was associated with higher EDSSFU and a faster progression rate. A similar results were found regarding the IgGloc. This confirms the well-known involvement of B-cells in PPMS but raises the possibility of a shift in the pathological role of B-cells along the course of the disease. Further studies are needed to confirm our findings. Disclosure Nothing to disclose P918 Two determinants of late disability progression in multiple sclerosis: early inflammatory disease and old age in damaged brain F. Fanelli1, M. Danni2, P. Cavalla3, E. Binello3, V. Barletta1, L. Prosperini1, L. Pinessi3, L. Provinciali2, C. Pozzilli1 1Sapienza University, Rome, 2Neurological Clinic, Ospedali Riuniti, Marche Polytechnic University, Ancones, 3Health & Science City Turin University Hospital, Turin, Italy Background: Natural history studies have suggested that the disability progression due to multiple sclerosis (MS) is a “two-stage”

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process, i.e. in the earlier stage inflammation and disability progression are associated, while in the later stage these two phenomena are independents. Nonetheless, the relationship between relapses and disability is still debated. Objective: To investigate the influence of relapses and paraclinical signs of inflammation detected at magnetic resonance imaging (MRI) on disability progression from an Expanded Disability Status Scale (EDSS) score of 3.5 (+/-0.5) to 6.0 or more. Methods: Data of patients regularly attending three tertiary MS centres in Italy (Rome, Ancones and Turin) were analyzed. A Cox proportional hazard model was built to assess the influence of some covariates on the risk of progression to an EDSS score of 6.0 or more (main outcome). These covariates included gender; age, MS duration, relapse rate and MRI activity at EDSS 3.5 (+/-0.5); onset symptom; time to first relapse; exposure to disease-modifying treatments (time-dependent covariate). The follow-up period was calculated as time elapsed from EDSS 3.5 (+/-0.5) to the main outcome, or the last available visit, whichever came first. Results: Data from 611 patients (409 F, 202 M) with mean age of 42.5 years and mean MS duration of 12.2 years at EDSS of 3.5 (+/-0.5) were collected. During a median follow-up time of 5 years (range 2-23), 361 patients reached an EDSS score of 6.0 or more. Out of these, 232 (64%) patients developed disability with superimposed relapses or paraclinical (i.e. gd-enhancement) signs of inflammation, while129 (36%) patients did not show any disease activity. Those patients presenting superimposed clinical/ MRI activity were younger, had shorter MS duration and higher relapse rate at EDSS 3.5 (+/-0.5) than those without activity (p-values< 0.001). The Cox regression model showed that the risk of disability progression was associated with older age (HR=1.03, p< 0.001) and shorter MS duration (HR=0.97, p=0.001) at EDSS 3.5 (+/-0.5). Discussion: Our findings suggest that the occurrence of inflammation may lead to disability progression in approximately two third of patients, especially in those ones who are younger, with shorter disease duration and higher relapse rate. Old age is an independent risk factor for disability progression and it is the only determinant for reaching an EDSS of 6.0 or more in patients without inflammatory disease. Disclosure This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Fulvia Fanelli, Valeria Barletta: no disclosures related to this project/manuscript. Maura Danni: no disclosures related to this project/manuscript. Paola Cavalla: no disclosures related to this project/manuscript. Luca Prosperini: consulting fees, and /or lecture fees, and/or travel grants from: Bayer Schering, Biogen Idec, Genzyme, Novartis and Teva. Lorenzo Pinessi: funding from Merck Serono, Biogen Idec, Teva and speaker honoraria from Novartis, Merck Serono, Biogen Idec, Teva, Genzyme. Leandro Provinciali: no disclosures related to this project/ manuscript. Carlo Pozzilli: consulting and/or lecture fees and research grants and/or travel grants from Almirall, Biogen Idec, Bayer Schering, Merck Serono, Novartis, Roche, Sanofi Genzyme and Teva.


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P919 Disability outcome and sample size considerations for PPMS clinical trial efficiency M.D. Davis1, J.R. Steinerman1, N. Sasson2, V. Knappertz1,3 1Teva Pharmaceuticals, Frazer, PA, United States, 2Teva Pharmaceutical Industries, Netanya, Israel, 3Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany Background: Efficient clinical trial design is needed to address the primary progressive multiple sclerosis (PPMS) therapeutic vacuum. All reported pivotal PPMS studies failed to meet their primary efficacy endpoint. In PROMiSe (glatiramer acetate), OLYMPUS (rituximab), and INFORMS (fingolimod), confirmed disease progression (CDP) definitions have included the EDSS, as well as the timed 25-foot walk (T25FW) or 9-hole peg test (9HPT) performance outcomes. Objectives: To explore how combinations of validated disability outcomes for PPMS clinical trials impact event rates and sample size. Methods: EDSS progression (⩾1 point increase from baseline [BL], or ⩾0.5 point increase for BL EDSS ⩾5.5), T25FW progression (20% increase from BL) and 9HPT progression (20% increase from BL) were considered separately as trial outcomes. In addition, combined endpoints were considered: EDSS or T25FW; T25FW or 9HPT; EDSS or T25FW or 9HPT. Three- and 6-month CDP rates from PROMiSe (all patients, N=943), OLYMPUS (placebo cohort, n=147), and INFORMS (all patients, N=823) were considered as available. Sample-size estimates were calculated to provide 80% power for a 2-year trial using a log-rank test for time to CDP as the primary outcome, assuming a 5% type I error rate, a 2:1 treatment allocation, an accrual time of 1 year, and 16% dropout rate. Results: Two-year progression rates based on EDSS alone were smaller in PROMiSe compared with OLYMPUS (3-month CDP: 27.5% vs 38.5%, 6-month CDP: 22.6% vs 30.4%). T25FW alone rates were markedly higher than EDSS (3-month CDP: 40.7% vs 51.0%, 6-month CDP: 36.6% vs 44.5%). The EDSS/T25FW/9HPT combined endpoint resulted in the highest progression rates (3-month CDP: 50.4% vs 61.9%, 6-month CDP: 44.9% vs 54.8%). INFORMS rates appear to be similar to OLYMPUS rates, but are not yet published in detail. Assuming a 30% treatment effect on 3-month CDP, sample size is reduced by 37%-43% using the T25FW alone endpoint and 57%-60% using the EDSS/ T25FW/9HPT combined endpoint compared with EDSS alone. Sample size increased 123%-154% compared with EDSS using the 9HPT alone endpoint. Conclusions: The use of performance outcomes in helping to define CDP can lead to a reduced sample size for an adequately powered PPMS trial. It is not known which CDP definition may be more sensitive to treatment effects. Collaborative efforts to aggregate PPMS data can further address methodological challenges to developing treatments for this distinctly underserved condition.

P920 A robust activation of complement in cortical grey matter lesions of progressive MS L.M. Watkins1, J.W. Neal2, S. Loveless2, R. Magliozzi3,4, M. Calabrese5, R. Reynolds4, N.P. Robertson2, B.P. Morgan2, O.W. Howell1,4 1Swansea University, Swansea, 2Cardiff University, Cardiff, United Kingdom, 3Istituto Superiore di Sanità, Rome, Italy, 4Imperial College London, London, United Kingdom, 5University Hospital Verona, Verona, Italy Background: Accumulation of neuronal and axonal damage underlies the increasing neurological disability in the progressive phase of multiple sclerosis (MS). Activation of the innate immune response, of which complement is a central player, is postulated to play a part in this pathology. Objectives: In order to better understand the pathomechanisms underlying disease progression we determined if complement activation is associated with demyelination and neurodegeneration in MS grey matter (GM). Methods: We analysed the expression of complement recognition molecules, activation fragments, regulators and anaphylatoxin receptors in post-mortem tissue from 22 progressive cases (13 SPMS, 9 male, median age at death 50yrs (38-66)); 8 inflammatory controls (viral encephalitis and stroke) and 10 non-diseased controls, in cortical, deep GM and white matter by immunocytochemistry and quantitative morphometry. Results: Expression of the complement activation fragment and opsonin C3b was notable in MS GM. The density of immunostained cells expressing the classical pathway protein C1q, and the alternative pathway activation fragment Bb, was significantly increased in cortical GM lesions in comparison to normal and control GM. Cell associated staining for the terminal complement complex (C5b-9) was elevated, indicating complement activation to completion. Key regulators of the classical and alternative pathway were not altered in their expression, whilst the density of activated microglia (HLA+) expressing the anaphylatoxin C5a receptor were increased in GM lesions. C3b labelled a greater proportion of cortical neurons in MS, whilst C3b+ neurons had an altered nuclear morphology (p< 0.0001) and stained weakly for factor H. The density of NeuN+ neurons was reduced in cortical lesions (p=0.002) in comparison to control. Conclusions: Complement activation is a notable in the MS grey matter and associates with lesions of the neocortex. We speculate that microglial activation via C5a receptor signalling and a dysfunction of complement regulation may underlie neuronal susceptibility to complement mediated damage in progressive MS. Disclosure This work was supported by the UK MS society (#993) and the International Progressive MS Alliance (#PA0124). L.M.Watkins, J.W. Neal, S. Loveless, R. Magliozzi, M. Calabrese, R.Reynolds, N.P. Robertson, B.P. Morgan & O.W.Howell: nothing to disclose.

Disclosure Joshua R. Steinerman, Mat Davis and Nissim Sasson are employees of Teva Pharmaceutical Industries. Volker Knappertz is an employee of Teva Pharmaceutical Industries and holds stock in Knopp Neurosciences.

P921 Combinatorial antibody phage display libraries constructed from B-cells infiltrating brain tissue of people with progressive multiple sclerosis


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Poster Session 2, 21(S11) C. Maggiore1, G. Giovannoni2, J.E. Martin3, A. Nissim4 Moorfields Eye Hospital NHS Trust, 2Neurology, Blizard Institute, Centre for Neuroscience and Trauma, Barts and the London School of Medicine and Dentistry, 3Pathology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4Experimental Medicine & Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom 1Neuro-Ophthalmology,

Background: The specificity of the immunoglobulins involved in the active demyelinating lesions is still debated and cross-reactivity among pathogens and myelin proteins is seen as the relevant mechanism for triggering autoimmunity. In particular the variable regions of the heavy chain could carry a double binding activity while the light chain appears to be responsible for “fine tuning” of antibody specificity. Objectives: Combinatorial single chain fragment variable (scFv) antibody libraries from multiple sclerosis patients from peripheral blood lymphocytes of MS patients were built previously and have been also used by other groups. In this study we built libraries directly from B cells infiltrating the brain tissue of people with progressive MS and compared the V gene repertoire with the expected germline genes distribution in healthy individuals. The libraries have been then screened against known autoantigens to test the hypothesis that these scFvs are a potential source of antibodies for targeting treatment to MS lesions. Methods: Snap-frozen brain blocks, supplied by the UK MS tissue bank, from 14 progressive MS cases with a ratio M:F of 2:5 and a median disease duration of 20.5 years have been used. Total RNA molecules were extracted and cDNA retrotranscribed and finally PCR was performed using heavy and light chain family-specific primers in conjunction with an external primer hybridising the constant region. The libraries’ V gene repertoire was analysed before selection against myelin proteins, i.e. myelin basic protein (MBP)-proteolipid protein (PLP) fusion protein MP4. Results: scFv library with a diversity of ~ 5.8*10^7 was built. The VH1 and VH2 families were significantly overrepresented compared with adult healthy controls and a typical long VH-CDR3 with average length of 16±6 aa was observed. The light chain sequences analysed were Vλ 6 family and represented half of the sequences. Following selection by 4 rounds of panning binders were raised against MP-4. Conclusion: Our data confirm a characteristic antigen-driven immune response. The library built from VH and VL MS repertoire showed higher stability of binding compared to library built from VH only MS repertoire supporting the role of VL in the specificity of the antibodies. Our library can potentially be utilised to raise antibodies for specific targeting of treatment to MS lesions. Disclosure Cosimo Maggiore: nothing to disclose. Gavin Giovannoni: nothing to disclose. Joanne E. Martin: nothing to disclose. Ahuva Nissim: nothing to disclose.

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P922 Fatigue predicts conversion to secondary progressive disease phenotype in relapsing-remitting multiple sclerosis patients M. Cavallari, M. Palotai, J.C. Prieto, B.C. Healy, S. Egorova, M. Polgar-Turcsanyi, M. Anderson, B. Glanz, T. Chitnis, C.R.G. Guttmann Brigham and Women’s Hospital / Harvard Medical School, Boston, MA, United States Fatigue, defined as overwhelming tiredness, lack of energy or exhaustion, affects 65-97% patients with multiple sclerosis (MS) and is considered the most severe symptom by 15-40% MS patients. Fatigue is reported more frequently in progressive than in relapsing-remitting (RR) patients. It is unclear whether fatigue is a consequence of disease progression or rather a predictive trait of conversion to a secondary progressive (SP) course. In this study we investigated the predictive value of fatigue towards conversion from the RR to the SP phase of disease. Study subjects were retrospectively selected from a larger cohort of over 800 prospectively followed patients that are assessed yearly with standardized clinical evaluation, magnetic resonance imaging (MRI) and quality of life measures, within the CLIMB (Comprehensive Longitudinal Investigations in MS at the Brigham and Women’s Hospital) study. We identified 37 patients who had at least 4 years of follow-up, and converted from RR to SP disease phenotype within this period. The Modified Fatigue Impact Scale (MFIS) was available for 29 out of the 37 patients during the RR phase of their disease. We selected a comparison group by matching each patient to one that did not convert to SPMS within the follow-up period, and was matched for age, gender, ethnicity and disease duration (DD). No match was found for 2/29 patients. Male/ Female ratio was 18/36. Time-points at least 1 year before SP diagnosis were assessed (mean±SD=1.9±1.2 years). Comparing 27 converters (C) to 27 matched non-converters (NC) mean±SD age was 48.7±10.9 vs 48.3±9.9, and DD was 11.4±7.4 vs 11.0±6.5. Total MFIS scores were significantly higher in C vs NC (41.9±14.7 vs 26.8±17.1; p=0.003). Expanded Disability Status Scale (EDSS) scores were also significantly higher in C (2.7±0.7 vs 1.3±1.1; p< 0.0001). Although we found an association between MFIS and Center for Epidemiologic Studies Depression Scale (CES-D) scores (rho=0.63, p< 0.0001), CES-D scores were not significantly different between C and NC. The difference in total MFIS scores between the groups remained significant after adjusting for EDSS and CES-D scores (p=0.02). MFIS scores were also associated with MRI-derived measures of T2 lesion volume (T2LV) (rho=0.34, p=0.02), while neither T2LV nor global brain atrophy showed significant differences between C and NC. Our findings raise the possibility that fatigue is an independent predictor of conversion to SP phenotype in RR MS patients. Disclosure M. Cavallari and J.C. Prieto are supported by Research Fellowship Award from Questor/Mallinckrodt Farmaceuticals. M. Palotai is supported by the MS International Federation McDonald Fellowship Award. B. Glanz receives research support from Merck Serono. B.C. Healy receives research support from Merck Serono, Novartis and Genzyme.


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S. Egorova receives research support from Merck Serono, Novartis and Foundation for Neurologic Diseases Boston. M. Polgar-Turcsanyi, M. Anderson, T. Chitnis and C.R.G. Guttmann report no disclosure. P923 Progressive multiple sclerosis: the beneficial effects of multimodal complex therapy M.R. Haupts1,2, S. Wichert1, D. Seidel1, H.-P. Hartung2 1Neurology, Augustahospital, Isselburg-Anholt, 2Neurology, H.Heine-University, Duesseldorf, Germany Therapy options for progressive MS are limited. Immunomedication is neither evidence-based nor labelled. Nevertheless a majority of patients in progessive stages of MS seeks relief and therapy. Corticoid pulses and symptomatic therapy are recommended in textbooks. For patients in acute progression or after acute relapses, a procedure for complex intensified therapies in hospitals is established in German DRG system (OPS 8-559). Objective: To assess effects of OPS 8-559 on measures of functional status and quality of life in persons with progressive MS. Methods: 44 patients with MS progression (5 PPMS, 39 SPMS ) received standardised inpatient rehabilitation according to the OPS 8-559 procedure including parenteral corticoid pulses (mean inpatient time 18,1 +/- 2 days). Mean age was 53,6+-7,4 yrs., mean EDSS 5,9+-0,9. Fatigue (FSMC), depression/anxiety (HADS), and quality of life (EQ5D VAS) were assessed, the latter re-evaluated 3 months after intervention. Results: Patients gained significant profit in motor function, affective status, and quality of life. EDSS improved significantly in 52% of patients (from mean 5,9 to 5,5+- 0,8, p< 0,0001). FSMC total score reduced from 77,0+12.2 to 75,3+-12,8 (p 0,28). HADS-D depression scores decreased from 80,6+-20,2 to 68,0+-27,7 (p 0,0008); EQ5D-VAS improved significantly from 55,9+-19,4 to 64,5+-16,9 (p 0,0009). There was additional benefit of parenteral corticoid pulses on EDSS and EQ5D improvement. Quality of life was still improved after 3 months compared to baseline (EQ5D 60,2+-20,4, ANOVA p 0,0028). -cf. FigureConclusions: Our data demonstrate the value of a standardised and MS-specialised complex inpatient concept in progressive stages of MS where the ability of walking is endangered or already lost. Corticosteroid pulses may be of additional value, as already reported in previous studies. As to the neural mechanisms, pharmacological activation/ deblockade of CNS networks, activation of neural functions resp. „neuroprotection“ through intense motor activity (as also known from other fields of neuroscience), reduction of physical weakness and deconditioning, lessening of depressive interaction, and restoration of physiological motor patterns (with lasting effects into future) may be hypothetized. The OPS 8-559 procedure is currently under economic dispute. It proves highly efficient in progressive MS. Disclosure All authors (Haupts, Wichert, Seidel, Hartung) have no conflicting interests to disclose. This investigation was part of a clinical project funded by the Gemeinnützige Hertie Stiftung, Germany.

Repairing mechanisms P924 Ermin as a marker of remyelination in MS I. Ahmad1, E. Oveland2, R.R. Lereim2, H. Barsnes2, K.-M. Myhr1,3, S. Wergeland1,3, F. Berven2, L. Bø1,3 1Department of Clinical Medicine, 2Department of Biomedicine, University of Bergen, 3Department of Neurology, Haukeland University Hospital, Bergen, Norway Background: Remyelination occurs in many multiple sclerosis (MS) lesions, but it becomes gradually insufficient and eventually ceases in the majority of lesions. There are no reliable clinical or paraclinical markers for remyelination. Objectives: To investigate potential molecular markers of remyelination in MS in an experimental model of de- and remyelination, the cuprizone (CPZ) model. Methods: We performed a high-throughput proteomic analysis of brain tissue from mice exposed to CPZ for six weeks, using TMTlabeling and label-free quantitative proteomics. Among 4375 quantified proteins, Ermin, a myelinating oligodendrocyte-specific protein was decreased in CPZ exposed mice compared to healthy controls. Ermin expression was further investigated immunohistochemically in brain tissue of CPZ-exposed mice and in MS brain tissue obtained at autopsy. Results: After one week, there was a significant reduction in the density of Ermin-immunopositive (Erm+) cells in CPZ-exposed mice compared to in healthy controls, in all regions investigated: Corpus callosum, cerebral cortex and deep gray matter (n=6 at each time point, p< 0.0005 in all regions, one-way ANOVA). After six weeks of CPZ exposure, the mean density of Erm+ cells (number of cellular profiles per 0.0625 mm2) in corpus callosum, cerebral cortex and deep gray matter was 15.0 ± SD 4.8, 0.0 ± SD 0.0, and 4.1 ± SD 2.2. The density of Erm+ cells was significantly reduced compared to in healthy controls (p< 0.0005) in all regions studied. In the remyelination phase, two weeks after ending cuprizone exposure, there was a significant increase in the Erm+ cell density in all regions studied (p < 0.01) compared to after six weeks of CPZ exposure. In active white matter MS lesions there was no difference in Ermin immunopositivity compared to in the white matter of controls. In chronic active MS lesions Ermin immunopositive oligodendrocytes were detected at the remyelinating lesion border, but not in the lesion center. Conclusion: These data highlights that Ermin is a potential molecular marker of remyelination in MS. Disclosure I. Ahmad: nothing to disclose. E. Oveland: nothing to disclose. R.R. Lereim: nothing to disclose. H. Barsnes: nothing to disclose. K.-M Myhr: nothing to disclose. S. Wergeland: nothing to disclose. F. Berven: nothing to disclose. L. Bø: nothing to disclose. P925 Systemically administered exosomes mediate recovery in the Theiler’s Mourine Ecephalomyelitis virus animal model of multiple sclerosis


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Poster Session 2, 21(S11) J. Ramos-Cejudo1, M. Fernández-Fournier2, M. GutiérrezFernández1, B. Rodríguez-Frutos1, L. Otero-Ortega1, A. Feliú3, F. Carrillo Salinas3, M. Mecha3, C. Guaza3, T. Navarro4, S. Cerdán4, E. Díez-Tejedor2 1Neuroscience Area of IdiPAZ, 2Multiple Sclerosis Unit, Neuroscience Area of IdiPAZ, La Paz University Hospital, Autonoma University of Madrid, 3Neuroimmunology, Functional and System Neurobiology Department, Cajal Institute, 4Laboratory for Imaging and Spectroscopy by Magnetic Resonance LISMAR, Institute of Biomedical Research Alberto Sols, Madrid, Spain Introduction: Exosomes (EXO) are small vesicles of 40 to 150nm released by different cell types, mediating intercellular communication. An animal model that has recently gained relevance in the study of Multiple Sclerosis is Theiler’s Mourine Encephalomyelitis Virus (TMEV). We aimed to study if the administration of exosomes derived from mesenchymal stem cells could mediate recovery in the TMEV model. Methods: Exosomes purified from human adipose tissue-derive mesenchymal stem cells were intravenously administered (25ug/ Kg,i.v.) to mice undergoing demyelinating disease induced by TMEV injection (2x10^6 viral units). Animals (n=27) were randomly divided into 3 groups (Sham, n=7; TMEV, n=10; TMEVEXO, n=10) and evaluated clinically and by Magnetic Resonance Imaging (MRI). Results: Fifteen days post-exosome administration motor activity and memory improved in EXO treated animals; 7-tesla MRI analysis showed partial resolution of both brain connectivity and ventricular atrophy. Myelin basic protein staining of the subcortical white matter showed higher myelination in treated mice. The number of KI-67 proliferating cells and the levels of Oligodendrocyte precursors’ markers PDGFR and CC1 were higher in the Subventricular Zone of treated mice. Proteomic content of exosomes in cell supernants was analyzed by Orbitrap identifying over 1,300 proteins, including a number of trophic factors and signaling molecules not previously identified in the literature. Conclusions: Our results suggest that exosomes derived from mesenchymal stem cells have the potential to mediate recovery after Central Nervous System demyelination and might provide a novel approach to treat autoimmune diseases such as Multiple Sclerosis. Disclosure Nothing to disclose P926 Differential viability, distribution and therapeutic efficacy of transplanted neural stem cells in the acute and chronic disease phases of experimental autoimmune encephalomyelitis A. Merlini1, D. De Feo1, F. Ruffini1, G. Comi2, G. Martino1 1Neuroimmunology Unit, 2Department of Neurology, San Raffaele Scientific Institute -Institute of Experimental Neurology, Milan, Italy Introduction: Intrathecal transplantation of adult neural stem/ precursor cells (NPCs) ameliorates disease severity in experimental autoimmune encephalomyelitis (EAE), the animal model of

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multiple sclerosis. We aimed at understanding if transplantation in the acute or chronic phase of EAE might affect NPC therapeutic efficacy. Methods: NPCs were derived from the subventricular zone of 8-week old female C57Bl/6 mice. EAE was induced in syngeneic mice by subcutaneous immunization with myelin oligodendrocyte glycoprotein 35-55 peptide. One million GFP-labelled NPCs or vehicle were transplanted intrathecally in the cisterna magna of EAE mice at peak of disease severity, ca 14 days post immunization (dpi), chronic phase (80 dpi) or healthy age-matched controls (HC). Each group comprised at least 4 animals. Results: When transplanted in the acute EAE phase, at 1 day post transplantation (dpt), NPCs distributed within few millimetres from the injection site (2,46 ±0,90 mm in EAE; 2,78 ± 0,57 in HC), no further migration was observed at 7 and 60 dpt. At 1 dpt, 8,1% of transplanted NPCs survived in HC and 7,5% in EAE. At 7 dpt the number of surviving NPCs further decreased in both groups (HC: 2,6%; EAE: 4,6%). A fraction of transplanted NPCs expressed the apoptotic marker activated caspase 3, with EAE mice showing a trend of reduced apoptosis at 1 dpt (HC: 3,2%; EAE: 1,5%) and at 7 dpt (HC: 3,8%; EAE: 1,4%; p< 0,05). Consistently, at 60 dpt NPCs transplanted in EAE mice displayed increased survival (2,7%) when compared to HC (0,3%; p< 0,05). Transplanted NPCs localized mainly in the subarachnoid spaces of the fourth ventricle or surrounding meninges at 1 dpt (EAE: 94,8% of surviving NPCs; HC: 87,6%) and 7 dpt (EAE: 98,5%; HC: 89,4%), with a small quota of NPCs integrating in the parenchyma. At 60 dpt, 93,5 % of surviving NPCs retained their meningeal localization in the EAE group, while in the HC group 89,4% of the surviving NPCs were found in the parenchyma. Finally, transplantation of NPCs in the chronic phase of EAE (80 dpi), when neuroinflammation has waned off, failed to retain NPC cells in the meninges and to induce clinical amelioration when compared to transplantation of NPCs in the acute phase of EAE. Conclusions: Neuroinflammation might influence long-term the viability, localization and therapeutic efficacy of transplanted NPCs in EAE. This finding has relevance for clinical translation of NPCs by defining the better disease window for NPC transplantation. Disclosure Arianna Merlini: nothing to disclose Donatella De Feo: nothing to disclose Francesca Ruffini: nothing to disclose Giancarlo Comi: Prof. Comi received personal compensation for speaking and consultancy activities from Bayer Schering Pharma, Merck Serono, Sanofi-Aventis, Biogen-Dompè, Novartis Farma and TEVA Pharmaceutical Ind. Ltd. Gianvito Martino: nothing to disclose P927 Vulnerability of oligodendrocyte precursor cells to death is modulated by key prostaglandins N.G. Carlson1, L. Schmidt2, J. Redd2, S. Bellamkonda2, B. Wood2, L.M. Weber2, M.M. Paz Soldan2, J.W. Rose2 1GRECC/Neurovirology, 2Neurovirology, VA SLC HSC, Salt Lake City, UT, United States Background: Recent studies have indicated that susceptibility of oligodendrocyte precursor cells (OPCs) to injury within the active


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demyelinating MS lesion can be a limiting factor for remyelination in MS. We previously showed that COX-2 activity in mouse OPCs renders these cells more vulnerable to excitotoxicity in vitro. In order to assess how COX-2 contributes to OPC death we examined which of the five major COX-2 derived prostaglandins (PGs) are synthesized after glutamate receptor activation with kainate (KA). Objective: We examined the hypothesis that OPC death is mediated by COX-2 generated prostaglandins acting on specific prostanoid receptors, which could limit remyelination. Methods: In order to identify candidate PGs, the amounts of the five major PGs (PGD2, PGI2, TxB2, PGE2 and PGF2α) were assessed in media from dispersed primary mouse OPC cultures treated with KA. The expression of receptors for candidate PGs was examined in cultured OPCs and in MS tissue by immunofluorescence confocal microscopy. The effect of antagonists for key PG receptors on viability of OPCs was assessed following exposure to KA and two other toxins Bz-ATP and TNFα. Results: Only two PGs, PGE2 and PGF2α were increased following exposure to KA relative to vehicle treated cultures. All the receptors for PGE2 (EP1-4) and PGF2α (FP) were expressed in cultured OPCs, but the most abundant receptors were EP3 and FP. Antagonists for the EP3 and FP receptors yielded a comparable amount of protection to COX-2 inhibitors with cultured OPCs treated with toxic concentrations of KA, BzATP and TNFα. Sublethal concentrations of these agents also increased expression of the FP receptor in cultured OPCs. In autopsy tissue from MS patients, the EP3 and FP receptors were expressed in OPCs near the active edge of MS plaques and were absent in control white matter, consistent with a role for these receptors in MS. Conclusions: Inhibitors of the EP3 and FP receptors enhance survival of OPCs following toxic challenge and may help facilitate remyelination. Disclosure All authors have nothing to disclose. This study is funded by VA Merit Grants to NGC and JWR.

Imaging P928 Corpus callosum index to measure brain volume loss in clinical practice in MS patients J.I. Rojas, F. Sanchez, L. Patrucco, J. Miguez, E. Cristiano Centro de Esclerosis Múltiple de Buenos Aires, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina Sophisticated MRI techniques, often inaccesible in clinical practice, are requiered to analyze brain volumen loss in multiple sclerosis (MS) patients. The corpus callosum index (CCI) is a normalized measurement that reflects changes of brain volumen and was proposed as an easy and practical tool to measure brain volume changes, however, it´s reliability was not entirely demonstrated with standard brain volumen loss techniques currently used. The objective of the study was to correlate CCI measurements at baseline and during the follow up with SIENAX and SIENA software in MS patients. Methods: A 2 year prospective study, enrolling consecutive relapsing-remitting MS (RRMS) patients with less than 3 years of diseaese onset was performed. On a conventional best mid-saggital

T13D sequence, CCI was obtained by measuring anterior, medium and posterior segments of CC, and normalized to its largest anteroposterior diameter. SIENA and SIENAX software was used as gold standard and to perform correlation. MRI was performed in all patients at baseline and every year during 2 years. Results: We included 54 RRMS patients, mean age 34 +-5 years, 65% women, mean EDSS 1.5 +- 0.5 and all under DMD treatment. CCI at diagnosis was 0.38 +/- 0.04 and correlated with total brain volumen at baseline (r 0.71 p< 0.001), at year 1 and 2 (r 0.68 p< 0.001 and r 0.73 p < 0.001 respectively). CCI anual decrease was 0.01 +- 0.01 and 0.02 +- 0.01 for year 1 and 2 respectively and strongly correlated with SIENA (r 0.68 p< 0.001and 0.73 p< 0.001 for year 1 and 2 respectively). Conclusion: CCI demonstrated a strongly correlation with more complex techniques used to measure brain volumen loss. Disclosure Authors declare no conflict of interest with the study research

P929 Longitudinal ultra-high field MRI study of brain lesions in neuromyelitis optica I. Kister1, K. Dadon1, M. Fox1, S. Chawla2, P. Dusek3,4, J. Wuerfel3,5,6, F. Paul5,7,8, T. Sinnecker5,9, Y. Ge2 1Multiple Sclerosis Care Center, Department of Neurology, NYU School of Medicine, 2Department of Radiology, NYU School of Medicine, New York, NY, United States, 3Institute of Neuroradiology, Universitätsmedizin, Göttingen, Germany, 4Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic, 5NeuroCure Clinical Research Center, Charité Universitätsmedizin, 6Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine, 7Clinical and Experimental Multiple Sclerosis Research Center, Charité - Universitätsmedizin, 8Department of Neurology, Charité - Universitätsmedizin, Berlin, 9Department of Neurology, Asklepios Fachklinikum Teupitz, Germany, Teupitz, Germany Objectives: To assess radiographic brain disease progression in Neuromyelitis Optica (NMO) over 2-3 year period using ultrahigh field MRI. Background: Little is known about radiographic disease course in NMO. Ultra-high field (e.g.7T) MR technology allows for exquisite visualization of brain lesions, determination of lesionvein relationship and quantitation of iron deposition within areas of interest. Methods: NMO patients who receive routine neurologic care at the NYU MS Center in New York and at the Charité in Berlin participated in the prospective study. Patients were imaged using identical whole-body human 7T MR systems (MAGNETOM, Siemens) equipped with 24-channel phased array coil (Nova Medical, Inc., MA) at 2 sites at baseline and 2-3 years subsequently. In addition to 2D spin-echo T2-weighted MRI (T2w), high resolution gradient-echo T2*w was performed for lesion-vein relationship, and 3D susceptibility-weighted imaging (SWI) was performed with inplane resolution of 0.23x0.23mm2 for iron quantification using quantitative susceptibility mapping (QSM) method.


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Poster Session 2, 21(S11) Results: Longitudinal data was available for 15 NMO patients. Mean age at baseline was 51.5 +/-14.6 years, disease duration was 5. 7 +/- 2.5 years; 93% female. All patients were on immunomodulatory therapy for NMO. Mean duration between baseline and follow up MRI was 30.1 +/- 4.6 months (range 23.7 - 38.3 months). Mean number of T2w hyperintense lesions at baseline was 5.1 +/-6.6, and at follow up was 5.7 +/-7.2. Increase in lesion number was observed in 47% of patients, decrease in 6% and no change in 47%. On baseline MRI, 95% of lesions were < 5 mm in size and 34% contained a central vein. None of the lesions were ‘iron-laden’ on SWI and QSM. No appreciable increase in existing lesion size, lesional iron content or lesion-vein relationship was observed over the follow-up period. Nearly half the patients (47%) experienced ⩾1 relapse between MRIs, but none of the relapses were within 3 months of the scan. There was no difference in new lesion rates between patients with and without a relapse. Conclusions: T2w-, or T2*w-hyperintense lesions, mostly small, subcortical and without a detectable central vein, were found in all but one NMO patients. Lesions persisted on follow-up MRI 2-3 years later in nearly every instance without any change in size, iron content or vein-lesion relationship. Updated results on the full cohort, as well as changes in brain volumetric parameters will be presented. Disclosure Ilya Kister: nothing to disclose, Koral Dadon: nothing to disclose, Michael Fox: nothing to disclose, Sanjeev Chawla: nothing to disclose, Petr Dusek: nothing to disclose, Jens Wuerfel: nothing to disclose, Friedemann Paul: nothing to disclose, Tim Sinnecker: nothing to disclose, Yulin Ge: nothing to disclose. *Study was supported by an investigator-initiated grant from the Guthy Jackson Charitable Foundation

P930 Neural correlates of cognitive variation in patients with clinically isolated syndrome F.M.C. Boonstra1, S. Gajamange1, A. Shelton2, M. Clough2,3, O. White3, J. Fielding2,3, S. Kolbe1 1Anatomy and Neuroscience, University of Melbourne, 2Psychological Sciences, Monash University, 3Medicine, University of Melbourne, Melbourne, VIC, Australia Background and aims: Cognitive dysfunction is a disabling symptom of Multiple Sclerosis (MS). Cognitive changes likely involve an interplay between irreversible loss of neural tissue causing cognitive impairment, and adaptive functional changes acting to preserve cognition. Functional changes could include network reorganization that can be assessed using fMRI connectivity analyses, with both the default mode network (DMN) and dorsal attention network (DAN) critical for cognition/executive functioning. Functional reorganization is likely to occur in early stages of the disease, prior to overt disability. This study aimed to assess cognitive variation in patients with clinically isolated syndrome (CIS) at risk of developing MS (⩾2 brain lesions), in terms

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of grey and white matter atrophy, and functional connectivity (FC) variation in networks previously implicated in cognitive decline in clinically defined MS. Methods: 15 CIS patients underwent neuropsychological testing: Paced Auditory Serial Addition Test, Symbol Digit Modality Test, digit span; and MRI: T1-weighted volumetric imaging and 6min resting-state fMRI. Cognitive scores were reduced to a single cognitive status score using principal components analysis that accounted for 60.3% of total variance. Structural MRI data were analysed using FreeSurfer to calculate cortical thickness (CT), corpus callosal volume (CCV) and thalamic volume (TV). FC between DMN and DAN nodes was calculated using partial correlation corrected for relative head motion parameters. Results: Reduced cognitive status in CIS patients was associated with reduced CCV (r=0.505, p=0.055) but not CT (r=0.106, p=0.706) or TV (r=-0.084, p=0.765). Loss of FC between core nodes of the DMN (medial Prefrontal Cortex and Posterior Cingulate Cortex) was associated with CT (r=0.693, p=0.006) and CCV (r=0.582, p=0.028). A trend for a positive correlation between reduced cognitive status and lower FC within the DMN (r=0.511, p=0.108) was detected after controlling for structural parameters. Cognitive status did not correlate with FC in DAN nodes, or between DMN and DAN nodes. Conclusions: This preliminary study shows that variation in cognition in the earliest stages of MS might be independently associated with loss of neural tissue and loss of FC within the DMN. Future larger longitudinal studies are required to confirm DMN connectivity loss as a substrate for cognitive decline in all stages of MS. Disclosure FB: nothing to disclose SG: declares no conflict of interest and receives salary support from the MS Research Australia Postgraduate Scholarships AS: declares no conflict of interest and receives salary support from the Australian Postgraduate Award MC: nothing to disclose JF: declares no conflict of interest and receives research support from Novartis and Biogen Idec. OW: declares no conflict of interest and receives research support from Novartis and Biogen Idec. SK: declares no conflict of interest and receives salary support from the National Health and Medical Research Council of Australia (APP1054147). P931 Grey matter atrophy and physical and cognitive function in very early MS: a longitudinal study B. Nourbakhsh1, J. Nunan-Saah2, A.-H. Maghzi1, L. Julian3, R. Spain4, C. Azevedo5, D. Pelletier5, E. Waubant1 1Neurology, University of California San Francisco, San Francisco, 2Palo Alto University, Palo Alto, 3Internal Medicine, University of California San Francisco, San Francisco, CA, 4Oregon Health & Science University, Portland, OR, 5Neurology,, University of Southern California, Los Angeles, CA, United States Background: Cortical thickness, and thalamic and cerebellar cortical volumes have been reported to be associated with different measures of disability and cognitive outcomes in MS patients.


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Objective: To study the association between MRI measures of brain grey matter atrophy and physical and cognitive outcomes in very early MS. Methods: Relapsing MS patients within 12 months of clinical onset were enrolled in a neuroprotection trial of riluzole versus placebo with 36 months of follow-up. MRI metrics measured by an automated, custom-made Freesurfer pipeline included cortical thickness, thalamic and cerebellar cortical volumes. Serial clinical and cognitive assessments were performed during the study (EDSS, PASAT, SDMT and CVLT-II). Mixed model regression measured time trends and associations between imaging and clinical and neuropsychological outcomes. Results: Forty-three patients were enrolled within 7.5 ± 4.9 months of clinical onset. The main association between longitudinal changes over time was between cortical thickness and verbal learning and memory as measured by California Verbal Learning Test- Second Edition (CVLT-II) total score: 0.1 mm decrease in mean cortical thickness over the course of the study was associated with 5.5 points decrease in CVLT-II total score (95% CI: 1.9 - 9.0, p=0.002). Baseline left hemisphere cerebellar cortical volume predicted subsequent change in EDSS (p=0.02). Baseline normalized left thalamic volume predicted subsequent change in CVLT-II (p=0.047). Conclusion: Cerebellar and thalamic volumes and cortical thickness are associated with changes in physical and cognitive function in patients with very early MS. Disclosure Dr. Nourbakhsh is an American Brain Foundation and Biogen Idec Postdoctoral Fellow. He is a grantee of National MS Society. Ms. Nunan-Saah report no disclosure. Dr. Maghzi was funded by the Multiple Sclerosis International Federation (www.msif.org) through a McDonald Fellowship. Dr. Julian is employed by Genentech. Dr. Azevedo, Dr. Spain report, Dr. Jin and Dr. Lazar report no disclosures. Dr. Pelletier has received consulting fees from CNS Imaging Consultant, LLC, and research grants to his academic institution from Hoffmann-LaRoche, Biogen Idec, and Genzyme. Dr. Waubant has received honorarium from Teva, Sanofi Aventis and Genentech for three educational lectures, and is on the advisory board for a trial of Novartis. Dr. Waubant has received free medication from Biogen Idec and Sanofi-Aventis for the trial from which these data were generated. This research was performed as a research grant funded by the National MS Society (PI Waubant, RG3932-A-2). P932 Analysis of normal appearing white matter in multiple sclerosis using myelin water imaging: a preliminary report I.H. Jeong1, J.Y. Choi2, S.-H. Kim3, J.-W. Hyun3, A. Joung3, J. Lee2, H.J. Kim3 1National Cancer Center, Goyang-si, 2Department of Electrical and Computer Engineering, Seoul National University, Seoul, 3Department of Neurology, National Cancer Center, Goyang-si, Republic of Korea Background: Several advanced MRI studies have shown the microstructural damage in the normal appearing white matter (NAWM) of the brain in patients with multiple sclerosis (MS).

Objectives: We evaluated the quantitative change of myelin in NAWM of MS patients using myelin water imaging (MWI): conventional and a recently proposed direct visualization of short transverse relaxation time component (ViSTa) MWI. Methods: For the comparison of the whole brain myelin water fraction (MWF) in NAWM between healthy controls (HC) and MS patients, 8 HC (32.5 ± 5.4, years) and 18 MS patients (34.5 ± 7.1, years), were scanned with a 3T MRI scanner (Siemens). The conventional and ViSTa MWIs were acquired by following parameters: 28 slices with voxel size of 1.5 x 1.5 x 4.0 mm3 and scan time of 14 minutes 5 seconds for conventional MWI and 32 slices with voxel size of 1.5 x 1.5 x 4.0 mm3 and scan time of 6 minutes 53 seconds for 3D ViSTa MWI. To make a whole brain NAWM mask without lesions in MS, standard T1, T2 spin echo weighted images, and FLAIR sequences were acquired. T1/T2 images were segmented to generate white matter masks and lesions on the masks were excluded by FLAIR image using FSL and MATLAB. Mean MWF from conventional MWI and ViSTa within the NAWM mask was calculated. Results: MWF at NAWM between two groups differed significantly in both conventional MWI (HC 10.39 ± 0.80, MS 7.69 ± 1.50, p< 0.001) and ViSTa MWI (HC 5.49 ± 0.50, MS 4.29 ± 0.52, p< 0.001). A significant correlation was observed between EDSS scores and ViSTa MWF values of NAWM (r=-0.61, p=0.008). Conclusion: Our preliminary result shows that MWF values of NAWM decrease significantly in MS. This new in vivo myelin measurement, ViSTa confirms the myelin damage of NAWM in MS. Disclosure This work was funded by UCB Pharma, Seoul, Korea.

P933 A novel MRI pipeline for assessing multiple sclerosis lesion evolution in the optic radiation C. Wang1, A. Klistorner2, R.A. Oliver1, L. Ly1, M.H. Barnett1 1University of Sydney, Brain and Mind Research Institute, 2Clinical Opthalmology and Eye Health, University of Sydney, Sydney, NSW, Australia Introduction: The integration of structural and functional magnetic resonance imaging (MRI) datasets holds promise for the development of composite biomarkers of axonal and myelin integrity in multiple sclerosis (MS). Diffusion tensor imaging (DTI) based probabilistic tractography (PT) can be used to delineate white matter (WM) tracts and generate diffusivity fibre profiles, a sensitive measure of WM integrity along the target fascicles.1,2 While this approach can be used for observing lesion development in individual patients, projecting both location and size of a 3D lesion onto a 2D diffusivity profile is problematic. Objective: To develop a quantitative neuroimaging analysis pipeline to measure lesion evolution within a particular WM tract. Methods: As proof of concept, longitudinal MRI data was acquired for 3 patients with relapsing MS and optic radiation (OR) lesions at baseline and 6 months. Sequences included 64 directions DTI, IR-FSPGR, Gadolinium T1-SE, FLAIR on 3T GE


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Poster Session 2, 21(S11) MR750 scanner. DTI was motion, eddy-current and EPI susceptibility distortion corrected, prior to tensor reconstruction and T1 co-registration. Seed points at lateral geniculate nucleus (LGN) and calcarine sulcus were chosen to reconstruct the OR using Contrack3. This was separated into lesional and non-lesional bundles using T2 lesion masks, and diffusivity profiles were generated bilaterally for both fibre bundles from LGN to visual cortex. Results: The radial diffusivity (RD), axial diffusivity (AD) and fractional anisotropy (FA) differences between lesional and adjacent non-lesional fibres were calculated in the lesional OR segment between the timepoints (Baseline/follow up): ΔRD = 0.24/0.23; 0.014/0.016; 0.11/0.23 µm2/ms; ΔAD =0.37/0.37; -0.11/-0.15; 0.27/0.62 µm2/ms; ΔFA=-0.03/-0.02,-0.06/-0.07; -0.01/0.01 for subjects 1, 2 and 3 respectively. Discordance in baseline/follow-up ΔRD and ΔAD in subject 3 suggests lesion evolution between timepoints, whereas relative stability in subjects 1 and 2 indicates chronicity. Conclusion: Quantification of lesional and non-lesional WM fascicle diffusivity, defined by probabilistic tractography, is a novel and potentially sensitive method for monitoring the evolution of MS lesions. The impact of topographic and longitudinal variance, which has limited the applicability of DTI to MS clinical trials, is minimized by this technique.

References 1. Yeatman,J. PLOS one(2012) 2. Pestilli, F. Nat. Meth. (2014) 3. Sherbondy, AJ. J. Vis. (2008)

of lesions. Lesions were classified as PV, if intralesional hypointense signal was observeded in at least 2 perpendicular planes and if it was completely surrounded by hyperintense signal. Results: 12 MS and 12 SAD were enrolled. The majority of the SAD patients (10/12) fulfilled 2010 McDonald MRI criteria for demonstration of dissemination in space. The SAD group included 4 Behcet Syndrome (BS), 4 Systemic Lupus Erythematosus (SLE) and 4 Antiphospholipid Syndrome (APS). Number of lesions was lower in MS, whereas their average volume was larger. Juxtacortical lesions were more frequent in SAD patients. PVL were 262/325 (80%) in the MS group (median= 86%, 46-96%) and 40/308 (13%) in the SAD group (median= 15%, 0-66%) (p< 0.05; Mann-Whitney) . BD patients presented the highest percentage of PV among SAD patients (38%), still lower than MS. Conclusion: This study demonstrated that the frequency of PVL is remarkably higher in MS than in CNS vasculitis, suggesting that this marker can be efficiently explored by MRI even at low field strength and can help in differential diagnosis between these two CNS disorders. Disclosure LV, AB, CM, ES, GE, LE, DP, MG, GC: nothing to disclose. LM has received financial support for participating in multicentric clinical trials from Biogen, Novartis and Teva and travel expenses for attending meetings from Biogen, Novartis, Teva, Genzyme and Merck Serono. AR has receiver financial support for talking from Biogen, Teva, Novartis, Genzyme

Disclosure Chenyu Wang: nothing to disclose. Ruth Oliver: nothing to disclose. Linda Ly: nothing to disclose. Alexander Klistorner: support received from Novartis and NMSS. Michael Barnett: nothing to disclose. P934 Imaging perivenular distribution can differentiate MS from CNS vasculitis L. Vuolo, G. Emmi, G. Carlucci, A.M. Repice, C. Mechi, M. Grammatico Di Tullio, E. Silvestri, A. Barilaro, D. Prisco, L. Emmi, L. Massacesi University of Florence, Florence, Italy Background: MRI is a sensitive tool for detecting brain white matter (WM) lesions, but its specificity may be low. As multiple sclerosis (MS) lesions develop along a central vein, imaging perivenular distribution could help discriminate other diseases associated to WM lesions. In this study, the frequency of brain perivenular lesions (PV) was evaluated in patients with systemic autoimmune diseases (SAD) with inflammatory vasculopathies involving brain and compared to that found in MS. Methods: Inclusion criteria: diagnosis of relapsing remitting MS; diagnosis of systemic autoimmune vasculitis with brain involvement. Each patient underwent one MRI scan in a 1.5T strenght field magnet (Philips). Volumetric T2*-EPI and FLAIR sequences were acquired after gadolinium injection. A single expert simultaneously evaluated the images, reporting number, size and location

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P935 Perivenular white matter lesions on SWI at 3-T MRI as a diagnostic sign to differentiate multiple sclerosis from neuromyelitis optica R. Cortese1, L. Magnollay1, F. De Angelis1, C. Tur1, F. Prados2, S. Ourselin2, M. Yiannakas1, D. Miller1, T. Yousry1, O. Ciccarelli1 1NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, UK., 2Translational Imaging Group, Centre for Medical Image Computing, UCL, London, United Kingdom Background: It is important to identify brain magnetic resonance imaging (MRI) features that may help the clinicians to differentiate between neuromyelitis optica (NMO) and multiple sclerosis (MS). A recent study demonstrated that the perivascular morphology of the white matter lesions (WMLs) seen at 7T MRI may distinguish NMO from MS. Objectives: To assess the discriminatory value of the perivenous distribution of brain WMLs in NMO and MS on susceptibility weighted imaging (SWI) at 3T. This is a technique that allows the visualization of the anatomic relationship between the cerebral WMLs and the penetrating veins. Methods: 14 NMO, 3 NMO spectrum disorder (13F, mean [SD] age 51 [±10.9] yrs) and 12 relapsing-remitting MS patients (8F, mean age 38 [±9.8] yrs) were scanned at 3T. The imaging protocol included a dual-echo PD/T2-weighted sequence for WML depiction and SWI using a 3D-FFE sequence with shifted echo (voxel size 1x1x1 mm3, reconstructed to 0.5 x 0.5 x 0.5 mm3). Each


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WML was first identified on the T2 image and classified as infratentorial, periventricular or subcortical. Subsequently, the presence of at least one vein (i.e. vein sign [VS]), depicted as a dark line coursing through the lesion or a dot tracked on contiguous slices, was assessed on SWI. Logistic regression models were used to assess the association between presence of VS and type of disease (MS vs. NMO), after adjusting for age, gender, and disease duration. Results: A total of 502 WMLs were seen in 12 of 12 MS patients; 200 WMLs were detected in 15 of 17 NMO patients. At least one vein within WML was identified in 400 (79.6%) MS-WMLs and 102 (51%) NMO-WMLs. In both groups, VS was especially present in periventricular (MS: 65.5%; NMO: 63.7%), followed by subcortical (MS: 24%; NMO: 23.5%), and infratentorial lesions (MS: 10.7%; NMO: 11.7%). The presence of at least one vein in the WML was strongly associated with this WML belonging to a MS patient (OR 4.26, 95% CI 2.86 to 6.36, p< 0.001). In 83% of MS and 30% of NMO patients, there were WMLs with at least two VS (p=0.008). Additionally, there was an association between showing more than one VS and having MS (OR = 9.0, 95% CI 1.39 to 58.44, p=0.021). Conclusions: The association between perivenular WMLs on SWI and MS makes the VS a diagnostic sign to differentiate MS from NMO, especially if there are at least two veins running through one WML. Disclosure R.Cortese, L. Magnollay, F. De Angelis, M. Yiannakas, F. Prados and S. Ourselin have nothing to disclose. O. Ciccarelli receives research grant support from the Multiple Sclerosis Society of Great Britain and Northern Ireland, the Department of Health Comprehensive Biomedical Centre, the International Spinal Cord Research Trust (ISRT) and the Engineering and Physical Sciences Research Council (EPSRC); she serves as a consultant for Novartis, Biogen and GE and payments are made to UCL Institute of Neurology. T. Yousry received honoraria (board membership) from UCB, Bristol-Myers Squibb, Biogen Idec, and grants (principal investigator or coprincipal investigator coordinator) from NIHR CBRC, MRC, MS Society, PSP, Stroke, BHF, Wellcome Trust, GSK, Biogen Idec, and Novartis. D.H. Miller has received honoraria, through payments to UCL Institute of Neurology, for Advisory Committee and/or Consultancy advice in multiple sclerosis studies from Biogen Idec, GlaxoSmithKline, Novartis, Merck, Chugai, Mitsubishi Pharma Europe and Bayer Schering Pharma and has received compensation through payments to UCL Institute of Neurology for performing central MRI analysis of multiple sclerosis trials from GlaxoSmithKline, Biogen Idec, Novartis and Merck. C. Tur received a McDonald Fellowship (from the Multiple Sclerosis International Federation) in 2007, and has received an ECTRIMS post-doctoral research fellowship in 2015. She has also received honoraria and support for travelling from BayerSchering, Teva, Merck-Serono and Serono Foundation, Biogen, Sanofi-Aventis, Novartis, and Ismar Healthcare.

P936 Longitudinal MRI study to measure cervical cord atrophy in multiple sclerosis patients F.X. Aymerich1,2, M. Alberich1, C. Auger1, J. Sastre-Garriga3, X. Montalban3, A. Rovira1 1Section of Neuroradiology and MR Unit (Department of Radiology), University Hospital Vall d’Hebron, 2Department of Automatic Control (ESAII), Universitat Politècnica de Catalunya-Barcelona Tech (UPC), 3Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Vall d’Hebron University Hospital, Barcelona, Spain Background and objective: Spinal cord atrophy occurs in multiple sclerosis (MS) and has been proposed as a measure of neurodegeneration. The aim of this longitudinal study is to quantify spinal cord atrophy to evaluate its association with clinical disability and other MRI measures. Materials and methods: 31 patients (12 women; median age, 51 years; age range, [33, 61], baseline EDSS median, 5.5; baseline EDSS range, [3, 6.5]) diagnosed of primary progressive MS, underwent three serial 1.5 T brain and spinal cord MRI examinations (baseline, year 2, and year 7), including the following sequences: PD/T2, 2D T1-weighted, and a spinal cord 3D magnetization prepared rapid acquisition gradient echo (MPRAGE) T1-weighted. Spinal cord from C1 to C5 was segmented in MRI scan using the spinal cord tool included in Jim 6.0. Using this method we evaluated global cross-sectional spinal cord area (CSA), and CSA at C2-C3 (C23), C3-C4 (C34), and C4-C5 (C45) levels. CSA measurements were then normalized (CSAn, C23n, C34n, C45n) to the intra-cranial cross-sectional area measured at the inferior margins of the corpus callosum on an axial slice of the proton density-weighted image of each subject. Percentage of change in spinal cord measurements between baseline and 7th year exam were averaged per year of evolution. T2 lesion load (T2LL), T1 lesion load (T1LL), and brain parenchymal fraction (BPF) were measured at each time point. EDSS was also evaluated as the area under the curve of EDSS values in each time point normalized by the maximum area (AUCNEDSS). Partial correlations controlled for age and sex were performed to evaluate the relationship between spinal cord measurements and radiological or clinical measurements. Results: All normalized CSA measurements showed moderate correlations with AUCNEDSS ranging between -0.4872 and -0.3717 (p< 0.05). In addition, the mean annual percentage of change in normalized CSA (pyCSAn: -0.7715%; pyC23n: -0.6155%; pyC34n: -0.7376%; pyC45n: -0.7720%) showed significant correlations with baseline BPF (pyC23n vs. BPF: r=-0.4514, p=0.014; pyC34n vs. BPF: r=-0.4556, p=0.013). Mean annual percentage of change in C34n also correlated with BPF at year 2 (r=-0.3688, p=0.049). Conclusions: Results suggest that development of spinal cord atrophy is associated with increasing disability. Moreover, patients presenting larger baseline BPF seem to show a greater tendency for future spinal cord atrophy development at some cervical levels. Disclosure F. Xavier Aymerich has nothing to disclose. Manel Alberich has nothing to disclose.


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Poster Session 2, 21(S11) Cristina Auger has received speaking honoraria from Novartis and Genzyme. Jaume Sastre-Garriga has received compensation for consulting services and speaking honoraria from Merck-Serono, BiogenIdec, Teva, Sanofi-Aventis and Novartis. Xavier Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall. Alex Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, and has received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Bracco, MerckSerono, Teva Pharmaceutical Industries Ltd, OLEA Medical, Stendhal, Novartis and Biogen Idec.

P937 High-resolution T1-relaxation time mapping displays subtle, but clinically relevant, gray matter damage in long-standing multiple sclerosis M.D. Steenwijk, H. Vrenken, L.E. Jonkman, M. Daams, J.J.G. Geurts, F. Barkhof, P.J.W. Pouwels VU University Medical Center, Amsterdam, The Netherlands Purpose: To investigate whether high spatial resolution T1 relaxation time (T1-RT) measurements can detect T1-RT changes in the cerebral normal-appearing gray matter (NAGM) of patients with long-standing multiple sclerosis (MS) and whether these changes are associated with measures of clinical and cognitive dysfunction. Methods and materials: The institutional review board approved the study; all subjects gave written informed consent. High spatial resolution 3D T1-RT measurements were performed at 3T in 156 long-standing MS patients and 54 healthy controls. 3D T1-weighted and FLAIR images were used to obtain segmentations of the NAGM, normal-appearing white matter (NAWM), cortex and thalamus. For each region, mean T1-RT and T1-RT histogram peak position, height, width and skewness were analyzed to investigate group differences. Stepwise multiple linear regression analysis was used to assess the relation of T1-RT changes with clinical and cognitive dysfunction. Results: In both thalamic and cortical NAGM, T1-RT skewness was significantly increased in patients compared to controls. In MS cortex, increased histogram skewness occurred mainly in the frontal and temporal lobes. Cortical T1-RT skewness showed a moderate association with average cognition (r=-0.36, p< 0.001). The final model for average cognition (p< 0.001; adj.R2=0.39) consisted of normalized thalamus volume, cortical T1-RT skewness and average WM lesion T1-RT. Conclusion: Subtle GM damage was present in the cortex and thalamus of MS patients, as shown by increased histogram skewness. Regression analysis revealed that increased cortical skewness is independently associated with cognitive dysfunction. Disclosure This study was sponsored by the Dutch MS Research Foundation through a program grant to the VUmc MS Center Amsterdam, grant number 09-358d.

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Mr. Steenwijk receives research support from the Dutch MS Research Foundation, grant 09-358d. Dr. Vrenken receives research support from the Dutch MS Research Foundation, grant numbers 05-358c, 09-358d and 10-718MS; has received support for research projects from Pfizer, Novartis, and Merck-Serono, and speaker honoraria from Novartis. All funds paid directly to his institution. Ms. Jonkman receives research support from the Dutch MS Research Foundation, grant 09-358d. Ms. Daams receives research support through a private sponsorship to the VUmc MS Center Amsterdam. Dr. Geurts is the deputy editor of Multiple Sclerosis Journal, and serves on the editorial boards of Neurology, BMC Neurology and MS International, as well as on the Scientific Advisory Board of the Dutch MS Research Foundation, the Progressive MS Alliance and of MS Academia, Merck-Serono; he has received consultancy fees from Merck-Serono, Biogen-Idec, Novartis, Genzyme and Teva. Dr. Barkhof serves on the editorial boards of Brain, European Radiology, Neuroradiology, Multiple Sclerosis and Radiology and serves as a consultant for Bayer-Schering Pharma, SanofiAventis, Biogen-Idec, Teva, Novartis, Roche, Synthon BV, Jansen Research. Dr. Pouwels reports no disclosures. P938 Tissue damage within normal-appearing whitematter in early MS: quantification by the ratio of T1/T2-weighted MR image intensities A. Peltz, V. Biberacher, P. Schmidt, R. Righart, D. Buck, A. Berthele, C. Zimmer, B. Hemmer, M. Mühlau Technische Universität München, Munich, Germany Background: Changes in normal-appearing whiter matter (NAWM) have been demonstrated in early stages of MS by several advanced imaging techniques. Here, we tested the hypothesis that a decrease in NAWM integrity can be demonstrated in early stages of MS by combining the information of two conventional MRI sequences. We determined the ratio of T1/T2-weighted (w) MR image intensities as this measure had been proposed to estimate the myelin content of the cerebral cortex (Glasser et al. J Neurosci 31:11597-616). Moreover, it may serve as an overall measure of NAWM integrity in MS as it may lower as a result of several aspects of MS-related pathology such as higher water content (inflammation), lower myelin content, and lower iron concentration. Methods: We established a pipeline to render individual T1w/ T2w ratio images of NAWM. T1w, FLAIR and T2w images (all 3D) were co-registered. Based on T1w and FLAIR images, lesions were segmented and filled; the normalization matrix was determined from the filled T1w images and applied to the co-registered, but otherwise original, T1w and T2w images; from the resulting images in MNI space, WM was segmented; only voxels with a probability of >0.9 for WM in both images (T1w and T2w) were used to calculate the T1w/T2w ratio images. Individual histograms of these images suggested a normal distribution of voxel values across NAWM. Only analyses of mean values are reported here. 78 healthy controls (HC) (age: 31+/-8) were compared to 244 patients in early disease stages (EDSS: 1.3 +/- 1.0; median,


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1.5; range, 0-6.0. Age in years: 37 +/- 10; median, 36; range 19-70. Disease duration in years: 3.1 +/- 2.3; median, 2.7; range, 0.1-10. CIS/RRMS: 40/204. Female/male: 165/79; all free from steroids for at least 2 weeks). Results: T1w/T2w ratio was lowered in the patient group (1.61 +/- 0.16 vs. 1.71 +/- 0.13; 2s P value of t-test, < 0.001). The difference remained significant after restricting the analysis to patients with an EDSS of 0 and a disease duration of 5 years or less (n=54; 2s P value of t-test, 0.002). Neither the exclusion of patients on disease-modifying drugs (n=28; 2s P value of t-test, < 0.001) nor correction for age and gender changed the results in a meaningful way. Conclusion: Because of its broad availability, we believe that T1w/T2w ratio images are a promising candidate to quantify MS-related tissue damage within NAWM. Disclosure B. Hemmer has served on scientific advisory boards for Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GSK, Chugai Pharmaceuticals, Micromet, Genentech and Genzyme Corporation; serves on the international advisory board of Archives of Neurology and Experimental Neurology; has received speaker honoraria from Bayer Schering, Novartis, Biogen Idec, Merck Serono, Roche, and Teva Pharmaceutical Industries Ltd; and has received research support from Biogen Idec, Bayer Schering, Merck Serono, Five prime, Metanomics, Chugai Pharmaceuticals and Novartis. He has been filed a patent for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and genetic determinants of neutralizing antibodies to interferon-beta. A. Berthele is a consultant for Biogen Idec, Bayer, Merck Serono; he has received research support from Bayer; he has received honoraria for lecturing from Biogen Idec, Bayer, Merck Serono, Teva Neuroscience, Novartis; he has received travel expenses for attending meetings from Biogen Idec, Merck Serono, Bayer, Teva Neuroscience, Novartis; he has received Investigator fees for Phase II-IV clinical studies from Biogen Idec, Novartis, Merck Serono, and Galapagos. M. Mühlau has received research support from Merck Serono and Novartis; he has received travel expenses for attending meetings from Bayer, and Merck Serono; he has received honoraria for lecturing from Merck Serono; he has received Investigator fees for a Phase III clinical study from Biogen Idec. D. Buck has received compensation for activities with Bayer HealthCare, BiogenIdec, MerckSerono, and Novartis. She is supported by the Abirisk Consortium. A. Peltz, V. Biberacher, P. Schmidt, R. Righart, C. and Zimmer have nothing to disclose. P939 Periventricular gradient in thalamic abnormalities in MS: a magnetisation transfer ratio imaging study M. Pardini1,2, Ö. Yaldizli1,3, V. Sethi1, N. Muhlert1,4, R.S. Samson1, S.H. van de Pavert1, M. Ron1, C.A. WheelerKingshott1, T.A. Yousry1, D.H. Miller1, D.T. Chard1 1UCL Institute of Neurology, London, United Kingdom, 2University of Genoa, Genoa, Italy, 3University Hospital Basel, Basel, Switzerland, 4Cardiff University, Cardiff, United Kingdom

Background: Periventricular regions are often affected in multiple sclerosis (MS). White matter (WM) lesions occur more frequently around the lateral ventricles than elsewhere in the brain, and disease effects on normal appearing white matter (NAWM) magnetisation transfer ratio (MTR) values have been found to decrease with distance from the lateral ventricles. Medial thalamic nuclei have also been shown to be more damaged than lateral nuclei in this population, however associations between thalamic abnormalities and distance from the ventricles, and between gradients in thalamic and NAWM abnormalities, have yet to be assessed. Methods: Seventy one people aged between 18 and 65 years with a diagnosis of relapse-onset MS and thirty-nine healthy controls were included in the study. In all subjects high resolution MTR imaging and T1 volumetric imaging (both 1 mm isotropic), and PD/T2-weighted scans, were acquired. A voxel-by-voxel distance map from the ventricles was computed in Montreal Neurological Institute (MNI) space and non-linearly registered to each subject’s MTR images. A thalamic mask was created for all subjects and intersected with the ventricular distance mask. Voxels were grouped in 1mm distance increments throughout the thalamus. The first band was discarded to avoid CSF contamination and then MTR values were computed in each thalamic band over 10 mm. WM lesion masks and a 2mm perilesional rim were subtracted from each subject’s brain WM segmentation to produce the NAWM mask. The same pipeline applied to thalamus was also applied to periventricular NAWM to evaluate the association between ventricles distance and NAWM MTR values. Results: In the MS group, thalamic and periventricular NAWM raw MTR values, as well as age and gender adjusted normalised to healthy controls’ values, were lowest adjacent to, and progressively increased with distance from, the ventricles. There was a correlation between normalised MTR in NAWM and thalamic GM over the first 3 mm adjacent to CSF (r=0.54, p< 0.001). Discussion: In MS, thalamic MTR abnormalities are greater close to the ventricles and decrease with distance from them. The gradient of pathology observed in the thalamus correlates with NAWM damage pattern, suggesting the possibility that similar factors may influence the spatial distribution of thalamic and periventricular NAWM pathology in MS. Support: MS Society in the UK, NIHR University College London Disclosure MP received research support from Novartis. ÖY has received lecture fees from Teva, Novartis and Bayer Schering used for funding of research and continuous medical education at the University Hospital Basel. VS received research support from Biogen Idec and Novartis. NM: reports no disclosures. RS: reports no disclosures SvP: reports no disclosures. MR: reports no disclosures. CWK: is on the advisory board for BG12. TY: has received honoraria and travel expenses from Bayer Schering, Biogen Idec, and Novartis; and research grants (held by UCL) from Biogen Idec, GlaxoSmithKline, Novartis, and Schering AG.


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Poster Session 2, 21(S11) DHM: received honoraria from Biogen Idec, Novartis, GlaxoSmithKline, and Bayer Schering, and research grant support by GlaxoSmithKline, Biogen Idec, and Novartis. DC: has received honoraria (paid to UCL) from Bayer, Teva and Serono for faculty-led education work, and Teva for advisory board work; support for meeting expenses from Teva; and holds stock in GlaxoSmithKline.

P940 Distribution of cerebellar white matter magnetisation transfer ratio abnormalities in multiple sclerosis M. Pardini1,2, Ö. Yaldizli1,3, V. Sethi1, N. Muhlert1,4, R.S. Samson1, S.H.P. van de Pavert1, M. Ron1, C.A. WheelerKingshott1, T. Yousry1, D.H. Miller1, D.T. Chard1 1UCL Institute of Neurology, London, United Kingdom, 2University of Genoa, Genoa, Italy, 3University Hospital Basel, Basel, Switzerland, 4Cardiff University, Cardiff, United Kingdom Background: Magnetisation transfer ratio (MTR) abnormalities in multiple sclerosis (MS) normal appearing white matter (NAWM) have been previously shown to decrease with distance from the lateral ventricles. It is not known if this occurs in WM regions that are adjacent to other parts of the ventricular system. In this study, we investigated the association between NAWM and WM lesion distribution in the cerebellum and distance from the fourth ventricle. Methods: Seventy relapse-onset MS subjects and thirty-nine healthy controls were recruited in the study. In all subjects high resolution MTR imaging and T1 volumetric imaging (both 1 mm isotropic), and PD/T2-weighted scans, were acquired. A voxel-byvoxel cerebellar distance map from the fourth ventricle was computed in Montreal Neurological Institute (MNI) space and non-linearly registered to each subject’s MTR. A WM mask was created segmenting the volumetric T1 scans. To mitigate potential effects of peri-lesional abnormalities on the NAWM measures, WM lesion and a 2mm perilesional rim was subtracted from each subject’s WM mask to produce the NAWM mask. Voxels were grouped in 1mm distance increments from the fourth ventricle to create 1 mm thick bands. The first band was discarded to avoid CSF contamination and then NAWM MTR values and the percentage of lesioned WM were quantified for each band over the first 1 cm.Associations between distance from WM lesions and NAWM abnormalities were also assessed. Results: In cerebellar NAWM MTR was lower in MS compared with HC subjects, and the difference decreased with distance from the fourth ventricle, even after controlling for age and gender. There was no association between cerebellar WM lesion density or MTR lesional values and distance from the fourth ventricle. There was no association between distance from WM lesions and NAWM MTR values. Discussion: Abnormality of cerebellar NAWM is more marked adjacent to the fourth ventricle. Support: MS Society in the UK, NIHR University College London Disclosure MP received research support from Novartis.

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ÖY has received lecture fees from Teva, Novartis and Bayer Schering used for funding of research and continuous medical education at the University Hospital Basel. VS received research support from Biogen Idec and Novartis. NM: reports no disclosures. RS: reports no disclosures SvP: reports no disclosures. MR: reports no disclosures. CWK: is on the advisory board for BG12. TY: has received honoraria and travel expenses from Bayer Schering, Biogen Idec, and Novartis; and research grants (held by UCL) from Biogen Idec, GlaxoSmithKline, Novartis, and Schering AG. DHM: received honoraria from Biogen Idec, Novartis, GlaxoSmithKline, and Bayer Schering, and research grant support by GlaxoSmithKline, Biogen Idec, and Novartis. DC: has received honoraria (paid to UCL) from Bayer, Teva and Serono for faculty-led education work, and Teva for advisory board work; support for meeting expenses from Teva; and holds stock in GlaxoSmithKline. P941 The cortical damage among MS patients with frequent early relapses A. Scalfari1, M. Mattoscio1, M.P. Sormani2, A. Morra3, R. Nicholas1, P. Muraro1, M. Calabrese4 1Imperial College Department Neuroscience, London, United Kingdom, 2Biostatistics Unit, Department of Health Sciences, University of Genova, Genova, 3Neuroradiology Unit, Euganea Medica, Albignasego, 4Department of Neurological and Movement Sciences, University Hospital of Verona, Verona, Italy Introduction: Relapsing remitting (RR) Multiple Sclerosis (MS) patients with a large number of early attacks are at higher risk of developing a progressive course and of reaching rapidly severe disability. In this study, we aimed at elucidating pathological changes, occurring in their grey matter. Methods: By using 3D Double Inversion Recovery and 3D T1 weighted imaging we compared the number of cortical lesions (CLs) and the level of cortical thinning between RR MS patients with 1 (n = 42) and ⩾ 3 (n = 41) relapses during the first 2 years, matched by similar disease duration (7.1 vs 7.2 mean years). Results: The two groups had similar symptoms at onset, however those with low number of early relapses were predominantly females (73.8% vs 46.3%; p < 0.001) and were older at first attack (35.4 vs 30.2 years; p < 0.001). At clinical onset, CLs were detected in 85% (n = 35; total number of CLs = 203) and in 64% (n = 27; total number of CLs = 102) of patients with high and low early relapses, respectively. Frequent early relapsers (⩾ 3 early attacks) were distinguished by a larger number (4.9 vs 2.4 mean lesions; p< 0.001) and volume (501.5 vs 192.3 mean mm3; p< 0.001) of CLs at disease onset, and had a more severe clinical outcome. By the end of the observation period, they had entered the progressive phase in larger percentage (41.4% vs 21.4%; p=0.08) and in significantly shorter time (61.1 vs 81.3 mean months; p< 0.001), and had accumulated more


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severe disability (mean EDSS score: 3.8 vs 2.9; p< 0.001). Their aggressive disease course was accompanied by a larger focal and diffuse accumulation of cortical damage. After 7.3 mean years from the disease onset they had a significantly greater increase of CLs volume (242.3% vs 178.9% increase; p < 0.001) and accrued a significantly higher number (14.5 vs 5.4 mean lesions; p < 0.001) and volume (1409.2 vs 381.7 mean mm3; p < 0.001) of CLs. In addition they had a significantly more severe global cortical thickness change (11.8% vs 6.1%; p < 0.001) and developed more prominent brain atrophy (cortical thickness = 2.28 vs 2.44 mean mm; p< 0.001). Conclusions: Frequent early relapses associate with a more severe accumulation of focal and global cortical damage in the long term. These data provide initial evidence for risk stratification of subgroups, potentially benefitting from early aggressive treatment, and highlight the grey matter pathology as important target for future therapies. Disclosure M. Calabrese has received consulting and/or lecture fees and/ot travel grants from Bayer Schering, Biogen Idec, Genzyme, Novartis and Teva Nicholas:Bayer - honorarium for speaking. Biogen - principal investigator, funds for staff, research, organising education, honorarium for speaking, advisory boards. Genzyme - honorarium for speaking, organising education, advisory boards. Merck Serono honorarium for speaking, advisory boards. Novartis - principal investigator, honorarium for speaking, advisory boards. Roche advisory boards. TEVA - principal investigator, funds for research Scalfari: Teva and Genzyme: honorarium for speaking. Biogen and Teva: travel grants Mattoscio: Biogen, Teva and Genzyme: travel grants Dr Muraro declares honoraria for speaking and travel support from Merck Serono, Biogen, Bayer, and Novartis.

P942 Assessing individual lesion myelination and its change over time C. Köhler1, H. Wahl1, J.C. Eisele2, T. Ziemssen2, H. Kitzler1 1Institut für Neuroradiologie, UKD, 2Multiple Sklerose Zentrum, Klinik und Poliklinik für Neurologie, UKD, Dresden, Germany Introduction: Myelin Imaging is a potential tool to parse differences in focal and non-focal myelin loss in Multiple Sclerosis (MS). To date it remains a challenge to select patients for new remyelination therapies since conventional magnetic resonance imaging (MRI) is unspecific [1] to differentiate potential responders. We used the in vivo whole-brain myelin imaging technique multicomponent Driven Equilibrium Single Pulse Observation of T1 and T2 (mcDESPOT) that allows the evaluation of myelination by means of measuring the volume fraction of myelin (VFM), a parameter related to brain white matter (WM) myelination [2]. Purpose: We developed a new lesion-tracking algorithm to study demyelination and remyelination in individual MS lesions in correlation to their volume change in longitudinal observations. Methods: MRI data of clinically isolated syndrome (CIS) patients were acquired at baseline and at 3, 6 and 12 months. A 3D-fluid

attenuated inversion recovery (FLAIR) sequence was obtained to segment WM lesions as single volumes of interest. VFM maps were derived using the established mcDESPOT processing method [2]. The lesion-tracking algorithm was designed in the MATLAB environment. MATLAB function bwlabeln was applied to tag MS lesions in the 3D mask. For every lesion from the baseline mask, the algorithm determines the intersection in space with labeled lesions from the follow-up to identify corresponding lesions. Individual lesion parameters were determined to identify lesions as growing, shrinking, or stable in volume. Reading out VFM enabled us to address myelination differences in individual lesions and their change over time Results: We examined 134 lesions longitudinally. Most lesions (86%) show a dynamic in de- and remyelination. Continous demyelination was found in (8%). A minor number of lesions (6%) showed only remyelination. Conclusion: Our findings demonstrate highly dynamic individual lesion myelination status in CIS and subsequent early MS. This may allow depicting phenotypes of the extent of myelin loss and its dynamic features to select patients for individualized therapeutic approaches.

References 1. Barkhof et al., Arch Neurol. 2003 Aug; 60(8):1073–81. 2. Deoni et al., Magn Reson Med. 2008 Dec; 60(6):1372–87. Disclosure Caroline Koehler: nothing to disclose P943 Temporal lobe damage is linked to epilepsy in multiple sclerosis patients M. Calabrese1, M. Castellaro2, A. De Luca3, F. Pizzini4, R. Magliozzi1,5, S. Zimatore4, G. Ricciardi4, S. Montemezzi6, M.D. Benedetti1, M. Pitteri1, G. Farina1, A. Bertoldo3, A. Gajofatto1, R. Reynolds7, O. Howell8, P. Manganotti9, S. Monaco1 1Department of Neurological and Movement Sciences, University Hospital of Verona, Verona, 2Department of Information Engineering, Universiity of Padova, 3Department of Information Engineering, University of Padova, Padova, 4Neuroradiology Unit, AOUI Verona, Verona, 5Istituto Superiore di Sanità, Cell Biology and Neuroscience, Rome, 6Radiology UOC, AOUI Verona, Verona, Italy, 7Imperial College London, London, 8Swansea University, Swansea, United Kingdom, 9University of Trieste, Trieste, Italy Introduction: Temporal lobe pathology may explain some of the relatively common symptoms of Multiple Sclerosis (MS) such as cognitive impairment, fatigue, and psychiatric disturbances but also less frequent clinical manifestations such as epileptic seizures. Although it has been already suggested that patients suffering from epilepsy and MS show a more aggressive cortical and deep grey matter (GM) damage, the role of temporal lobe - and especially hippocampus - damage in this group of patients has not been clarified yet. Objectives: To investigate the involvement of temporal lobe in MS patients suffering from epilepsy, by the application of an advanced regional multimodal 3T MRI analysis.


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Poster Session 2, 21(S11) Patients and methods: 20 consecutive relapsing remitting MS patients who presented epileptic seizures that could not be explained by any cause other than MS (RRMS/E) and 20 age and disease-duration-matched consecutive RRMS patients were enrolled. Each patients underwent advanced 3T MRI protocol specifically designed to evaluate GM damage and including a combination of Double Inversion Recovery, Neurite Orientation Dispersion and Density Imaging, and an estimation of the cortical thickness performed using the Automatic Normalization Tools. Results: The number of GM lesions was significantly higher in RRMS/E than in RRMS (p>0.001): 87 CLs were observed in 13 of the 20 RRMS patients (median 2.0; range 0-10) and 194 in 18 of the 20 RRMS/E (median 5.0; range= 0-15). The regional analysis revealed that the hippocampus was the brain region more affected by GMLs (16.9%) followed by cingulate (13.1%) and insula (11.8%). Significant difference of the NODDI indices (ODI and KAPPA) was observed in the left hippocampus of RRMS/E (mean ODI 0.510±0.366, p=0.039; mean KAPPA = 0.103±0.013; p=0.031) compared to RRMS (mean ODI 0.560±0.490; mean KAPPA = 0.088±0.012). Significant cortical thinning was observed both in left and right inferior temporal gyrus, in the middle temporal gyrus, in the superior temporal gyrus, in the precentral gyrus, and insula of RRMS/E compared to RRMS. Discussion: Our data suggest that MS patients suffering from epilepsy are characterized by a more aggressive cortical pathology. Nevertheless our data indicate that the temporal lobe is particularly exposed to grey matter damage in these patients, thus also explaining why seizures are so frequent in MS patients and why ín this group of patients the symptoms of cognitive impairment are so early. Disclosure M. Calabrese has received consulting and/or lecture fees and/ot travel grants from Bayer Schering, Biogen Idec, Genzyme, Novartis and Teva. Dr. Farina has received travel grants from Biogen Idec, Genzyme, Novartis and Teva. M. Castellaro, A. De Luca, F. Pizzini, R. Magliozzi, S. Zimatore, G. Ricciardi, S. Montemezzi, MD. Benedetti, M. Pitteri, A. Bertoldo, A. Gajofatto, R. Reynolds, P. Manganotti, and S. Monaco have no disclosures related to this paper. P944 Positron emission tomography imaging in multiple sclerosis highlights a diffuse inflammatory response in brain that appears normal on conventional magnetic resonance imaging G. Datta1, M. Battaglini2, G. Scott1, Ö. Yaldizli3,4, A. Santos Ribeiro1, M.B. Wall5, R. Gunn1,5, E.A. Rabiner5,6, O. Ciccarelli4, R. Nicholas7, N.D. Stefano2, P.M. Matthews1 1Department of Medicine, Imperial College London, Division of Brain Sciences, London, United Kingdom, 2Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy, 3University Hospital Basel, Basel, Switzerland, 4University College London Institute of Neurology, Queen Square Multiple Sclerosis Centre, 5Imanova Ltd, 6Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 7Department of Neurology, Imperial College Healthcare NHS Trust, London, United Kingdom

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Background: Multiple sclerosis (in all disease stages) is associated with a chronic, innate immune activation involving microglia and astrocytes. While this plays roles in repair, it may also contribute to neurodegeneration. Here we describe the use of positron emission tomography (PET) with [11C] PBR28, a radioligand for the 18kDa translocator protein (TSPO), for the study of a group of multiple sclerosis (MS) patients as a marker of activated microglia/macrophages. Objectives: To characterize the distribution of the inflammatory response in the brain and its relationship to magnetic resonance imaging (MRI) markers of pathology in people with MS. Methods: Twelve people with MS (10 women: 2 men; Expanded Disability Status Score (EDSS) range 1.0-7.0; aged 31-65; 9 relapsing remitting: 3 secondary progressive MS) underwent a PET scan with [11C]PBR28 and correlative 3T MRI including magnetization transfer imaging. We stratified subjects based on the rs6971 polymorphism that determines TSPO binding affinity. T2 hyperintense white matter lesions (WML), and high and low magnetization transfer ratio (MTR) regions of T2-weighted normal appearing white matter (NAWM) were segmented on correlative MRI. A [11C]PBR28 distribution volume ratio (DVR) was estimated using the Logan graphical method with the high MTR NAWM as a reference region. Results: DVR in WML (mean +/- SD, 0.83 +/- 0.06) was lower than in surrounding NAWM (1.02 +/- 0.02, p < 1x10-5). Low MTR NAWM had higher DVR (1.05 +/- 0.04) than whole NAWM (1.02 +/- 0.02, p = 0.002). The cortex had a higher mean DVR (1.13 +/- 0.09) than the NAWM (p = 0.001). Subcortical grey matter showed striking differences in DVR (thalamus, 1.21 +/- 0.15; caudate, 0.67 +/- 0.20, p < 1x10-6). There was a strong correlation between the NAWM MTR and the cortical grey matter (Spearman’s rho = 0.74, p = 0.006) and thalamic (rho = 0.75, p = 0.005) DVR. Conclusions: [11C]PBR28 highlights in vivo that chronic T2 hyperintense lesions show little inflammatory response relative to NAWM. Low MTR NAWM shows evidence for an active inflammatory response. The strong correlations between MTR in NAWM and grey matter inflammation may reflect microglial responsiveness to neurodegeneration along the neuroaxonal unit. Disclosure ÖY has received honoraria for lectures from Teva (2011) and Bayer Schering (2012) (both paid to University Hospital Basel). ÖY received research funding from MAGNIMS / ECTRIMS, the University of Basel, the Swiss MS Society and Free Academy Basel, Switzerland. RG is a consultant for GSK, Abbvie, UCB and ITI. EAR holds stock in GSK, has received research funds from AbbVie, and consultancy/speaker fees (paid to King’s College or Imanova) from GSK, BioTie, Gedeon Richter, Teva and Lighlake Therapeutics. OC receives research grant support from the Multiple Sclerosis Society of Great Britain and Northern Ireland, the Department of Health Comprehensive Biomedical Centre, the International Spinal Cord Research Trust (ISRT) and the Engineering and Physical Sciences Research Council (EPSRC); she serves as a consultant for Novartis, Biogen and GE and payments are made to UCL Institute of Neurology.


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RN has received honoraria for speaking from Bayer. Biogen principal investigator, funds for staff, research, organising education, honorarium for speaking, advisory boards. Genzyme - honorarium for speaking, organising education, advisory boards. Merck Serono - honorarium for speaking, advisory boards. Novartis - principal investigator, honorarium for speaking, advisory boards. Roche - advisory boards. TEVA - principal investigator, funds for research NDS has received honoraria from Schering, Biogen-Idec, Teva, Novartis, Genzyme, and Merck Serono S.A. for consulting services, speaking and travel support. He serves on advisory boards for Merck Serono S.A. and Novartis. He has received research grant support from the Italian MS Society. PMM holds stock in GSK, has received research funds from Biogen and GSK, and consultancy/speaker fees (paid to Imperial College) from IXICO, GSK, Biogen, Novartis and Adelphi Communications. P945 Comparison of myelin water fraction values in periventricular white matter lesions between multiple sclerosis and neuromyelitis optica spectrum disorder: a preliminary report I.H. Jeong1, J.Y. Choi2, S.-H. Kim1, J.-W. Hyun1, A. Joung1, J. Lee2, H.J. Kim1 1Department of Neurology, National Cancer Center, Goyang-si, 2Department of Electrical and Computer Engineering, Seoul National University, Seoul, Republic of Korea Background: Both multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are autoimmune inflammatory diseases of the central nervous system, which commonly involve the brain. Objectives: We investigated whether myelin damage of brain lesions unrelated with visual and motor pathways differs quantitatively between MS and NMOSD using myelin water imaging (MWI). Methods: To date, 13 MS and 10 NMOSD patients without acute relapse within 3 months prior to scans were enrolled in this study. MWIs were acquired using a 3T MRI scanner (Siemens) with the following parameters: 28 slices, voxel size: 1.5 x 1.5 x 4.0 mm3 and scan time: 14 minutes 5 seconds. As the baseline MWF value varies according to the location in the brain, we selected and analysed periventricular white matter (PVWM) lesions around the posterior horn of the lateral ventricle as regions of interest. The Mann-Whitney test was performed to compare the mean MWF value of PVWM lesions in MS with lesions in NMOSD. Results: Thirteen PVWM lesions from 13 MS patients and 14 lesions from 10 NMOSD patients were analysed. There were no significant differences in the current age, disease duration and EDSS scores between two groups. However, female to male ratio was higher in NMOSD (9:1 vs. 7:6) than in MS. The mean MWF value of PVWM lesions was significantly lower in MS compared to NMOSD (4.31±2.35 vs. 7.20±2.84, p=0.02). Analysis of lesion MWF values according to T1 signal intensities is still in progress and will be presented. Conclusion: Although tissue damage of the optic nerves and spinal cord is known to be severe in NMOSD, PVWM lesions appear to exhibit more severe myelin loss in MS than in NMOSD.

Disclosure This work was funded by UCB Pharma, Seoul, Korea. P946 Iron deposit within focal lesions in patients with clinically isolated syndrome F.X. Aymerich1,2, A. Palomar1, C. Auger1, J. Sastre-Garriga3, M. Tintoré3, X. Montalban3, A. Rovira1 1Section of Neuroradiology and MR Unit (Department of Radiology), University Hospital Vall d’Hebron, 2Department of Automatic Control (ESAII), Universitat Politècnica de CatalunyaBarcelona Tech (UPC), 3Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Vall d’Hebron University Hospital, Barcelona, Spain Background and objective: Iron accumulation within focal lesions has been described in multiple sclerosis (MS). In early stages of the disease iron deposition may be associated with the progression of the disease. The aim of this study is to assess the association of iron deposit in T2 focal brain lesions in patients presenting with a clinically isolated syndrome (CIS), and the clinical/MRI diagnosis of MS. Materials and methods: 30 patients (21 women; median age, 33.5 years; EDSS range, [0, 4.5]; mean disease duration, 3.07 months) diagnosed of CIS, underwent a 3.0 T brain MRI scan that include proton density (PD) and T2-weighted, and susceptibility weighted (SW) sequences. Lesion masks were obtained on PD/ T2-weighted images using Jim software and registered to SW images. Iron content of lesions was measured on filtered-phase SW images as the increase with regard to normal appearing white matter (NAWM) values. For analysis purposes two regions of interest were defined: PD/T2 lesion mask (ROI-1), and region with high iron content (ROI-2) defined by the region within ROI-1 where phase values were greater than the values obtained in 17 healthy controls (15 women; median age, 35 years) for NAWM plus two SD. The measurements involved were: Fe increase per tissue gram in ROI-1 (iFe1) and in ROI-2 (iFe2), and number of pixels in ROI-2 (NP). In all patients we analyzed the fulfilment of MRI criteria for dissemination in space (DIS), dissemination in time (DIT), and both dissemination in space and time (DIST). Moreover, conversion to clinically definite MS (new relapse) was also analyzed. Statistical analysis involved Student t-test to evaluate differences between groups in Fe measurements. Results: Differences between the presence of a new relapse groups were found for iFe2 (yes, 25.45; no, 18.89; p=0.034), between DIS groups for NP (yes, 296.94; no, 36.14; p=0.001), between DIT groups for iFe1 (yes, 2.37; no, -0.48; p=0.011), for iFe2 (yes, 24.10; no, 17.60; p=0.013), and for NP (yes, 338.77; no, 50.18; p=0.003), and between DIST groups for iFe1 (yes, 2.13; no, 0.07; p=0.048), for iFe2 (yes, 24.40; no, 18.43; p=0.032), and for NP (yes, 430.0; no, 47.85; p=0.001). Conclusions: The results of this study suggest that some variables involving iron deposit within visible PD/T2 lesions may be useful to discriminate CIS patients who fulfilled the criteria for establishing the diagnosis of MS. Disclosure F. Xavier Aymerich has nothing to disclose. Alicia Palomar has nothing to disclose.


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Poster Session 2, 21(S11) Cristina Auger has received speaking honoraria from Novartis and Genzyme. Jaume Sastre-Garriga has received compensation for consulting services and speaking honoraria from Merck-Serono, BiogenIdec, Teva, Sanofi-Aventis and Novartis. Mar Tintoré has received compensation for consulting services and speaking honoraria from Bayer-Schering, Merck-Serono, Biogen-Idec, Teva, Sanofi-Aventis, and Novartis. Xavier Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall. Alex Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, and has received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Bracco, MerckSerono, Teva Pharmaceutical Industries Ltd, OLEA Medical, Stendhal, Novartis and Biogen Idec. P947 Association between iron deposit within focal lesions and radiological/clinical measurements in patients with clinically isolated syndrome F.X. Aymerich1,2, A. Palomar1, C. Auger1, J. Sastre-Garriga3, M. Tintoré3, X. Montalban3, A. Rovira1 1Section of Neuroradiology and MR Unit (Department of Radiology), University Hospital Vall d’Hebron, 2Department of Automatic Control (ESAII), Universitat Politècnica de Catalunya-Barcelona Tech (UPC), 3Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Vall d’Hebron University Hospital, Barcelona, Spain Background and objective: In early stages of multiple sclerosis (MS) iron deposits may within focal T2 lesions be associated with the progression of the disease. The aim of this study is to evaluate the association between iron deposit within focal lesions and radiological and clinical measurements in patients with clinically isolated syndrome (CIS). Materials and methods: 30 patients (21 women; median age, 33.5 years; EDSS range, [0, 4.5]; mean disease duration, 3.07 months) with CIS. Baseline (B) and 12 month (M12) proton density and T2-weighted, and susceptibility weighted (SW) images were acquired on a 3.0T MRI. Iron content of lesions was measured on filtered-phase SW images as the increase with regard to white matter values in 17 healthy controls (15 women; median age, 35 years). Two regions of interest (ROI) were defined at B exam: T2 lesion mask (ROI-1), and high iron content region (ROI-2) within ROI-1. Measurements involved were: Fe increase per tissue gram in ROI-1 (iFe1B) and in ROI-2 (iFe2B) at B, number of pixels in ROI-2 (NPB) at B, number (NGdB, NGdM12) and volume (VGdB, VGdM12) of gadoliniumenhanced lesions at B and M12, brain parenchymal fraction (BPFB, BPFM12) at B and M12, number (NT2B) and volume (VT2B) of T2 lesions at B, number (NNT2M12) and volume (VNT2M12) of new lesions at M12, percentage of brain volume change (PBVC) between B and M12, EDSS, and disease duration. Statistical analysis involved Spearman rank correlation to test association between iron deposits and clinical and radiological variables.

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Results: Some associations between measurements involving iron deposits and radiological measurements were found (NPB vs. NT2B [0.840, p< 0.001]; iFe2B vs. VT2B [0.415, p=0.022]; NPB vs. VT2B [0.970, p< 0.001]; iFe1B vs. NGdB [0.405, p=0.026]; iFe2B vs. NGdB [0.433, p=0.017]; NPB vs. NGdB [0.639, p< 0.001]; iFe1B vs. VGdB [0.430, p=0.018]; iFe2B vs. VGdB [0.468, p=0.009]; NPB vs. VGdB [0.633, p< 0.001]; iFe1B vs. NNT2M12 [0.467, p=0.009]; NPB vs. NNT2M12 [0.659, p< 0.001]; iFe1B vs. VNT2M12 [0.385, p=0.035]; NPB vs. VNT2M12 [0.537, p=0.002]; iFe2B vs. BPFM12 [-0.380, p=0.038]; NPB vs. BPFM12 [-0.500, p=0.005]). Conclusions: Moderate to strong associations found in this study suggest that in early stages of MS the presence of baseline iron deposits within focal T2 lesions are related to lesion load. Moreover, the presence of abnormal iron deposits also seems to be associated with new lesions and brain atrophy at month 12. Disclosure F. Xavier Aymerich has nothing to disclose. Alicia Palomar has nothing to disclose. Cristina Auger has received speaking honoraria from Novartis and Genzyme. Jaume Sastre-Garriga has received compensation for consulting services and speaking honoraria from Merck-Serono, BiogenIdec, Teva, Sanofi-Aventis and Novartis. Mar Tintoré has received compensation for consulting services and speaking honoraria from Bayer-Schering, Merck-Serono, Biogen-Idec, Teva, Sanofi-Aventis, and Novartis. Xavier Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall. Alex Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, and has received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Bracco, MerckSerono, Teva Pharmaceutical Industries Ltd, OLEA Medical, Stendhal, Novartis and Biogen Idec.

P948 Iron deposits within new T2 lesions in patients with clinically isolated syndrome F.X. Aymerich1,2, A. Palomar1, C. Auger1, J. Sastre-Garriga3, M. Tintoré3, X. Montalban3, A. Rovira1 1Section of Neuroradiology and MR Unit (Department of Radiology), University Hospital Vall d’Hebron, 2Department of Automatic Control (ESAII), Universitat Politècnica de Catalunya-Barcelona Tech (UPC), 3Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Vall d’Hebron University Hospital, Barcelona, Spain Background and objective: In early stages of multiple sclerosis (MS) iron deposits within focal T2 lesions may be associated with the progression of the disease. The aim of this study is to evaluate the association between iron deposit within new T2 lesions and some radiological and clinical measurements in patients with clinically isolated syndrome (CIS).


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Materials and methods: 17 patients (9 women; median age, 31 years; EDSS range, [0, 4.5]; mean disease duration, 3.29 months) with CIS. Baseline and 12 months proton density (PD) and T2-weighted, and susceptibility weighted (SW) sequences were acquired on a 3.0T MRI. Iron content within new T2 lesions at month-12 (M12) MRI was measured on filtered-phase SW images as the increase with regard to white matter values obtained from 17 healthy controls (15 women; median age, 35 years). Two regions of interest (ROI) were defined at M12 MRI: PD/T2 new lesion mask (ROI-1), and region with high iron content (ROI-2) within ROI-1. The measurements analyzed were: Fe increase per tissue gram in ROI-1 (iFe1M12) and in ROI-2 (iFe2M12) at M12, number of pixels in ROI-2 (NPM12) at M12, number (NGdM12) and volume (VGdM12) of gadolinium-enhanced lesions at M12, brain parenchymal fraction (BPFM12) at M12, number (NNT2M12) and volume (VNT2M12) of new lesions at M12, the percentage of brain volume change (PBVC) between baseline and M12, EDSS, and disease duration. Statistical analysis involved Spearman rank correlation to test correlation between iron deposits and clinical and radiological variables. Results: Some correlations between measurements involving iron deposits and radiological measurements were found (iFe2M12 vs. NNT2M12 [0.700, p=0.002]; NPM12 vs. NNT2M12 [0.808, p< 0.001]; iFe2M12 vs. VNT2M12 [0.544, p=0.024]; NPM12 vs. VNT2M12 [0.886, p< 0.001]; NPM12 vs. NGdM12 [0.765, p< 0.001]; NPM12 vs. VGdM12 [0.757, p< 0.001]). Conclusions: The results obtained suggest a strong association in CIS patients between the presence of new T2 lesions and the extension or the level of abnormal iron deposits within them. The extension of the high iron content region is also correlated to the presence of active lesions. Disclosure F. Xavier Aymerich has nothing to disclose. Alicia Palomar has nothing to disclose. Cristina Auger has received speaking honoraria from Novartis and Genzyme. Jaume Sastre-Garriga has received compensation for consulting services and speaking honoraria from Merck-Serono, BiogenIdec, Teva, Sanofi-Aventis and Novartis. Mar Tintoré has received compensation for consulting services and speaking honoraria from Bayer-Schering, Merck-Serono, Biogen-Idec, Teva, Sanofi-Aventis, and Novartis. Xavier Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall. Alex Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, and has received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Bracco, MerckSerono, Teva Pharmaceutical Industries Ltd, OLEA Medical, Stendhal, Novartis and Biogen Idec. P949 Imaging of Rituximab-Zirconium-89 uptake with PET scans in active relapsing-remitting MS patients

M.H.J. Hagens1, J. Killestein1, G.A.M.S. van Dongen2, F. Barkhof2, B.M.M. van Berckel2 1Neurology, 2Radiology and Nuclear Medicine, VU Medical Center, Amsterdam, The Netherlands Introduction: Recent studies suggest that Rituximab, a genetically engineered chimeric monoclonal antibody (MAb) against the CD20 molecule on mature B lymphocytes, reduces active inflammatory MRI lesions in MS patients. Remarkably, this effect can be seen as early as 4 weeks after the first dose. The exact mechanism responsible for this early reduction in disease activity is not fully understood. It is currently unclear if rituximab is able to enter the brain. To resolve this question we labelled rituximab with the positron emitter Zirconinium-89 (89Zr). If rituximab could penetrate central nervous system (CNS), this could be an explanation for a direct (early) effect of this MAb on disease activity. Methods: 89Zr was produced and coupled to rituximab according to the procedures described by Verel et al and following Good Manufacturing Practice standards. Patients diagnosed with RRMS according to the McDonald criteria, with an EDSS up to 5.0 and documented disease activity were included. All patients received 1000mg intravenous infusions of rituximab on study days 1 and 15. Only the first gift was partially labelled with 37 MBq of 89Zr. Results: We included three radiologically and clinically active RRMS patients, two of whom had gadolinium enhanced lesions on the baseline MRI. PET-scans were performed within seven days after the baseline MRI. No significant adverse events occurred with administration of 89Zr-rituximab. Profound peripheral B-cell depletion was seen in all patients the first days after injection. Visual inspection by an experienced nuclear medicine physician did not show specific uptake of 89Zr-rituximab in the brain. Results of quantitative analysis will be presented. Conclusion: With this pilot study we demonstrated the feasibility and safety of labelling MAbs with positron emitters. This provides a molecular imaging technique to assess in vivo CNS penetration of therapeutic MAbs in MS and relate this to disease activity and outcome.Preliminary results suggest that the early therapeutic effects of rituximab in RRMS is independent of CNS penetration. Disclosure M.H.J. Hagens: nothing to disclose. J. Killestein: has accepted speaker and consulting fees from Merck-Serono, Biogen Idec, Teva, Genzyme and Novartis. G.A.M.S. van Dongen: nothing to disclose. F. Barkhof: serves on the editorial boards of Brain, Neurology, Neuroradiology, Multiple Sclerosis Journal and Radiology, and serves as a consultant for Bayer-Schering Pharma, Sanofi-Aventis, Genzyme, Biogen-Idec, Teva, Novartis, Roche, Synthon BV and Jansen Research B.A.M. van Berckel: receives research support from Netherlands Organisation for Scientific Research (NWO) and Janssen Pharmaceuticals, he does not receive personal compensation for these activities. P950 The effect of lesions on automated deep gray matter segmentation


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Poster Session 2, 21(S11) N. Bergsland1,2,3, M.G. Dwyer1, G. Baselli3, M. Rovaris4, R. Zivadinov1,5 1Buffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States, 2MRI Research Laboratory, IRCCS Don Gnocchi Foundation ONLUS, 3Department of Electronics, Information and Bioengineering, Politecnico di Milano, 4UORN- MS Center, IRCCS Don Gnocchi Foundation ONLUS, Milan, Italy, 5MR Imaging Clinical Translational Research Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States Background: White matter (WM) lesions are known to impact MRI-based tissue segmentation and cortical reconstruction techniques. However, there are conflicting reports regarding their effect on automated segmentation of the deep gray matter (DGM) structures. Objectives: To investigate the effect of WM lesions on automated segmentation of DGM structures Methods: 152 relapsing remitting MS patients were examined with a 1.5T scanner. Fluid attenuated inversion recovery (FLAIR) and 3D T1 images were acquired. Lesions were segmented on FLAIR images and then co-registered to the corresponding 3D T1. An inpainting algorithm was used to create a lesion-filled version of the 3D T1. FMRIB’s Integrated Registration and Segmentation Tool (FIRST) was used to segment the thalamus (THA), caudate (CAUD), globus pallidus (GP) and putamen (PUT) (left and right separately). For each subject, FIRST was run four times with the following as inputs: ORIG - the original 3D T1; LF - the lesion filled 3D T1; ORIG-WITH-LF-MAT - the original 3D T1, using the registration matrix calculated in LF; LF-WITH-ORIG-MAT the lesion filled 3D T1, using the registration matrix calculated in ORIG. The same brain mask was used for all to avoid differences due to brain extraction. Differences in segmented volumes were tested using a one-way repeated measures ANOVA with Bonferroni correction for assessing pairwise comparisons. Vertex analysis of surfaces and lesion probability mapping was also performed to assess the impact of lesion presence on DGM segmentations. Results: With respect to the ORIG segmentations, LF volumes were significantly smaller for both left and right segmentations of the THA (p < .01) and CAUD (p < .001) but not GP and PUT. However, no significant differences were found when comparing volumes from ORIG with LF-WITH-ORIG-MAT nor when comparing those from LF with ORIG-WITH-LF-MAT. Vertex-wise analysis of the surfaces yielded similar results but showed that large portions of the surface were affected beyond just areas of focal lesions. Conclusions: WM lesions bias both volumetric- and surfacebased measures of the thalamus and caudate obtained with FIRST software. Differences due to WM lesions appear to be driven by their effect on the registration step, rather than during the fitting of the learned models used by FIRST. Lesion filling prior to using FIRST is recommended to reduce the impact of WM lesions on subsequent segmentations. Disclosure Niels Bergsland has nothing to disclose. Michael G. Dwyer has received personal compensation from Claret Medical and EMD Serono, and research grant support from Novartis.

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Giuseppe Baselli has nothing to disclose. Marco Rovaris has nothing to disclose. Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health. P951 Assessing the relationship between white matter lesion accumulation and gray matter atrophy development: a serial 10-year voxel-based morphometry and lesion probability mapping follow-up study of early relapsing-remitting MS patients N. Bergsland1,2,3, D. Horakova4, T. Uher1,4, M. Vaneckova5, D.P. Ramasamy1, M. Tyblova5, Z. Seidl5, M.G. Dwyer1, J. Krasensky5, E. Havrdova4, R. Zivadinov1,6 1Buffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States, 2MRI Research Laboratory, IRCCS Don Gnocchi Foundation ONLUS, 3Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy, 4Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, First Faculty of Medicine and General University Hospital, 5Department of Radiology, 1st Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic, 6MR Imaging Clinical Translational Research Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States Background: The exact mechanism by which white matter (WM) lesions lead to gray matter (GM) damage in MS remains unclear at this time. Moreover, there is evidence that WM lesions may preferentially affect deep GM more heavily than the cortex. There are only few studies that have investigated the interplay between WM and GM damage over the long term using serialy yearly MRI scans. Objectives: To investigate the spatial-temporal relationships between the development of GM atrophy and WM lesion presence. Methods: 181 early RRMS patients (mean disease duration of 5 years), who started treatment with intramuscular interferon beta1a (30 µg/week) received yearly clinical and 1.5T assessments on the same MRI scanner with the same protocol serialy over 10 years. 3D-T1 and fluid attenuated inversion recovery (FLAIR) images were acquired for all time points. Between subsequent time points, the following analyses were performed: 1) an optimized, longitudinal voxel-based morphometry (VBM) pipeline was implemented for analyzing GM changes and 2) T2-lesion probability change maps (LPCM). Analyses were adjusted for age and sex and permutation-based inferences with threshold-free cluster enhancement were carried out. VBM and LPCM results between timepoints were visually overlaid to asses spatial relationships between the two. Significance was set at p < 0.05. Results: At 1-year followup, VBM results revealed widespread atrophy in both the deep GM and the cortex with respect to the


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baseline. This pattern persisted throughout the first 6 years of the study. In this regard, the thalamus and anterior cingulate (AC) showed a consistent involvement with continuing atrophy at yearly followups. From year seven onwards, atrophy was restricted to cortical areas, with the AC consistently affected. In terms of the LPCM analysis, several areas of increased lesion probability were found throughout the first 8 years. The clusters tended to be periventricular, mainly in the posterior limb of the internal capsule and in the optic radiations. No areas of increased lesion probability were found for the remaining years of the study. Conclusions: The results from this study suggest an evolving pattern of GM damage and seem to confirm the hypothesis that DGM areas are more affected in the earlier years of follow-up. The LPCM results suggest that WM lesion presence is more strongly linked, at least in the short term, to atrophy in the DGM than in the cortex. Disclosure The study is an investigator-initiated study that was supported by Czech Ministries of Education and Health [NT13237-4/2012, PRVOUK-P26/LF1/4, RVO-VFN64165/2012]. The MRI acquisition part of the study was supported by Gedeon Richter and Biogen Idec. The MRI analysis part was supported in part by Biogen Idec. Financial Relationships/Potential Conflicts of Interest: Mr. Bergsland has nothing to disclose. Dr. Horakova received compensation for travel, speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck Serono, Bayer Shering, and Teva, as well as support for research activities from Biogen Idec. Dr. Uher received financial support for conference travel and honoraria from Biogen Idec, Novartis, Merck Serono and Genzyme. Dr. Tyblova received compensation for travel and honoraria from Biogen Idec, Sanofi Aventis, Teva and Merck Serono. Drs. Seidl, Vaneckova, and Krasensky received financial support for research activities from Biogen Idec. Dr. Dwyer has received personal compensation from Claret Medical and EMD Serono, and research grant support from Novartis. Dr. Havrdova received speaker honoraria and consultant fees from Biogen Idec, Merck Serono, Novartis, Genzyme and Teva, as well as support for research activities from Biogen Idec and Merck Serono. Robert Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health. P952 Spinal cord gray matter atrophy in early multiple sclerosis R. Schlaeger1,2, N. Papinutto1, A.H. Zhu1, V. Panara1, I. v Lobach3, C.J. Bevan1, M. Bucci1, A. Castellano1, J.M. Gelfand1, J.S. Graves1, A.J. Green1,4, K.M. Jordan1,5, A. Keshavan1,5, W.A. Stern1, H.-C. von Buedingen1, E. Waubant1, D.S. Goodin1, B.A.C. Cree1, S.L. Hauser1, R.G. Henry1,5,6 1Neurology, UCSF, San Francisco, CA, United States,

2Neurology,

University Hospital Basel and University of Basel, Basel, Switzerland, 3UCSF, Departments of Epidemiology and Biostatistics, 4Ophthalmology, UCSF, San Francisco, 5UCSF and Berkeley, Bioengineering Graduate Group, San Francisco and Berkeley, 6Radiology and Biomedical Imaging, UCSF, San Francisco, CA, United States Background: Spinal cord gray matter (GM) atrophy has been recently described in vivo in patients with long-standing Multiple Sclerosis (MS) and has been shown to correlate with disability and disease type. The goal of this study was to assess whether spinal cord GM atrophy starts early in the disease and whether it equally affects the cervical and thoracic cord. Methods: 40 patients at an early stage of MS (mean age 36.5 years, 29 women, mean disease duration from first symptom onset: 1.3 years (range 0-3.7 years)) and 20 age and sex matched healthy controls were scanned at 3T. Axial 2D-phase sensitive inversion recovery MR images were acquired at the intervertebral disc levels C2/C3 and T9/10. Total cord areas (TCA) were segmented semi-automatically, spinal cord GM areas were segmented manually, and spinal cord white matter (WM) areas were calculated as their difference. Differences in areas between patients and controls were assessed with age and sex as covariates using multivariable regression analysis. Results: In the cervical and thoracic spinal cord MS patients had significantly smaller spinal cord GM areas than age and sex matched controls (Coefficient of variation (COV) 7%, p< 0.001 at C2/C3 and 7%, p=0.04 at T9/T10), but had no significant difference in either the spinal cord WM area or TCA. Conclusions: These observations demonstrate that spinal cord GM atrophy can be detected already at an early stage of MS, in the absence of WM atrophy, and equally affects both the cervical and thoracic cord. Longitudinal, prospective studies are necessary to clarify the role of cord GM changes in monitoring and predicting MS disability and progression. Disclosure The authors acknowledge support from research grant funding from the National Multiple Sclerosis Society, The Conrad H. Hilton Foundation, Department of Defense, NIH R01 NS 026799, NIH R01 NS049477, NIH K02 NS072288, National Defense Science and Engineering Fellowship (NDSEG), and Nancy Davis Foundation. RS has received grants from the Swiss MS Society and the Gottfried and Julia Bangerter-Rhyner Foundation, Switzerland. Her institution (University Hospital Basel) has received advisory board fees from Biogen, which were exclusively used for research support. NP, AHZ, IvL, CJB, MB, KMJ, AC, AK, VP, WAS, EW, JSG: nothing to disclose. RH has received grants from Stem Cells Inc, and Roche, outside the submitted work. JMG is funded by NIH KL2TR000143. He has received compensation from Medimmune for consulting on a scientific advisory board; compensation from Quest Diagnostics for work developing a dementia care pathway; and compensation for medical-legal consulting. AG reports personal fees from Inception Sciences and Mylan, Pharmaceuticals and grants/awards from the National Multiple


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Poster Session 2, 21(S11) Sclerosis Society, Novartis, UCSF CTSI, and That Man May See as well as philanthropic support from the Rachelff Family and the Robert Dale Family. He also reported serving on an end point adjudication committees for Biogen and Medimmune. He serves on trial steering committees for Novartis and Scientific Advisory Board for Bionure. BACC has received personal compensation for consulting from Abbvie, Biogen Idec, EMD Serono, MedImmune, Novartis, Genzyme/sanofi aventis, Teva and has received contracted research support (including clinical trials) from Acorda, Biogen Idec, EMD Serono, Hoffman La Roche, MedImmune, Novartis and Teva. HCvB has received research support from Roche, Genentech, and Pfizer, and personal compensation for consulting from Roche and Novartis. DSG has participated a principal investigator in several clinical trials in MS and has given many public lectures regarding the epidemiology of MS and/or its treatment. These clinical trials and many of these lectures have been sponsored by various pharmaceutical companies including Biogen Idec, Bayer Schering, Novartis, EMD Serono, Genzyme, and Teva pharmaceuticals. SLH currently serves on the SAB of Symbiotix, Annexon, and Bionure. P953 Brain MRI assessment in clinical practice: descriptive analysis of a cohort of MS patients at Hospital Federal da Lagoa - Rio de Janeiro (Brazil) M.P. Alvarenga1,2, F. Rueda3, E. Gasparetto3, C.C. Vasconcelos2, H. Alvarenga Filho2, R.M. Papais Alvarenga1,2 1Hospital da Lagoa, 2UNIRIO, 3CDPI - Clínica de Diagnóstico por Imagem, Rio de Janeiro, Brazil Background: Clinical and brain MRI assessments are important when monitoring MS patients in routine practice. Working together with neurologists and neuro-radiologists we have integrated MRI imaging analysis into clinical research but there is still a need to bring MRI assessments into routine clinical practice to provide better care for our patients. Here we present data from an MS patient cohort that integrates clinical assessment and brain MRI parameters obtained using automated software analysis tools. Objectives and methods: To describe a cohort of 40 MS patients who attended the MS clinic in our centre. Clinical data including MS disease duration, relapses and EDSS scores was combined with brain imaging assessments such as T2 lesion load, whole brain volume and grey mater volumes. MRI analysis was perfomed using MS Metrix (IcoMetrix, Belgium). Results: Patients were divided into two groups based on disease duration of less or more than 10 years. Those with shorter disease duration had a mean (±SD) 5.7 ± 2 years of onset, mean age of 33 ±7 years and EDSS of 3.2 ±2.1. The longer disease duration group had 13.4 ±4 years of onset, mean age of 45.6 ±11 years and EDSS of 5 ±1.8. Brain MRI parameters by group were in line with that expected for a shorter and longer MS disease duration cohort. Whole brain volume and grey matter volumes were lower in patients with longer disease duration compared to those with shorter disease onset: 1420.8 ml vs 1384.9 ml for whole brain volume respectively and 826.02 vs 861 ml for grey brain volume respectively. Lesion volumes indicated a larger burden of disease

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in patients with longer disease duration with a total T2 lesion volume of 34.7 ml for those diagnosed for 10 years or more compared to 19.3 ml in more recently diagnosed patients. Conclusion: Clinical and radiological parameters are important variables to be considered when monitoring MS patients. Our experience demonstrates that current MRI analysis technology is easy to use and can be conveniently integrated into clinical practice. Disclosure Marcos Alvarenga: Is medical advisor for Novartis Brazil. Regina Alvarenga: nothing to disclose Claudia Vasconcelos: nothing to disclose Helcio Alvarenga: nothing to disclose

P954 Diagnosing multiple sclerosis using the central vein sign. What is the agreement between a blinded rater and the final diagnosis using T2* weighted sequences at 3T MRI? M. Clarke1, A.P. Samaraweera2, A. Connolly3, O. Mougin4, R.A. Dineen5, P.S. Morgan6, N. Evangelou2 1Clinical Neurology, Nottingham University Hospitals NHS Trust, 2Division of Clinical Neuroscience, 3School of Medicine, 4Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, 5Radiological Sciences, 6Medical Physics, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom Background: There is no simple diagnostic test for multiple sclerosis (MS). White matter lesion (WML) central veins (CV) seen on MRI both at 3 and 7T have proved a useful imaging biomarker in preventing the misdiagnosis of MS. For clinical translation diagnostic criteria must be simple to use and inter-rater agreement needs to be high. A simple rule of 6 was proposed previously (if there are more than 6 WMLs with CV the diagnosis is MS, if there are less than 6 WMLs in total, but the majority of them have CV the diagnosis is MS and if only a minority have CV, MS cannot be diagnosed). Objectives: We wanted to test the reliability of the rule in experienced and inexperienced observers. Methods: 10 MS and 10 SVI (small vessel ischaemia) patients were scanned on a 3T Philips Achieva and GE MR750 MR scanners. Susceptibility Weighted Imaging (SWI), T2* weighted imaging, T2* with high EPI factor and SWAN imaging were acquired. Each rater made a diagnosis of MS or SVI based on the ‘rule of 6’ previously published. Only the presence of a CV was used in the radiological diagnosis of MS. All other features of the lesions were discounted. Cohen’s kappa (ĸ) was used to determine a level of agreement with the final clinical diagnosis. Results: Experienced observers were very accurate in the radiological diagnosis when the ‘rule of 6’ was used. On the other hand the level of agreement with the clinical diagnosis was fair when inexperienced raters used SWAN (ĸ=0.37-0.69), moderate with T2* and T2* with high EPI (ĸ=0.60-0.80, 0.56-0.78 respectively) and moderate with SWI (ĸ=0.50). Discussion: As the identification of CV in WMLs appear useful in the diagnosis of MS, it is anticipated that to be clinically practical, criteria will need to be refined using a subset of the total


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WMLs seen. SVI scans were more likely to be misclassified as MS by inexperienced raters. As diagnostic tests are used by clinicians of variable experience, further work is warranted in developing more specific rules defining what constitutes a CV or not for MS. Disclosure Margareta Clarke: nothing to disclose; Dr Samaraweera: nothing to disclose; Amy Connolly: nothing to disclose; Dr Mougin: nothing to disclose; Dr Dineen: nothing to disclose; Professor Morgan: nothing to disclose; Dr Evangelou: nothing to disclose. P955 Using diffusion MRI to study demyelination in deep gray matter in animal model of multiple sclerosis S. Wergeland1, V. Flatberg2, R. Gruner2,3, L. Bø1,4, T. Pavlin3,5 1Department of Neurology, Haukeland University Hospital, 2Department of Physics, University of Bergen, 3Department of Radiology, Haukeland University Hospital, 4Institute of Clinical Medicine, 5Molecular Imaging Center, Department of Biomedicine, University of Bergen, Bergen, Norway Background: Diffusion tensor imaging (DTI) is a magnetic resonance imaging technique sensitive to changes in tissue structure at a cellular level, but is inherently unspecific. By using biophysical models of tissue microstructure, specific markers of tissue microstructure in normal, developing and diseased brain can be identified. In this work we use a neurite density model to detect demyelination and axonal loss in deep grey matter (DGM) and cortex in the murine cuprizone (CPZ) model of multiple sclerosis. Objective: To detect demyelination and axonal loss in the murine brain using DTI, and validate results by immunohistochemical assessment of myelin content and axonal integrity. Methods: 18 female c57Bl/6 mice were exposed to CPZ for 3 (n=6) and 5 (n=6) weeks, and 4 weeks after ending CPZ exposure (n=6). 6 mice were not exposed to CPZ (healthy controls). Diffusion-weighted echo planar images of mouse brains were acquired ex vivo on a 7T horizontal-bore magnet, using a standard spin-echo diffusion preparation (Stejskal-Tanner). MRI data was fitted in MATLAB using Jespersen’s et al. dendrite density model for grey matter (Neuroimage 2007 and 2010). Region-of interest analysis of dendrite density in the cortex and DGM were performed on parametric maps. Brain sections were stained for myelin (myelin proteolipid protein, PLP) and axons (neurofilament light chain, NFL). Results: We detected significant differences in neurite density and longitudinal diffusion between baseline and at 3 and 5 weeks of cuprizone exposure in both DGM and cortex. After 3 weeks of exposure, neurite density decreased by 16% and longitudinal diffusion increased by 20%. Both returned to baseline levels (0.5 and 0.8-1.0 mm2/ms, respectively) after remyelination. There were no significant differences between 3 and 5 weeks of exposure. Extracellular diffusion in DGM and cortex did not change significantly as a result of cuprizone exposure (range 0.27 to 0.35 mm2/

ms for all experimental groups). There was a significant reduction in PLP immunopositivity in both cortex and DGM after 3 and 5 weeks of CPZ exposure, and an incomplete remyelination 4 weeks after ending CPZ exposure. A corresponding non-significant reduction of NFL immunopositivity was observed during CPZ exposure, with no change after ending CPZ exposure. Conclusion: The dendrite density model developed by Jespersen can potentially be applied to detect grey matter demyelination in multiple sclerosis. Disclosure Stig Wergeland: nothing to disclose. Vanja Flatberg: nothing to disclose. Renate Gruner: nothing to disclose. Lars Bø: nothing to disclose. Tina Pavlin: nothing to disclose. P956 Cerebellar functional connectivity alterations and their association with balance deficit in multiple sclerosis F. Tona1, E. Sbardella1, L. Prosperini1, N. Upadhyay1, N. Petsas1, C. Giannì1, M.C. Piattella1, C. Pozzilli1, P. Pantano1,2 1Sapienza University, Rome, 2IRCSS Neuromed, Pozzilli, Italy Background: Although the relationship between cerebellar function and balance capability is well known, only few studies explored cerebellar functional connectivity abnormalities underlying clinical impairment in patients with multiple sclerosis (MS), and no one was focused on postural balance deficit. Objective: The aim of our study was to investigate, by using resting-state functional magnetic resonance imaging (RS-fMRI), the alterations of functional connections between the cerebellum and other brain structures in patients with MS. Correlations between functional connectivity of cerebellum and postural balance impairment were also investigated. Methods: Thirty fully ambulatory patients with MS and 25 healthy subjects (HS) underwent a RS-fMRI with a 3.0-Tesla magnet and a static posturography assessment to calculate the body´s center of pressure displacement (COP path) in 30 seconds. Functional imaging data were analyzed with tools from FMRIB Software Library, by using the seed-based method to identify the cerebellar resting-state network (RSN); both dentate nuclei were used as seed region. Results: There were no significant differences between MS and HS groups in terms of demographics characteristics, such as gender, age, body mass index (p=n.s.). When compared to HS, patients with MS had worse postural sway (p < 0.001). RS-fMRI analysis revealed an altered connectivity within the cerebellar RSN in patients with MS, with an increased connectivity in several brain areas mainly belonging to the prefrontal cortex, bilaterally (p < 0.05, cluster-level corrected). Moreover, in the patient group, a significant inverse correlation was found between the length of COP path and the increased functional connectivity in the left dorso-lateral prefrontal and orbito-frontal cortices (p< 0.001, uncorrected). Discussion: Our findings indicate an increased functional connectivity within the cerebellar RSN in patients with MS, mainly involving the frontal cortex. The association between increased


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Poster Session 2, 21(S11) functional connectivity in some frontal cortical areas and less severe postural deficit suggests that neuroplastic changes in these areas may play an adaptive role in maintaining the balance control despite the brain damage due to MS. Disclosure This research was supported by the Italian MS SocietyFondazione Italiana Sclerosi Multipla (grant 2012/R/12). F. Tona: nothing to disclose. E. Sbardella: nothing to disclose. L. Prosperini: consulting fees, and /or lecture fees, and/or travel grants from: Bayer Schering, Biogen Idec, Genzyme, Novartis and Teva. N. Upadhyay: nothing to disclose. N. Petsas: speaker honoraria from Biogen Idec. C. Giannì: nothing to disclose. M.C. Piattella: nothing to disclose. C. Pozzilli: consulting and/or lecture fees and research grants and/ or travel grants from Almirall, Biogen Idec, Bayer Schering, Merck Serono, Novartis, Roche, Sanofi Genzyme and Teva. P. Pantano: nothing to disclose. P957 Multivariate combination of quantitative T2* and T1 at 7T MRI detects in vivo subpial demyelination in the early stages of MS G. Mangeat1,2, C. Louapre2,3, E. Herranz2,3, C.A. Treaba2,3, R. Ouellette2, J.A. Sloane3,4, E.C. Klawiter2,3,5, J. Cohen-Adad1,6, C. Mainero2,3 1Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, QC, Canada, 2A. A. Martinos Center for Biomedical Imaging, MGH, Charlestown, 3Harvard Medical School, 4Beth Israel Deaconess Medical Center, 5Department of Neurology, MGH, Boston, MA, United States, 6Functional Neuroimaging Unit, CRIUGM, Université de Montréal, Montreal, QC, Canada Background and goals: Subpial demyelination occurs early in the course of multiple sclerosis (MS), but in vivo detection is challenging due low contrast at conventional field strengths. Quantitative mapping of T2* and T1 relaxation rates at 7T MRI was shown to be sensitive to cortical myelin content, and to cortical MS demyelination associated with clinical measures. Given that several confounds hamper the specificity of both metrics, we used multivariate statistics to combine cortical T1 and T2* maps to gain specificity to subpial demyelination in early MS. This approach has shown improved sensitivity to cortical myelin content in healthy subjects. Methods: In 5 healthy controls (HC, 34±12 years, 3 females) and 10 early MS patients (37±9 years; 8 females; disease duration⩽3 years, median, range Expanded Disability Status Scale score=1, 0-3) we obtained 7T high resolution quantitative T2* (0.5x0.5x0.5mm3) and T1 (0.75x0.75x0.75mm3) maps. For each subject, T1 and T2* were sampled at 25% depth from the pial surface. We applied a first order correction for partial volume effect to both metrics. A spatial Independent Component Analysis was used to extract the shared myelin-related signal in T1 and T2* maps, thus creating the Combined Myelin Estimation (CME), a new metric more specific to myelin than T1 or T2* separately. A

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General Linear Model (GLM), including age and gender as adjustment factors, was used to compare T1, T2* and CME in MS vs HC in whole cortex and in selected Brodmann areas (BA). Results: In the whole cortex, CME was increased while T1 and T2* were decreased in MS vs HC (CME=47±0.8% vs 49±1.3%; T1=1727±56 vs 1654±70 ms; T2*=34.0±1.2 vs 33.0±1.1 ms). Whole cortex GLM of CME showed significant loss of myelin (p< 0.05), though variations of T2* and T1 were not significant. The GLM of CME within BAs showed significant loss of myelin in sensory, motor (BA3, BA4, BA6) and prefrontal (BA10) areas (p< 0.05). A significant higher T1 was observed in frontal cortex (BA45, p< 0.05). No regions were significantly different using T2*. Discussion: CME, a multivariate statistical framework combining quantitative T1 and T2* from ultra high resolution 7T scans, shows increased sensitivity to detect changes in early MS compared to HC, and supports subpial demyelination as an early event in MS, even in the presence of mild neurological disability. Disclosure - The study was funded by R01 NS078322-03 - G. Mangeat: nothing to disclose. - C. Louapre: has received a fellowship from ARSEP foundation. - E. Harranz: nothing to disclose. - C. A. Treaba: nothing to disclose. - R. Ouellette: nothing to disclose. - J. A. Sloane: nothing to disclose. - E. C. Klawiter: has received consulting fees from Biogen Idec and Mallinckrodt Pharmaceuticals and research funding from Roche and Atlas5d. - J. Cohen-Adad: nothing to disclose. - C. Mainero: nothing to disclose. P958 Motor practice effect on functional connectivity is modulated in time by interferon beta treatment in multiple sclerosis N. Petsas1, V. Tomassini2,3, E. Sbardella1, F. Tona1, C. Pozzilli1, R.G. Wise4, P. Pantano1,5 1Dpt of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy, 2Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff, United Kingdom, 3Laboratory of Clinical and Behavioural Neuroloscience, IRCCS Santa Lucia Foundation, Rome, Italy, 4Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff, United Kingdom, 5IRCCS Neuromed, Pozzilli, Italy Multiple Sclerosis (MS) patients show FC alterations which are associated with altered motor function and disability. Neuroinflammation influences negatively recovery also by interfering neuroplasticity processes. In MS, inflammatory modulation, that can be induced by disease-modifying treatment (e.g.interferon beta - IFNb), may facilitate neuroplastic events in a more succesful reorganization. The resulting functional reorganization in motor networks can be probed by inducing changes in motor-related FC, e.g with motor practice. Aim: Assessment of the effects of motor practice on resting FC and its modulation with IFNb.


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Methods: Twenty-one (mean disease duration 1.8 years +/- 2.18 sd) MS patients, naive to disease modifying therapy, and nineteen, age- and sex-matched, healthy subjects (HS) underwent two runs of rest-fMRI, just before (run1) and after (run2) 25-minute practice of right thumb flexion (RTF). Patients had 3 scans, at recruitment (S1), after 6 weeks (S2) and after 12-week IFNb treatment (S3); HS were scanned once. In a seed-correlation analysis on the atlas-selected left hand’s omega (corresponding to practicing hand), spatial maps of FC for each run were obtained and betweenrun contrasts were defined and entered in within- and betweengroup t-tests. Results: In all cases we observed a significant FC increase (FCi), i.e run2 > run1, that resulted higher in patients at S1 than in HS in the posterior cingulate cortex. No significant differences in FCi were observed between S1 and S2 in patients. After IFNb, FCi was significantly lower at S3 with respect to S1; at S3, FCi was focused on the motor cortical areas and decreased in occipito/parietal areas, including the posterior cingulate cortex. No differences in FCi were observed between patients at S3 and HS. For contrast run1 > run2, no significant results were obtained at group-level. Conclusion: Motor cortex FC modifications in response to practice are less pronounced after treatment. Presumably, IFNb treatment-induced neuroinflammatory modulation in a 12-week time span contributed in reducing abnormal FC reactivity, as reflected by lower FC increase in non-motor areas. Clinical implications and perspectives for neuroimaging-driven intervention on neuroplasticity have to be furtherly investigated. Disclosure N. Petsas received lecture fees from Biogen Idec. V.Tomassini: nothing to disclose. E.Sbardella: nothing to disclose. F.Tona: nothing to disclose. C. Pozzilli consulting and/or lecture fees and research grants and/ or travel grants from Almirall, Biogen Idec, Bayer Schering, Merck Serono, Novartis, Roche, Sanofi Genzyme and Teva. R.G.Wise: nothing to disclose. P. Pantano: nothing to disclose. P959 Validation of automated versus manual T2 lesion segmentation applied on FLAIR- and DIR-sequences C. Egger1, T. Kepp2, L. Spies2, R. Opfer2, S. Schippling1 1Neuroimmunology and Multiple Sclerosis Research, Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland, 2jung diagnostics GmbH, Hamburg, Germany Introduction: Magnetic resonance imaging (MRI) is key in the diagnostic process and disease monitoring of patients with multiple sclerosis (MS). T2 lesion load next to Gadolinium enhancing T1 lesions is a true surrogate of clinical disease activity and serves as an important endpoint in clinical trials in MS. Until to date, T2 lesion quantification - due to methodological constraints - is mostly performed manually although strong efforts have been made to allow automated quantitative lesion segmentation. In 2012, Schmidt and co-workers published an algorithm to be applied on fluid-attenuated inversion recovery (FLAIR) sequences.

Objectives: To apply the Schmidt algorithm on FLAIR data on an independent data set and compare automated versus manual T2 lesion segmentation. To put these results in relation to inter-rater variability of manual segmentation of FLAIR data. Further, we wanted to test the validity of the algorithm when applied on double inversion recovery (DIR) images in addition to FLAIR. Methods: MRIs were performed on a 3T MRI scanner (Ingenia, Philips, Netherlands). T2-lesion load was determined in 27 MS patients using open source software (Statistical Parametric Mapping SPM8) and an automated segmentation algorithm first described by Schmidt et al. (2012). Hyperintensities on 3D FLAIR and 3D DIR images were automatically determined using lesion belief masks. Manual segmentation was performed by two independent raters. Correlation between manual and automated segmentation was calculated for both FLAIR- and DIR analysis. Further, inter-rater reliability has been calculated for FLAIR segmentation. Results: We found a strong correlation between manual and automated lesion segmentation, regarding lesion volume and lesion number (R2=0.984 / p< 0.0001 and R2=0.808 / p< 0.0001 respectively), when the Schmidt algorithm was applied on 3D FLAIR data sets. Between-rater agreement was good for both lesion volume and number assessment on FLAIR images (R2=0.932 / p< 0.0001 and R2=0.807 / p< 0.0001 respectively). Performance of automated lesion segmentation in DIR data was comparable to the FLAIR results regarding lesion volume (R2=0.909 / p< 0.0001) but much weaker for lesion number (R2=0.399 / p=3.23E-4). Conclusion: Automated lesion quantification can be applied on FLAIR data sets using the algorithm of Schmidt et al. and shows good agreement with manual segmentation. Performance on DIR images appears weaker for lesion counts. Disclosure Christine Egger: nothing to disclose Timo Kepp: nothing to disclose Lothar Spies: nothing to disclose Roland Opfer: nothing to disclose Sven Schippling has received research grants from Biogen Idec, Bayer Healthcare and Genzyme and consulting/speaker fees from Bayer Healthcare, Biogen Idec, Merck Serono, Novartis Pharma, TEVA and Genzyme/Sanofi-Aventis. P960 Cortical myelin mapping in MS using the T1w/T2w ratio R. Righart, V. Biberacher, P. Schmidt, D. Buck, A. Berthele, C. Zimmer, B. Hemmer, M. Mühlau Technische Universität München, Munich, Germany Background: In MS, neuropathological examination has shown widespread demyelination in the cortex [1]. Hence, an MRI technique to estimate cortical demyelination in vivo is desirable. Here, we performed cortical surface-based measures to investigate cortical demyelination in early MS. Method: T1w/T2w ratios enable to estimate cortical myelin content [2,3]. 285 MS patients and 80 control participants (CP) were investigated. Freesurfer was used for cortical surface-based analyses. T2w MR images were registered to T1w images using


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Poster Session 2, 21(S11) Freesurfer´s bbregister and the ratio between T1w and T2w images was sampled at the midthickness surface [2,3]. Results: Whole cortex T1w/T2w ratio images showed the highest myelin concentrations in the primary cortical areas, which is in line with previous work [2,3]. A positive relation was observed between age and cortical myelin [3]. Further, the relation between cortical thickness and myelin was region-specific suggesting that T1w/T2w ratios are not a simple reflection of thickness. MS and CP showed no significant differences for average myelin levels across the cortex. However, region-specific GLM analysis showed that MS patients had lower myelin levels in the medial occipital cortex and posterior cingulate cortex in both hemispheres. Finally, we found that particularly the myelin levels in the posterior cingulate cortex were related with several clinical measures of mental processing speed in MS patients. These correlations remained significant after correction for age, sex, whitematter lesion volume and cortical volume. Discussion: T1w/T2w ratio images reflect a part of MS pathology, most likely cortical myelin loss, which is not covered by conventional image analysis. We believe that this method is promising with regard to in vivo research on cortical pathology in MS. Given its broad availability, it is a potential candidate for monitoring of cortical pathology in the clinical context.

References: 1. Lucchinetti et al. NEJM 2011 2. Glasser & Van Essen. J Neurosci. 2011 3. Grydeland et al. J Neurosci. 2013 Disclosure R. Righart: has received research support from Hertie Foundation. V. Biberacher: nothing to disclose P. Schmidt: nothing to disclose D. Buck: has received compensation for activities with Bayer HealthCare, BiogenIdec, MerckSerono, and Novartis. She is supported by the Abirisk Consortium. A. Berthele: is a consultant for Biogen Idec, Bayer, Merck Serono; he has received research support from Bayer; he has received honoraria for lecturing from Biogen Idec, Bayer, Merck Serono, Teva Neuroscience, Novartis; he has received travel expenses for attending meetings from Biogen Idec, Merck Serono, Bayer, Teva Neuroscience, Novartis; he has received Investigator fees for Phase II-IV clinical studies from Biogen Idec, Novartis, Merck Serono, and Galapagos. C. Zimmer: nothing to disclose B. Hemmer: has served on scientific advisory boards for Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GSK, Chugai Pharmaceuticals, Micromet, Genentech and Genzyme Corporation; serves on the international advisory board of Archives of Neurology and Experimental Neurology; has received speaker honoraria from Bayer Schering, Novartis, Biogen Idec, Merck Serono, Roche, and Teva Pharmaceutical Industries Ltd; and has received research support from Biogen Idec, Bayer Schering, Merck Serono, Five prime, Metanomics, Chugai Pharmaceuticals and Novartis. He has been filed a patent for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and genetic determinants of neutralizing antibodies to interferon-beta.

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M. Mühlau: has received research support from Merck Serono and Novartis; he has received travel expenses for attending meetings from Bayer, and Merck Serono; he has received honoraria for lecturing from Merck Serono; he has received Investigator fees for a Phase III clinical study from Biogen Idec. P961 Assessment of whole brain blood flow changes in multiple sclerosis: phase contrast MRI versus ASL Y. Ge1, O. Marshall1, I. Kister1, H. Lu2, M. Sadowski1, R.I. Grossman1 1New York University School of Medicine, New York City, 2Johns Hopkins University School of Medicine, Baltimore, NY, United States Purpose: Cerebral blood flow (CBF) is an important hemodynamic characteristic of the brain since it reflects the availability of blood to enable healthy neuronal function. Previous studies in multiple sclerosis (MS) have shown regional hemodynamic changes indicating a state of increased or decreased perfusion, which can offer insights into vascular abnormalities and neurodegeneration of the disease. This study is to investigate whether global CBF levels are affected in MS compared to healthy controls using two different imaging techniques to obtain whole brain CBF. Methods: 70 controls (39 male, 31 female, 37.6±12.4 years old) and 81 MS patients (30 male, 51 female, 41.6±11.0 years old) underwent MRI scans to assess whole brain CBF measured by pseudocontinuous arterial spin labeling (pCASL) and singleslice phase-contrast (PC) MRI. pCASL was acquired to cover the whole brain with 5mm slice thickness and 32 slices. PC was acquired with the imaging position placed above the carotid artery bifurcation (at C2-C3 levels) oriented perpendicular to the internal carotid (ICA) and vertebral arteries (VA) determined on a time-of-flight angiogram. Additionally, a high resolution anatomical T1 image was acquired for image co-registration and segmentation. Whole brain CBF (mL/100g/min) was measured from the PC data as the total blood flow through the bilateral four arteries (ICA+VA) divided by the total brain parenchyma volume. Whole brain CBF based on pCASL was calculated as the average of all gray and white matter voxels. Global CBF acquired by both methods was compared between patient and control groups using a two-sample t-test, with a p-value< 0.05 considered significant. Results: A significant correlation (R =0.43, p< 0.0001) is seen between whole brain CBF values as calculated using PC MRI and using pCASL perfusion MRI, showing high coherence between the two methods. Whole brain CBF comparison showed lower value of PC- based compared with pCASL-based method. However, we did not find significant difference of global CBF using either method between patients and controls. There was a slightly increased global CBF on pCASL and PC in MS versus control group. Discussion: Although previous studies have shown both increased and decreased areas of perfusion throughout the brain, our data showed no significant change of global CBF in MS using either ASL or PC method, which may have relevant implications for interpretation of findings from other global measures.


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Disclosure This work was supported by NIH R01 Grants (NS029029-20S1 and NS076588), National MS Society Research Grant (RG4707A), and was performed under the rubric of the Center for Advanced Imaging Innovation and Research (CAI2R, www.cai2r.net), a NIBIB Biomedical Technology Resource Center (NIH P41 EB017183). P962 Spontaneous remyelination in MS improves clinical prognosis and protects from neuro-axonal degeneration B. Bodini1,2,3, E. Poirion1, M. Battaglini4, D. Garcia-Lorenzo1, M. Veronese2, C. Papeix5, N. De Stefano4, B. Zalc1, C. Lubetzki1,5, M. Bottlaender3, F. Turkheimer2, B. Stankoff1,3,6 1UPMC Univ Paris 06, UMR S 1127, CNRS UMR 7225 and ICM, Sorbonne Universités, Paris, France, 2Department of Neuroimaging, Institute of Psychiatry, King’s College London, London, United Kingdom, 3Service Hospitalier Frédéric Joliot, Institut d’Imagerie Biomédicale, I2BM, CEA, Orsay, France, 4Department of Behavioural and Neurological Sciences, University of Siena, Siena, Italy, 5APHP, Hôpital de la Salpêtrière, 6APHP, Hôpital Saint-Antoine, Paris, France Background: Positron emission tomography (PET) with [11C] PIB has been proposed as a promising biomarker for measuring dynamic myelin content changes in vivo in multiple sclerosis (MS). Whether spontaneous remyelination improves clinical prognosis and prevents neuro-axonal degeneration in patients with MS remains an unanswered question. Objectives: In this longitudinal study, we employed [11C]PIBPET to stratify patients with MS according to their remyelination potential, and to measure the impact of spontaneous remyelination on clinical prognosis and on magnetic resonance imaging (MRI) metrics reflecting axonal loss. Methods: Nineteen patients with active MS were clinically assessed and underwent PET with [11C]PIB as well as conventional and diffusion-weighted MRI at baseline and after 2-4 months. An index of remyelination was calculated for each patient from maps of [11C]PIB distribution volume ratio, based on changes in lesional myelin content over the follow-up, that was correlated with the Expanded Disability Status Scale (EDSS) and the MS Severity Scale (MSSS) with multiple linear regressions. Patients were classified in “good remyelinators” and “bad remyelinators” based on their remyelination index. Using multiple linear regressions, the two groups were compared with respect to the mean fractional anisotropy (FA) of the major white matter tracts after lesion subtraction, and the normalized thalamic volume, which are indices reflecting neuro-axonal damage. Results: A high between-patient variability was found for the index of remyelination (range 7.8%-22.6%), which allowed classifying patients in “good remyelinators” (n=10) and “bad remyelinators” (n=9). The index of remyelination was inversely correlated with clinical scores (p=0.004, beta-coefficient=-0.68 with EDSS, p=0.002, beta-coefficient=-0.67 with MSSS). When compared to “bad remyelinators”, “good remyelinators” showed higher normalized thalamic volumes (p=0.03), as well as higher FA values in the forceps major (p=0.01), right cingulate gyrus (p=0.04), and in the right superior longitudinal fasciculus (p=0.02).

Conclusions: [11C]PIB-PET allows to stratify MS patients according to their remyelination potential. A higher index of remyelination is correlated with a milder clinical disability, suggesting that an efficient process of myelin repair is one of the discriminant factors in determining a better prognosis, probably through an active prevention of neuroaxonal degeneration. Disclosure The study was funded by specific grants from ELA (European Leukodystrophy Association, grant 2007-0481), and INSERMDHOS. MV and FT were funded by the MRC-UK PET Methodology Programme Grant, NO. G1100809/1, and ARSEP travel grant. B. Bodini is funded by the ECTRIMS Post Doctoral Research Followship. E. Poirion: nothing to disclose M. Battiglini: nothing to disclose D. Garcia-Lorenzo: nothing to disclose M. Veronese: nothing to disclose C. Papeix reports receiving consulting fees from Biogen Idec, Novartis, Merck Serono, Sanofi-Aventis, Teva-Pharma Bayerschering, Genzyme and Roche. N. De Stefano has received honoraria from Schering, BiogenIdec, Teva, Novartis, Genzyme, and Merck Serono S.A. for consulting services, speaking and travel support. He serves on advisory boards for Merck Serono S.A. and Novartis. He has received research grant support from the Italian MS Society. B. Zalc: nothing to disclose C. Lubetzki participates in therapeutic trials in multiple sclerosis with Biogen, Novartis, Genzyme, Roche, to advisory boards of Biogen, Novartis, Gennzyme, Roche and Vertex, and has an ongoing scientific collaboration with Vertex. M. Bottlaender: nothing to disclose F. Turkheimer: nothing to disclose B. Stankoff reports receiving consulting and lecture fees from Biogen, Novartis, Merck Serono, Sanofi-Aventis, Teva and research support from Sanofi-Aventis-Genzyme and Merck Serono. P963 Influence of focal gray matter and white matter lesions on normal-appearing tissues in multiple sclerosis A. Pitiot1, R. Abdel Fahim2, O. Mougin3, P.S. Morgan2, P.A. Gowland3, N. Evangelou2 1School of Psychology, 2School of Medicine, 3SPMIC, University of Nottingham, Nottingham, United Kingdom Background: Pathological and Magnetic Resonance Imaging (MRI) studies have shown that white matter lesions cause axonal loss in the Normal Appearing White Matter (NAWM) but the role that focal gray matter demyelination plays in determining NAWM or NAGM pathology has not been systematically explored yet, due to the difficulties in detecting cortical demyelination using conventional MR imaging. Magnetisation Transfer Ratio (MTR) at ultra-high field benefits from increased signal to noise ratio and increased sensitivity to MT, which makes it possible to study small variations across both WM and GM.


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Poster Session 2, 21(S11) Objectives: To explore the relationship between focal GM/WM lesions and NAWM/NAGM in patients with MS, using ultra-high resolution MT imaging. Method: 40 MS patients (16 males/24 females; all major subtypes; age= 46±10 years; EDSS= 3.5±2.4; disease duration= 6.3±5.7 years) and 10 age-matched controls were scanned on a Philips 7T platform. For each participant we acquired high-resolution, 0.63 mm3, PSIR and MTR images, on which GM and WM lesions were manually segmented by 2 trained operators. We estimated tissue maps using SPM8 and calculated the mean MTR ratios for NAWM or NAGM as a function of the distance to the nearest GM or WM lesion. The ratios were obtained by normalising the MTR value at each voxel by the average MTR value across the corresponding normal appearing tissue. When considering NAWM, we computed a fibre tract-weighted mean rather than an arithmetic mean using the JHU tractography atlas, to model the influence of fibres. In order to distinguish between natural spatial variations in MTR and those induced by the presence of lesions, we repeated the above analysis by substituting control scans for the patient ones. Results: In agreement with the literature, we found that NAWM MTR was significantly reduced in the vicinity of WM lesions with respect to controls, up to 10mm away from the closest lesions. We found a similar effect of cortical lesions on both NAGM and NAWM but at shorter range (up to 3mm). Discussion: GM lesions appear to cause much less prominent long distance tissue damage in the NAWM and NAGM compared to WM lesions as detected with MTR. This is probably due to the arborisation of cortical neurons and the much simpler pathways of white matter tracts. It might also be that GM lesions cause neuronal dysfunction rather than tissue loss. Functional studies might be most appropriate to assess the role of GM lesions in clinical disability. Disclosure Alain Pitiot: nothing to disclose. Rasha Abdel Fahim: nothing to disclose. Olivier Mougin: nothing to disclose. Paul Morgan: nothing to disclose. Penny Gowland: nothing to disclose. Nikos Evangelou: nothing to disclose. P964 Regional grey matter atrophy in multiple sclerosis: a meta-analysis of voxel-based morphometry studies using a novel coordinate-based method C.R. Tench, R. Tanasescu, C.S. Constantinescu University of Nottingham, Nottingham, United Kingdom Background: Structural neuroimaging studies using whole-brain voxel-based morphometry (VBM) have provided inconsistent reports on the regional distribution of grey matter (GM) atrophy in multiple sclerosis (MS). To identify the commonalities, coordinate based meta-analysis has been performed. However, previous meta-analyses of VBM studies use techniques with methodological issues and may have overestimated the number of consistent regions of brain atrophy in MS. Objective: To perform an updated coordinate based meta-analysis of regional GM volume loss in MS utilising a novel method that reduces the false positive results.

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Methods: 27 studies reporting whole-brain voxel-wise comparisons of GM volume between MS subtypes and controls (1087 patients and 546 HC; 22 relapsing remitting (RR) MS and clinically isolated syndrome (CIS) and 5 progressive MS studies) were identified from medical databases or other sources. Meta-analysis was performed using LocalAle[1,2] software. Mann-Whitney U-test was used to assess the association between regional GM atrophy and the degree of functional disability (EDSS). Results: Significant clusters of regional GM volume loss in RR MS and CIS patients involved the thalamus bilaterally and left precentral gyrus. Median EDSS was not different in studies that reported GM loss at these sites compared to studies that did not. No consistent significant cluster of GM volumetric reduction in progressive MS patients was identified. Conclusions: Using a coordinate-based approach with a proper control of false positives we show thalamus and precentral gyrus as the most consistent sites of localized GM atrophy in RR MS and CIS. Thalamus has extensive reciprocal cortical and subcortical connections which make it vulnerable to effects from pathology in widespread areas. [1] Coordinate Based Meta-Analysis of Functional Neuroimaging Data; False Discovery Control and Diagnostics. Plos one. 2013. Coordinate Based Meta-Analysis of Functional [2] Neuroimaging Data Using Activation Likelihood Estimation; Full Width Half Max and Group Comparisons. Plos one. 2014. Disclosure Christopher Tench: nothing to disclose Radu Tanasescu: nothing to disclose Cris Constantinescu: nothing to disclose P965 Neurite orientation dispersion and density imaging (NODDI) at ultra high gradient strength reveals axon pathology in multiple sclerosis J.D. Bireley1, S.Y. Huang1, S. Tobyne1, V. Smith1, D. Boratyn1, A. Nummenmaa2, T. Witzel2, L.L. Wald2, E.C. Klawiter1 1Neurology, 2Massachusetts General Hospital, Charlestown, MA, United States Background: Axonal damage is considered a primary contributor to clinical disability in relapsing-remitting multiple sclerosis (RRMS). Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion imaging technique that provides information about axon density (neurite density index, NDI) and angular variation of axon orientation (orientation dispersion index, ODI). Utilizing ultra-high gradient strength diffusion imaging has the potential to improve tissue microstructure characterization. Objective: To investigate with NODDI the microstructural changes that occur in normal appearing white matter (NAWM) and lesioned white matter in RRMS patients compared to healthy control white matter (HCWM) using a three-shell q-ball sequence at ultra-high gradient strength. Methods: Twenty-nine RRMS subjects (mean age 40±10yrs) and 50 HCs (mean age 31±8yrs) were scanned using a CONNECTOM


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3T MRI scanner capable of a max gradient strength of 300 mT/m. Diffusion images were acquired using a multishell q-ball sequence (b-values=1k/5k/10k s/mm2; 64/128/128 directions; 1.5mm isotropic voxels; whole brain coverage). MS subjects had a median Expanded Disability Status Scale (EDSS) of 2.0 (range 1.0-6.5). FreeSurfer’s automated segmentation was used to generate WM masks for each subject. NAWM and lesioned tissue were manually segmented using FLAIR images in MS subjects. Voxel-wise NDI, ODI, and isotropic volume fraction (isoVF) metrics were calculated within each mask in each subject. An independent samples t-test was used to compare mean ODI, NDI, and isoVF values between lesioned WM, NAWM, and HCWM. Kendall’s tau-b was used to correlate diffusion outcomes with EDSS. Results: NDI in MS lesioned WM was significantly lower than in HCWM (0.535±0.059 vs. 0.644±0.027, p< 0.001) with a trend toward decrease in NAWM (0.631±0.039, p=0.09). ODI in MS NAWM was significantly higher than in HCWM (0.364±0.013 vs. 0.349±0.011, p< 0.001) but no significant difference was seen in ODI in MS lesioned WM compared to HCWM (0.349±0.036, p=0.9). isoVF in MS lesioned WM was significantly higher than in HCWM (0.164±0.058 vs. 0.073±0.016, p< 0.001). Lesion NDI trended towards a significant correlation with EDSS (tau=-0.24, p=0.09). Conclusions: Three-shell NODDI collected at ultra-high gradient strength is capable of characterizing axon pathology in MS in vivo. Decreased axonal density was appreciated in white matter lesions and may contribute to worsened disability in MS. Disclosure The study was supported by the National Institutes of Health (K23 NS078044-04, ECK) and the National Multiple Sclerosis Society (PP1853, ECK). JB, SYH, ST, VS, DB, AN, TW, and LW have nothing to disclose. ECK has received consulting fess from Biogen Idec and Mallinckrodt Pharmaceuticals. ECK has received research funding from Roche and Atlas5d. P966 Spinal cord lesions and relationship to spinal cord atrophy and disability in multiple sclerosis N. Seraji-Bozorgzad, F. Bao, S. Sriwastava, E. Bernitsas, C. Santiago, J. Chorostecki, A. Piassecki, C. Caon, I. Zak, K. Omar Wayne State University School of Medicine, Detroit, MI, United States Objective: To examine the relationship between spinal cord atrophy, spinal cord lesions, and disability across phenotypes in MS. Background: Studies have shown spinal cord atrophy to predict disability across clinical phenotypes in MS. However, few studies have investigated the relationship between spinal cord lesions and spinal cord atrophy or disability across phenotypes. Methods: We performed a study to examine cervical cord volume and lesions in patients with relapsing-remitting (RRMS) and progressive MS (SPMS and PPMS). Cervical cord cross-sectional area at C2 level (CSA-C2) was measured using Losseff’s semiautomated technique. The number of cervical cord T2 lesions (CCTL) were classified as 0, 1, 2, or ⩾ 3 lesions.

Results: 150 MS patients (93 RRMS, 57 progressive), mean age 41.3 years, EDSS 3.8, disease duration 11.2 years, mean CSA-C2 80.2 mm2 were included. Correlation between EDSS and CSA was -0.75 (p< 0.0001), between EDSS and CCTL 0.64 (p< 0.0001), and between CCTL and CSA was -0.53 (p< 0.0001). Sub-analysis showed 61% of RRMS vs 91% of progressive MS with at least 1 cord lesion. (p< 0.0001). Mean CSA-C2 in the RRMS cohort was 87.3 mm2 and 68.6 mm2 in the progressive cohort (p< 0.0001), mean CCTL was 0.7 vs 1.9 in the RRMS and progressive cohorts (p< 0.0001). In the RRMS cohort, correlation between EDSS and CSA was -0.36 (p=0.0004), between EDSS and CCTL 0.18 (p=0.07). In the progressive cohort, correlation between EDSS and CSA was -0.39 (p=0.002), between EDSS and CCTL 0.42 (p=0.001). Regression analysis showed that both CSA-C2 and CCTL predicted the severity of clinical disability as measured by EDSS. Conclusions: Cervical cord atrophy and lesions predict the severity of clinical disability across phenotypes. The number of spinal cord lesions correlated with spinal cord atrophy. Progressive MS has significantly greater cord atrophy and lesions compared to RRMS. This may serve as a potential biomarker in longitudinal therapeutic studies in progressive MS. Disclosure Navid Seraji-Bozorgzad: nothing to disclose Fen Bao: nothing to disclose Shitiz Sriwastava: nothing to disclose Evanthia Bernitsas: nothing to disclose Carla Santiago: nothing to disclose Jessica Chorostecki: nothing to disclose Anna Piassecki: nothing to disclose Christina Caon: nothing to disclose Omar Khan: nothing to disclose P967 Intra- and interscanner variability of magnetic resonance imaging based volumetry in multiple sclerosis V. Biberacher1, P. Schmidt1,2, C.C. Boucard1, R. Righart1, P. Sämann3, D. Fröbel4, C. Zimmer4, B. Hemmer1, M. Mühlau1 1Neurology, Technische Universität München, 2Statistics, LMU München, 3Neuroimaging Core Unit, Max Planck Institute of Psychiatry, 4Neuroradiology, Technische Universität München, München, Germany Brain morphometric measurements in multiple sclerosis (MS) reflect not only disease-related processes but also physiological and scanner-related variability. The latter two have to be considered especially in longitudinal and multicenter studies. Of note, there is evidence that these changes fluctuate over several days so that simple repositioning experiments may underestimate their effect size. One patient with stable relapsing remitting MS was scanned (T1-weighted and FLAIR, 3D) 18 times over 3 weeks at 3 different 3 Tesla magnetic resonance scanners (Philips Achieva; Siemens Verio; GE Signa MR750). T2-hyperintense lesion volumes (T2L) were assessed by an automated lesion segmentation tool. Volumes of grey matter (GM), white matter (WM)


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Poster Session 2, 21(S11) and cerebrospinal fluid (CSF) were determined by voxel based morphometry (VBM) from the lesion-filled T1-weighted images. Brain volume (WM and GM) changes were quantified by FSLSiena and VBM. Global brain tissue volumes (ml) and their intrascanner variability differed between the scanners (mean and coefficient of variation (CV) for GM: GE 541.49, 0.85%; Philips 543.16, 1.73%; Siemens 526.41, 1.52%; WM: GE 396.9, 0.81%; Philips 377.93, 0.25%; Siemens 404.22, 0.29%; CSF: GE 201.45, 1.92%; Philips 281.83, 1.58%; Siemens 237.07, 0.63%; brain: GE 938.38, 0.38%; Philips 921.09, 1.06%; Siemens 930.63, 0.92%). Similarly, T2L (in ml) differed across scanners in terms of mean and CV: GE 8.93, 1.8%; Philips 7.59, 3.5%; Siemens 4.80, 3.0%. The percentage brain volume change (PBVC) between two scans (derived from all possible pairs of scans of 1 scanner) was similar when assessed by SIENA or VBM, but pretended (false positive) brain volume changes, partially contrasting between scanners (mean difference ± standard deviation SIENA/VBM: GE, -0.2% ± 0.13 / -0.2% ± 0.52; Philips: 0.41% ± 0.46 / 0.3% ± 1.55; Siemens: 0.28% ± 1.23 / 0.75% ± 1.12). In conclusion, the effect of different scanners needs to be taken into account in multicentre studies. For longitudinal analysis, mixed effects models, accounting for subject specific variation should be used and the effect size should exceed the false positive results obtained in this study. Assuming a physiological loss of brain grey matter of 0.3% per year (Good et al. NeuroImage 14:21-36), which may double in MS (De Stefano et al. Neurology 74:1868-76), reliable estimation of brain atrophy in individual patients seems only possible over periods of several years. Disclosure Viola Biberacher received research support from Merck Serono. Paul Schmidt has nothing to disclose. Christine Claudia Boucard has nothing to disclose. Ruthger Righart has received research support from the Hertie Foundation (Grand number P1140092). Philipp Sämann has nothing to disclose. Daniel Fröbel has nothing to disclose. Claus Zimmer has nothing to disclose. Bernhard Hemmer has served on scientific advisory boards for Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GSK, Chugai Pharmaceuticals, Micromet, Genentech and Genzyme Corporation; serves on the international advisory board of Archives of Neurology and Experimental Neurology; has received speaker honoraria from Bayer Schering, Novartis, Biogen Idec, Merck Serono, Roche, and Teva Pharmaceutical Industries Ltd; and has received research support from Biogen Idec, Bayer Schering, Merck Serono, Five prime, Metanomics, Chugai Pharmaceuticals and Novartis. He has been filed a patent for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and genetic determinants of neutralizing antibodies to interferon-beta. Mark Mühlau has received research support from Merck Serono and Novartis; he has received travel expenses for attending meetings from Bayer, and Merck Serono; he has received honoraria for lecturing from Merck Serono; he has received Investigator fees for a Phase III clinical study from Biogen Idec.

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P968 Energy dysregulation and neuro-axonal dysfunction in MS measured in-vivo with diffusion-weighed spectroscopy B. Bodini1,2,3, F. Branzoli1,4, E. Poirion1, D. Garcia-Lorenzo1,4, E. Maillart5, J. Socha1, G. Bera5, I. Ronen6, C. Lubetzki1,5, S. Lehéricy1,4, B. Stankoff1,3,7 1UPMC Univ Paris 06, UMR S 1127, CNRS UMR 7225 and ICM, Sorbonne Universités, Paris, France, 2Department of Neuroimaging, Institute of Psychiatry, King’s College London, London, United Kingdom, 3Service Hospitalier Frédéric Joliot, Institut d’Imagerie Biomédicale, I2BM, CEA, Orsay, 4Centre de Neuroimagerie de Recherche, CENIR, Institut du Cerveau et de la Moëlle Epinière, 5APHP, Hôpital de la Salpêtrière, Paris, France, 6C. J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands, 7APHP, Hôpital Saint-Antoine, Paris, France Background: Diffusion-weighted spectroscopy (DWS) is a recently implemented technique that allows to measure the diffusion properties of intracellular metabolites such as total N-acetylaspartate (NAA), a specific neuro-axonal marker, and total Creatine (Cr), which reflects the energy metabolism status in neural and glial cells. In this study we employed DWS to explore the concentration as well as the diffusion properties of NAA and Cr in the white and deep grey matter of patients with MS. Methods: Twenty-five MS patients (17 relapsing and 8 progressive) underwent a clinical and neuropsychological assessment which included Expanded Disability Status Scale (EDSS), Timedwalked test (TWT), Symbol Digit Modalities Test (SDMT), and a verbal fluency test (VF). On a 3T scanner, we collected conventional imaging from patients and from a group of 20 age- and gender-matched healthy controls (HC), and we implemented a cardiac-gated PRESS sequence equipped with diffusion gradients to extract the concentration and apparent diffusion coefficient of NAA and Cr from the normal-appearing white matter (NAWM) of the corona radiate and the thalami of all subjects. DWS-derived data were compared between patients and HC with multiple linear regressions, that were also employed to correlate metabolite diffusivities with clinical and cognitive scores in patients. Results: In the corona radiata, NAA concentration was reduced in patients compared with HC (p=0.001). While Cr concentration did not significantly change between groups, there was a reduction in Cr diffusivity in patients (p=0.022). In the thalamus, both concentration and diffusivity of NAA and Cr were lower in patients compared with HC (p=0.006 and p=0.06 for NAA and p=0,01 and p=0.03 for Cr). In the WM, Cr diffusivity correlated with VF (p=0.005). In the thalami, NAA diffusivity correlated with EDSS (p=0.01), TWT (p=0.04), VF (p=0.02) and SDMT (p=0.03), and Cr diffusivity was associated with TWT (p=0.03). Conclusions: DWS is feasible at 3T in both the NAWM and the deep grey matter of patients with MS, and allows to simultaneously capture the concentration and the diffusivity properties of intracellular metabolites. Decreased Cr and NAA diffusivity in patients may indicate an ongoing functional, and potentially reversible component of energy dysregulation and neuroaxonal injury. This might precede a subsequent decrease in Cr and NAA concentration, which in turn may reflect irreversible tissue damage.


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Disclosure This study was funded by ANR MNP2008-007125, PHRC 2010AOM 10 207, and program “Investissements d’avenir” ANR-10-IAIHU-06.B. Bodini is funded by the ECTRIMS Post Doctoral Research followship. F. Branzoli: nothing to disclose. E. Poirion: nothing to disclose. D. Garcia-Lorenzo: nothing to disclose. E. Maillart: nothing to disclose. J. Socha: nothing to disclose. G. Bera: nothing to disclose. C. Lubetzki participates in therapeutic trials in multiple sclerosis with Biogen, Novartis, Genzyme, Roche, to advisory boards of Biogen, Novartis, Gennzyme, Roche and Vertex, and has an ongoing scientific collaboration with Vertex. S. Lehéricy: nothing to disclose. B. Stankoff reports receiving consulting and lecture fees from Biogen, Novartis, Merck Serono, Sanofi-Aventis, Teva and research support from Sanofi-Aventis-Genzyme and Merck Serono. P969 Demonstration of hypometabolic cortical areas in clinically isolated syndromes: a 3T 18F-FDG PET/MRI study D. Cecchin1, D. Poggiali2, A. Favaretto2, A. Lazzarotto2, M. Margoni2, A. Riccardi2, F. Bui1, P. Gallo2 1Department of Medicine-DIMED- University Hospital of Padova, 2The Multiple Sclerosis Centre -Veneto Region (CeSMuV), Department of Neurosciences, University of Padova, Padova, Italy Background: The cortex is severely damaged in multiple sclerosis (MS). Cortical atrophy can be demonstrated in some patients at clinical onset and its progression associates with physical and cognitive disability. Once established, atrophy is irreversible. Whether a cortical metabolic dysfunction may precede atrophy and can be demonstrated in very early disease phases has not been investigated yet. Objectives: To identify metabolic abnormalities in the cortex of patients with clinically isolated syndrome suggestive of MS (CIS) and analyse their association with a decreased cortical thickness by means of a fully integrated Positron Emission Tomography/ Magnetic Resonance Imaging (PET/MRI) system. Methods: Ten cognitively normal CIS and 10 relapsing remitting MS (RRMS) with evidence of cognitive impairment were enrolled in the study. 3T 18F-FDG-PET/MRI (Siemens Biograph mMR PET System) images were obtained from all patients. Image-derived Input Function (IDIF) was obtained with a new methodology using PMOD 3.6 software: the tracer was injected while acquiring PET dynamic images of the thoracic aorta for 10 minutes and, after resting for 40 minutes out of the scanner, for 5 minutes on the same region. Then, early and late data were interpolated to obtain a complete IDIF and fitted using Patlak plot to PET brain curves obtained by segmentation on simultaneously acquired 3D-T1 images. The so obtained absolute metabolic rate of glucose is an accurate way of describing cortical kinetics. Regional cortical thickness was obtained from a data sets of

anatomical 3D-T1 by Freesurfer suite and compared to that of 10 age-matched healthy controls. Results: In both CIS and RRMS, areas of cortical hypometabolism were found in the frontal and parietal lobes and in the insula of both emispheres, and in left temporal lobe. In CIS patients no correlation was observed between hypometabolism and reduced cortical thickness (R=0.003, p=0.6). A slight trend of correlation, that however did not reach the significance due to the low number of patients, was observed between hypometabolic and atrophic areas in RRMS. Discussion: Areas of hypometabolism could be demonstrated in morphologically normal (non atrophic) cortex of CIS and RRMS. This suggests that a metabolic dysfunction may precede the irreversible structural damage of the cortex in MS. The identification of these areas in a very early disease phases may have important pathological and clinical (therapeutic) consequences. Disclosure Dr. Diego Cecchin has nothing to disclose. Dr. Davide Poggiali has nothing to disclose Dr. Alice Favaretto has received honoraria from Novartis, Teva and Almirall. Dr. Andrea Lazzarotto has nothing to disclose. Dr. Monica Margoni has nothing to disclose. Dr. Alice Riccardi has received honoraria from Merck serono, Novartis and Biogen Idec. Dr. Franco Bui has nothing to disclose. Prof. Paolo Gallo has received honoraria from Bayer Schering, Biogen Idec/Elan, Merck Serono, Novartis, Sanofi-Aventis and Teva; has been a consultant for Bayer Schering, Biogen Idec, Genzyme, Merck Serono and Novartis; has received research support from Bayer, Biogen Idec/Elan, Merk Serono, Genzyme and Teva; and has received research grant from the University of Padova, Veneto Region of Italy, the Italian Association for Multiple Sclerosis, the Italian Ministry of Public Health. P970 Hippocampal inflammation and depression in multiple sclerosis: integrating evidence from TSPO PET and resting state fMRI A. Colasanti1,2, Q. Guo3, P. Giannetti1, M. Wall3, R.D. Newbould3, C. Bishop3, M. Onega3, R. Nicholas4, O. Ciccarelli5, P. Muraro1, O. Malik4, D. Owen1, A.H. Young2, R. Gunn3, P. Piccini1, P.M. Matthews1, E.A. Rabiner3 1Imperial College London, Division of Brain Sciences, 2Institute of Psychiatry, Psychology & Neuroscience; King’s College London, 3Imanova Ltd, 4Imperial College Healthcare NHS Trust, 5Department of Neuroinflammation, UCL Institute of Neurology, London, United Kingdom Depression is highly prevalent in patients with multiple sclerosis (MS) and is associated more generally with elevated inflammatory markers, suggesting common pathophysiological mechanisms. The hippocampus is implicated in the pathophysiology of depression and is susceptible to neuroinflammation in MS. We hypothesise that the high prevalence of depression in MS is a consequence of the chronic immune activation in the hippocampus.


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Poster Session 2, 21(S11) We characterized the relationship between depressive symptoms and hippocampal microglial activation in MS patients using the 2nd generation TSPO radioligand [18F]-PBR111. To evaluate pathophysiological mechanisms, we explored the relationships between hippocampal inflammation, depressive symptoms and hippocampal functional connectivity as defined by resting state fMRI. 11 patients with multiple sclerosis and 22 healthy controls were administered the Beck’s Depression Inventory (BDI) and were genotyped for the SNP rs6971 of the TSPO gene, prior to PET and fMRI scanning. The Distribution Volume Ratio (DVR) of [18F]-PBR111 in the hippocampus was estimated as an index of activated microglia density. For the analysis of functional connectivity, the hippocampus was used as the seed region. We compared [18F]-PBR111 uptake in the hippocampus of MS patients relative to healthy controls and examined the correlations between [18F]-PBR111 uptake, BDI scores, and hippocampal functional connectivities in patients with MS. [18F]-PBR111 DVR was higher in the hippocampus of MS patients relative to healthy controls (F=5.73; p=0.024) and in MS patients the hippocampal DVR was correlated with the intensity of depressive symptoms (r=0.86, p=0.006). The strength of hippocampal functional connectivity to prefrontal regions, including the subgenual cingulate, and parietal regions, such as posterior cingulate and precuneus, correlated with both depressive symptoms and [18F]-PBR111 DVR (p< 0.05 or z=2.3; cluster-corrected for multiple comparisons). Our results provide evidence that hippocampal microglial activation in MS impairs the brain functional connectivities in regions contributing to maintenance of a normal affective state. They suggest a rationale for the responsiveness of depression in some people with MS to effective control of brain inflammation. Disclosure GSK contributed PET scanning time and operational support for the study. A. Colasanti was supported by a GSK/Wellcome Trust fellowship. R. Nicholas received honoraria or funding from Bayer, Biogen, Genzyme, Merck Serono, Novartis, Roche, Teva. O. Ciccarelli receives grant support from the Multiple Sclerosis Society of Great Britain and Northern Ireland, the Department of Health Comprehensive Biomedical Centre, the ISCRT and the EPSRC; she serves as a consultant for Novartis, Biogen and GE and payments are made to UCL Institute of Neurology. P.A. Muraro declares honoraria for speaking and travel support from Merck Serono, Biogen, Bayer, and Novartis. O. Malik received honoraria from Biogen, Scheering, Teva and Novartis for lectures and advisory panels and received travel grants for conferences from Biogen and Novartis. A.H. Young declares paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders, and no share holdings in pharmaceutical companies. R. Gunn is a consultant for GSK, Abbvie, UCB and ITI. P. Piccini has received ád hoc’ consultancies from TEVA, Michael J Fox Foundation (US), CHDI (US), Parkinson UK, Network European CNS Transplantation and Restoration (NECTAR), Evaluation Committee of PRTS of the French National Research Agency, Canada Research Chairs Program, France Parkinson «Grand Appel d’Offres». All honoraria paid for these consultancies goes to Imperial College London.

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P.M. Matthews holds stock in GSK, has received research funds from Biogen and GSK, and consultancy/speaker fees from IXICO, GSK, Biogen, Novartis and Adelphi Communications. All honoraria paid for these consultancies goes to Imperial College London. E.A. Rabiner holds stock in GSK, and consultancy/speaker fees from Lightlake Therapeutics, Gedeon Richter, AbbVie, BioTie. Q. Guo, P. Giannetti, M. Wall, R.D. Newbould, C. Bishop, M. Onega, D. Owen, have nothing to disclose. P971 Value of cortical and corpus callosum lesions in the diagnosis of MS: inter-rater reliability first G. Arrambide1, M. Tintoré1, J.F. Corral2, J. Sastre-Garriga1, J. Castilló1, J. Río1, À. Vidal-Jordana1, I. Galán1, C. Nos1, B. Rodríguez1, L. Midaglia1, M. Comabella1, E. Huerga2, C. Auger2, X. Montalban1, Á. Rovira2 1Multiple Sclerosis Centre of Catalonia/Neuroimmunology Department, 2MRI Unit, Radiology Department, Vall d’Hebron University Hospital & VHIR, Barcelona, Spain Background: Intracortical lesions (ICL) on double inversion recovery (DIR) have been proposed as part of the diagnostic criteria for multiple sclerosis (MS). However, there is great inter-rater variability, mainly in the case of pure ICL. Additionally, MS lesions of the corpus callosum (CC) are common; however, previous attempts to assess their diagnostic value were hindered by unavailability of sagittal planes and T2-fluid-attenuated inversion recovery (FLAIR) sequences. Goals: To assess the inter-rater reliability (IRR) in identifying ICL, cortico-juxtacortical lesions (JCL), and CC lesions (CCL) through conventional or non-conventional magnetic resonance imaging (MRI) sequences. Methods: From an ongoing clinically isolated syndrome (CIS) cohort, patients with an abnormal brain MRI at 3.0 Tesla performed within 3-5 months of the CIS, and with availability of the following sequences were included: transverse PD/T2-weighted fast spin echo, sagittal and transverse T2-weighted FLAIR, transverse unenhanced and contrast-enhanced T1-weighted spin echo, 3D sagittal T1-weighted magnetization-prepared and rapid gradient-echo (MP RAGE), and transverse DIR. After a training phase, two raters independently assessed the supratentorial presence of pure ICL and juxtacortical lesions (JCL) on transverse DIR, and of combined ICL and CJL (CJCL) on transverse T2-FLAIR and DIR; if needed, PD/T2 or phase sensitive inversion recovery (PSIR, obtained from 2012) sequences could be used as references. The presence and callosal-septal location of CCL were assessed using the T2-FLAIR sagittal sequences. Each sequence was evaluated at a different time point in each patient to avoid bias. The IRR was calculated using Cohen´s kappa for nominal variables and two coders. IRR agreement was assessed as follows: 0.0-0.2 = slight, 0.21-0.4 = fair, 0.41-0.6 = moderate, 0.61-0.8 = substantial, 0.81-1.0 = almost perfect/perfect. Results: Sixty-four patients were identified. Of these, CCL were assessed by both raters in 56 cases; ICL, JCL, and CJCL on DIR sequences in 52; and CJCL on T2-FLAIR sequences in 62. IRR was 0.477 for ICL, 0.430 for JCL, 0.730 for CJCL on DIR, 0.838 for CJCL on T2-FLAIR, 0.857 for CCL, and 0.821 for callosalseptal lesions.


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Conclusions: We confirm that IRR of ICL on DIR is moderate whereas the IRR of CCL and CJCL on T2-FLAIR is highly reliable. These results suggest conventional MRI techniques may suffice to assess a combined parameter integrating ICL and JCL. Disclosure G Arrambide has received compensation for consulting services from Biogen. M Tintoré compensation for consulting services and speaking honoraria from Bayer, Merck-Serono, Biogen, Teva, Sanofi, and Novartis. J Sastre-Garriga compensation for consulting services or speaking honoraria from Merck-Serono, Biogen, Teva, Almirall and Novartis. J Río speaking honoraria and personal compensation for participating on Advisory Boards from: Almirall; Bayer; Biogen; Genzyme; Merck-Serono; Novartis; Teva and Sanofi. M Comabella compensation for consulting services and speaking honoraria from Bayer, Merk Serono, Biogen, Teva, Sanofi, and Novartis. X Montalban speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi, Teva and Almirall. A Rovira serves on scientific advisory boards for NeuroTEC and on the editorial board of the American Journal of Neuroradiology and Neuroradiology, has received speaker honoraria from Bayer, Sanofi, Bracco, Merck Serono, Teva and Biogen, receives research support from Bayer, and serves as a consultant for Novartis. JF Corral, J Castilló, A Vidal-Jordana, I Galán, C Nos, B Rodríguez, L Midaglia, E Huerga, C Auger report no conflict of interest related to this work. P972 Spinal cord microstructural alterations and grey matter atrophy in RMS E. Datta, R. Schlaeger, N. Papinutto, A. Castellano, V. Panara, A. Zhu, K. Jordan, C. Bevan, J. Gelfand, D. Goodin, J. Graves, A. Green, H.-C. Von Buedingen, E. Waubant, B.A.C. Cree, S.L. Hauser, R.G. Henry UCSF, San Francisco, CA, United States Background: The spinal cord plays a large role in multiple sclerosis (MS) and may be responsible for much of motor disability of patients. Historically MS spinal cord studies were limited due to poor contrast and low spatial resolution. However, phase-sensitive inversion recovery (PSIR) MRI efficiently (obtained from a single section in less than 2 minutes) provides high quality images of the spinal cord1. PSIR images allow for precise grey matter segmentation in the cord which provides the strongest MRI correlate of EDSS2,3. Histopathological studies have shown that MRI intensity variations correlate with demyelination and axonal loss4 and have been shown to correlate with EDSS5. Methods: PSIR images were acquired from 92 relapsing MS (RMS) and 37 progressive MS patients (PMS). For each image, cord and grey matter masks were generated. The areas and mean

intensity gradients were calculated for these regions. Univariate Spearman correlations were computed between EDSS and these metrics. Additionally, grey matter area, cord gradient, age, disease duration, and sex were used in a multivariate model for EDSS. Results: A quadratic behavior for the cord gradient metrics was found indicating an upward trend in RMS patients with lower EDSS and a downward trend in PMS patients with higher EDSS. To capture these trends, the data was separated by disease type. No significant correlations were found in PMS patients. However, strong correlations were found in RMS patients for both cord gradient (rho=.48, p< .0001) and grey matter area (rho=.38, p=.0002) with EDSS score. The results from the multivariate model showed that the mean gradient (standard beta=.31, p=.004) and grey matter area (standard beta=-.25, p=.026) were independently associated with EDSS in RMS; age, gender, and disease duration were not significant. Conclusions: These results suggest that cord gradient provides a complementary correlate of EDSS in RMS patients and may be an early indicator of microdamage in the spinal cord that precedes grey matter loss. Cord gradient is easily applicable in a clinical setting, as it does not require segmentation. 1. Papinutto, N., et al. Journal of Magnetic Resonance Imaging. 2014. 2. Schlaeger, R., et al. Annals of Neurology. 2014. 3. Schlaeger, R., et al. JAMA Neurology. 2015. 4. Zhang, Y., et al. Annals of Neurology 2013. Mathias, J. M., P. S. Tofts, N. A. Losseff. Magnetic 5. Resonance in Medicine. 1999. Disclosure ED, NP, AC, VP, AZ, KJ, CB, JGe, DG, JGr, EW: nothing to disclose RS has received grants from the Swiss MS Society and the Gottfried and Julia Bangerter-Rhyner Foundation, Switzerland. Her institution (University Hospital Basel) has received advisory board fees from Biogen, which were exclusively used for research support. AG reports personal fees from Inception Sciences and Mylan, Pharmaceuticals and grants/awards from the National Multiple Sclerosis Society, Novartis, UCSF CTSI, and That Man May See as well as philanthropic support from the Rachelff Family and the Robert Dale Family. He also reported serving on an end point adjudication committees for Biogen and Medimmune. He serves on trial steering committees for Novartis and Scientific Advisory Board for Bionure. HCvB has received research support from Roche, Genentech, and Pfizer, and personal compensation for consulting from Roche and Novartis. BACC has received personal compensation for consulting from Abbvie, Biogen Idec, EMD Serono, MedImmune, Novartis, Genzyme/sanofi aventis, Teva and has received contracted research support (including clinical trials) from Acorda, Biogen Idec, EMD Serono, Hoffman La Roche, MedImmune, Novartis and Teva. SLH currently serves on the SAB of Symbiotix, Annexon, and Bionure. RGH has received grants from Stem Cells Inc, and Roche, outside the submitted work.


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Poster Session 2, 21(S11) P973 Deep gray matter segmentation from 1.5T vs. 3T MRI in normal controls and patients with multiple sclerosis R. Chu1, S. Hurwitz2, S. Tauhid1, R. Bakshi1 1Brigham & Women’s Hospital, Partners MS Center, Harvard Medical School, 2Brigham and Women’s Hospital / Harvard Medical School, Boston, MA, United States Background: The cerebral subcortical deep gray matter nuclei (DGM) are a common and clinically-relevant site of atrophy in the early stages of multiple sclerosis (MS). Efficient and reliable segmentation of these structures has proved difficult with existing MRI acquisitions and processing pipelines. The availability of such a tool could prove useful in the evaluation of putative neuroprotective MS therapies. Objective: To evaluate the sensitivity and reliability of DGM volumes obtained from 1.5T vs. 3T MRI scans in normal controls (NCs) and patients with MS. Methods: Fourteen patients with MS [age (mean, range) 50.2 (32.0-60.8) years, 3 men, 10 (71%) relapsing-remitting, Expanded Disability Status Scale score 3.1 (0-6), timed 25 foot walk 6.16 (3.5-13 seconds)] and 15 NC [age 37.7 (24.8-51.6), six men] underwent 1.5T (GE Signa, voxel size: 0.94x0.94x1.2 mm) and 3T (Siemens Skyra, 1x1x1 mm) scans and rescans on the same day using 3D T1-weighted gradient-echo sequences. DGM (caudate, thalamus, globus pallidus, and putamen) volumes were obtained by the fully automated segmentation pipeline in the FMRIB Integrated Registration and Segmentation Tool. Statistical analyses included t-tests, rank tests, and intraclass correlation coefficients (ICCs) with 95% confidence intervals (CIs). Results: 3T showed slightly better differentiation (caudate: p=0.04; thalamus: p=0.015; globus pallidus: p=0.0006; putamen: p=0.002) than 1.5T (caudate: p=0.04; thalamus: p=0.06; globus pallidus: p=0.003; putamen: p=0.02) for detecting DGM atrophy in MS vs. NC. Across all subjects, scan-rescan reliability was generally very high for both methods. However, 3T generally showed somewhat higher reliabilities [ICC (95% CI): caudate: 0.98 (0.95, 0.99); thalamus: 0.99 (0.98, 0.99); globus pallidus: 0.99 (0.97, 0.99); putamen: 0.98 (0.96, 0.99)] than 1.5T [caudate: 0.97 (0.94, 0.99); thalamus: 0.98 (0.96, 0.99); globus pallidus: 0.98 (0.95, 0.99); putamen: 0.96 (0.91, 0.98)]. Similar results were seen separately within the MS and NC groups. Conclusions: These results suggest a higher sensitivity and reliability of DGM volumes obtained from 3T vs. 1.5T MRI. Further studies are warranted to assess the role of this 3T pipeline in tracking potential neurotherapeutic effects in MS.

Imaging of the Brain, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom Background: Global brain volume loss, as measured by magnetic resonance imaging (MRI) based methods, has been recently used as a reliable marker of disease outcome in clinical research trials of multiple sclerosis (MS). More difficult is, however, the assessment of gray matter (GM) and white matter (WM) tissue loss, due to the relative large error of most of the segmentation techniques with respect to the relative small changes occurring in these brain compartments. Recently, the use of the jacobian integration has shown to significantly reduce errors of GM volume measurements. Objective: To improve the assessment of GM and WM volume changes in MS patients by using a new mixed segmentation and registration procedure. Methods: The new procedure is based on SIENAX but includes i) a new approach to separate brain from non-brain structures, by using brain masks non-linearly registered on the native T1-weighted (T1-W) MRI; ii) new image preprocessing, where the intensity histograms of two or more T1-W MRIs of the same subject are linearly changed to minimize the differences between their pure tissue intensity histograms. The new procedure was tested against the traditional SIENAX on: a) a synthetic dataset, which was built from segmented tissue maps of 10 3D T1-W of healthy controls (HC) to obtain images with known GM and WM intensities; b) 182 scan-rescan pairs of real T1-W images, from 132 HC (3D-T1W) and 60 MS patients (19 in group1, with 3D T1-W, 41 in the group2 with 2D T1-W). Furthermore, the GM masks obtained on HC scan-rescans with the new procedure and the traditional SIENAX were used to assess errors in GM volume measures when a Jacobian integration was added to both processes. Errors were expressed as absolute percentage differences (apd). Results: The new procedure greatly reduced the error of GM and WM volume measurements both on synthetic and scanrescan real data. GM-apd was significantly (p< 0.001) reduced by 77% on synthetic data, 55% on HC data, 73% on group1 data and 54% on group2 data. The reduction of WM-apd was of 54%, 45%, 30% and 45%, respectively (p< 0.05). Finally, using the Jacobian integration, the error was lower with the new procedure than with the traditional SIENAX (0.13± 0.13 vs 0.28±0.36; p< 0.001). Conclusions: This new approach of the SIENAX procedure for tissue class analysis of longitudinal data greatly reduces the measurement errors. It might be very useful for clinical trial analysis of WM and GM volume changes.

Disclosure Dr. Bakshi received consulting fees from AbbVie, Alkermes, Biogen, Novartis, and Questcor and research support from Biogen, Merck-Serono, Novartis, Genzyme and Teva. The other authors have nothing to disclose. P974 Improving measurement errors in the assessment of GM and WM volume changes using a new sienax procedure M. Battaglini1, M. Jenkinson2, N. De Stefano1 1Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy, 2Oxford Centre for Functional Magnetic Resonance

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Disclosure Marco Battaglini: nothing to disclose Mark Jenkinson receives royalties from the licensing of FSL to profit-making entities via ISIS, the University of Oxford’s commercialisation company Nicola De Stefano has received honoraria from Schering, Biogen-Idec, Teva, Novartis, Genzyme, and Merck Serono S.A. for consulting services, speaking and travel support. He serves on advisory boards for Merck Serono S.A. and Novartis. He has received research grant support from the Italian MS Society.


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P975 Gray matter volume changes in patients with multiple sclerosis: contribution of measurements using two independent methods, voxel-basel morphometry and source-based morphometry M. Dufek1, J. Tomčík1, R. Mareček1,2, J. Zelinková1,2, J. Vaníček3, M. Brázdil1,2 1Neurology, Masaryk University, Faculty of Medicine and St. Anne’s University Hospital, Brno, 2Behavioural and Social Neuroscience Research Group, CEITEC - Central European Institute of Technology, Masaryk University, 3Department of Imaging Methods, Masaryk University, Faculty of Medicine and St. Anne’s University Hospital, Brno, Czech Republic Background: Voxel-Based Morphometry (VBM) and SourceBased Morphometry (SBM) can be used to measure gray matter atrophy in patients with multiple sclerosis (MS). The aim of the present study was to localize the most affected areas of the brain and to compare these two methods in measuring of local gray matter volume (GMV) changes. Materials and methods: We used data obtained by 1.5 T high-resolution magnetic resonance images from 88 patients and 76 agematched and gender-matched controls. The images were segmented into the gray matter segments and registered to the common space using software SPM8 and its toolbox DARTEL. The resulting GMV images were subjected to the VBM (mass univariate approach) and SBM (multivariate approach) to find differences in local GMV at the group level. Further, we correlated the measure of atrophy revealed by SBM with clinical data (duration of MS, disability level and disability progression rate means worsening of disability over time). Resuls: VBM disclosed GMV loss in both thalami and in both putamina in patients with multiple sclerosis. No clear differences were recognized in cortical GM volume. SBM analysis found significant effect in 3 of 17 independent components (ICA) for differences between groups. In both-sided thalami, caudates and putamina SBM also found GMV loss in MS patients, but furthermore significant differences have been observed in cortical GM: both-sided parietal lobes and precunei. In addition SBM analysis showed, that MS patients had more GMV than healthy controls in bilateral basal temporal lobes. In MS group GMV loss correlated strongly with disability (measured by Kurtzke scale) in all of 3 ICA components and weakly with disease duration (in 2 of 3 components, but these differences did not survive Bonferroni correction). No correlation was found between GMV loss and disability progression rate. Conclusions: Our results demonstrate that both VBM and SBM are suitable methods for characterisation of the pattern of GMV changes in MS subjects. Multivariate analysis of GMV (SBM) seems to be more sensitive for these changes than previously used mass univariate approach (VBM). Disclosure Michal Dufek: nothing to disclose Jan Tomčík: nothing to disclose Radek Mareček: nothing to disclose Jana Zelinková: nothing to disclose Jiří Vaníček: nothing to disclose Milan Brázdil: nothing to disclose

P976 Anterograde trans-synaptic degeneration after optic neuritis: earlier optic nerve atrophy predicts later optic radiation damage C. Tur1, O. Goodkin1, D.R. Altmann2, T.M. Jenkins1, A. Mirigliani1, C. Fini1, C.A.M. Wheeler-Kingshott1, A.J. Thompson1, O. Ciccarelli1, A.T. Toosy1 1Queen Square MS Centre, University College of London, UCL Institute of Neurology, 2Medical Statistics Department, London School of Hygiene and Tropical Medicine, University of London, London, United Kingdom

Introduction: Optic neuritis (ON) is used as a model to understand mechanisms of damage in multiple sclerosis (MS), such as trans-synaptic degeneration. We assessed longitudinally 1) changes in the diffusion properties of optic radiations (OR) after ON suggesting trans-synaptic degeneration; 2) the predictive value of early optic nerve MRI measures for late OR changes; 3) the impact on visual outcome of both optic nerve and brain post-ON changes. Methods: 28 consecutive ON patients (mean (SD) age: 32.0 (6.5) yrs., 23 females (F)) and 8 controls (30.9 (3.1) yrs., 7F) were assessed visually (logMAR, colour vision, and Sloan 1.25%, 5%, 25%) and by Magnetic Resonance Imaging (MRI), at baseline, 3, 6, and 12 months. MRI sequences performed (and metrics obtained) were: Fluid-attenuated inversion-recovery (optic nerve cross-sectional area [CA]), fast spin-echo (optic nerve lesion length [ONLL]), post-gadolinium (Gd) T1-weighted (Gd-enhanced lesion length [Gd-ONLL]), and diffusion-weighted imaging (fractional anisotropy [FA], radial diffusivity [RD], and axial diffusivity [AD]; both hemispheres were averaged out). Mixed-effects and multivariate structural equation models (SEM) adjusting for age, gender, and optic radiation lesion load identified changes over time and associations between early optic nerve measures and 1-year global OR/clinical measures. SEM allows several dependent variables to be predicted jointly through systems of simultaneous linear equations, thus minimising the rate of false positives (conservative approach). Results: 1) Patients’ OR FA decreased (p=0.018) and RD increased (p=0.002) over the year following ON; OR measures did not change in controls. CA of affected optic nerves decreased and ONLL increased over time (both p< 0.001). 2) Smaller CA of affected optic nerves at 3 months post-ON predicted lower FA and higher RD at 1 year (joint-test p=0.007) in the ORs; none of the inflammatory measures (ONLL, Gd-ONLL) of the optic nerve predicted changes in OR. 3) Longer Gd-LL at baseline predicted worse global visual function (joint-test p=0.034) and was associated with longer ONLL at 1 year (p=0.034). Neither CA of the affected optic nerve after ON nor the damage in OR was associated with 1-year visual outcome. Conclusions: After ON there is progressive damage to the OR, which is greater in patients with residual optic nerve atrophy, even after adjusting for OR lesions, suggesting anterograde trans- synaptic degeneration.


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Poster Session 2, 21(S11) Disclosure CT received a McDonald Fellowship (MSIF, 2007), and an ECTRIMS post-doctoral research fellowship (2015). She received honoraria from Bayer-Schering, Teva, Merck-Serono, Serono Foundation, Biogen, Sanofi-Aventis, Novartis, and Ismar Healthcare. CWK receives research funding from EPSRC, UK MS Society, Horizon2020, Biogen Idec, Novartis, Wings for Life. AJT received honoraria from Novartis, Eisai, Weleda/Society for Clinical Research, Hoffman La Roche, UCB Pharma, Serono Foundation, Sanofi-Aventis, and UK MS Society. He is editor-inchief of Multiple Sclerosis for which he receives an honorarium from Sage Publications. OC receives research grant support from: UK MS Society, Department of Health Comprehensive Biomedical Centre, ISRT, and EPSRC; she serves as a consultant for Novartis, Biogen and GE and payments are made to UCL Institute of Neurology. ATT received speaker honoraria from Biomedia, Serono Symposia International Foundation and Bayer. OG, DRA, TMJ, AM, CF: nothing to disclose. P977 Motor fatigue scores correlate with task-related activity in cerebellum during a non-fatiguing precision grip task O. Svolgaard1, K.W. Andersen1, C. Bauer1,2, P. Iversen1, K. Madsen1, M. Blinkenberg3, F. Sellebjerg3, H.R. Siebner1,2,4 1Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, 2Metropolitan University College, 3Danish Multiple Sclerosis Center, Copenhagen University Hospital Rigshospitalet, Copenhagen, 4Department of Neurology, Copenhagen University Hospital, Bispebjerg, Denmark Background: Fatigue is one of the most disabling symptoms in multiple sclerosis (MS) and there is an urgent need for a better understanding of the mechanisms causing fatigue. This includes identification of fatigue-specific abnormalities in brain activation that can be used to reliably predict the presence and severity of fatigue and fatigability in MS. Method: We enrolled 36 right-handed relapsing-remitting MS patients and 22 age- and sex-matched healthy controls (HC). Subjective fatigue was evaluated with Fatigue Scale for Motor and Cognitive Functions (FSMC). Additional examinations included a neurological examination, Nine-Hole Peg Test and Jebsen-Taylor Hand Function Test. Whole-brain functional magnetic resonance imaging on a 3 T scanner was used to map regional neuronal activity during alternating periods of rest and a nonfatiguing precision grip task which required the subjects to continuously press a force transducer with their right thumb and index finger. The grip force target was indicated by a visual display and corresponded to 15% of maximal grip force. Statistical Parametric Mapping was used to identify brain regions where neural activity during the non-fatiguing grip force task showed a linear relationship with individual fatigue ratings. Clusters were considered significant at a PFWE< 0.05 level. Results: The MS group had a mean age of 35 (25-52) years, a female-male ratio 25:11, mean Expanded Disability Status Scale

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(EDSS) 2.2 (0-3.5) and no major impairment of right upper extremity function. For total, motor and cognitive FSMC, the mean MS group scores were 59, 29 and 30, and the mean HC group scores were 24, 9 and 12, respectively (all p< 0.01). In the MS group, FSMC-motor scores positively correlated with brain activity during the pre-fatiguing hand contractions in a cluster in the left cerebellum, including the declive, culmen and cerebellar tonsil (PFWE = 0.018). Conclusion: Our findings suggest a coupling between the magnitude of cerebellar activity during a non-fatiguing task and the severity of motor fatigue in MS. Disclosure Olivia Svolgaard: funded by the Danish Multiple Sclerosis Society and has received support for congress participation from Biogen Idec. Kasper W. Andersen: funded by a grant from Biogen Idec. Christian Bauer: nothing to disclose. Kristoffer Madsen: nothing to disclose. Pernille Iversen: has received conference fee payment and speaker honoraria from Biogen Idec. Morten Blinkenberg: has served on scientific advisory boards for Biogen Idec, Merck-Serono, Novartis, Sanofi and Teva; has received speaker honoraria from Biogen Idec, Merck-Serono, Bayer-Schering, Novartis, Teva and Sanofi; has received consulting honoraria from the Danish Multiple Sclerosis Society, Biogen Idec and Merck-Serono; has received funding for travel from Biogen Idec, Merck-Serono, Sanofi; has received research support from Merck-Serono and the Danish Multiple Sclerosis Society. Finn Sellebjerg: has served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen Idec, Genzyme, Lundbeck, Merck Serono, Novo Nordisk, Novartis, Sanofi-Aventis, Schering Plough and Teva. Hartwig R. Siebner: has served on a scientific advisory board for Lundbeck A/S, Valby Denmark, and has received honoraria as speaker from Biogen Idec, Denmark A/S, Genzyme, Denmark and MerckSerono, Denmark, has received honoraria as editor from Elsevier Publishers, Amsterdam, The Netherlands and Springer Publishing, Stuttgart, Germany, has received travel support from MagVenture, Denmark, and has received a research fund from Biogen-idec.

P978 Regional and tissue-type based assessment of Gaussian and non-Gaussian diffusion MRI indices in three subtypes of multiple sclerosis using diffusional kurtosis imaging P. Lee1,2, P. Adany1, D.R. Danney3, A.J. Hughes3, S.G. Lynch4, I.-Y. Choi1,2,4 1Hoglund Brain Imaging Center, 2Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, 3Psychology, University of Kansas, Lawrence, 4Neurology, University of Kansas Medical Center, Kansas City, KS, United States

Background: Increasing evidence suggests gray matter pathology in multiple sclerosis (MS) and that seems to be closely associated


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with disease status and cognitive deficits. Among new generation of proposed MRI techniques, diffusional kurtosis imaging (DKI) is a powerful, emerging tool that can characterize microstructural organization at the cellular level through evaluation of both Gaussian and non-Gaussian properties of water diffusion. Therefore, noninvasive measures of microstructural changes could offer a promising source of biomarkers that can characterize early, yet subtle changes in MS. Objectives: To characterize region and tissue-type specific tissue abnormality in three MS subtypes (RRMS, SPMS, PPMS) assessed by the anisotropic and isotropic microstructural changes using DKI and DTI techniques; and to investigate their association with cognitive performance and clinical status. Method: A total of 53 MS patients (20 RRMS, 17 SPMS, 16 PPMS) and 18 healthy controls were scanned at 3T using a spinecho EPI sequence with 30 directional diffusion weighing parameters. Diffusion MRI indices were calculated on a pixel by pixel basis over sub-brain regions. A battery of cognitive tests was also performed on all subjects, yielding scores on memory and executive function and processing speed. ANOVA, Pearson and Spearman correlation analyses were performed. Results: Among DKI/DTI indices, FA, MD, DR, MK in the corpus callosum, corpus striatum and white matter found to be the most sensitive measures to differentiate degenerative phases of MS (SPMS, PPMS) from RRMS or controls. FA in the thalamus were significantly different between SPMS and controls, while MK, KA and KR in the cerebellum and brainstem were different between PPMS and controls. Cortical gray matter MD values were higher in SPMS than in controls (p=.04). Particularly, MD in the corpus callosum and MK in the thalamus were correlated with the duration of MS. All diffusivity values in the corpus callosum and FA in the brainstem were correlated with EDSS (p< .03). A set of DKI/DTI indices in the brainstem were correlated with processing speed, while those in the corpus callosum and white matter with executive planning and those in the corpus striatum with both processing speed and executive planning. Conclusion: A various DKI/DTI parameters indicate different pathologic features of MS in a region specific manner and promises to serve as sensitive biomarkers of MS pathophysiology in all subtypes. Disclosure Phil Lee: This study was supported in part by grants from US National Institute of Health (Clinical and Translational Science Award and a K-INBRE) awarded to the University of Kansas Medical Center and National Multiple Sclerosis Society. Peter Adany: nothing to disclose. Douglas R. Denney: nothing to disclose. Sharon G. Lynch has participated in Multi-center MS trials and grants funded by biogen, Teva, Novatis, Acorda, Opexa, Roche, Genentech, Genzyme, Sun Pharma, Vaccinex, Actelion, NMSS, and NIH. Abbey J. Hughes: nothing to disclose. In-Young Choi: nothing to disclose. P979 Predicting conversion to clinically definite multiple sclerosis using machine learning on the basis of cerebral grey matter segmentations

K. Bendfeldt1, B. Taschler2, L. Gaetano1,3, P. Madoerin1, P. Kuster1, N. Mueller-Lenke1, M. Amann1,3, H. Vrenken4, F. Barkhof4, S. Borgwardt1,5,6, S. Klöppel7, T.E. Nichols2, G. Suarez8, L. Kappos3, G. Edan9, M.S. Freedman10, X. Montalban11, H.-P. Hartung12, C. Pohl13,14, R. Sandbrink12,13, J. Würfel1,15,16, E.-W. Radue1, T. Sprenger1,3 1Medical Image Analysis Centre, University Hospital Basel, Basel, Switzerland, 2Dept. of Statistics, University of Warwick, Coventry, United Kingdom, 3Department of Neurology, University Hospital Basel, Basel, Switzerland, 4VU University Medical Center, Amsterdam, The Netherlands, 5Department of Psychiatry (1), University of Basel, Basel, Switzerland, 6Department of Psychosis Studies, King’s College London, Institute of Psychiatry, London, United Kingdom, 7Department of Psychiatry and Psychotherapy, Department of Neurology, University Medical Center Freiburg, Freiburg Brain Imaging, Freiburg, Germany, 8Bayer HealthCare Pharmaceuticals, Whippany, NJ, United States, 9CHU-Hopital Pontchaillou, Rennes, France, 10University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada, 11Hospital Universitari Vall d’Hebron, Barcelona, Spain, 12Department of Neurology, Heinrich-Heine Universität, Düsseldorf, 13Bayer Pharma AG, Berlin, 14University Hospital of Bonn, Bonn, 15Charité University Medicine Berlin, Berlin, 16University Medicine Goettingen, Goettingen, Germany Introduction: Evidence indicates that grey matter (GM) atrophy is a relevant contributor to early conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS). Multivariate pattern classification techniques, such as support vector machines (SVMs), allow classifying single subjects to a given group in a fully automated, strictly data driven way. We applied SVMs to MRI data, to assess the value of cortical GM patterns to predict the subsequent conversion to clinically definite MS (CDMS) from CIS. Methods: This is a post-hoc analysis of MRI and clinical data from the BENEFIT study. Patients with an initial clinical demyelinating event within the past 60 days (N=468) were randomized to interferon beta-1b (250 µg subcutaneously) (n=292) or placebo (n=176) until CDMS was diagnosed or up to 24 months, if CDMS was not diagnosed. We compared converters to CDMS vs. nonconverters acquired on 1.5T MR-scanners with sufficient quality for the analysis (n=50 placebo, and n=96 interferon beta-1b). We applied linear SVMs and leave-one-out cross-validation (http://www.csie.ntu.edu.tw/-cjlin/libsvm) to classify the patients based on the cerebral cortical GM segmentations of 2D-T1-weighted MR scans interpolated to an isotropic resolution of 1 mm3 obtained with VBM8-DARTEL preprocessing. Age, sex, and scanner were included as covariates of no interest in the model. Results: SVMs correctly predicted CDMS in 66.0% of placebotreated patients (p=0.04), with a sensitivity of 72% (converters correctly identified) and a specificity of 60% (non-converters correctly identified). Middle and medial frontal, superior and middle temporal, anterior and posterior cingulate, middle temporal, fusiform, middle occipital, and insular regions contributed to the classification accuracy. 42.9% and 53.1% of interferon beta-1b-treated patients (total accuracy 48%; p=0.6) were correctly classified as converters and non-converters, respectively.


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Poster Session 2, 21(S11) Conclusions: SVMs allow prediction of conversion to CDMS with moderate accuracy based on the analysis of subtle structural alterations in the cerebral cortex of placebo-treated but not IFNB1b treated individuals. Overall results suggest that SVMs has the potential to contribute to clinical decision making in CIS. Including other imaging measures and relevant features may further improve classification accuracy. Disclosure ● K Bendfeldt has nothing to disclose. ● B Taschler has nothing to disclose. ● L Gaetano has nothing to disclose. ● P Madoerin has nothing to disclose. ● P Kuster has nothing to disclose. ● N Mueller-Lenke has nothing to disclose. ● M Amann has nothing to disclose. ● H Vrenken has received research grants from Pfizer, Novartis and MerckSerono, and speaker honoraria from Novartis. All funds were paid directly to his institution. ● F Barkhof has received compensation for consultancy from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis, Genzyme, Roche, and Teva, and has received research support from the Dutch Foundation for MS research (an NGO). ● S Borgward I wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. I received contributions or honoraria from Janssen-Cilag AG, Eli Lilly (Suisse) S.A., Takeda Pharma AG, Lundbeck (Schweiz) AG, Pfizer AG not relating to the current article. ● S Klöppel has nothing to disclose. ● TE Nichols has nothing to disclose. ● G Suarez is a salaried employee of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. ● L Kappos’ institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof Kappos’ activities as principal investigator and member or chair of planning and steering committees or advisory boards in trials sponsored by Actelion, Addex, Bayer HealthCare Pharmaceuticals, Bayer Schering Pharma, Biogen Idec, CLC Behring, Genentech, GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Praxicon, Roche, Sanofi-Aventis, Santhera, Siemens and Teva and royalties from Neurostatus GmbH. Prof Kappos has received grants from the Swiss MS Society, Swiss National Research Foundation, the European Union, Gianni Rubatto Foundation, and the Novartis and Roche Research foundations. ● G Edan has received honoraria for lectures or consulting from Biogen Idec, Merck Serono, and Sanofi-Aventis, and received personal compensation for serving on the BENEFIT scientific advisory board and for speaking from Bayer Pharma AG. He has also received research support from Serono, (a grant to University Hospital to support a research program on MRI in MS) and from Teva (a grant to support a research program on anti-IBF neutralizing antibodies). ● MS Freedman has received compensation from Bayer HealthCare, Biogen Idec, EMD Canada, Chugai, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, and Teva Canada

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Innovation for consulting services. He also participates in a Genzyme-sponsored speakers bureau. ● X Montalbán has received speaking honoraria and travel expenses for scientific meetings and has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer, Biogen Idec, EMD, Genentech, Genzyme, Merck Serono, Neurotec, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, and Almirall. ● H-P Hartung has received honoraria for consulting and speaking at symposia from Bayer Pharma AG, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva, and SanofiAventis, with approval by the rector of Heinrich-Heine University. ● C Pohl is a salaried employee of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. He owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. ● R Sandbrink is a salaried employee of Bayer Pharma AG/ Bayer HealthCare Pharmaceuticals. He owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. ● J Würfel [Dr. J. Wuerfel is CEO of MIAC AG, Switzerland. He served on advisory boards for Novartis and Biogen Idec. He received a research grant from Novartis, and speaker honoraria from Bayer, Novartis, Teva and Biogen Idec. He is supported by the German ministry of science and economy (DFG, BMWI and BMBF/KKNMS). ● E-W Radue has received personal compensation from Biogen Idec, Genzyme, Novartis, Merck Serono, Synthon and MorphoSys for consulting and speaking services. He has received financial support for research activities from Actelion, Basilea Pharmaceutica Ltd, Biogen Idec, Fondazione Italiana Sclerosi Multipla (FISM), Novartis, Roche, SAKK, Synarc and the University Hospital Basel. T Sprenger Author´s institution, the University Hospital ● Basel, has received payments used exclusively for research for consulting and speaking activities for Mitsubishi Pharma, Eli Lilly, Genzyme, Novartis, ATI, Actelion, Electrocore, Biogen Idec and Allergan. T Sprenger has received grants from the Swiss MS Society, Swiss National Research Foundation, EFIC-Grünenthal and Novartis Pharmaceuticals Switzerland. P980 A composite scale using MRI-defined cerebral lesions and atrophy to assess the therapeutic effect of glatiramer acetate in multiple sclerosis S. Tauhid1, G. Kim1, S.L. Dupuy1, S. Tummala1, F. Khalid1, B.C. Healy2, R. Bakshi1 1Laboratory for Neuroimaging Research, Brigham & Women’s Hospital, Harvard Medical School, 2Neurology, Brigham & Women’s Hospital, Partners MS Center, Harvard Medical School, Boston, MA, United States Background: We have previously defined the Magnetic Resonance Severity Scale (MRDSS), using cerebral lesions and atrophy, to assess multiple sclerosis (MS). MRDSS has shown higher effects sizes in differentiating relapsing-remitting (RR) and


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secondary progressive patients as well as higher longitudinal sensitivity to change vs. the individual MRI measures. Objective: To assess the sensitivity of MRDSS for two-year monitoring of treatment response to glatiramer acetate (GA) in RR MS. Methods: This was a retrospective non-randomized two-arm observational study of 44 RR patients who underwent brain MRI at baseline and two years later. They were either newly started on daily GA, or were not receiving disease-modifying therapy (NoDMT), continuing for two years. The GA group included 23 patients [15 (65%) women, age (mean±SD) 40.3±7.7 years, disease duration 5.0±6.0 years, Expanded Disability Status Scale (EDSS) score 1.2±1.0]. NoDMT included 21 patients [19 (90%) women, age 43.9±8.7, disease duration 10.4±8.8, EDSS 0.6±0.8]. MRDSS comprised three measures: log transformed T2 hyperintense lesion volume (T2LV), the ratio of T1 hypointense LV to T2LV (T1/T2) with logistic transformation, and brain parenchymal fraction (BPF) multiplied by negative 1. Each measure was normalized to calculate a z-score using a reference sample; the composite scale was calculated by adding the component z-scores. The two groups were compared by a Wilcoxon rank sum test, and within subject change by a Wilcoxon signed rank test. Results: Comparing on-study change, GA subjects had less progression than NoDMT on T1/T2 [(median change in Z score (range), 0 (-1.07, 1.20) vs. 0.41 (-0.30, 2.51), p=0.003)] and MRDSS [0.01 (-1.33, 1.28) vs. 0.46 (-1.57, 2.46), p=0.01]; however not on BPF [0.12 (-0.18, 0.58) vs. 0.10 (-1.47,0.50), p=0.59] and T2LV [-0.03 (-0.90, 0.57) vs. 0.01 (-1.69, 0.34), p=0.40]. Considering within group on-study change, GA subjects worsened only on BPF [0.12 (-0.18, 0.58), p=0.001]. In contrast, NoDMT worsened on BPF [0.10 (-1.47, 0.50), p=0.002], T1/T2 [0.41 (-0.30, 2.51), p=0.0002], and MRDSS [0.46 (-1.57, 2.46), p=0.0006]. Conclusions: Changes in MRDSS and an index of the destructive potential of lesions were significantly smaller in GA treated vs. untreated subjects, while no significant difference in changes were observed for T2 hyperintense lesions or whole brain atrophy. We thus hypothesize that these new MRI measures improve sensitivity to treatment effects. Disclosure Dr. Healy received research support from Merck-Serono, Genzyme, and Novartis. Dr. Bakshi received consulting fees from AbbVie, Alkermes, Biogen, Novartis, and Questcor and research support from Biogen, Merck-Serono, Novartis, Genzyme and Teva. The other authors have nothing to disclose. Study supported by: Teva Pharmaceuticals P981 MRI Bookend perfusion discriminates cognitively intact and impaired patients with RRMS R. Aviv1, S.-P. Hojjat1, C.G. Cantrell2, A. Feinstein1, K. Lanctot1, W. Swardfager1, L. Zhang1, L. Lee1, P. O’Connor1, T. Carroll2 1University of Toronto, Toronto, ON, Canada, 2Northwestern University, Chicago, IL, United States Background: Cognitive impairment (CI) is present in ~45% of MS patients. Gray matter (GM) demyelination is increasingly

recognized as complicit in cognitive impairment and disability. Cortical lesions remain challenging to image clinically. We therefore sought to determine whether MRI Bookend perfusion of cortical GM can distinguish between RRMS patients with (RRMS-I) and without (RRMS (-NI) CI. Methods: Prospective study of age and gender matched healthy controls (n=19), RRMS-I (n=20) and RRMS-NI (n=19) undergoing MRI and MACFIMS testing < 1 week apart. Volumetric T1 was segmented into lobar GM, white matter (WM) and CSF. White matter lesions and T1 holes were manually traced. CI was defined as 2 or more tests with z score >1.5 standard deviations below normal. General linear regression assessed the relationship between lobar WM volume and GM/WM perfusion (Cerebral blood flow, volume and transit time (CBF, CBV and MTT)) and between lobar WM and GM perfusion. Mean GM/WM segmented lobar perfusion values were obtained to test the relationship between GM/WM perfusion metric and impairment. A generalized linear model with logit link function was used including SAS Proc GENMOD function for model fit. Bonferroni adjusted p-value < 0.005 was considered statistically significant. Results: No significant differences were seen for age, gender, disease duration, any fractional brain or lesion volume for RRMS-NI versus RRMS-I. All perfusion metrics were significantly lower in RRMS-I versus RRMS-NI. No association was present between lobar WM volume and any lobar GM or WM perfusion metric. Significant strong positive associations (ß range 0.83-.99) were present for WM and GM perfusion for all lobar perfusion metrics (p< 0.0001 all regions). Lobar GM CBF and CBV and WM CBF were significantly associated with CI (all p< 0.0001). Conclusion: Despite structural and lesional similarities, important functional perfusion differences are identified between RRMS-I versus NI suggesting an important potential biomarker for discrimination or monitoring. Disclosure Dr Aviv is a recipient of a Biogen fellowship funding award P982 Increased accuracy and reproducibility of MS lesion volume quantification by using publicly available BrainSeg3D image analysis software Ž. Lesjak, A. Galimzianova, B. Likar, F. Pernuš, Ž. Špiclin Faculty of Electrical Engineering, University of Ljubljana, Ljubljana, Slovenia Background: Dissemination of brain lesions in space is an important biomarker of MS disease, which can be quantified by segmenting the lesions in MR images. As clinical trials require segmentation of several MR images, the use of advanced software tools can increase accuracy and reproducibility of the lesion segmentations, but also reduce the time to perform the segmentation. Here we assess BrainSeg3D, which is an open source, publicly available software based on Seg3D that provides a user-friendly interface and various tools dedicated to brain image analysis. Objectives: The assessment of accuracy and reproducibility, and the required time, of MS lesion segmentation and lesion volume quantification by the use of manual and semi-automated brain image analysis tools in BrainSeg3D.


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Poster Session 2, 21(S11) Methods: Brain image analysis tools in BrainSeg3D include, among others, MR bias field correction, automated brain extraction, automated MR image and brain atlas co-registration, various manual, semi-automated and automated segmentation tools and morphological analysis. These tools were tested on a clinical image database of 30 MS patients imaged with 3T Siemens MR scanner. Each dataset consisted of T1-, T2-weighted, and FLAIR MR sequences acquired in transaxial plane with 3 mm interslice gaps. From these datasets a total of 413 MS lesions were identified by an expert rater. The identified lesions were segmented two times by two expert raters using manual and semi-automated segmentation tools in BrainSeg3D. Reference segmentation of MS lesions was obtained by a consensus between the two expert raters. The segmentation overlap and the spatial agreement between the obtained and reference segmentations were measured by Dice similarity index (SI). Results: Intra-rater segmentation overlap was SI=0.82 with the manual and SI=0.87 with semi-automatic segmentation tools. Inter-rater segmentation overlap was SI=0.77 with the manual and SI=0.82 with semi-automatic segmentation tools. The use of semi-automated segmentation tools, instead of manual segmentation, resulted in 6.7 % higher SI with respect to the reference segmentations. The time required to perform lesion segmentations was reduced by 25% with the use of semi-automated versus manual tools. Conclusions: The use of semi-automated tools in BrainSeg3D increased intra- and inter-observer overlap of the raters´ MS lesions segmentations and reduced by 25% the time needed to segment the MS lesions. Disclosure Nothing to disclose. P983 Brain contrast enhancement in neuromyelitis optica: its relation to acute attacks and clinical disease severity G. Orman1, Y. Pekcevik1, C. Thompson2, M. Mealy3, M. Levy3, I. Izbudak1 1Radiology/Neuroradiology, Johns Hopkins Hospital, 2Biostatistics, Johns Hopkins Bloomberg School of Public Health, 3Neurology, Johns Hopkins Hospital, Baltimore, MD, United States Purpose: Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system that presents with acute transverse myelitis (TM) and/or optic neuritis (ON). NMO is associated with antibodies to aquaporin 4 (AQP4), a water channel highly concentrated in astrocytic end-feet at the blood brain barrier. Brain findings by MRI are described in 50-85% of the patients with NMO, some of which are considered typical for NMO. The purpose of this study is to investigate if contrast enhancement (CE) on brain MRI occurs during an acute attack (AA) of TM or ON, and if CE of the brain is correlated with clinical disease severity. Materials and methods: This is a retrospective study of patients diagnosed with NMO or NMO spectrum disorders whose brain MRIs were evaluated by a neuroradiologist and a radiologist in consensus during an acute attack of TM or ON. Epidemiological

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data, attack status, NMO IgG status, CE presence, diffusion weighted imaging results, disease duration and relapse rates (RR) were noted. Fisher’s exact and Mann-Whitney tests were used for statistical analysis. Results: Seventy-seven patients (11 male, 66 female) were included in the study. The mean age at last follow-up brain MRI was 47.6 years (range 6-91 years). There were 47 AfricanAmerican, 24 Caucasian and 6 Hispanic patients. Sixty-six patients were NMO IgG positive, 9 were negative and 2 were not tested. Fifty-nine were scanned during AA. Twenty-one of 59 patients (35.6%) showed CE during AA and 5/18 (27.8%) showed CE during non-acute phase (p=0.78). AA patients with CE were more likely to have shorter disease duration (p=0.05), higher RR (p< 0.05) and increased diffusion in the lesion (p=0.05). Conclusion: Our results suggest that brain CE may be seen during AA of NMO. CE during AA correlates with the clinical disease severity. Disclosure Dr. Michael Levy receives research support from NIH, Guthy Jackson Charitable Foundation, Viropharma, Acorda, Sanofi, NeuralStem and Genentech, and serves as a consultant for Chugai Pharmaceuticals, GlaxoSmithKline, Alexion and Medimmune. Drs Izlem Izbudak, Gunes Orman, Yeliz Pekcevik and Ms Maureen Mealy and Carol Thompson have nothing to disclose P984 Longitudinal evolution of neuromyelitis optica brain lesions on MRI and correlation to disability scores G. Orman1, Y. Pekcevik1, C. Thompson2, L. Siddique3, M. Mealy3, M. Levy3, I. Izbudak1 1Radiology/Neuroradiology, Johns Hopkins Hospital, 2Biostatistics, Johns Hopkins Bloomberg School of Public Health, 3Neurology, Johns Hopkins Hospital, Baltimore, MD, United States Purpose: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder that predominately targets the optic nerves and spinal cord and also involves the brain in 51 to 89 % of patients; however the degree and extent of brain involvement has not been correlated with clinical disease. The aims of the study are to describe the evolution of brain lesions over time and determine how brain disease is correlated with neurologic outcomes including number of clinical relapses, time interval between first and last brain MRIs, aquaporin-4 antibody seropositivity, and demographic factors such as sex and race. Materials and methods: This is a retrospective study of 42 patients with NMOSDs in whom serial brain MRIs were reviewed. Brain lesions were classified as: peri-ependymal (PE), white matter (WM), brainstem+corticospinal tract (BS+CST) and other lesions. Comparisons between the first and last MRI were analyzed using Wilcoxon signed-rank, Mann-Whitney and Spearman correlations. Results: Forty-two patients (35 female, 7 male) with a mean age of 47 (range 6-76) years were evaluated over a mean duration of 42.2 (range 0.37-144.57) months. A significant increase of PE (p=0.014), WM (p< 0.001) and total (p< 0.001) lesions were


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notable between the first and last MRIs. Disability scores were correlated with BS+CST lesions (p=0.03). Conclusion: Brain lesions in patients with NMO/NMOSD increase in number over time and correlate with disability.

indicates that high-sensitivity Gd protocols do increase power to detect treatment effects. Conclusion: Increasing sensitivity to Gd-enhancement increases the power to detect treatment effects.

Disclosure

Disclosure

Dr. Michael Levy receives research support from NIH, Guthy Jackson Charitable Foundation, Viropharma, Acorda, Sanofi, NeuralStem and Genentech, and serves as a consultant for Chugai Pharmaceuticals, GlaxoSmithKline, Alexion and Medimmune. Drs Izlem Izbudak, Gunes Orman, Yeliz Pekcevik and Ms Maureen Mealy and Carol Thompson have nothing to disclose

This work was supported by a research grant from the Multiple Sclerosis Society of Canada. The BECOME trial was funded by Bayer Healthcare Pharmaceuticals but was investigator initiated and remains the intellectual property of New Jersey Medical School. Robert Brown has received personal compensation from NeuroRx Research for consulting services. Dr. Narayanan has received personal compensation for consulting activities from NeuroRx Research. Stuart Cook participated in the original BECOME study. Diego Cadavid is a full time employee of Biogen, to which the work on the BECOME study is not related. Leo Wolansky was one of two principle investigators for the original BECOME study and received salary support from Bayer. Douglas Arnold is president and CEO of NeuroRx Research.

P985 Improved lesion detection rates with high sensitivity gadolinium enhanced magnetic resonance imaging protocols translate into increased statistical power for clinical trials in MS R.A. Brown1, S. Narayanan1, S. Cook2, D. Cadavid2, L. Wolansky2, D. Arnold1 1McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada, 2Rutgers University New Jersey Medical School, Newark, NJ, United States Background: Lesions that appear on gadolinium contrastenhanced magnetic resonance imaging (CE-MRI) are an important marker of disease activity in multiple sclerosis (MS). High sensitivity CE-MRI protocols involving scanning at 3 T, increased delay between contrast administration and scanning, and higher doses of contrast agent reveal subtly enhancing lesions that are not appreciated with standard protocols. However, it is unknown whether this increased sensitivity also provides a greater ability to detect treatment effects and increased power in clinical trials. Objectives: To determine whether high sensitivity CE-MRI protocols provide better detection of treatment effects on Gd lesion count in MS clinical trials. Methods: Subjects enrolled in the BECOME study of glatiramer acetate (GA) versus interferon β-1b (IFN) received monthly triple-dose, delayed CE-MRI at 3T for one year. Gd lesion masks were produced in these 75 subjects by a blinded rater. Quantitative Gadolinium uptake index (GUI) maps were calculated using preand post-contrast images. In a previous experiment we determined that a GUI of 1058 was the minimum detectable on a standard 1.5 T single-dose CE-MRI. Using a series of GUI thresholds up to 1058 we re-segmented lesions for each subject to simulate Gd lesion masks and determine lesion counts that would have been obtained by lower sensitivity protocols. For each threshold, a negative binomial model was used to determine the Cohen’s d effect size for the difference between treatment groups. The relationship between effect size and GUI threshold was then fit using linear regression. Results: A positive linear relationship between GUI threshold and effect size was observed (adjusted R2 = 0.94, p < 10-6) from an effect size for the simulated standard protocol of 0.100 to 0.187 for the high-sensitivity 3 T triple-dose protocol. These correspond to approximate per-arm required sample sizes of 1238 and 355 subjects (t-test; α = 0.05; β = 0.8; single-tailed) for studies similar to BECOME. This result

P986 Increase in magnetic susceptibility after MS lesion formation and potential diagnostic utility Y. Zhang1, S. Gauthier2, L. Tu1, A. Gupta1, J. Comunale1, G.C.-Y. Chiang1, D. Zhou1, Y. Wang1 1Radiology, 2Neurology, Weill Cornell Medical College, NYC, NY, United States Background: Multiple sclerosis (MS) lesion formation is associated with phase change on MRI gradient echo (GRE) images, which recently has attracted a great deal of interest. Phase changes result from changes in tissue magnetic susceptibility properties, which can be extracted from the phase data using quantitative susceptibility mapping (QSM). Goals: To measure the longitudinal change in MS lesion susceptibility in a cohort of MS patients using QSM, and to assess if QSM without Gd injection can be used to identify new enhancing MS lesions. Methods: MS MRI cases from 2011/8 to 2014/8 were screened to identify patients meeting the following inclusion criteria: 1) baseline MRI session that included T2-weighted (T2w) and Gd-enhanced T1-weighted (T1w+Gd), and 2) at least one followup MRI session within < 1 year that include T2w, T1w+Gd and GRE. A subset of patients were found to have new enhancing lesions on the first follow-up MRI that became non-enhancing on the second follow-up MRI. GRE data were processed using QSM to measure mean susceptibility in the lesions relative to normalappearing white matter (NAWM). Results: 20 patients had two follow-up MRIs with enhancing lesions on the 1st follow-up having 3.27 ± 6.79 ppb susceptibility and 19.56 ± 8.33 ppb susceptibility on the 2nd follow up (P< .01, generalized estimating equations model). 43 patients had at least one follow-up MRI, and the receiver operating characteristics (ROC) analysis for relative susceptibility to discriminate enhancing from non-enhancing lesions had an area under the curve


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Poster Session 2, 21(S11) (AUC) of 0.956, providing a sensitivity of 86.6% and specificity of 94.1% at a cutoff of 8.8 ppb. Conclusions: MS lesion magnetic susceptibility does not change when it is Gd-enhancing and increases when it becomes Gd-nonenhancing. Susceptibility measured on QSM shows promise for differentiating enhancing from non-enhancing MS lesions, without the use of an intravenous contrast agent.

known to regulate IL-10 expression in T cells. These findings will be validated in separate group of patients. Conclusion: Our data suggest that serum miRNAs are related to brain MRI lesions and atrophy in patients with multiple sclerosis. A different set of miRNAs linked to lesions than the ones linked to atrophy, suggesting the ability to identify surrogate marker in serum for the inflammatory vs. neurodegenerative aspects of the underlying disease process.

Disclosure Yan Zhang: nothing to disclose. Susan Gauthier: nothing to disclose. Lijie Tu: nothing to disclose. Ajay Gupta: nothing to disclose. Joseph Comunale: nothing to disclose. Gloria Chia-Yi Chiang: nothing to disclose. Dong Zhou: nothing to disclose. Yi Wang: nothing to disclose. P987 Serum microRNAs are related to brain MRI lesions and atrophy in patients with multiple sclerosis R. Gandhi, B.C. Healy, K. Regev, A. Paul, F. Von Glenn, R. Chu, S.L. Dupuy, G. Kim, F. Khalid, H.L. Weiner, R. Bakshi Brigham & Women’s Hospital, Partners MS Center, Harvard Medical School, Boston, MA, United States Purpose: To determine the relationship between miRNAs and MRI-defined cerebral involvement in patients with MS. Methods: Circulating miRNAs in serum from 41 patients with multiple sclerosis (MS) were measured using using a SybR green PCR method (Exiqon). 1.5T brain MRI employed axial 3-mm (no interslice gap) conventional spin-echo T2-weighted (dual-echo) and T1-weighted sequences. MRI was expert-traced to quantify whole brain T2 hyperintense (T2LV) and T1 hypointense lesion volume (T1LV). Segmentation in SPM8 determined normalized whole brain parenchymal (BPF) and cortical gray matter (GMF) fractions to assess atrophy. miRNA analysis results were correlated to various MRI measures using Spearman’s correlation coefficients. This is a discovery set in which we correlated the expression of 800 miRNAs with MRI. Results: We identified 22 miRNAs that correlated with T2LV and 21 miRNAs that were correlated to T1LV. Ten miRNAs showed a common correlation with both T2LV and T1LV. Among these, we found that the miR145 was correlated to both T2LV and T1LV; this miRNA has been previously shown to differentiate MS patients from controls with high sensitivity and specificity. There were 29 miRNAs that correlated with BPF; among these, 14 were negatively correlated suggesting that increased miRNA expression linked to a higher rate of whole brain atrophy. We found 43 miRNAs that correlated with GMF; among these 26 were negatively correlated. Twelve miRNAs showed a common correlation with both BPF and GMF, including the Let 7 and miR-30 miRNA families. We have previously shown that let-7a differentiated secondary progressive from relapsing remitting (RR) MS and healthy controls. The let-7 miRNA family regulates stem cell differentiation and T cell activation, activates Toll-like receptor 7, and is linked to neurodegeneration. miR-30 differentiated RR MS from controls and is

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Disclosure Dr. Gandhi received research support from Biogen, Novartis, and Merck-Serono. Dr. Healy received research support from Merck-Serono, Novartis and Genzyme. Howard has research support from Serono, Biogen, Therapix, Novartis, Genzyme, Teva. Dr. Bakshi received consulting fees from AbbVie, Alkermes, Biogen, Novartis, and Questcor and research support from Biogen, Merck-Serono, Novartis, Genzyme and Teva. The other authors have nothing to disclose. P988 Walking performance is associated with the integrity of cognitive motor network structures in relapsing-remitting MS D. Wenzel1,2, S. Siemonsen1,3, J.-P. Stellmann1,2, T. Kjølhede4, S. Ringgaard5, B.G. Pedersen5, E. Stenager6,7, T. Petersen8, C. Heesen1,2, K. Vissing4, U. Dalgas4 1Institute of Neuroimmunology and MS (INIMS), 2Department of Neurology, University Medical Center Hamburg Eppendorf, 3Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg Eppendorf, Hamburg, Germany, 4Section of Sport Science, Department of Public Health, Faculty of Health, Aarhus University, 5The MR Research Centre, Aarhus University Hospital, Aarhus, 6Institute of Regional Health Research, University of Southern Denmark, Odense, 7The Multiple Sclerosis Clinic of Southern Jutland, Department of Neurology, SDU Hospital, Sønderborg, 8The Multiple Sclerosis Clinic, Department of Neurology, Aarhus University Hospital, Aarhus, Denmark Background: Mobility is one of the most valuable bodily functions for patients with Multiple Sclerosis (MS). However, the association between walking impairment and global Magnet Resonance Imaging (MRI) parameters is weak. Focal volume measures as well as diffusion tensor imaging (DTI)-based integrity parameters of white matter tracts might help to identify structures associated with walking impairment. Objective: To explore the association between mobility tests and subcortical grey matter volumes as well as DTI-based MRI parameters. Methods: 35 MS-patients (43y; median Expanded Disability Status Scale 3 [2-4]) in the relapsing-remitting phase of the disease and on Interferon-β 1A or 1B therapy were included in the study. Mobility measures (Timed 25-Foot Walk, 2-Minute-Walk, 5-Times-Sit-Stand-Test) were recorded and an MRI-scan of the brain (T1w, T2w, DTI) was performed on a 1.5 Tesla scanner. Standard MRI atrophy measures included FSL-SIENAX derived global volumes and lesion load as well as subcortical volumes


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were calculated. Tract-specific diffusion measures were determined using FSL-TRACULA. All correlations were corrected for age and gender as well as for multiple testing. Results: A significant correlation between grey matter volume and the Sit-Stand-Test (R2=0.4, p< 0.05) was observed, however other global volumes, including T2-lesion volumes, were not significantly correlated with mobility tests. The volumes of the caudate nucleus of both hemispheres were associated with the 25-Foot-Walk and the 2-Minute-Walk (R2=0.3, p< 0.05). Global integrity parameters including mean fractional anisotropy (FA) of the normal appearing white matter were not significantly correlated. Out of the TRACULA-derived white matter tracts, mean FA of the cingular anterior bundle correlated with all three mobility tests (R2=0.3, p< 0.05). Conclusion: Two standard walking tests in MS were correlated with structures that are known to be important for cognitive motor control. In our cohort the integrity of the accessory motor system seems to be closer linked to walking performance than the primary motor system including the cortico-spinal tract. Disclosure Jan-Patrick Stellmann: nothing to disclose. Susanne Siemonsen: nothing to disclose. Tue Kjølhede: nothing to disclose. Damian Wenzel: nothing to disclose. Steffen Ringgaard: nothing to disclose. Bodil G Pedersen: nothing to disclose. Egon Stenager: nothing to disclose. Thor Petersen: nothing to disclose. Christoph Heesen: nothing to disclose. Kristian Vissing: nothing to disclose. Ulrik Dalgas: nothing to disclose. P989 Resistance training increases cortical thickness in RRMS - results of a pilot RCT S. Siemonsen1,2, J.-P. Stellmann1,3, T. Kjølhede4, D. Wenzel1,3, S. Ringgaard5, B.G. Pedersen5, E. Stenager6,7, T. Petersen8, C. Heesen1,3, K. Vissing4, U. Dalgas4 1Institute of Neuroimmunology and MS (INIMS), 2Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg Eppendorf, 3Department of Neurology, University Medical Center Hamburg Eppendorf, Hamburg, Germany, 4Section of Sport Science, Department of Public Health, Faculty of Health, Aarhus University, 5The MR Research Centre, Aarhus University Hospital, Aarhus, 6Institute of Regional Health Research, University of Southern Denmark, Odense, 7The Multiple Sclerosis Clinic of Southern Jutland, Department of Neurology, SDU Hospital, Sønderborg, 8The Multiple Sclerosis Clinic, Department of Neurology, Aarhus University Hospital, Aarhus, Denmark Background: It has been suggested that exercise therapy has a disease modifying effect in people with Multiple Sclerosis (MS). Changes of structural Magnetic Resonance Imaging (MRI) measures following exercise interventions such as progressive resistance training (PRT), represent a substantial indicator of neuroprotective effects as reported in other clinical as well as healthy populations.

Objective: To evaluate the effects of PRT on global brain volumes and regional cortical thickness following 24 weeks of PRT. Methods: This study was a 24-week randomised controlled trial, with a training group (n=17, 24 weeks of supervised PRT) and a waitlist group (n=12, continuing their habitual lifestyle). During an extension of another 24 weeks the waitlist group were offered the same PRT program. All patients (44y; median Expanded Disability Status Scale 3 [2-4]) were in the relapsing-remitting phase of the disease and treated with interferon-β 1A or 1B therapy. Three cranial MRIs (T1w, T2w images) were obtained on a 1.5 Tesla scanner. Standard MRI atrophy measures included FSLSIENAX derived global volumes, lesion load and percentage brain volume change (PBVC). Cortical thickness estimates from T1w images were automatically processed by FreeSurfer. Thickness of each of the 74 cortical segments was then compared pairwise before and after PRT for all patients. In addition, cortical thickness changes through PRT were compared between the two groups. All analyses were corrected for age and gender as well as for multiple testing. Results: EDSS as well as T2 lesion load did not change. Global volumes as well as PBVC were also not significantly altered after PRT and did not differ between the two groups. A higher absolute cortical thickness was found in nine cortical regions (p< 0.05) after PRT. Two of them, the superior part of the precentral sulcus and the occipito-temporal lateral fusiform gyrus could be as well confirmed when comparing relative cortical thickness changes between both groups (p< 0.05). Conclusion: PRT seems to induce a measurable increase in cortical thickness of the precentral sulcus and fusiform gyrus and probable in other cortical regions. Our findings indicate that exercise interventions might have a neuroprotective or even a neuroregenerative effect in MS. Disclosure Jan-Patrick Stellmann: nothing to disclose Susanne Siemonsen: nothing to disclose Tue Kjølhede: nothing to disclose Damian Wenzel: nothing to disclose Steffen Ringgaard: nothing to disclose Bodil G Pedersen: nothing to disclose Egon Stenager: nothing to disclose Thor Petersen: nothing to disclose Christoph Heesen: nothing to disclose Kristian Vissing: nothing to disclose Ulrik Dalgas: nothing to disclose P990 MRI characteristics of short myelitis lesions in NMOIgG-positive neuromyelitis optica spectrum disorders Y.-M. Lim, J.Y. Jin, J. Lee, K.-K. Kim Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Longitudinally extensive transverse myelitis (LETM) is the most characteristic MRI findings of spinal attacks in neuromyelitis optica spectrum disorders (NMOSD), whereas recent studies suggested short transverse myelitis (STM), less than 3 vertebral segments, is not infrequent in NMOSD. The purpose of this study was to determine the frequency of short segment myelitis in


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Poster Session 2, 21(S11) NMO-IgG-seropositive NMOSD patients and evaluate the MRI features of STM. We analyzed 116 spinal MRIs obtained within 30 days from symptom onset in 42 NMOSD patients. Longitudinal and axial extents of spinal cord lesions were investigated. LETM were observed in 89 spinal attacks, whereas short myelitis was observed in 27 attacks. Multifocal involvements were observed in 16 attacks. In LETM, median lesion length was 5 segments (range, 3-19). The lesions most frequently affected the upper-thoracic cord (n=49), followed by middle-thoracic (n=44), upper-cervical cord (n=37). The medulla oblongata was affected in 15 spinal attacks. The entire spinal cord was affected in 3 attacks. On the axial plane, most lesions occupied the holocord (n=38), and central cord or H-type gray matter (n=42). In STM, median lesion length was 1 segment (range, 1-2). The upper cervical cord (n=8) was the most commonly involved, followed by middle thoracic (n=7), upper-cervical (n=5) and lower-thoracic cord (n=5). Axially, lesions were centrally located in 14 attacks and hemicord involvement was in 9 attacks. Eight patients have short segment myelitis in the initial manifestations of spinal attacks, and 3 patients have only STM in their disease course. Short segment myelitis was not uncommon in NMO-IgG-seropositive NMOSD, and STM can be the initial manifestations of spinal attacks. Although it is very rare, some patients may show only STM in the disease course. Therefore, NMO-IgG testing should be performed even in short myelitis lesions.

Anxiety Inventory (STAI) and Beck Depression Inventory (BDI), respectively. None of the patients had major psychiatric illnesses, such as major depression or anxiety disorder. Results: 27/48 patients had high FIS scores (>72; hf-MP), 19/48 had high STAI scores (>54; ha-MP) and 9/48 showed high BDI scores (>16). STAI (p< 0.0001) and BDI (p< 0.0001) scores were significantly higher in hf-MP versus patients with low or no fatigue (lf-MP). Similarly, FIS (p< 0.001) and BDI (p< 0.0001) scores were significantly higher in ha-MP compared to patients with low or no anxiety (la-MP). We found no significant difference in total or regional WMLL between hf-MP and lf-MP. However, the total WMLL (p=0.036) and the regional WMLLs in the splenium of the corpus callosum (p=0.040), column and body of fornix (p=0.011), crus of fornix/stria terminalis (p=0.011), anterior corona radiata (p=0.022), posterior corona radiata (p=0.011), posterior thalamic radiation (p=0.025) and uncinate fasciculus (p=0.023) were significantly higher in ha-MP versus la-MP. Multivariate analysis controlling for age, depression, fatigue and total WMLL, showed significant independent association between WMLL of the column and body of the fornix and anxiety (OR=1.270, 95%CI=1.009-1.598, p=0.042). Conclusion: In spite of several remaining limitations of scope and approach, this study has pinpointed neuroanatomic substrates of clinically relevant anxiety in MS patients that require further validation in targeted prospective studies.

Disclosure

Disclosure

All authors have nothing to disclose

Dr. Palotai is currently a recipient of the McDonald Fellowship from the Multiple Sclerosis International Federation. Dr. Mike was supported by a McDonald Fellowship from the Multiple Sclerosis International Federation. Dr. Cavallari is supported by a Research Fellowship from Mallinckrodt Pharmaceuticals. Dr. Orsi was supported by grants of the European Economic Area/ Norwegian Financial Mechanism HU 0114; and National Bureau of Research Development, HKTH INNODIAG. Dr. Illes was supported by the Hungarian National Research Fund (OTKA K77892), the Hungarian Neuroimaging Foundation. Dr. Guttmann reports no conflict of interest.

P991 Associations of global and regional white matter lesion load with anxiety and fatigue in multiple sclerosis M. Palotai1, A. Mike1,2, M. Cavallari1, E. Strammer1,2, G. Orsi3, Z. Illes2,3,4, C.R.G. Guttmann1 1Center for Neurological Imaging, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States, 2Division of Clinical and Experimental Neuroimmunology, Department of Neurology, 3MTA-PTE Clinical Neuroscience MR Research Group, University of Pecs, Pecs, Hungary, 4Department of Neurology, Institute of Clinical Research, Odense University Hospital, University of Southern Denmark, Odense, Denmark Background: Fatigue, depression and anxiety are common disabling symptoms in patients with multiple sclerosis (MS). Previous studies raised the intriguing hypothesis that structural damage to specific white matter (WM) connections can contribute to the development of these symptoms in MS patients. Aims: In this study, we investigated the associations of fatigue and anxiety with total as well as tract-specific white matter lesion load (WMLL) in MS with increased anatomical detail. Methods: Total and regional T2 WMLL for 19 tracts was assessed in 48 MS patients (30 female). ICBM (International Consortium for Brain Mapping) DTI-81 atlas-based parcellation of the WM was combined with semi-automated segmentation of WM lesions on T2-weighted FLAIR 3T magnetic resonance (MR) images. On the day of the MR scan, fatigue, anxiety and depression were assessed using the Fatigue Impact Scale (FIS), Spielberger Trait

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P992 Cerebrospinal fluid gadolinium concentration in multiple sclerosis M.A. Pawlak1, B. Gierczyk2, M. Frankowski2, E. Jodlowska1, E. Kotecka-Sowinska3, R. Kazmierski1 1Department of Neurology and Cerebrovascular Disorders, Poznan University of Medical Sciences, 2Faculty of Chemistry, Adam Mickiewicz University, 3Department of Radiology, Bierkowski Hospital, Poznan, Poland Background: Intravenous administration of gadolinium based contrast agents (GBCA) is a part of routine diagnostic evaluation of patients assessed for multiple sclerosis (MS) and is commonly used in assessment of brain tissue injury during disease monitoring. GBCAs are considered to be intravascular contrast agents, yet presence of blood brain barrier disruption in MS enables the Gadolinium (Gd) chelates to enter the brain and cerebrospinal fluid (CSF). Since free gadolinium is toxic there is a need for


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more safety data on Gd concentration in the CSF of patients frequently exposed to GBCA agents. Aim: To identify the presence of Gadolinium (Gd) in cerebrospinal fluid in patients with multiple sclerosis following intravenous injection of Gadolinium Based Contrast Agents. Methods: This is a retrospective cohort study of consecutive sample of MS patients who had their CSF stored in our Department’s csf database and had Gd contrast enhanced MRI study up to 3 days prior to lumbar puncture. Concentration of gadolinium was measured in CSF samples after mineralization with nitric acid. The Inductively coupled plasma atomic emission spectroscopy (ICP-OES) measurements were performed on Shimadzu ICPE9800 spectrometer at 342.247 nm wavelength. Results: Twenty three patients had GBCA injection prior to the lumbar puncture were identified between 2011 and 2014. Gadolinium was present in all evaluated samples. Median Gadolinium concentration was 313 ppb (IQR 164 - 341,5). CSF was acquired between 1 and 66 hours following Gadolinium injection (median 20 hours 27 minutes; IQR 15h30m - 32h47m). Conclusion: Our data indicate that Gd is present in the CSF following intravenous injection in subjects without renal function impairment. Its presence in MS patients should be taken into account when planning contrast enhanced MRI. There is a need for further evaluation of Gd CSF concentration changes over time (clearance). Further studies will be conducted to assess the impact of multiple contrast administration on CSF Gd concentration. Measurement of Gd CSF concentration might be an indirect method for blood brain barrier disruption in MS clinical trials and assessment of disease progression. Disclosure Mikolaj A. Pawlak: was supported by the Polish National Science Centre grant2011/01/D/NZ4/05801. Elzbieta Jodlowska: nothing to disclose. Blazej Gierczyk: nothing to disclose. Marcin Frankowski: nothing to disclose. Ewa Kotecka Sowinska: nothing to disclose. Radoslaw Kazmierski: nothing to disclose. P993 Estimation of inflammatory microscopic tissue injury after cessation of fingolimod or natalizumab in patients with multiple sclerosis N. Seraji-Bozogzad, F. Bao, C. Caon, A. Tselis, E. Bernitsas, S. Reed, J. Chorostecki, C. Santiago, I. Zak, O. Khan Wayne State University, Detroit, MI, United States Objective: To investigate the characteristics of microscopic tissue injury after cessation of fingolimod (FTY) or natalizumab (NTZ) therapy in patients with MS. Background: Both FTY and NTZ have profound effect on inhibiting lymphocyte migration into the CNS. Cessation of therapy with FTY or NTZ has been shown to be associated with return of MRI activity by the presence of contrast enhancing lesions (CEL). Few studies have examined microscopic tissue injury in patients coming off either FTY or NTZ therapy. Methods: This was a retrospective study in which relapsing MS patients were withdrawn off either FTY or NTZ therapy for

various clinical reasons but not PML. Brain MRI scans obtained within 1 to 3 months after cessation of FTY or NTZ therapy as part of routine clinical care to establish new reference MRI scan and then again approximately 12 months later as part of routine disease monitoring. MTR sequences were obtained with and without saturation pulse. Results: 35 consecutive relapsing MS patients who discontinued FTY or NTZ therapy (mean age 35.7 years, EDSS 3.8, Disease Duration: 7.3 years, Duration of FTY or NTZ therapy: 14 months) were included in the study. Mean of 1.7 CEL lesion seen in the first scan (reference scan) obtained 1 to 3 months after cessation of therapy. Mean MTR in the CEL was 20.7% and at month 12 the same ROI from co-registered images was 29% (p< 0.0001). Subgroup analysis of patients on reference MRI scan in patients previously on NTZ showed mean lesion MTR 20.7% compared to 20.6% in the FTY group. At month 12 MRI scan mean MTR from prior CEL lesions was (28.7% vs 29.7%, p=0.87). However, compared to patients who received injectable DMT, the mean CEL MTR values from the reference scan in the NTZ (20.7 vs 31.2, p< 0.0001) FTY (20.6 vs 29.7, p< 0.0001) group were significantly lower. Similarly, 12 months later, the ROI from prior CEL in the NTZ (28.7 vs 36.7, p< 0.0001) and FTY (29.7 vs 36.7, p=0.0002) showed significant microscopic tissue compared to similar ROI in patients receiving injectable DMT. Additional analyses including clinical correlations will be presented. Conclusion: Discontinuation of NTZ and FTY may induce greater microscopic tissue injury compared to MTR values of CEL in patients receiving injectable DMT. These data are consistent with the immunologic MOA of NTZ and FTY therapy. These data warrant long-term follow up and appropriate intervention to minimize tissue injury in these patients. Disclosure All authors have nothing to disclose in regards to this project. P994 Effect of smoking cessation on brain volume in patients with multiple sclerosis N. Seraji-Bozogzad, F. Bao, S. Razmjou, A. Tselis, C. Caon, J. Chorostecki, C. Santiago, I. Zak, O. Khan Wayne State University, Detroit, MI, United States Objective: To determine if cessation of smoking has an effect on brain volume loss in patients with MS. Background: Smoking has been shown to increase T2 lesion load and rate of brain atrophy in patients with MS. However, no study has evaluated the effect of smoking cessation on brain volume in patients with MS. Methods: In this retrospective analysis, we examined the records of relapsing MS patients on whom smoking information was available. From brain MRI scans done at our center on 3T MRI scanner as part of routine clinical monitoring of disease, we evaluated the percent change in brain volume (SIENA) in patients who stopped smoking compared to patients who continued to smoke. Results: 254 relapsing MS patients qualified for inclusion in the study. All patients had smoked cigarettes for > 5 years. Smoking or cessation of smoking was self reported and documented in medical charts. The mean age was 32.8 years, disease duration 4.8


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Poster Session 2, 21(S11) years, duration of DMT 2.5 years, and was EDSS 1.7. Baseline T2 lesion load was 8.2 ml, mean CEL number was 0.7, mean baseline brain volume was 1521 ml. Of 254, 148 continued to smoke while 106 stopped smoking. There were no significant differences between the two groups at baseline. PBVC measured by SIENA was divided into two phases. Phase I was from baseline scan to year 4 scan during which both groups continued to smoke. Phase II was from year 4 to year 6, during which one group continued to smoke while the other group stopped smoking. The annual PBVC in the group that continued smoking was -0.54 in phase I and -0.51 in phase II (p=0.036). The annual PBVC in the group who stopped smoking was -0.55 in phase I and -0.38 in phase II (p< 0.0001). Compared to patients who continued to smoke from in phase II from year 4 to year 6, patients who stopped smoking demonstrated significant decline in the rate of brain volume loss (PBVC: -0.38 vs -0.51, p< 0.0001). Conclusions: To the best of our knowledge, this is the first study indicating that cessation of smoking decelerates loss of brain volume in patients with MS. Long-term clinical correlations are warranted. Cessation of smoking should be actively counseled to patients with MS and should be included as a covariate in studies examining brain atrophy in MS.

parameters were derived both from WML and NAWM using the manually modified WML mask, and using the original non-modified WML mask (with and without GM exclusion mask). Differences in perfusion measures between WML and NAWM were analyzed using paired samples t-test (SPSS version 21). Results: CBF in WML (mean 101.97 ± 28.99 arbitrary units (a.u.)) was significantly lower (p< 0.001) compared to NAWM (130.32 ± 41.91 a.u.) and MTT in WML (4.34 ± 0.86 sec.) was significantly higher (p< 0.001) compared to NAWM (3.45 ± 0.73 sec.). CBV did not show significant difference (p=0.627) between WML (7.82 ± 2.39 a.u.) and NAWM (7.98 ± 2.31 a.u.). The nonmodified WML mask gave similar results as manually modified WML mask if the GM exclusion mask was used in the analysis. Not using GM exclusion mask resulted in significant increase of CBV and MTT in WML compared to NAWM (p=0.001 and p< 0.001 respectively) while CBF did not show significant difference between WML and NAWM (p=0.248). Conclusions: DSC PWI revealed lower CBF and higher MTT, consistent with reduced perfusion, in WML compared to NAWM in patients with early MS. Fully automated method gave same results as manually modified method provided a proper correction with GM exclusion mask was used in the analysis. Binary masks are a promising tool in perfusion analysis of WML in MS.

Disclosure All authors have nothing to disclose in regards to this study. P995 Reduced perfusion in white matter lesions in multiple sclerosis P. Sowa1,2, A. Bjørnerud3,4, G.O. Nygaard2,5, S. Damangir6, G. Spulber6, E.G. Celius2,5, P. Due-Tønnessen1,2, H.F. Harbo2,5, M.K. Beyer1,7 1Dept. of Radiology and Nuclear Medicine, Oslo University Hospital, 2Institute of Clinical Medicine, University of Oslo, 3Intervention Center, 4Dept. of Physics, 5Dept. of Neurology, Oslo University Hospital, Oslo, Norway, 6Dept. of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden, 7Dept. of Life Sciences and Health, Oslo and Akershus University College of Applied Sciences, Oslo, Norway Background and purpose: White matter lesions (WML) in multiple sclerosis (MS) have demonstrated perfusion abnormalities compared to normal appearing white matter (NAWM) but perfusion changes in MS are not well documented. The purpose of this study was to investigate dynamic susceptibility contrast (DSC) perfusion weighted imaging (PWI) in WML in patients with MS using automatically generated binary masks of brain tissue. Methods: DSC PWI was performed at 1.5 Tesla in 69 newly diagnosed MS patients (mean age 35.3 ± 7.2 years, female-male ratio: 2:1, mean EDSS score 2.0 ± 0.95, mean disease duration 30 ± 29.2 months (range 3-158), relapsing remitting MS 66, progressive MS 3). Parametric perfusion maps representing cerebral blood volume (CBV), cerebral blood flow (CBF) and mean transit time (MTT) were obtained using population-based arterial input function. Binary masks of WML, white matter (WM) and grey matter (GM) were automatically generated and co-registered to the perfusion maps. The WML mask was manually edited and modified to correct for errors in the automatic lesion detection. Perfusion

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Disclosure Piotr Sowa received speaking fees from Novartis, Genzyme and Biogen Idec. Atle Bjørnerud is a consultant for NordicNeuroLab AS, Bergen, Norway. Gro O. Nygaard received unrestricted research grants from Novartis and from the Odd Fellow’s Foundation for Multiple Sclerosis Research. Elisabeth G. Celius received funding for travel and speaking fees from Almirall, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Teva, and received research support from Biogen Idec and Novartis. Hanne F. Harbo received an unrestricted research grant from Novartis, and support for travelling and speaking fees from Biogen Idec, Novartis, Sanofi-Aventis and Teva. Soheil Damangir: nothing to disclose. Gabriela Spulber: nothing to disclose. Paulina Due-Tønnessen: nothing to disclose. Mona K. Beyer: nothing to disclose. P996 Spinal cord MRI and its role in monitoring disease progression: prognostic value at the time of a clinically isolated syndrome G. Arrambide1, M. Tintoré1, Á. Rovira2, J. Sastre-Garriga2, J. Castilló2, J. Río1, À. Vidal-Jordana1, I. Galán1, C. Nos1, B. Rodríguez1, L. Midaglia1, M. Comabella1, E. Huerga2, C. Auger2, X. Montalban1 1Multiple Sclerosis Centre of Catalonia/Neuroimmunology Department, 2MRI Unit, Radiology Dept, Vall d’Hebron University Hospital & VHIR, Barcelona, Spain Background: In a previous study, we found that the presence of spinal cord (SC) lesions was significant for predicting evolution


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to multiple sclerosis (MS) in different clinically isolated syndrome (CIS) subtypes, whereas the added value for fulfilling the 2010 McDonald criteria was modest. Goals: To evaluate the added value of SC lesions in CIS for predicting disability accumulation. Methods: Study based on an ongoing CIS cohort. Baseline brain MRI was performed within 3-5 months of disease onset. SC MRI was routinely performed since 2007. From this cohort, 207 patients with brain and SC MRI were identified. Conventional descriptive statistics and hazard ratios (HR) were calculated according to presence of SC lesions with EDSS >=3.0 as the outcome in all cases (n=207) and in the following sub-groups: SC CIS (n=64) and nonSC CIS (n=143). Covariates for adjusted HR (aHR) were age, gender, CIS topography, IgG oligoclonal bands, number of T2 lesions, magnet field strength, and disease-modifying treatment. The performance of SC lesions was assessed at two years. Results: Of the 207 patients, 64 (30.9%) had a SC CIS and 143 (69.1%) a non-SC CIS. The mean (SD) follow-up was 35.7 (15.8) months. The SC MRI demonstrated the presence of at least one lesion in 93 (44.9%) of all patients (78.1% SC versus 30.1% nonSC cases, p< 0.0001). Thirteen 13 of 207 (6.3%) patients reached an EDSS >=3.0 (9.4% SC versus 4.8% non-SC, p=0.171). The presence of at least one SC lesion was associated with an EDSS >=3.0 in 11/93 (11.8%) compared to 2/114 (2.0%) patients without SC lesions (p=0.003). The aHR (95% CI) for reaching an EDSS >=3.0 was 5.4, (0.8-34.2), p=0.076 in all patients, 0.8, (0.1-12.3), p=0.902 in SC CIS, and 35.3, (1.3-864.4), p=0.029 in non-SC CIS. As for performance at two years (n, sensitivity: Se, specificity: Sp, accuracy: Acc, positive predictive value: PPV, negative predictive value: NPV), presence of SC lesions was highly sensitive for reaching an EDSS >=3.0 as the outcome in all patients (n=157, Se: 84.6, Sp 52.8, Acc 55.4, PPV 13.9, NPV 97.4), in SC CIS (n=53, Se 83.3, Sp 19.2, Acc 26.4, PPV 11.6, NPV 90.0), and in non-SC CIS (n=104, Se 85.7, Sp 69.1, Acc 70.2, PPV 16.7, NPV 98.5). Conclusions: The presence of at least one SC lesion at the time of the CIS is associated with short-term disability and further contributes to estimate the risk of disability accumulation, particularly in non-SC CIS. These results warrant validation in a mid-term follow-up. Disclosure G Arrambide has received compensation for consulting services from Biogen-Idec. M Tintoré has received compensation for consulting services and speaking honoraria from Bayer-Schering, Merck-Serono, BiogenIdec, Teva, Sanofi-Aventis, and Novartis. A Rovira serves on scientific advisory boards for NeuroTEC and on the editorial board of the American Journal of Neuroradiology and Neuroradiology, has received speaker honoraria from Bayer Schering Pharma, Sanofi-Aventis, Bracco, Merck Serono, Teva Pharmaceutical Industries Ltd. and Biogen Idec, receives research support from Bayer Schering Pharma, and serves as a consultant for Novartis. J Sastre-Garriga has received compensation for consulting services or speaking honoraria from Merck-Serono, Biogen-Idec, Teva, Almirall and Novartis. J Río has received speaking honoraria and personal compensation for participating on Advisory Boards from: Almirall; BayerSchering Healthcare; Biogen-Idec; Genzyme; Merck-Serono; Novartis; Teva and Sanofi-Aventis.

M Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, and Novartis. X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall. J Castilló, Vidal-Jordana A, I Galán, C Nos, B Rodríguez, L Midaglia, E Huerga, and C Auger report no conflict of interest related to this work.

OCT P997 Role of retinal nerve fibre layer thinning in monitoring multiple sclerosis M. Pisa, G. Di Maggio, S. Guerrieri, R. Santangelo, S. Medaglini, M. Rodegher, B. Colombo, L. Moiola, U. Del Carro, V. Martinelli, G. Comi, L. Leocani Neurologia, Ospedale San Raffaele, Milan, Italy Background: The availability of instrumental markers to monitor and predict disability progression in Multiple Sclerosis (MS) is fundamental to assess the efficacy of therapeutic interventions. The visual pathway is receiving increasing attention as a putative window into brain neurodegeneration. Objective: To investigate the usefulness of visual evoked potentials (VEPs) and optical coherence tomography (OCT) in monitoring MS disability. Methods: We performed VEPs, OCT with measurement of retinal nerve fiber layer (RNFL) and clinico-neuroradiological assessment at baseline and after 2 years follow-up in 59 subjects with defined MS and without optic neuritis (ON) within 6 months from baseline assessment. Results: We found that the mean binocular RNFL loss had a strong correlation with accumulation of disability (r = - 0,587; sig. < 0,0001) and was significantly lower in patients without accumulation of disability during the follow-up (n = 31) compared to patients with an increase of 0,5 points in the EDSS score (n = 11; p = 0,012; T test) or more (n = 17; p < 0,0001; T test). In a subset of 51 patients with a complete neuroradiological evaluation of disease activity during the follow-up, we found that the average binocular RNFL loss in patient with clinical or neuroradiological activity (26 patient) was -3,25 µm while in patients without disease activity (25 patients) it was -1,02 µm (T test; p < 0,0001). The number of new or reactivated brain lesions at MRI scans during the follow-up correlated with the RNFL mean loss (r = -0,510; p < 0,0001). In our cohort we found that changes in nervous conduction, evaluated as modifications of P100 latency in VEP during the followup, especially when they occurred in altered baseline VEPs, correlated with loss of RNFL (r = -0,240 sig. 0,009 considering all the 116 eyes with measurable cortical responses at VEP; r = -0,459 sig. 0,002 considering 45 eyes with measurable but abnormal cortical responses at baseline VEP). Although baseline RNFL was correlated with EDSS change at follow-up, this correlation lost significance after correcting for baseline EDSS.


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Poster Session 2, 21(S11) Conclusions: Progressive reduction of RNFL can be due to disease activity along the visual pathways or to global neurodegeneration processes. OCT may be more useful for monitoring neurodegeneration rather than as a prognostic indicator. Disclosure Marco Pisa: nothing to disclose P998 Structural functional relationship in the visual system in multiple sclerosis P. Tewarie1, L.J. Balk1, B.M. Uitdehaag1, C.J. Stam1, A. Petzold1,2 1VU Medical Center, Amsterdam, The Netherlands, 2UCL Institute of Neurology, London, United Kingdom Background: There is evidence that multiple sclerosis lesions in the visual pathways trigger retrograde trans-synaptic axonal degeneration which results in inner retinal layer degeneration. Patients frequently report a reduced visual quality of life despite relative preserved high contrast visual acuity. This study tested if loss of functional connectivity in the visual cortex can be related to structural changes in the retina. Methods: 102 patients with multiple sclerosis were included in this combined optical coherence tomography (OCT) and magnetoencephalography (MEG) study. Retinal spectral-domain OCT data were collected from the optic disc and macular region. Automated retinal layer segmentation was followed by qualitycontrol (OSCAR-IB). Average functional connectivity between visual areas was calculated by computing the phase lag index (PLI). Generalised estimating equations (GEE) were used for statistical analyses. Results: The mean age of the patients was 54.3 years (65% females) with a mean disease duration of 18.2 years and an averaged EDSS of 4. The disease course was relapsing remitting in 68, secondary progressive in 24 and primary progressive in 10. Unilateral multiple sclerosis associated optic neuritis (MSON) was present in 44 and bilateral MSON in 16 patients. There was a significant relationship of visual cortex resting state network connectivity with retinal layers. The findings were influenced by presence of optic neuritis, particular for the higher frequency bands (beta, alpha) and the outer macular layers. In absence of MSON this relationship was dominated by the lower frequency bands (theta, delta) with inner and outer retinal layers. Conclusion: These data suggest a frequency band specific relationship of the resting state visual cortex with retinal layers responsible for different levels of early visual processing. This relationship is influenced by optic neuritis. There is a need to investigate if these findings could be of future clinical relevance by testing network connectivity for relevant visual tasks. Disclosure Prejaas Tewarie received travel support from Novartis Pharma AG Lisanne J Balk reports no conflict of interests Bernard M.J. Uitdehaag has received personal compensation for consulting from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche en TEVA.

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Cornelis J Stam reports no conflict of interests Axel Petzold reports no conflict of interests

P999 Evidence of functional retinal impairment in the absence of sustained structural damage following MS-related optic neuritis J.V. Hanson1,2, S. Lukas2, K. Landau1, R. Martin2, C. GerthKahlert1, S. Schippling2 1Ophthalmology, University Hospital Zurich, 2Neuroimmunology and Multiple Sclerosis Research, University Hospital Zürich and University of Zürich, Zurich, Switzerland Background: Recent evidence suggests that the retinal nerve fibre layer (RNFL) and ganglion cell-inner plexiform complex (GCIP) are thinned following acute optic neuritis (ON), with mild thickening of the mid- and outer retina1. At 12 months post-ON, RNFL and GCIP remain abnormally thinned2 but the status of more distal layers at this time remains unknown. We have embarked on a detailed investigation of multiple sclerosis (MS) patients with and without ON using multimodal imaging, electrophysiological and clinical measurements in order to characterise MS phenotypes. We analysed the data from a subset of patients in order to search for structural and functional changes in the midand outer retina following ON. Patients and methods: Six patients (mean 33.7 years; 5 females) were identified from our study group as having had a single, unilateral ON more than 12 months previously (mean time since ON: 20 months). All were examined using OCT, electrophysiology (visual evoked potential (VEP), electroretinography (ERG), multifocal ERG (MF-ERG)), and high- and low-contrast visual acuity charts. 18 normal subjects (mean 31.7 years; 14 females) underwent OCT imaging in order to obtain normative data. All OCT scans were segmented in order to obtain measures for total macular volume (TMV), thickness of the full retina (FR), RNFL, GCIP, inner nuclear layer (INL), outer nuclear layer (ONL), outer plexiform layer (OPL), and photoreceptor complex (PR). Results: In MS eyes with a history of ON, TMV was reduced (3/6 eyes), and FR (3/6), RNFL (4/6) and GCIP (5/6) were thinned, whilst OPL thickness was increased in 1/6 eyes. No thinning of layers distal to GCIP was observed. All six patients had abnormal VEP, with 3/6 also having abnormal ERG and 2/5 abnormal MF-ERG suggestive of bipolar cell dysfunction. Abnormality in ERG and/or MF-ERG was associated with poorer clinical outcomes. Conclusion: Our study provides electrophysiological evidence of functional impairment of retinal layers that appear structurally normal on OCT following MS-related ON. ERG and/or MF-ERG indicative of bipolar cell dysfunction was recorded in three patients, in whom no corresponding structural changes in INL or other mid- or outer retinal layers were observed. 1 Gabilondo et al. Annals of Neurology 77, 517-528 (2015) 2 Costello et al. Journal of Neurology, Neurosurgery & Psychiatry doi:10.1136/jnnp-2014-309704 (in press) Disclosure James V.M. Hanson has received speaker fees from Biogen Idec Sebastian Lukas has received speaker fees from Heidelberg Engineering, Genzyme and Biogen Idec


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Klara Landau: nothing to disclose Roland Martin has received consulting/speaker fees from Novartis, Biogen Idec and Genzyme/Sanofi-Aventis Christina Gerth-Kahlert: nothing to disclose Sven Schippling has received research grants from Biogen Idec, Bayer Healthcare and Genzyme and consulting/speaker fees from Bayer Healthcare, Biogen Idec, Merck Serono, Novartis Pharma, TEVA and Genzyme/Sanofi-Aventis. P1000 Disease modifying therapy in relapsing remitting multiple sclerosis reduces inner nuclear layer volumes as measured by optical coherence tomography B. Knier1, L. Aly1, A. Berthele1, D. Buck1, M. Mühlau1,2, B. Hemmer1,2, T. Korn1,2 1Department of Neurology, Klinikum rechts der Isar, TU München, 2Munich Cluster of Systems Neurology (SyNergy), München, Germany Optical coherence tomography (OCT) of the retina allows accurate quantification of different retinal layers. It has previously been shown that disease activity in patients with relapsing remitting multiple sclerosis (RRMS) correlates positively with thickness of the inner nuclear layer (INL) as measured by OCT. Healthy controls (n=20), RRMS patients starting first disease modifying therapy (n=30) and RRMS patients denying therapy (n=30) were analyzed by spectral domain OCT at baseline and after 12 months. At baseline, INL volume was lower in healthy controls (0.96 ± 0.05 mm³) than in RRMS patients (treated: 1.0 ± 0.06 mm³; untreated: 0.99 ± 0.05 mm³). After 12 months, INL volumes remained unchanged in healthy controls (0.96 ± 0.06 mm³) and untreated RRMS patients (1.0 ± 0.05 mm³), whereas INL volumes significantly decreased in treated RRMS patients (0.97 ± 0.06 mm³; - 0.02 ± 0.03 mm³, p < 0.001). RRMS patients, in whom first immunotherapy failed during first 12 months, showed no reduction in INL volume at examination after one year. Taken together, INL volume is affected by immunotherapy in RRMS patients and could be a marker for therapeutic success. Disclosure Achim Berthele reports grants from Bayer Healthcare, personal fees from Biogen, Merck Serono, Teva, Novartis, and Genzyme, and compensations for clinical trials from Biogen, Novartis, Genzyme, Roche, and Alexion Pharmaceuticals - outside the submitted work. Dorothea Buck has received compensation for activities with Bayer HealthCare, BiogenIdec, MerckSerono, and Novartis. She is supported by the Abirisk Consortium. Mark Mühlau has received research support from Merck Serono and Novartis. Bernhard Hemmer has served on scientific advisory boards for Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GSK, Chugai Pharmaceuticals, Micromet, and Genzyme Corporation; he has received speaker honoraria from Bayer Schering, Novartis, Biogen Idec, Merck Serono, Roche, and Teva Pharmaceutical Industries Ltd.; he has received research support from Biogen Idec, Bayer Schering, Merck Serono, Five prime, Metanomics, Chugai Pharmaceuticals, Roche and Novartis.

Thomas Korn is funded by the DFG and SyNergy and receives a research grant from Biogen Idec. Lilian Aly and Benjamin Knier declare no financial disclosures. P1001 Afferent visual system damage in MOG-antibody seropositive opticospinal inflammatory disease H.G. Zimmermann1, F. Pache1,2, J. Mikolajczak1, S. Schumacher1, A. Lacheta1, S. Jarius3, B. Wildemann3, M. Reindl4, A. Waldman5, K. Ruprecht2, F. Paul1,2,6, A.U. Brandt1 1NeuroCure Clinical Research Center, 2Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, 3Division of Molecular Neuroimmunology, Department of Neurology, University of Heidelberg, Heidelberg, Germany, 4Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria, 5Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States, 6Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité Universitätsmedizin Berlin, Berlin, Germany Background: Antibodies against myelin oligodendrocyte glycoprotein (MOG-Ab) have been reported in patients with recurrent optic neuritis (ON) and aquaporin-4 antibody-negative neuromyelitis optica spectrum disorders. Objective: To describe patterns of retinal damage in patients with MOG-ab seropositive opticospinal inflammatory disease. Methods: Afferent visual system damage was assessed in a caseseries of seven MOG-ab seropositive patients by ON history, retinal optical coherence tomography, visual acuity, and visually evoked potentials. Results: Two patients with previous neuromyelitis optica spectrum disorder without aquaporin-4 antibodies and five patients with recurrent optic neuritis or chronic remitting inflammatory optic neuropathy who tested seropositive for MOG-ab were included in the study. All patients had ON episodes (12 out of 14 eyes) which were recurrent except in one eye. Eyes with a history of ON showed severely reduced retinal nerve fiber layer (48±6 µm) and ganglion cell and inner plexiform layer thickness (47±7 µm). Visual acuity was reduced in most eyes (0.73±0.84 logMAR) and P100 latency was abnormal in seven eyes. Four eyes had a visual acuity score worse than 1 logMAR. In all patients, response to acute optic neuritis therapy was poor. Conclusions: The spectrum of MOG-ab seropositive opticospinal inflammatory disease phenotype may be broader than initially described. Patients with otherwise unexplained ON should be tested for MOG-ab. Furthermore, these patients can have severe retinal axonal damage while retaining visual function. MOG-ab seropositive optic neuritis may be refractory and monitoring treatment efficacy will be crucial in limiting axonal and myelin damage in these patients. Disclosure HZ reports no conflicts of interest; HZ received speaking fees unrelated to this study from TEVA. FlP reports no conflicts of interest; FlP received research support from the German Ministry for Education and Research (Competence Network Multiple Sclerosis).


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Poster Session 2, 21(S11) JM reports no conflicts of interest; JM received speaking fees unrelated to this study from TEVA. SH reports no conflicts of interest. SH has nothing to disclose. AL reports no conflicts of interest. AL has nothing to disclose. SJ reports no conflicts of interest. SJ has nothing to disclose. BW reports no conflicts of interest; BW has received honoraria for speaking/consultation and travel grants from Bayer Healthcare, Biogen Idec, Merck Serono, Genzyme, a Sanofi Company, Novartis Pharmaceuticals, and Teva Pharma GmbH and research grants from Biogen Idec, Biotest, Merck Serono, Novartis Pharamceuricals, Teva Pharma GmbH, the German Ministry of Education and Research, and the Dietmar Hopp Foundation. MR reports no conflicts of interest; MR received research grants from Eugene Devic European Network (EDEN) project (ERANet ERARE 2, and Austrian Science Fund FWF project I916) AW reports no conflicts of interest; AW received funding unrelated to this study from the National Institutes of Health (USA) and Biogen Idec and is also a site PI for a clinical trial sponsored by Novartis Pharmaceuticals. KR reports no conflicts of interest; KR received research support unrelated to this study from Novartis as well as speaking fees and travel grants from Guthy Jackson Charitable Foundation, Bayer Healthcare, Biogen Idec, Merck Serono, sanofi-aventis/Genzyme, Teva, and Novartis and is supported by the German Ministry of Education and Research (BMBF/KKNMS, Competence Network Multiple Sclerosis). FrP reports no conflicts of interest; FrP received research support from the German Ministry for Education and Research (Competence Network Multiple Sclerosis), the Guthy Jackson Charitable Foundation and National Multiple Sclerosis Society, research grants and speaker honoraria unrelated to this study from Bayer, Teva, Genzyme, Merck, Novartis, MedImmune and is member of the steering committee of the OCTIMS study (Novartis). AUB reports no conflicts of interest; AUB received consulting fees unrelated to this study from Biogen, Novartis, Teva, Nexus, and Motognosis; AUB received funding unrelated to this study for research from Novartis, Biogen, BMWi and BMBF. P1002 Optic coherence tomography (OCT) and visual evoked potentials (VEPs): which is more sensitive to detect visual pathway abnormalities in NMO spectrum disorders (NMOSDs)? H. Jang, H.-J. Cho, E.B. Cho, J.M. Seok, H. Park, B.J. Kim, K.H. Lee, J.-H. Min Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Background: Neuromyelitis optica (NMO) is a severe disabling disorder affecting optic nerve, as well as spinal cord and brain. Objectives: We investigated the sensitivity of optic coherence tomography (OCT) and visual evoked potentials (VEPs) to detect visual pathway abnormalities in patients with NMO spectrum disorders (NMOSDs). Methods: Among 57 NMOSD patients with anti-aquaporin4antibody, 17 patients performed VEP and OCT, in the acute phase (within 1 month after attack) or in the chronic phase (at least 6

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months after attacks) of optic neuritis. Age, sex, disease duration, Expanded Disability Status Scale (EDSS) and visual acuity were also collected. Results: In the acute phase, VEPs showed abnormality in 91 % of eyes, although OCT was abnormal in only 9% of eyes. When analyzing 24 eyes in the acute phase (11 eyes with ON and 13 eyes without ON), VEPs and OCT sensitivity (G-RNFL) were significantly unbalanced in favour of VEPs (McNemar p=0.065). However, when analyzing 23 eyes in the chronic phase (12 eyes with chronic ON and 11 eyes without ON), no sensitivity difference was found between OCT and VEP. (McNemar p=0.125). Considering all eyes, global retinal nerve fiber layer (G-RNFL) showed significant correlation with disease duration (rho=-0.426, p=0.043). Conclusions: We demonstrate that VEP is more reflective of its earlier change compared with OCT, in NMOSD patients, although VEP and OCT showed no difference of sensitivity in eyes with chronic ON. Moreover, the correlation between G-RNFL and disease duration suggests that OCT may be useful as surrogate marker of disease burden in NMOSD. Further large cohort studies are needed in the future. Disclosure Hyemin Jang: nothing to disclose Hye-Jin Cho: nothing to disclose Eun Bin Cho: nothing to disclose Jin Myoung Seok: nothing to disclose Hearee Park: nothing to disclose Byoung Joon Kim: nothing to disclose Kwang Ho Lee: nothing to disclose Ju-Hong Min: nothing to disclose

P1003 Retinal structure injury and CSF humoral response in multiple sclerosis J. Chorostecki1, N. Seraji-Bozogzad1, F. Bao1, S. Reed1, C. Caon1, C. Santiago1, E. Bernitsas1, E. Frohman2, T. Bhatti3, B. Cree4, O. Khan1 1Wayne State University, Detroit, MI, 2University of Texas Southwestern, Dallas, TX, 3Duke University, Durham, NC, 4Univerisity of California San Francisco, San Francisco, CA, United States Objective: To examine retinal structure injury by measuring retinal nerve fiber layer (RNFL) thickness and macular volume (MV) in a cohort of MS patients who also underwent CSF and brain MRI studies. Sub-analysis was performed in African-American (AA) and Caucasian-American (CA) Multiple Sclerosis (MS) patients to examine the effect of ethnicity on the study outcomes. Background: Studies have shown a more aggressive disease course and higher CSF IgG Index in AA than CA with MS. The relationship between CSF humoral response and retinal structure injury in MS, and how ethnicity may influence this relationship, remains unexplored. Methods: Cross-sectional study in MS patients who underwent Spectral-Domain OCT, CSF studies including CSF IgG Index, and brain MRI scans. 35 healthy controls (HC) with OCT testing were also included for comparison.


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Results: 79 MS patients (69% females, mean age 42.2 years, disease duration 9.2 years, DMT exposure 6.6 years, EDSS 3.3) who fulfilled the criteria were included in the study. Mean RNFL thickness and MV was 88 um and 8.28 mm3 compared to 99.9 um vs 8.70 mm3 in HC (p< 0.0001). Sub-analysis showed lower RNFL and MV in AA-MS compared to CA-MS patients (85.2 vs 90.2, p=0.02; 8.17 vs 8.37, p=0.01). Mean CSF IgG Index was 1.58 in AA-MS vs 1.09 in CA-MS (p< 0.0001). Only AA-MS and not CA-MS, showed significant correlation between CSF IgG Index and RNFL (-0.41, p=0.0004), and CSF IgG Index and MV (-0.37, p=0.002). Only CSF IgG index, of all the clinical and MRI variables, predicted RNFL thickness and MV. Additional analyses including macular segmentation and brain tissue are ongoing. Conclusions: In AA-MS patients, CSF IgG Index inversely correlates with RNFL thickness and MV. This effect is not observed in CA-MS patients. These observations provide further insight into possibly humorally mediated retinal tissue injury in AA-MS patients. Disclosure Source of funding: Sastry Foundation. All authors have nothing to disclose relevant to this work.

P1004 Brain metabolites and retinal nerve fibre layer thickness and their relation to disability in multiple sclerosis: a longitudinal high-field proton magnetic resonance spectroscopy and optical coherence tomography study M. Pardini1,2, D. Botzkowski3, S. Müller4, J. Vehoff4, J. Kuhle5, A. Gass6, J. Wuerfel7,8,9, C. Valmaggia10, B. Tettenborn4, N. Putzki3, Ö. Yaldizli1,5 1Queen Square MS Centre, University College London, London, United Kingdom, 2Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy, 3Novartis, Basel, 4Neurologische Klinik, Kantonsspital St. Gallen, St. Gallen, 5Department of Neurology, University Hospital Basel, Basel, Switzerland, 6Universitätsklinik Mannheim, Mannheim, Germany, 7Medical Image Analysis Center, Universitätsspital Basel, Switzerland, Basel, Switzerland, 8CharitéUniversitätsmedizin Berlin, Neurocure Clinical Research Center, Berlin, 9Institut für Neuroradiologie, Universitätsmedizin Göttingen, Göttingen, Germany, 10Augenklinik, Kantonsspital St. Gallen, St. Gallen, Switzerland Background: In multiple sclerosis (MS), the retinal nerve fibre layer thickness (RNFLT) has been shown to correlate with brain atrophy, T2 white matter lesion load and diffusion tensor imaging abnormalities in normal-appearing white matter (NAWM). If this is true, we might expect similar associations between RNFLT and brain metabolites in NAWM quantified using proton magnetic resonance spectroscopy (H-MRS). Aim: To investigate associations between N-acetylaspartate (NAA) and Choline (Chol) levels relative to creatine (Crea) in T2 WM lesions, NAWM and RNFLT, their dynamics over time and associations with clinical outcome measures in clinically isolated syndrome (CIS), relapsing-remitting (RR) and secondary-progressive (SP)MS.

Methods: In total, 43 patients (mean age 40.1±9.9 years; disease duration 5.5±7.3 years; median EDSS 2.0 (range 0-6.0); 15 CIS, 21 RRMS, 7 SPMS) underwent standardised neurological examination including Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores, optical coherence tomography and 3T MRI including H-MRS at baseline and after one year. Results: During follow-up, none of the patients changed disease modifying therapy. The median EDSS remained constant. In all patients, mean NAA/Crea was lower in T2 WM lesions than NAWM (1.64±0.16 vs. 1.89±0.26, p< 0.001). Mean NAA/Crea was marginally lower in MS than CIS both in NAWM (1.84±0.23 vs. 1.97±0.25, p=0.12) and T2 WM lesions (1.62±0.17 vs. 1.68±0.12, p=0.18). During follow-up, mean NAA/Crea decreased in T2 WM lesions (1.60±0.15 vs. 1.64±0.16, p=0.02) and by trend in NAWM (1.76±0.53 vs. 1.88±0.24, p=0.098). In NAWM, relative NAA/Crea change over time was similar in CIS and MS. Mean RNFLT was higher in CIS than MS (100.71+9.86 vs. 92.23±12.8 µm, p=0.038). In all patients, mean RNFLT decreased over one year (94.27±11.40 vs. 92.64±10.87 µm, p=0.008). At baseline, EDSS correlated with NAA/Crea in T2 WM lesions (Spearman Rho=0.39) and MSFC correlated with NAA/Crea in T2 WM lesions (Rho=0.39) and NAWM (Rho=0.38; all p< 0.05). At baseline, RNFLT correlated with NAA/Crea in NAWM (Rho=0.46) and T2 WM lesions (Rho=0.63, both p< 0.05). In NAWM, relative NAA/Crea change correlated modestly with the RNFLT change over time (Rho=0.43, p< 0.05). Conclusions: In NAWM, relative NAA/Crea change correlated with RNFLT change over one year in a clinically stable MS population suggesting that both techniques are sensitive to detect subclinical disease progression. Disclosure Matteo Pardini received research support from Novartis. Daliah Botzkowski is employee of Novartis. Stefanie Müller received honoraria for travel, honoraria for lectures/consulting and/or grants for studies from Biogen idec, Novartis, Teva, Merck-Serono, Genzyme and Bayer Schweiz AG. Jochen Vehoff: nothing to disclose. Christophe Valmaggia: nothing to disclose. Jens Kuhle has received research support by an ECTRIMS Research Fellowship Programme, University of Basel, Swiss MS Society, Swiss National Science Foundation, Protagen AG, Roche, Genzyme and Novartis. Achim Gass: nothing to disclose. Jens Wuerfel: nothing to disclose. Barbara Tettenborn: nothing to disclose. Norman Putzki is employee of Novartis. Özgür Yaldizli has received honoraria for lectures from Teva (2011) and Bayer Schering (2012; both paid to University Hospital Basel) and research funding from MAGNIMS / ECTRIMS, the University of Basel, the Swiss MS Society and Free Academy Basel, Switzerland. P1005 Effect of age and MS disease duration on RNFL C. Fjeldstad1, J.P. Weir2, G. Pardo1 1MS Center of Excellence, Oklahoma Medical Research Foundation, Oklahoma City, OK, 2Department of Health, Sport,


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Poster Session 2, 21(S11) and Exercise Sciences, University of Kansas, Lawrence, KS, United States Background: The Retinal Nerve Fiber Layer (RNFL) has been identified as undergoing process of increased thinning over time in various neurodegenerative diseases, to include Multiple Sclerosis (MS). As this measurement represents a neuronal compartment exclusively, it is being evaluated as a possible surrogate marker for neuronal loss in the central nervous system. RNFL thinning has been shown to correlate with brain atrophy in MS patients without a history of optic neuritis (ON). Objective: To identify the effect that age and MS disease duration have on RNFL thickness. Method: This was a cross-sectional study of 515 MS patients with mean age of 48.0 (± .54) years, 89% of which had relapsing remitting MS. Only eyes without previous history of ON were included. The sample consisted of 79% females and 21% males. Mean disease duration was 9.8 ±.26 years; 89% were on disease modifying therapies. Each subject had Optical Coherence Tomography (OCT) measured using spectral domain modality at 2 different time points separated by 1 to 3 years. Separate bivariate regression analyses were performed examining the effect of age and MS duration on RNFL thickness. In addition, a multiple regression analysis was performed where age was forced into the equation 1st (a covariate), and MS duration was forced in 2nd. Results: The bivariate regression analyses showed significant relationships between age (RNFL = 94.5 - 0.77 age (years), r = -0.17, p 13) and 33 nondepressed Relapsing-Remitting MS patients, 16 depressed patients, and 32 healthy controls. Four RT tasks requiring an increasing level of effortful processing were administered: two Simple RT (SRT and SRT-SART), and two Choice RT (CRT and CRT-Visual Search) tasks. Data were analyzed with Student’s t-test and repeated measures ANOVAs. Results: The two MS groups did not differ in EDSS (p=.206), nor in disease duration (p=.541). The two depressed groups did not differ in the level of severity of depression (p=.364). Statistical comparison revealed that non-depressed MS patients obtained longer RTs in all RT tasks as compared to healthy controls (ps< .01). On the contrary, depressed patients were slower that healthy controls only in the most effortful task (CRT-Visual Search; p=.022). Finally, depressed MS patients obtained longer RTs not only in the most complex task (CRT-Visual Search; p=.026), but also in the other Choice RT task (CRT; p=.02) as compared to non-depressed MS. Conclusion: The contribution of MS and depression to SIP seems to be mediated by task complexity. In fact MS entirely accounts for deficits in less demanding speeded tasks; in tasks requiring more complex cognitive demands, depression exacerbates the information processing deficit due to the disease itself. Our findings suggest that a true understanding of the nature of SIP in MS would be incomplete without considering the important role played by depression. Disclosure G. Lubrini: nothing to disclose. J.A. Periáñez: nothing to disclose. M. Ríos Lago: nothing to disclose. C. De Dios:nothing to disclose. M. Fernández Fourier: nothing to disclose. A. Tallón Barranco: nothing to disclose. E. Díez Tejedor: nothing to disclose. P1026 Long-term follow-up of cognition by monthly symbol digit modalities test in multiple sclerosis patients treated with natalizumab M. Eriksen, Z. Illes, T. Sejbaek Department of Neurology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark Background: Symbol Digit Modalities Test (SDMT) is a clinical tool to assess cognition in MS. In patients treated with natalizumab, SDMT is applied to screen for early signs of progressive multifocal leukoencephalopathy. Objectives: To evaluate long-term monthly SDMT performance during natalizumab treatment, and examine effect of rearranging the order of SDMT symbols. Methods: 80 patients were examined with monthly SDMTs up to 37 months. Subgroup analyses were performed regarding gender, age, Extended Disability Status Scale (EDSS) and relapses. Lastly, the order of SDMT symbols was changed and performance was compared to baseline.


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Results: Continuous improvement in SDMT performance was found, averaging 1.2points/test the first six months and 0.4points/ test throughout. Such improvement was characteristic of all subgroups, except EDSS score 6. No influence of gender, treatment before SDMT testing or relapses was found. Higher age resulted in lower scores but equal improvement. Rearranging the order of symbols reversed SDMT scores to baseline regardless of EDSS and number of SDMT examinations. Conclusions: Until 37 months, SDMT performance continuously improves, except in patients rated EDSS 6. The new key reversed scores, indicating a learning effect. Results indicate that cognition remains stable two years during natalizumab treatment regardless of disease severity and progression. Disclosure Z. Illes has received research support from Biogen Idec and travel grants and speaking fees from Bayer Healthcare, Biogen Idec, Merck Serono, Sanofi-aventis/Genzyme, Teva Pharmaceuticals, and Novartis, research grants from Biogen Idec, Lundbeckfonden and Scleroseforeningen (Denmark). T. Sejbaek has received received travel grants and speaking fees from Biogen Idec, Merck Serono, Sanofi-aventis/Genzyme, Teva Pharmaceuticals and Novartis. M. Eriksen has received travel grants from Merck Serono. P1027 Impact of psychological factors on job retention in multiple sclerosis K. Ward1, C.R. Wicks1, A. Tennant2, A. Stroud1, H.L. Ford1 1Centre for Neuroscience, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom, 2Schweizer Paraplegiker-Forschung, Nottwil, Switzerland For people with MS (PWMS) the relationship between job retention and psychological factors is unclear. This may lead to psychological interventions to aid job retention. This study aims to investigate relationships between psychological factors, work instability and MS in a longitudinal prospective study of PWMS in paid employment. Participants completed two time point questionnaire packs of validated scales with repeat testing planned. 221 employed PWMS were recruited. Mean age was 40.6; 75.1% were female. 91% had relapsing-remitting MS (RRMS). 213 (96.4%) completed the baseline questionnaire, 199 completed month 8. Disease progression was mostly stable with just 3% transitioning from RRMS. 57.2% were at medium/high risk of job loss, with only marginal changes in work instability at 8 months. 14% reported high physical and psychological impact of MS at baseline which remained unchanged. There was a strong association between risk of job loss and both physical and psychological variables. Some psychological variables fluctuated, e.g. depression fell from 24.6% to 14.5%. No changes were reported in levels of fatigue or pain over this period. Psychological attributes in MS appear to fluctuate but contribute to work instability. Further investigation will clarify this relationship and inform possible intervention strategies. Disclosure No conflict of interests to declare. Funding from the MS Society (UK)

P1028 A simple measure of cognitive reserve predicts cognitive performance in a large group of MS patients A. Gallo1, R. Sacco1, G. Santangelo2,3, C. Somma1, M. De Stefano1, M. Della Corte1, G. Muzzo1, R. Docimo1, L. Lavorgna1, S. Bonavita1, G. Tedeschi1,4 1Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, 2Department of Psychology, Second University of Naples, Caserta, 3IDC-Hermitage-Capodimonte, 4MRI Research Centre SUN-FISM, IDC-Hermitage-Capodimonte, Naples, Italy Objectives: To assess, in a large group of MS patients, the relationship between CR measures and cognitive performances after controlling for multiple clinical and demographic parameters. Methods: 157 patients diagnosed with clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS) and secondaryprogressive MS (SPMS) were enrolled in the study. All patients underwent a careful revision of their medical history as well as a neurological evaluation including the Expanded Disability Status Scale (EDSS), the Fatigue Severity Scale (FSS) and the Chicago Multiscale Depression Inventory (CMDI). Two measures of CR were acquired: 1) the number of years of formal/academic education (EDU), 2) the acquired vocabulary knowledge (VOC), as assessed by the vocabulary task of the Wechsler Abbreviated Scale of Intelligence. On the same day of neurological and CR evaluation, cognitive functioning was assessed in all patients using the Brief Repeatable Battery (BRB) of neuropsychological tests. The relationships between CR measures and neuropsychological performance was assessed using a linear multivariate regression analysis including multiple demographic (i.e. age and sex) and clinical parameters (i.e. disease duration, EDSS, FSS, CMDI) as covariates. Results: Higher VOC was the best independent predictor of better performance on all BRB tests (0.01 < p < 0.001). Age, sex and EDSS also emerged as independent predictors of cognitive performances, but only in a few BRB tests. Conclusions: In the present study, conducted on a large singlecenter group of MS patients, we were able to show that a simple measure of CR such as the VOC was the stronger and more consistent predictor of cognitive performances on the BRB. Future multi-center studies with a longitudinal design and including magnetic resonance imaging (MRI) parameters, will have to further assess the utility of this simple CR measure as a clinicalmeaningful predictor of cognitive performances in MS patients. Disclosure Antonio Gallo: received speakers honoraria from Biogen Idec, Novartis, and Merck-Serono. Rosaria Sacco: nothing to disclose. Gabriella Santangelo: nothing to disclose. Carmela Somma: nothing to disclose. Manuela De Stefano: nothing to disclose. Marida Della Corte: nothing to disclose. Giulia Muzzo: nothing to disclose. Renato Docimo: nothing to disclose. Luigi Lavorgna: nothing to disclose.


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Poster Session 2, 21(S11) Simona Bonavita: received speakers honoraria from Biogen Idec, Novartis, and Merck-Serono. Gioacchino Tedeschi: has received compensation for consulting services and/or speaking activities from Bayer Schering Pharma, Biogen Idec, Merck Serono, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck Serono, and Fondazione Italiana Sclerosi Multipla.

Conclusion: Our data confirm earlier reports from crosssectional studies which found an association between cognition and PA. Longitudinal assessment in CogniPlus will further characterize the relation of cognitive function with PA, and may help improve advice to patients about behaviours that may help preserve cognitive function. Disclosure

P1029 Relation between cognitive function and physical activity in multiple sclerosis patients treated with interferon beta-1b - the CogniPlus study B. Brochet1, A. Tallner2, I.K. Penner3, U. Bauer-Steinhusen4, C. Tückmantel5, E.-M. Wicklein6, D.W. Langdon7 1University of Bordeaux, Bordeaux Cedex, France, 2University of Erlangen, Erlangen, Germany, 3University of Basel and University Hospital Basel, Basel, Switzerland, 4Bayer Vital GmbH, Leverkusen, 5Bayer Pharma AG, Wuppertal, 6Bayer Pharma AG, Berlin, Germany, 7Royal Holloway University of London, London, United Kingdom Background: Maintaining cognitive function in multiple sclerosis is a major concern. It is a priority to identify factors that can help preserve cognition, in addition to formal treatment. Physical activity has been suggested as a possible positive influence on cognition. Objective: The aim of the CogniPlus longitudinal study is to investigate the relationship of PA and cognitive function in interferon beta-1b treated patients with relapsing-remitting MS (RRMS). Methods: Patients with RRMS who walk unaided are followed over 2 yrs in this international prospective study. Cognition assessments include the Brief International Cognitive Assessment for MS (BICAMS, including Symbol Digit Modalities Test; SDMT, California Verbal Learning Test; CVLT, Brief-visual Memory test-revised; BVMT-R) performed at baseline and last visit. PA is assessed every 6 months by the Baecke questionnaire, a PA diary and the 2-min walking test. Fatigue (Fatigue scale for motor and cognitive fatigue, FSMC), depression (Center of Epidemiological Studies Depression scale, CES-D), healthrelated quality of life (hrQoL; Short Form-12, SF12) and pain (patient report and visual analogue scale) are also assessed every 6 months. Baseline data is presented. Results: A cohort of 637 patients performed the SDMT at baseline; 317 completed the CVLT (N=317) and 143 the BVMT-R. According to preliminary data, median age at baseline was 37 years (IQR 30.0-47.0), 66.8% are females, time from MS diagnosis was 20.9 months (IQR 4.4-77.0), median EDSS was 2.0 (IQR 1.0-3.0); 40.8% reported depressive symptoms, 75% fatigue and 46.9% pain at clinical levels. Median SDMT score was 45 (IQR 33.5-56.0) and scores correlated significantly with PA as measured by the Baecke questionnaire (0.28, p=< 0.0001) and with the 2min walking test (0.36, p< 0.0001); CVLT correlated weakly with PA according to the Baecke questionnaire (0.14, p= 0.04) as did the BVMT-R (0.24, p=0.03). SDMT, CVLT and BVMT were also significantly related with years of education and hrQoL and inversely with age and disease duration, SDMT and CVLT with depressive symptoms and fatigue, SDMT was inversely related with pain.

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The study is sponsored by Bayer Pharma AG. B Brochet or his institution received research grants and/or consulting fees from Biogen, Bayer, Novartis, Genzyme, Roche, Medday, Merck-Serono, and Teva. A Tallner has received honoraria for consultancy and lectures including travel costs from Novartis, Teva, Bayer Healthcare and Biogen. IK Penner has received honoraria for speaking at scientific meetings, serving at scientific advisory boards and consulting activities from Actelion, Bayer-Schering, Biogen Nordic, Merck Serono, Novartis, Roche and Teva Sanofi-Aventis. U Bauer-Steinhusen is a salaried employee at Bayer Vital and owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. C Tueckmantel is a salaried employee at Bayer Pharma AG and owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. EM Wicklein is a salaried employee at Bayer Pharma AG. DW Langdon has received research grants from Bayer, Novartis, Biogen, consultancy fees from Bayer, Teva and Novartis and has participated in speaker`s bureaus sponsored by Bayer, Biogen, Roche, Novartis and Teva

P1030 Proposed cut scores for tests of the brief international cognitive assessment of multiple sclerosis (BICAMS) M. Beier1, E.S. Gromisch2,3, A. Hughes1, K. Alschuler1, R. Madathil1, N. Chiaravalloti4,5,6, F.W. Foley2,7 1Department of Rehabilitation Medicine, University of Washington, Seattle, WA, 2Ferkauf Graduate School of Psychology, Yeshiva University, Bronx, NY, 3VA Connecticut Healthcare System, West Haven, CT, 4Kessler Foundation Research Center, West Orange, 5Department of Physical Medicine and Rehabilitation, 6Department of Neurosciences, Rutgers New Jersey Medical School, Newark, 7Holy Name Medical Center Multiple Sclerosis Center, Teaneck, NJ, United States Background: Cognitive impairment is common in multiple sclerosis (MS). Over the past decade, an international consensus committee developed the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS); a cognitive battery which targets cognitive impairments commonly seen in MS. Unfortunately, traditional scoring of the BICAMS neuropsychological tests can be quite cumbersome and time-consuming. Cutscores may help to (1) identify patients with cognitive impairments, (2) aid in clinical decision making, and (3) reduce administration time. The aim of this study was to establish cut scores for the neuropsychological tests of the BICAMS.


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Methods: Data for this study was collected from two MS Centers. Participants were given neuropsychological evaluations for clinical purposes, but provided consent for results to be used in research. ROC curve analysis was used to identify cut scores yielding the best balance of sensitivity and specificity. Impairment was defined in two ways: 1.5 and 2 standard deviations (SD) below the normative mean. Results: All cut scores yielded good sensitivity and specificity for identifying impaired cognitive performance. On the Symbol Digit Modalities Test, a cut score of 44, based on 1.5 SD, identified the best balance between sensitivity (.951) and specificity (.867) (AUC = 0.964, p < .0001, 95% CI [.949, .98]). For 2 SD, the best cut score was 38 (AUC = 0.976, p < .0001, 95% CI [.961, .99], sensitivity .939, specificity .926). On the California Verbal Learning Test - II (CVLT-II), a cut score of 39 (1.5 SD) yielded the best sensitivity (.955) and specificity (.883) (AUC=0.975, p < .0001, 95% CI [.960, .989]). For 2 SD, a cut-score of 35 was best (AUC = .974, p < .0001, 95% CI [.96, .989], sensitivity .943, specificity .092). On the Brief Visuospatial Memory Test-Revised (BVMT-R), the best cut scores were 17 at 1.5 SD (AUC=0.987, p < .0001, 95% CI [.979, .996], sensitivity .943, specificity .925) and 16 at 2 SD (AUC = .977, p < .0001, 95% CI [.964, .99], sensitivity .936, specificity .895). Conclusions: Cut scores can accurately identify cognitive impairment on all subtests of the BICAMS. Use of cut scores may improve screening for cognitive impairment while reducing administrative burden. Disclosure Meghan Beier: Nothing to disclose Elizabeth S. Gromisch: Nothing to disclose Abbey Hughes: National Multiple Sclerosis Society (grant no. MB 0026) Kevin Alschuler: Nothing to disclose Renee Madathil: Nothing to disclose Nancy Chiaravalloti: Nothing to disclose Frederick W. Foley: BICAMS committee member

Immunomodulation/Immunosuppression P1031 Effect of teriflunomide on relapses associated with disability worsening: results from the TEMSO and TOWER studies P.W. O’Connor1, G. Comi2, K. Thangavelu3, P. Truffinet4, L. Kappos5 1University of Toronto, Toronto, ON, Canada, 2University VitaSalute San Raffaele, Milan, Italy, 3Genzyme, a Sanofi company, Cambridge, MA, United States, 4Genzyme, a Sanofi company, ChillyMazarin, France, 5University Hospital Basel, Basel, Switzerland Background: Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting MS. In 2 pivotal phase 3 clinical trials in patients with relapsing forms of MS (TEMSO, NCT00134563 and TOWER, NCT00751881), teriflunomide 14 mg significantly reduced the annualized relapse rate by 31.5% (P< 0.001, TEMSO) and 36.3% (P< 0.001, TOWER), and significantly

reduced the risk of disability progression sustained for 12 weeks by 29.8% (P=0.028, TEMSO) and 31.5% (P=0.044, TOWER) compared with placebo. Objective: To assess the effect of teriflunomide 14 mg on relapses associated with confirmed disability worsening in a post-hoc analysis of the pooled TEMSO and TOWER data set. Methods: This analysis was performed on the pooled data set from TEMSO and TOWER, and included 728 patients in the 14 mg group and 751 patients in the placebo group. In the subgroup of patients who relapsed, treatment group comparisons were made using a logistic regression model for those patients who had disability progression starting at any time after a relapse and confirmed at a scheduled visit at least 12 weeks later. Results: In the pooled data set, 36.1% (n=263) of patients treated with teriflunomide 14 mg had relapses, compared with 49.3% (n=370) in the placebo group (P< 0.0001). Of these patients, 22% (n=58) in the 14-mg group vs 29% (n=106) in the placebo group had disability progression (OR 1.455; 95% CI: 1.002, 2.111; P=0.0486). In the majority of patients who experienced 12-week confirmed disability progression any time after a relapse, progression started within 30 days of relapse onset. Approximately 90% of patients in both treatment groups who remained free of relapses also remained free from 12-week confirmed disability progression. Conclusions: Patients with MS who experience relapse are at greater risk of 12-week confirmed disability worsening. In patients who relapsed in the TEMSO and TOWER studies, treatment with teriflunomide 14 mg significantly increased the probability of remaining disability free. Disclosure Study supported by Genzyme, a Sanofi company. PWO: Consulting fees (Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, Sanofi, Teva, all related to MS clinical trials); contracted research (Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, Sanofi, Teva, for clinical trials work). GC: Consulting fees (Almirall, Bayer, Chugai, Excemed, Genzyme, Merck Serono, Novartis, Receptos, Sanofi, Serono Symposia International Foundation [SSIF], Teva); fees from nonCME services (Almirall, Bayer, Biogen, Excemed, Genzyme, Merck Serono, Novartis, Receptos, Sanofi, SSIF, Teva). KT: Employee of Genzyme. PT: Employee of Genzyme, with ownership interest. LK: Author´s institution (University Hospital Basel) has received in the last 3 years and used exclusively for research support: steering committee, advisory board, and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, Xenoport); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, Teva); support of educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva); royalties (Neurostatus Systems GmbH); grants (Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society, Swiss National Research Foundation).


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Poster Session 2, 21(S11) P1032 The oral immunomodulator laquinimod affects experimental autoimmune encephalomyelitis via the aryl hydrocarbon receptor J. Berg1, Y. Mahmoudjanlou1, A. Duscha1, C. Esser2, R. Gold1, A. Haghikia1 1Department of Neurology, Ruhr University Bochum, Bochum, 2Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany

P1033 Teriflunomide mechanism of action: linking species’ sensitivities to pregnancy outcomes L. Davenport1, A. Edling2, P. Finn2, P. Truffinet3, S. Cavalier4 1Sanofi, Bridgewater, NJ, 2Genzyme, a Sanofi company, Framingham, MA, United States, 3Genzyme, a Sanofi company, Chilly-Mazarin, France, 4Genzyme, a Sanofi company, Cambridge, MA, United States

Background: The orally administered immunomodulator laquinimod is currently reassessed for therapy of multiple sclerosis (MS), whereby growing insight into its mode of action (MoA) is of particular interest. Concurrently, the involvement of the ligandactivated aryl hydrocarbon receptor (AhR) in immune responses and T cell differentiation is increasingly revealed. So far, the cellular receptor mediating laquinimods MoA is unknown. Targets: We investigated whether the previously described neuroprotective effect of laquinimod is mediated by the AhR. Furthermore we examined its impact on differentiation and proliferation of several pro- and anti-inflammatory immune cell populations. Methods: MOG35-55 EAE was induced in 8-week old AhR knockouts (KOs) and their wild-type (WT) littermates which were daily treated with 200 µl laquinimod (5 mg/kg) or the solvent (H2O) via oral gavage for 25 days. Mice were perfused with 4 % PFA followed by embedding spinal cord and spleen in paraffin and sectioning into 5 µm slices. DAB stainings for CD3+ T cell and Mac3+ macrophage infiltration as well as LFB + PAS staining for demyelination and Bielschowsky silver impregnation for axonal density were performed and analyzed. Furthermore, we performed extensive immune assays including T cell differentiation under polarizing conditions for TH1, TH17 and Treg from healthy WT and KO animals in the presence or absence of different concentrations of laquinimod before quantifying via FACS. Results: Laquinimod treated WTs show a significant amelioration of EAE in contrast to the KO animals, which resemble the H2Otreated controls in disease course. Analyses of the spinal cord reveal a significant decrease of demyelination, axonal loss, and immune cell infiltration in the treated WTs. However, treatment with laquinimod did not diminish the infiltration of T cells and macrophages in the treated KOs. Conclusions: Here we show a potential receptor for the mediation of laquinimod´s previously described capacity to ameliorate the course of EAE in mice. Our functional data reveal that the amelioration observed in the WTs is absent in the KO animals hence indicating that transduction of laquinimod´s neuroprotection is mediated by the AhR. While the decrease of demyelination and axonal loss were found in both treated groups, the KOs lack the preservation from T cell and macrophage infiltration into the CNS.

Introduction: Teriflunomide is a once-daily oral immunomodulator for treatment of relapsing-remitting MS. The primary mechanism of action involves selective, reversible and non-competitive inhibition of dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme required for de novo pyrimidine synthesis. Animals are generally more sensitive to teriflunomide than humans. Teriflunomide is embryo-toxic and teratogenic in rats and rabbits and therefore is contraindicated in pregnancy.1 However, available data from the clinical programme have shown no signal for human teratogenicity. Objectives: To investigate inter-species differences in teriflunomide pharmacology as a possible source of the discrepancy between clinical and non-clinical outcomes. Methods: Teriflunomide was administered to pregnant rats or rabbits during organogenesis, and fetal examinations conducted. Data on human fetal exposure were taken from the teriflunomide clinical programme. Enzyme kinetic experiments performed in human and animal cells provide a mechanistic rationale for the species differences in sensitivity to teriflunomide. Results: Fetal malformations and embryo-fetal deaths were observed when teriflunomide was administered to pregnant rats and rabbits during organogenesis. Animal maternal plasma exposure at the no-effect level for embryo-fetal toxicity was less than in humans at the maximum recommended dose. As of 12 March 2015, no signal of human teratogenicity was reported from teriflunomide. This is based on the teriflunomide clinical programme (70 embryos were exposed in female patients with 26 live births) and clinical and post-marketing data, from women with rheumatoid arthritis exposed to leflunomide, the parent compound of teriflunomide. A higher binding affinity of teriflunomide was observed for rat DHODH (Ki: 25.8 nM) vs human DHODH (Ki: 1050 nM). Inhibition of rat DHODH (IC50: 18 nM) was more pronounced than human DHODH (IC50: 773 nM). Anti-proliferative activity of teriflunomide was 145 times greater in rats than humans. Conclusions: These studies suggest that differences in enzyme kinetics may be responsible for species differences in teriflunomide pharmacology, with animals being more sensitive to teriflunomide than humans. Differences in enzyme kinetics may also help explain the teratogenicity observed in animals but not in humans at similar exposures to date. 1. AUBAGIO® (teriflunomide) SmPC. Sanofi-Aventis, 2014.

Disclosure Johannes Berg: nothing to disclose Yasaman Mahmoudjanlou: nothing to disclose Alexander Duscha: nothing to disclose Charlotte Esser: nothing to disclose Ralf Gold: nothing to disclose Aiden Haghikia: nothing to disclose

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Disclosure Study supported by Genzyme, a Sanofi company. LD: Employee of Sanofi. AE and PF: Employees of Genzyme. PT and SC: Employees of Genzyme, with ownership interest.


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P1035 Compliance and discontinuation rates with Gilenya® and other disease-modifying therapies: Canadian real-world experience P. Duquette1,2, M. Yeung3, R. Schecter4, P. Haddad4 1Notre Dame Hospital, Montreal, 2Faculté de Médecine, Université de Montréal, Montréal, QC, 3Multiple Sclerosis Clinic, University of Calgary, Calgary, AB, 4Novartis Pharmaceuticals Canada Inc., Dorval, QC, Canada Background: Current pharmacological management of relapseremitting multiple sclerosis (RRMS) includes the use of oral, injectable, or infusible Disease Modifying Therapies (DMTs). Achieving therapeutic goals in chronic conditions such as MS requires strict adherence to the medication and administration schedule. Objective: To assess compliance and discontinuation rates with Gilenya® compared to other oral, injectable or infusible DMTs in Canadian patients with RRMS. Methods: This non-interventional, retrospective analysis was based on private claims from patient cohorts accessed through IMS Brogan Rx Dynamics®. Patients had at least one prescription filled for each DMT (oral: Gilenya®, Tecfidera®, Aubagio®; injectable: Betaseron®, Rebif®, Avonex®, Copaxone®, Extavia® (BRACE); infusible: Tysabri®). Patients were deemed compliant if the medication possession ratio (MPR) was ⩾80%. The discontinuation rate was calculated based on patients who stopped therapy or who were switched to another DMT. Both compliance and discontinuation rates were collected at 6-month intervals after starting a new DMT. Period for compliance cohorts were from August 2011 to December 2014 (rolling 36 months total). Period for discontinuation cohorts were from September 2011 to January 2015. Results: The compliance data was collected for 10315 patients (Gilenya®, n=1524; Tecfidera®, n=1828; Aubagio®, n=456; Tysabri®, n=604; BRACE, n=5903). The compliance rate across Canadian provinces was higher for Gilenya® (78%) compared to other DMTs, including Tysabri® (72%), Tecfidera® (70%), and BRACE (56%). In Quebec, Gilenya® had a compliance rate of 80%, particularly higher than Tecfidera® (68%) and BRACE (65%). Patients treated with Gilenya® had the lowest discontinuation rate across Canada (22%), compared to Tysabri® (30%) and BRACE (47%). In Quebec, Tecfidera® had a higher discontinuation rate (29%) than other orals (Gilenya®, 20%; Aubagio®, 23%) and Tysabri® (25%). Conclusions: In a real-world setting across Canada, the compliance rate with Gilenya® was higher than for other oral or injectable/infusible DMTs. In addition, the discontinuation rate with Gilenya® was lower compared to other DMTs. These findings may facilitate MS management strategies which may lead to improved clinical and economic outcomes. IMS Brogan Rx Dynamics®, Betaseron®, Rebif®, Avonex®, Copaxone®, Extavia®, Tysabri®, Gilenya®, Tecfidera® and Aubagio® are registered trademarks. Disclosure Pierre Duquette - Has received honoraria for advisory boards, for CMEs from Novartis, Biogen-Idec, Genzyme, EMD Serono and Teva Neurosience. Dr Duquette has taken part in

Investigator-initiated trials funded by Novartis, Biogen-Idec, Genzyme and EMD Serono. Dr Duquette has received funding from peer-reviewed agencies such as the Canadian Institutes for Health Research (CIHR) and the MS Society of Canada. Michael Yeung - Has received consultation fees from EMD Serono, Genzyme and Novartis, and the Canadian Agency for Drugs and Technologies in Health (CADTH)/Health Canada, and research support from Biogen-Idec, Genzyme, Hoffmann-La Roche, Novartis, and Teva Canada Innovation. Robyn Schecter - Employee of Novartis Pharmaceuticals Canada Inc. Paola Haddad - Employee of Novartis Pharmaceuticals Canada Inc. P1036 Treatment patterns and efficacy in multiple sclerosis in a real life setting: a prospective cohort study P. Duquette1, T. Ducruet2, E. Desplats2, P. Despault1 1Neurosciences, CHUM Notre-Dame, 2Statistics, CHUMèreEnfant, Montréal, QC, Canada Background: Recent clinical trials have shown improvement in disease outcomes and survival in Multiple Sclerosis (MS) patients. Due to the complexity of the disease, effectiveness of treatment in a real-life setting is less known and prone to potential indication, treatment observance and switching treatment biases. Objective: To describe treatment patterns and study factors associated to the change in the course of the disease and effectiveness of treatments. Methods: The CHUM Notre-Dame MS Clinic, in operation since 1975, has prospectively collected data in a predominantly FrenchCanadian population, using the iMed database. Time to EDSS scores 4, 6, 8, and 10 were assessed using Kaplan-Meier estimates. A Cox proportional hazard was applied to identify factors associated to time to those EDSS scores. Demographic data (age at onset of disease course, gender) and the following comorbidities were assessed: hypertension, depression, dyslipidemia, diabetes, stroke, heart disease, cancer, and COPD. Treatments were grouped according to therapeutic area and studied as time-dependant variables in the survival model using the treatment initiation date as the index date. Unexposed patients were used as the reference class. Sensitivity analyses were applied to take into account recent time change in treatment exposure. Results: The total MS population is 3758, comprised of 2754 women (73.3%) and 1004 men (26.7%). The median age at onset is 30.7 years. The clinical course is RRMS in 87% and PPMS in 13% of patients. Median times to EDSS Score 4, 6, and 10 were 21.5, 27.6, and 42.9 years, respectively. Gender (male), age at onset of the disease (older age), smoking habits and type of MS disease were negatively associated to time-to-event (p< .001). Treatments were found associated to time to the EDSS scores, but we were unable to completely control for indication bias. As treatments have been available only since 1998, it has been impossible to evaluate the impact on higher EDSS levels, namely EDSS 8 and 10, as too few patients have reached that stage. Conclusions: Our study was able to identify risk factors associated to disease course (EDSS levels). Alternate designs, such as matched cohorts, to study treatment efficiency in a real-life setting should be investigated.


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Poster Session 2, 21(S11) Disclosure

Disclosure

T Ducruet, P Duquette, P Despault, E Desplats: nothing to disclose.

Study supported by Genzyme, a Sanofi company. AC: Consulting fees, speaker honoraria (Almirall, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi, Teva); research support (Biogen Idec, Genzyme, Novartis); has served as country lead investigator (Germany) for TEMSO and TENERE trials (sponsored by Sanofi). JdS: Consulting services, advisory boards (Genzyme). KT: Employee of Genzyme. PT: Employee of Genzyme, with ownership interest. PR: Employee of Genzyme. MC: Consulting services, speaking honoraria (Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi, Teva)

P1037 Efficacy of teriflunomide treatment in achieving no evidence of disease activity over a period of 6 months to 2 years in the TEMSO study A. Chan1, J. de Seze2, P. Truffinet3, K. Thangavelu4, P. Rufi3, M. Comabella5 1St Josef Hospital, Ruhr University Bochum, Bochum, Germany, 2Strasbourg University, Hôpital Civil, Strasbourg, 3Genzyme, a Sanofi company, Chilly-Mazarin, France, 4Genzyme, a Sanofi company, Cambridge, MA, United States, 5Centre d’Esclerosi Múltiple de Catalunya, Institut de Recerca Vall d’Hebron, Hospital Universitari Vall d’Hebron, Barcelona, Spain Background: Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting MS. It has demonstrated consistent efficacy in placebo-controlled clinical trials in patients with relapsing forms of MS, and has a well-characterized safety and tolerability profile. Over a 2-year period the likelihood of patients achieving no evidence of disease activity (NEDA) was greater for patients receiving teriflunomide 14 mg (OR 2.06; 95% CI 1.35, 3.13; P=0.0007) and 7 mg (OR 1.52; 95% CI 0.98, 2.34; P=0.0574) vs placebo (Chan et al., European Academy of Neurology 2015). Objectives: To evaluate the efficacy of teriflunomide in achieving NEDA, once teriflunomide is fully active, using a post hoc analysis of the TEMSO study (NCT00134563). Methods: Patients with relapsing forms of MS (N=1088) were randomized (1:1:1) and treated with teriflunomide 14 mg, 7 mg, or placebo for 108 weeks. Over the period of 6 months to 2 years, the proportion of patients with a composite measure of NEDA (defined as no gadolinium-enhancing [Gd+] T1 lesions or no new/ enlarging T2 lesions, and no clinical relapse or 12-week sustained disability progression) was reported. The proportion of patients free of clinical disease activity (CDA) (no clinical relapse or 12-week sustained disability progression) or MRI activity (no Gd+ T1 lesions, and no new/enlarging T2 lesions) was also reported. Treatment group comparisons vs placebo were made using a logistic regression model. Results: Over the study period, the proportion of patients with NEDA was significantly greater in patients receiving teriflunomide 14 mg (28.1%, P< 0.0001) or teriflunomide 7 mg (21.5%, P=0.0180) vs placebo (14.3%). The proportion of patients free from CDA was significantly higher in the 14-mg group vs placebo (61.3% vs 49.2%, P=0.0022). The proportion of patients free of MRI activity was significantly higher in both the 14-mg (45.1%, P< 0.0001) and 7-mg (35.4%, P=0.0029) groups vs placebo (24.6%), with teriflunomide 14 mg exhibiting superiority over teriflunomide 7 mg (P=0.0141). Conclusions: Teriflunomide was associated with a significant, dose-dependent increase in the proportion of patients with NEDA over the period 6 months to 2 years in the TEMSO study. This post hoc analysis provides further evidence for the sustained effects of teriflunomide on overall disease activity.

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P1038 Concomitant granule cell neuronopathy in patients with natalizumab-associated PML M.T. Wijburg1,2, D. Siepman3, J.J. van Eijk4, J. Killestein1, M.P. Wattjes2 1Department of Neurology, 2Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, 3Department of Neurology, Erasmus Medical Centre, Rotterdam, 4Department of Neurology, Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands Background: Granule cell neuronopathy (GCN) is a rare JC virus (JCV) infection of the cerebellar granule cell neurons in immunocompromised patients. On brain imaging, GCN is characterized by cerebellar atrophy which can be accompanied by infratentorial white matter lesions. It has been shown that GCN may occur concomitant to progressive multifocal leukoencephalopathy (PML). Objective: To investigate the occurrence of imaging findings suggestive of GCN in natalizumab-associated PML cases. Methods: Brain MRIs of 44 natalizumab-associated PML cases were retrospectively reviewed by a neuro-radiologist with expertise in diagnosis and treatment of PML and GCN for the degree of cerebellar atrophy before, during and after PML diagnosis. We defined the extent of atrophy as follows: grade 0: no atrophy; grade 1: dilated sulci; grade 2: loss of volume; grade 3: end stage atrophy. Results: Of the 44 PML patients, 36 had solely supratentorial PML and 8 had infratentorial PML or a combination of both. Three patients developed cerebellar atrophy or showed progressive cerebellar atrophy after the diagnosis of PML (none before PML diagnosis). In two of them cerebellar atrophy developed from grade 0 at the time of the diagnosis of supratentorial PML, to grade 1 and 2 after 2.5 and 3 months respectively, without the occurrence of infratentorial white matter lesions. The third patient showed progression of cerebellar atrophy from grade 1 to grade 2 in the 3 months following infratentorial PML diagnosis. In the first two patients GCN, concomitant to supratentorial PML, most likely caused the cerebellar atrophy. In the third patient the increase of cerebellar atrophy may be caused either by GCN concomitant to PML or, secondary, by volume loss resulting from the infratentorial PML manifestations. However, none of the other seven infratentorial PML cases developed cerebellar atrophy.


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Conclusion: Among 44 natalizumab-associated PML patients we found three radiological suspected GCN cases. This suggests that imaging findings suggestive of GCN are probably more common than previously thought, especially in natalizumab-associated PML patients. No evidence of a link between infratentorial PML and imaging findings suggestive of GCN was observed. Disclosure M.T. Wijburg: nothing to disclose. D. Siepman: nothing to disclose. J.J.J. van Eijk: nothing to disclose. J. Killestein: accepted speaker and consulting fees from MerckSerono, Biogen Idec, Teva, Genzyme and Novartis. M.P. Wattjes: received consultancy fees from Biogen Idec and Roche.

P1039 Safety and efficacy of transitioning to teriflunomide in patients switching from other diseasemodifying therapies, including natalizumab K. Edwards1, M.S. Freedman2 1Multiple Sclerosis Center of Northeastern New York, Latham, NY, United States, 2University of Ottawa and The Ottawa Hospital Research Institute, Ottowa, ON, Canada Background: Teriflunomide, a once-daily oral immunomodulator approved in relapsing-remitting MS, maintains efficacy with numerically greater relative reductions in relapse rate and disease progression in patients switching from other disease-modifying therapies (DMTs), as shown in phase 3 clinical trials (TEMSO [NCT00134563], TOWER [NCT00751881], and TENERE [NCT00883337]). In these trials, most patients switched from a prior therapy other than natalizumab (NTZ). Transitioning from NTZ may be problematic, given the potential risk of progressive multifocal leukoencephalopathy (PML) post-transition and the risk of severe rebound of disease upon cessation of NTZ. Objective: To review the safety and efficacy of teriflunomide in patients switching from other DMTs, including NTZ, in randomized clinical trials and clinical practice at a single center. Methods: Post-hoc analyses of pooled TEMSO and TOWER data (n=2251) were performed for annualized relapse rate (ARR) and 12-week confirmed disability progression according to patient subgroups separated by DMT use (⩾2 prior DMTs; 1 prior DMT; 0 prior DMTs). In the TENERE extension, patients (n=237) received teriflunomide 14 mg, without washout, regardless of treatment in the core study (interferon beta [IFNβ]-1a or teriflunomide 14 mg), and ARR was evaluated. A prospective study of patients (n=15) switching to teriflunomide 14 mg within 4 weeks of their final NTZ dose due to increased risk of PML assessed regular 3T brain MRI, expanded disability status score (EDSS), and laboratory evaluation on a monthly basis. Results: A consistent efficacy and safety profile was seen in the pooled TEMSO/TOWER data across all prior DMT subgroups. In the TENERE extension, relapse rates remained low in patients switching from IFNβ-1a and continuing teriflunomide 14 mg, with a similar incidence of adverse events. In the 6-month interim analysis of patients switching from NTZ to teriflunomide 14 mg: 13/15 patients remained stable at Month 6, with improvement (or

no change) in EDSS; 2 patients experienced a relapse with new contrast-enhancing lesions, and there was no emergence of PML. Conclusions: Teriflunomide has shown a consistent safety and efficacy profile in patients switching from DMTs. Initial analysis of patients switching from NTZ showed teriflunomide to be safe and effective in minimizing “rebound” clinical and MRI activity, with no new safety signals. More patients and a longer observation period are needed to confirm these findings. Disclosure Study supported by Genzyme, a Sanofi company. KRE: Consulting services (Biogen, Genzyme); Speakers Bereau (Biogen, Genzyme, Novartis); research support (Biogen, Eli Lilly, Eisai Inc, Forum Pharmaceuticals, Genentech, Genzyme, Hoffman-La Roche, Novartis, Pfizer, Merz Pharmaceuticals, Vaccinex). MSF: Consulting fees (Bayer HealthCare, Biogen Idec, Chugai, EMD Canada, Genzyme, Novartis, Sanofi, Teva Canada Innovation); member of company advisory boards/board of directors/other similar group (Bayer HealthCare, Biogen Idec, Hoffman La-Roche, Merck Serono, Novartis, Opexa, Sanofi); speaker bureaus (Genzyme). P1040 Comparative effectiveness using a matching-adjusted indirect comparison between delayed-release dimethyl fumarate and fingolimod for the treatment of relapsing-remitting multiple sclerosis R.J. Fox1, G. Cutter2, A. Chan3, J. Xiao4, M. Okwuokenye4, D. Levison4, J.B. Lewin4, M.R. Edwards4, J.L. Marantz4 1Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, 2University of Alabama at Birmingham, Birmingham, AL, United States, 3St. Josef Hospital, Ruhr University, Bochum, Germany, 4Biogen, Inc., Cambridge, MA, United States Background: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) and fingolimod are oral diseasemodifying treatments for relapsing-remitting multiple sclerosis (RRMS). Direct comparisons of these agents are not possible due to a lack of head-to-head trials. Matching-adjusted indirect comparison is a technique in which individual patient data from a study (or pooled studies) of one agent are compared with aggregate data from a study (or pooled studies) of another agent. Objectives: Conduct comparative effectiveness research by indirectly comparing treatment or efficacy outcomes (including annualized relapse rate [ARR] and time to 12-week confirmed disability progression [CDP]) at 2 years with DMF or fingolimod treatment of RRMS in Phase 3 studies. Methods: Individual patient data from the DEFINE (Gold et al. 2012) and CONFIRM (Fox et al. 2012) studies of DMF (pooled) and aggregate data from the FREEDOMS (Kappos et al. 2010) and FREEDOMS II (Calabresi et al. 2014) studies of fingolimod (pooled using random effects meta-analysis) were utilized. The glatiramer acetate (GA) arm of CONFIRM was excluded because GA was a reference comparator and was not included in DEFINE. Matching-adjusted indirect comparison was conducted as described in Signorovitch et al (2010). Patients in the pooled


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Poster Session 2, 21(S11) DMF trials were weighted such that their average baseline characteristics (age, gender, time from onset of symptoms, EDSS score, number of relapses in previous year) matched those reported for patients in pooled fingolimod trials. After matching, treatment outcomes (weighted efficacy outcomes) for patients treated with the approved dose of DMF (240 mg twice daily) were compared with summary efficacy outcomes for patients treated with the approved dose of fingolimod (0.5 mg once daily). Results: After matching, all baseline characteristics were balanced between the pooled DMF trials and the pooled fingolimod trials. At 2 years, ARR rate ratio (95% confidence interval [CI]) for DMF vs placebo was 0.52 (0.43, 0.62) and for fingolimod vs placebo was 0.48 (0.42, 0.55). 12-week CDP (0.57, 0.85) and for fingolimod vs placebo was 0.76 (0.61, 0.95). Additional data, including comparison of DMF vs fingolimod, will be presented. Conclusions: In a matching-adjusted indirect comparison, the efficacy of DMF was similar to that of fingolimod on clinical measures of relapse and disability progression. Disclosure This study is supported by Biogen, Inc. Robert J. Fox: consultant fees from Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Biogen, and Novartis; research grant funding from Novartis. Gary Cutter: serves on data safety monitoring committees for Antisense Therapeutics Limited, Sanofi-Aventis, Bayhill Pharmaceuticals, Bayer Pharmaceuticals, BioMS Pharmaceuticals, Daichi-Sankyo, Glaxo Smith Klein Pharmaceuticals, Genmab Biopharmaceuticals, Medivation, Peptimmune, PTC Therapeutics, Teva, Vivus, NHLBI, NINDS, National MS Society; and receives consulting or speaking fees from Alexion, Accentia, Barofold, CibaVision, Biogen, Novartis, Consortium of MS Centers, KleinBuendel Incorporated, Enzo Pharmaceuticals, Somnus Pharmaceuticals, Teva, Advanced Health Media, EMD Serono, EDJ Associates, Aegis Creative Marketing, Eli Lilly, UT Southwestern University, Klein Buendel, University of Illinois Health Policy Center, Somnus Therapeutics. Andrew Chan: personal compensation for activities with Allmirall Hermal, Bayer Schering, Biogen, Genzyme, Merck Serono, Novartis, Sanofi Aventis, and Teva Neuroscience; research support from Biogen, Genzyme, and Novartis. James Xiao: employee of and holds stock/stock options in Biogen, Inc. Macaulay Okwuokenye: employee of and holds stock/stock options in Biogen, Inc. Dane Levison: employee of and holds stock/stock options in Biogen, Inc. James B. Lewin: employee of and holds stock/stock options in Biogen, Inc. Michael R. Edwards: employee of and holds stock/stock options in Biogen, Inc. Jing L. Marantz: employee of and holds stock/stock options in Biogen, Inc. P1042 Efficacy of teriflunomide in MS patients with a primary presentation of optic neuritis: a subgroup analysis from the phase 3 TOPIC study A.E. Miller1, D. Rog2, K. Thangavelu3, P. Truffinet4, S.

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Cavalier3, J.S. Wolinsky5 1Icahn School of Medicine at Mount Sinai, New York, NY, United States, 2Greater Manchester Neurosciences Centre, Salford Royal NHS Foundation Trust, Salford, United Kingdom, 3Genzyme, a Sanofi company, Cambridge, MA, United States, 4Genzyme, a Sanofi company, Chilly-Mazarin, France, 5University of Texas Health Science Center at Houston, Houston, TX, United States Background: TOPIC (NCT00622700) was a phase 3 study to evaluate the efficacy and safety of teriflunomide, a once-daily oral immunomodulator approved for relapsing-remitting MS, in patients with a first clinical episode suggestive of MS. In this study, teriflunomide 14 mg significantly reduced the risk of relapse determining conversion to clinically definite MS (CDMS; primary endpoint) by 42.6% (P=0.0087) and the occurrence of relapse or new MRI lesion by 34.9% (P=0.0003) vs placebo. The corresponding reductions for teriflunomide 7 mg vs placebo were 37.2% (P=0.0271) and 31.4% (P=0.0020), respectively. Objective: To report results of a subgroup analysis on the treatment effects of teriflunomide in patients from the TOPIC study whose clinical assessment involved a primary presentation of optic neuritis (ON). Methods: Patients with a primary presentation of ON were identified post-hoc based on the description of symptoms by the investigators. These patients were further stratified according to baseline monofocal or multifocal status. Results: Of 614 patients randomized and treated, 200 had a primary presentation of ON. In patients with ON, teriflunomide 14 mg significantly decreased the risk of relapse determining conversion to CDMS by 58.4% (P=0.0458 vs placebo), while a trend was observed with teriflunomide 7 mg (44.9% reduction; P=0.0755). More patients had a monofocal (n=147) than a multifocal (n=53) presentation. Patients with a monofocal presentation on teriflunomide 14 mg had a significant reduction in the risk of further relapse (75.7%; P=0.0325); however, the reduction observed for teriflunomide 7 mg was not significant (43.6%, P=0.2312). In patients with a multifocal presentation, reductions were not significant for either teriflunomide dose vs placebo (14 mg: 10.7%, P=0.8604; and 7 mg: 50.5%, P=0.3012). The treatment effect of teriflunomide on relapse or MRI lesion was generally consistent with that observed for relapse determining conversion to CDMS. Conclusions: Teriflunomide 14 mg significantly reduced the risk of relapse, or relapse or new MRI lesion, in patients with a primary presentation of ON. A strong effect was observed in patients with a monofocal presentation of ON; the effect was not significant in those with multifocal ON, likely due to small subgroup size. Taken together with results from studies in patients with relapsing MS, these data demonstrate the consistent efficacy of teriflunomide across a range of patient types. Disclosure Study supported by Genzyme, a Sanofi company. AEM: Consulting fees (Accordant Health Services, Acorda Therapeutics, Alkermes, Biogen Idec, EMD Serono, Genentech, Genzyme, GSK, Mallinckrodt Pharmaceuticals [Questcor], Novartis, Roche, Teva); contracted research (Biogen Idec, Genentech, Novartis, Questcor, Roche, Sanofi).


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DR: Consulting fees (Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi, Teva Neuroscience); research support (Biogen Idec, Genzyme, GW Pharma, Merck Serono, Mitsubishi, Novartis, Teva Neuroscience). KT: Employee of Genzyme PT and SC: Employees of Genzyme with ownership interests JSW: Consulting fees (AbbVie, Actelion, Alkermes, Athersys, EMD Serono, Forward Pharma, Genentech, Genzyme, Novartis, Roche, Teva, Teva Neuroscience, to-BBB, XenoPort); contracted research (Genzyme, National Institutes of Health, National MS Society through the University of Texas Health Science Center at Houston, Sanofi); royalties (University of Texas Health Science Center at Houston for monoclonal antibodies out-licensed to Chemicon International). P1043 Cognitive impairment rebound in multiple sclerosis patients after natalizumab discontinuation P. Iaffaldano, R.G. Viterbo, V. Direnzo, M. D’Onghia, C. Tortorella, D. Paolicelli, M. Trojano Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy Background: Natalizumab (NTZ) treatment exerts a positive impact on cognitive functions in Relapsing Multiple Sclerosis (RRMS) patients. Clinical and radiological disease reactivation has been described after NTZ discontinuation. Whether this disease reactivation involves also cognitive functions is not known to date. Objectives: To assess the persistence of the effect of NTZ treatment on cognitive functions after NTZ discontinuation. Methods: All the RRMS patients scheduled for NTZ treatment at our MS centre underwent a neuropsychological evaluation using the Brief Repeatable Battery (BRB), and the Stroop Test (ST) before, during and after the NTZ treatment . The Cognitive Impairment Index (CII) as a measure of global cognitive function was calculated for each patient. The annualized-relapse-rate (ARR) and the number of gadolinium enhancing lesions (GD) were also recorded for each patient, before, during and after the NTZ treatment. The Wilcoxon test for paired samples was used to assess the significance of the changes over time of the mean CII, the mean ARR and of the mean number of GD lesions. Results: Thirty RRMS patients stopping NTZ due to PML concern were evaluated before and at the end of NTZ treatment and after 1 year from the NTZ stop. The mean ARR significantly (p=0.04) increased during the first year after NTZ discontinuation (0.87±0.82) in comparison to that at the end of NTZ treatment (0.50±0.63), although it remained significantly (p=0.003) lower than the ARR in the year prior NTZ (1.50±0.82). At the end of NTZ treatment the mean number of GD lesions was close to zero (0.07±0.25) and significantly (p< 0.0001) lower than that before NTZ initiation (1.13±1.25), but it significantly increased (0.93±1.93, p=0.002) in the year after NTZ stopping. The mean CII significantly (p< 0.0001) decreased during the NTZ exposure (9.30±8.09) compared to that before NTZ initiation (12.63±7.87),but the beneficial effect of NTZ on cognitive functions was completely lost (p< 0.0001) during the first year after NTZ discontinuation (12.23±7.85).

Conclusions: The rebound of the cognitive impairment after NTZ discontinuation goes in parallel with the clinical and radiological disease reactivation. Our data reinforce the hypothesis that, in the short-term, NTZ exerts its positive impact on cognitive functions by means of its anti-inflammatory properties. Disclosure Iaffaldano P. has served on scientific advisory boards for Biogen Idec, and has received funding for travel and/or speaker honoraria from Sanofi-Aventis, Biogen Idec, Teva and Novartis. Viterbo RG, Direnzo V and DÓnghia M have nothing to disclose. Paolicelli D. received honoraria for consultancy and/or speaking from Biogen Idec, Merck-Serono, Sanofi-Aventis, TEVA, Novartis, and Genzyme. Tortorella C. has served on scientific advisory boards for Biogen, Merck Serono, Bayer-Schering and Novartis. She received also funding for travel, consulting and speaker honoraria from Biogen, Merck Serono, Bayer-Schering, Teva, Genzyme, Novartis and Almirall. Trojano M. has received honoraria for consultancy or speaking from Biogen, Sanofi-Aventis, Merck Serono and Bayer-Schering and research grants from Merck Serono, Biogen and Novartis. No ad hoc funding has been obtained to conduct this study.

P1044 Characterizing the impact of teriflunomide on adaptive immune cell subsets, repertoire and function in patients with relapsing-remitting MS: TERI-DYNAMIC H. Wiendl1, C.C. Gross1, M. Lindner1, M. Eschborn1, L. Weisser1, A. Posevitz-Fejfar1, A. Schulte-Mecklenbeck1, B. Van Wijmeersch2, R. Hupperts3, C. Lunven4, S. Brette5, T.J. Turner6, L. Klotz1 1University of Münster, Münster, Germany, 2Hasselt University, Hasselt, Belgium, 3Maastricht University, Maastricht, The Netherlands, 4Sanofi, Chilly-Mazarin, 5Lincoln, BoulogneBillancourt, France, 6Genzyme, a Sanofi company, Cambridge, MA, United States Background: Teriflunomide, an immunomodulator approved for patients with relapsing-remitting MS (RRMS), exerts a cytostatic effect specifically on activated lymphocytes. The TERIDYNAMIC study (NCT01863888) was conducted to improve characterization of the effects of teriflunomide treatment on lymphocytes in patients with RRMS. Objective: To explore the effects of teriflunomide on the population dynamics, function and repertoire of adaptive immune cell subsets in patients with RRMS. Methods: Patients with RRMS received once-daily oral teriflunomide 14mg for 24 weeks; healthy controls (HCs) were not treated. Blood was collected at baseline and Week 24, and peripheral blood mononuclear cells (PBMCs) were isolated. Adaptive immune cell subsets, specifically T cells (CD4+ T helper, CD8+ T cytotoxic, Treg, Th1 and Th17 cells), were analysed by flow cytometry. CD4+ T-cell function was assessed by ex vivo proliferation assays. Changes in absolute number and clonal diversity of CD4+ T-cell receptors were evaluated by deep sequencing and entropy analyses, respectively.


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Poster Session 2, 21(S11) Results: Participants included 38 patients with RRMS and 19 HCs. In patients, lymphocyte counts were reduced after 24 weeks (least squares [LS] mean [SE] change from baseline [CFB]: -3.05 [1.43]% of PBMC; P=0.040), while the relative size of the CD4+ population increased (median [min:max] CFB: 1.6 [-15:6]% of CD3+; P=0.006), and the CD4+/CD8+ ratio was elevated (median [min:max] CFB: 0.6 [-6:24]; P=0.008). In the CD4+ population, there was a proportional increase in induced Treg (iTreg; LS mean [SE] CFB: 0.29 [0.1]% of total CD4+ cells; P=0.007), a decrease in Th1 cells (median [min:max] CFB: -0.4 [-5:2]; P=0.2747), whereas Th17 cells were unaltered. T cells from patients did not differ in their proliferative response to mitogen. Teriflunomide reduced absolute number of unique CD4+ T-cell receptor clones (median [min:max] CFB: -33886 [-178155:112498]; P=0.028) and increased clonality (median [min:max] CFB: 0.004 [-0.06:0.17]; P=0.070), resulting in decreased overall clonal diversity (median [min:max] CFB: -0.4 [-5:2]; P=0.016). Conclusions: Teriflunomide treatment lowered lymphocyte counts, increased CD4+/CD8+ T-cell ratios, and resulted in reciprocally increased iTreg and reduced Th1 frequencies. Deep sequencing analysis showed that teriflunomide significantly reduced clonal diversity of CD4+ T cells. These insights extend our understanding of the immunomodulatory mechanism of action of teriflunomide. Disclosure Study supported by Genzyme, a Sanofi company. HW: Compensation for serving on scientific advisory boards (Bayer HealthCare, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi); speaker honoraria and travel support (Bayer Schering AG, Bayer Vital GmbH, Biogen Idec, CSL Behring, Fresenius Medical Care, Genzyme, GSK, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi); compensation as consultant (Biogen Idec, Merck Serono, Novartis, Sanofi). CCG: Speaker honoraria and travel support (Bayer Healthcare, Genzyme). ML, ME, LW, AS-M: Nothing to disclose. AP-F: Honoraria for consultancy (Genzyme). BVW: Financial support regarding study grants, speaker fees and advisory board membership (Bayer, Biogen, Genzyme/Sanofi, Merck Serono, Novartis, Teva). RH: Compensation for lectures, advisory boards and consultancy, plus research grants (Biogen Idec, Merck Serono, Novartis, Sanofi, Teva) in past 5 years. CW and CL: Employees of Sanofi. SB: Employee of Lincoln, mandated by Sanofi. TJT: Employee of Genzyme. LK: Compensation for serving on scientific advisory boards (Genzyme, Novartis); speaker honoraria and travel support (CSL Behring, Merck Serono, Novartis); research support (Biogen Idec, Novartis). P1045 Characteristics of leukocyte recovery following treatment with humanized anti-CD52 (alemtuzumab/Lemtrada) in multiple sclerosis W. Gilmore1, B.T. Lund1, A. Traboulsee2, A. Javed3, J.E. Dunn4, L.P. Weiner1, P. Li1, E.E. Kelland1, A.M. Levy1

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University of Southern California, Los Angeles, CA, United States, 2University of British Columbia, Vancouver, BC, Canada, 3University of Chicago School of Medicine, Chicago, IL, 4Neurology and Neurological Sciences, Stanford University, Stanford, CA, United States Background and goals: Alemtuzumab (marketed as Lemtrada for use in MS) is a humanized monoclonal antibody against CD52, a molecule widely expressed on cells of myeloid and lymphoid lineages. Upon intravenous infusion, it causes rapid depletion of circulating leukocytes, followed by homeostatic sequential repopulation of leukocyte subpopulations. The overall purpose of this study is to develop a better understanding of the characteristics of leukocyte repopulation in relapsing-remitting MS patients treated with two annual courses of alemtuzumab: baseline (M0) and month 12 (M12). The ultimate goals are to identify mechanisms underlying treatment efficacy and to yield new insights into mechanisms of immune pathogenesis in MS. Design and methods: The study was designed as an add on, prospective, multi-center longitudinal cohort analysis of changes in leukocyte phenotypes in blood samples collected prior to the first course of alemtuzumab treatment at (M0) and at 5, 11, 17 and 23 month timepoints. Patients were recruited from the University of Southern California, Stanford University, University of British Columbia and University of Chicago. Whole blood and PBMC were subjected to immunofluorescence staining and FACS analysis to detect changes in a comprehensive assessment of T cell subsets, B cells, NK cells, monocytes and granulocytes. Results: Similar to previous reports, alemtuzumab treatment was followed by reduced percentages of CD4+ T cells, with selectivity for naïve CD4+CD45RA+ cells, most prominent at M5. CD4+ T cells exhibiting regulatory phenotypes, including classical CD4+CD25hiCD127lo foxP3+ regulatory T cells and CD4+foxP3+ cells expressing CD39 or CD46, clearly increased at M5, with variable increases at M17 compared with M0 and M11. CD56hi natural killer (NK) cells, believed to represent a regulatory phenotype, increased at M5 and remained elevated at M11, M17, and M23. A similar pattern of repopulation occurred in CD19+ B cells, CD8+ T cells, VLA-4+ T cells and chemokine receptor bearing CD4+ T cells. CD4+ cells capable of secreting interferon-gamma increased at M5. Significant changes in IL-17+ CD4+ T cells and myeloid cells were not observed at the timepoints included in this study. Conclusions: Early recovery from leukopenia in alemtuzumabtreated MS patients is accompanied by an increase in multiple regulatory lymphoid cell types that may reset immune homeostasis in favor of regulatory, rather than pathogenic immune mechanisms. Disclosure Dr. Gilmore has received grant support from Genzyme/Sanofi. Dr. Lund has received research funding from Teva and Novartis. Dr. Traboulsee received grant support from Hoffman La Roche and Genzyme/Sanofi, steering committee membership for Hoffman La Roche, consultancy for Biogen, Chugai, EMD Serono, Hoffman la Roche, Medimmune, Genzyme/Sanofi and Teva. Dr. Javed has received honoraria and consulting fees from Bayer, Biogen, Teva, Novartis, Genzyme, and Mallinckrodt.


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Dr. Dunn has received grant support for clinical trial research from Actelion and Roche-Genentech, honoraria for consulting from Biogen-Idec and Genzyme. Dr. Weiner has received grant support from Teva, has served as consultant for Mallinkrodt and Teva and on advisory boards for Teva, Novartis, Genzyme, Geron and Malinckrodt. Dr. Kelland has received research funding from Novartis and Teva. Peili Li: nothing to disclose. Alex M. Levy: nothing to disclose. P1046 Early reconstitution of the peripheral immune repertoire following withdrawal of fingolimod therapy M. Ghadiri1,2, L. Fitz-Gerald3, A. Rezk1, R. Li1, M. Nyirenda1, D. Haegert3, P. Giacomini1, A. Bar-Or1, J. Antel1 1Montreal Neurological Institute, Montreal, QC, Canada, 2University of Sydney, Sydney, NSW, Australia, 3McGill University, Montreal, QC, Canada Objectives: To study the profile of peripheral blood lymphocytes emerging following withdrawal of fingolimod. Background: The immunomodulatory effects of fingolimod are attributed to sequestration of CCR7+ T cells within lymph nodes, though it may also alter immune function by direct signalling mechanisms. Peripheral blood total lymphocyte counts (TLCs) generally reach 80% of baseline within 3 months of drug cessation, but dynamics of early reconstitution and factors contributing to individual variability are uncertain. Methods: TLCs, CD4+ and CD8+ T cell counts were measured in 14 multiple sclerosis patients pre-treatment, on fingolimod, and 10-14 days after drug interruption. Five patients had a second drug interruption. In 4 patients, T cell subsets were analysed by flow cytometry using cryopreserved peripheral blood mononuclear cells; subsets included naïve (TN), central memory (TCM), effector memory (TEM), terminally differentiated effector memory (TEMRA) and regulatory (Treg) T cells. Results: Mean on-treatment TLC was 0.4 x 10^9 cells/L, representing a reduction to 21% of pre-treatment TLC. Mean TLC after drug interruption was 0.7 x 10^9 cells/L (35% of pre-treatment TLC). The degree of reconstitution was heterogeneous (range 14-69% of pre-treatment TLC), and did not correlate with age, treatment duration, pre- or on-treatment TLC. In 4 of 5 patients with a range of early reconstitution responses, a second drug interruption resulted in a similar change in TLC. Changes in proportions of circulating T cell subsets on- compared with pre-treatment were in line with previous reports, and included a reduction in the CD4+/CD8+ ratio, a reduction in CD4+ and CD8+ TN frequencies and a relative increase in CD4+ TEM and CD8+ TEMRA frequencies. Following drug interruption, all T cell subsets trended towards pre-treatment proportions, with statistically significant increases in the CD4+/CD8+ ratio and CD4+ TN subset proportion. The frequency of Tregs within the CD4+ compartment remained stable between time-points. Conclusions: At 10-14 days after drug withdrawal, peripheral lymphocyte reconstitution remains limited with significant inter-individual heterogeneity. The pattern of T cell subset reconstitution does not suggest a selective depletion of any subset. To be determined is whether heterogeneity in reconstitution

kinetics links to capacity to mount immune responses on therapy or to the rate of re-emergence of disease activity following fingolimod cessation. Disclosure This study was supported in part by a grant from Novartis Pharmaceuticals Canada. Mahtab Ghadiri is a recipient of the BMRI/McGill University Multiple Sclerosis scholarship, funded by Novartis. Leslie Fitz-Gerald: nothing to disclose. Ayman Rezk: nothing to disclose. Rui Li: nothing to disclose. Mukanthu Nyrirenda: nothing to disclose. David Haegert: nothing to disclose. Paul Giacomini has served on advisory boards for and/or received consulting, lecture and/or speaker fees from Genzyme, Teva Innovation Canada, Novartis, EMD Serono and Biogen Idec. Jack Antel serves on advisory/safety monitoring boards for Novartis, Sanofi-Genzyme, Biogen Idec, EMD Serono and Medday Pharmaceuticals, and as editor of the Americas, Multiple Sclerosis Journal. Amit Bar-Or has participated as a speaker at meetings sponsored by, received consulting fees and/or received grant support from: Amplimmune, Bayhill Therapeutics, Berlex/Bayer, Biogen Idec, Diogenix, Eli-Lilly, Genentech, GlaxoSmithKline, GuthyJackson/GGF, Merck/EMD Serono, Medimmune, Mitsubishi Pharma, Novartis, Ono Pharma, Receptos, Roche, SanofiGenzyme, Teva Neuroscience, Wyeth.

P1047 Efficacy of teriflunomide treatment in achieving no evidence of disease activity in the TEMSO long-term extension study J.S. Wolinsky1, M.S. Freedman2, K. Thangavelu3, P. Truffinet4, P. Rufi4, P.W. O’Connor5 1University of Texas Health Sciences Center, Houston, TX, United States, 2University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada, 3Genzyme, a Sanofi company, Cambridge, MA, United States, 4Genzyme, a Sanofi company, Chilly-Mazarin, France, 5University of Toronto, Toronto, ON, Canada Background: Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting MS. It has a demonstrated consistent efficacy in placebo-controlled clinical trials in patients with relapsing forms of MS (RMS) and has a well-characterized safety and tolerability profile. Objective: To evaluate the efficacy of teriflunomide in achieving no evidence of disease activity (NEDA) over time in the TEMSO study (NCT00134563) and its extension (NCT00803049). Methods: In TEMSO, patients with RMS were randomized 1:1:1 to receive teriflunomide 14 mg, 7 mg, or placebo. Patients completing the 2-year study were eligible to enter the double-blind extension. Patients previously receiving teriflunomide remained on their original dose; those previously receiving placebo were re-randomized 1:1 to teriflunomide 14 mg or 7 mg. NEDA was defined as no gadolinium-enhancing T1 lesions or new/enlarging T2 lesions, and no clinical relapse or 12-week


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Poster Session 2, 21(S11) sustained disability progression. Patients must have non-missing components for MRI activity and clinical activity to be evaluable for NEDA. Results, based on a post hoc analysis, are presented up to extension year (EY) 4, when ⩾30% of patients had contributing MRI data. Results: In the TEMSO core study, the proportion of patients with NEDA over the complete 2-year study period was significantly higher in the 14-mg group (21.2%; n=340; P=0.0007) compared with placebo (11.6%; n=346). The proportion with NEDA was also higher with teriflunomide 7 mg (16.6%; n=350), but not statistically significant. In the TEMSO extension study, for patients continuing teriflunomide 14-mg treatment from the core to the extension, the proportion achieving NEDA was higher than in the core study and remained ⩾40% over the 4-year extension period (EY1: 40.5%, n=222; EY4: 41.3%, n=104). In patients continuing on teriflunomide 7 mg, the proportion of patients with NEDA increased from 31.7% (EY1, n=224) to 40.4% (EY4, n=99). The proportion with NEDA also increased for patients switching from placebo to 14 mg (EY1: 33.3%, n=90; EY2: 36.1%, n=83; EY4: 40.5%, n=37). Similar increases were seen for patients switching from placebo to the 7-mg dose (EY1: 35.6%, n=118; EY2: 39.6%, n=101; EY4: 42.9%, n=49). Conclusion: In the TEMSO long-term extension, the proportions of patients with NEDA in all treatment groups were consistently higher than in the core study. These analyses support the continued efficacy benefits of ongoing treatment with teriflunomide. Disclosure Study supported by Genzyme, a Sanofi company. JSW: Consulting fees (AbbVie, Actelion, Alkermes, Athersys, EMD Serono, Forward Pharma, Genentech, Genzyme, Novartis, Roche, Teva, Teva Neuroscience, to-BBB, XenoPort); contracted research (Genzyme, National Institutes of Health, National MS Society through the University of Texas Health Science Center at Houston, Sanofi); royalties (University of Texas Health Science Center at Houston for monoclonal antibodies out-licensed to Chemicon International). MSF: Consulting fees (Bayer HealthCare, Biogen Idec, Chugai, EMD Canada, Genzyme, Novartis, Sanofi, Teva Canada Innovation); member of company advisory boards/board of directors/other similar group (Bayer HealthCare, Biogen Idec, Hoffman La-Roche, Merck Serono, Novartis, Opexa, Sanofi); speaker bureau (Genzyme). KT: Employee of Genzyme, a Sanofi company PT: Employee of Genzyme, a Sanofi company PR: Employee of Genzyme, a Sanofi company PWO: Consulting fees (Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, Sanofi, Teva, all related to MS clinical trials); contracted research (Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, Sanofi, Teva, for clinical trials work). P1048 Teriflunomide efficacy in subsets of patients with relapsing MS: results from TEMSO and TOWER studies G. Comi1, K. Thangavelu2, P. Truffinet3, P. Rufi3, J. de Seze4 1University Vita-Salute San Raffaele, Milan, Italy, 2Genzyme,

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a Sanofi company, Cambridge, MA, United States, 3Genzyme, a Sanofi company, Chilly-Mazarin, 4Strasbourg University, Hôpital Civil, Strasbourg, France Background: Teriflunomide is a once-daily oral immunomodulator for treatment of relapsing-remitting MS (RRMS). In TEMSO (NCT00134563) and TOWER (NCT00751881), teriflunomide demonstrated efficacy on annualized relapse rate (ARR), disability progression, and magnetic resonance imaging (MRI) parameters (MRI was performed in TEMSO only). The study populations included patients with progressive forms of MS, although most patients had RRMS (TEMSO, 91%; TOWER, 97%). Objectives: To report efficacy outcomes from analyses of the relapsing MS subpopulations in TEMSO and TOWER. Methods: In TEMSO/TOWER, patients with RMS (1086/1165) were randomized (1:1:1) and treated with once-daily teriflunomide 14 mg, 7 mg, or placebo. In this post-hoc analysis, ARR and disability progression confirmed for 12 weeks were evaluated in RRMS patients from TEMSO/TOWER (993/1134). MRI outcomes were analysed in patients with RRMS from TEMSO. These endpoints were also analysed for the non-RRMS population. All statistical analyses were the same as for the individual studies. Results: In TEMSO/TOWER, teriflunomide 14 mg significantly reduced ARR by 33.9% (P=0.0002)/37.2% (P< 0.0001), respectively, vs placebo. The 7-mg dose also significantly reduced ARR vs placebo. The risk of disability progression confirmed for 12 weeks was significantly reduced by teriflunomide 14 mg by 27.9% (P=0.0475)/33.7% (0.0336) in TEMSO/TOWER, respectively. Although there was a reduction in the risk of disability progression with the 7-mg dose in the RRMS populations in both studies, the results were not statistically significant. For MRI endpoints in the TEMSO RRMS 14-mg group, there were significant reductions vs placebo in the number of gadolinium-enhancing lesions per scan over 108 weeks (77.6% [P< 0.0001], and in combined unique active lesions per scan (68.3% [P< 0.0001]. In the non-RRMS group, there was benefit on disability progression, statistically non-significant possibly due to low numbers of patients; however, the effect on MRI parameters was significant, and consistent with the RRMS group. Conclusions: The dose-dependent efficacy of teriflunomide was demonstrated in the RRMS subpopulation in the TEMSO and TOWER studies. These results reflect those in the overall RMS populations. MRI results from the RRMS and non-RRMS groups in the TEMSO study are also consistent with those observed in the overall RMS population. Disclosure Study supported by Genzyme, a Sanofi company. GC: Consulting fees (Almirall, Bayer, Chugai, Excemed, Genzyme, Merck Serono, Novartis, Receptos, Sanofi, Serono Symposia International Foundation [SSIF], Teva); fees from nonCME services (Almirall, Bayer, Biogen, Excemed, Genzyme, Merck Serono, Novartis, Receptos, Sanofi, SSIF, Teva). JS: Consulting services, advisory boards (Genzyme). KT: Employee of Genzyme. PT: Employee of Genzyme, with ownership interests. PR: Employee of Genzyme. LK: Author´s institution (University Hospital Basel) has received in the last 3 years and used exclusively for research support: steering


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committee, advisory board and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, Xenoport); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, Teva); support of educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva); royalties (Neurostatus Systems GmbH); grants (Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society, Swiss National Research Foundation). P1049 Comparison of fingolimod and dimethyl fumarate in the treatment of multiple sclerosis: one year experience B.L. Vollmer1, K. Nair2, S.H. Sillau1, M. Strobel1, L. Robinson1, J. Corboy1, T. Vollmer1, E. Alvarez1 1Department of Neurology, University of Colorado Denver School of Medicine, 2Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, United States Objective: To compare the first year experience of fingolimod(FTY) and dimethyl fumarate(DMF) including discontinuation rates, efficacy, and tolerability. Background: FTY and DMF are the two most common MS oral treatments becoming available in 2010 and 2013, respectively. There is limited comparative effectiveness data after one year of treatment. Methods: Patients prescribed FTY or DMF at the Rocky Mountain MS Center at Anschutz Medical Campus (University of Colorado) prior to April 2014 were identified. Clinician-reported data including relapse history, adverse events, medications, MRI outcomes, disease history and patient characteristics were retrospectively collected. Primary outcome was the probability of discontinuing drug by the end of year one. Reasons for discontinuation were also evaluated. Simple logistic regression, propensity matching with 1:1 greedy matching without replacement and 1:3 nearest neighbor matching were used for data analysis controlling for age, disease duration, type of MS, previous natalizumab use, gender, and disease burden at baseline (missing, mild, moderate, severe) to estimate differences in the primary outcome. Results: A total of 317 and 492 patients initiated FTY and DMF and were followed for one year. Patients had a mean age of 45.4 (FTY) and 47.3 (DMF) years; were predominantly female (72.6% FTY; 70.7% DMF); and had a mean MS disease duration of 11 years for both groups. For the entire study cohort, 21(6.30%) FTY patients had a clinical relapse compared to 31(6.62%) patients on DMF. At ⩽12 months, 62(19.6%) and 124(25.2%) discontinued FTY and DMF respectively with an unadjusted odds ratio (OR) of 1.386(95%CI 0.982-1.956, p=0.063) and adjusted OR of 1.548(95%CI 1.000-2.394, p=0.050) with 3:1 matching with replacement. Primary reason for discontinuation was adverse events which was lower for FTY 39(12.3%) compared to DMF 80(16.3%)(OR 1.384, 95%CI 0.917-2.090, p=0.122). New Disease activity (relapses and/or new MRI lesions) had discontinuation in 12(3.8%)of FTY and 32(6.5%) of DMF patients(unadjusted OR 1.768, 95%CI 0.896-3.488, p=0.100). Median time to discontinuation was 5 and 4 months for FTY and DMF, respectively.

Conclusions: There was a trend towards fewer discontinuations with FTY over DMF. Discontinuation rates in the first year were driven by tolerability issues, and two year data needs to be examined to better evaluate effect on disease activity. Preliminary two year data also will be presented. Disclosure Brandi Vollmer: nothing to disclose Kavita Nair: Astellas, Eli Lilly, Gilead, Genentech, Biogen Idec, Stefan H. Sillau: nothing to disclose Molly Strobel: nothing to disclose Lorraina Robinson: nothing to disclose John Corboy: • PI for clinical trial: NIH, Novartis, Sun Pharma, Celgene Therapeutics, National Multiple Sclerosis Society (NMSS) • Research grants: Juvenile Diabetes Research Foundation (Biomarker in MS), NMSS (MS Tissue Bank), Diogenix (adjudicator for diagnosis of MS) • Consultant: Novartis (to design clinical trials and safety information processing), Celgene Therapeutics (to design clinical trials), Teva Neurosciences (advisory board), Biogen Idec (to answer a survey to identify consensus treatment statements in MS) • Honoraria to give talk:Pro CE, Rocky Mountain MS Center, via Genzyme, Grand Rounds at multiple academic institutions • Other:Medical-legal work, Editor, Neurology: Clinical Practice, • Board Member on NMSS Colorado-Wyoming Chapter Timothy Vollmer: • Consulting: Acorda, Biogen Idec, Consortium of MS Centers (CME presentation), DeltaQuest, Genentech, Novartis, Novartis Canada, Novartis, Japan, Teva, Teva Canada, Xenoport, Mylan, Medscape • Clinical Research:Accelerated Cure Project, Acorda, Avanir, Biogen Idec, EMD Serono, Genzyme, Jensen Research, MedImmune, NIH, Novartis Pharmaceuticals, Ono Pharmaceuticals, Rky Mnt MS Center, Teva, Neuroscience, Vaccinex, Roche Enrique Alvarez: • Consulting: Teva Neuroscience, Genzyme, and Biogen IDEC. • Clinical Research: Novartis, Biogen Idec, Rocky Mountain MS Center P1050 Switching from branded to generic glatiramer acetate: two-year clinical data from the GATE trial further support the continued efficacy and tolerability of generic glatiramer acetate J.A. Cohen1, A. Belova2, F. Barkhof3, C. Wolf4, E.R.W. van den Tweel5, J.J.L. Oberyé5, R. Mulder5, N.P. Koper5, K. Selmaj6, on behalf of the GATE Study Group 1Mellen Center, Cleveland Clinic, Cleveland, OH, United States, 2Functional Diagnostics, Research Institute of Traumatology and Othopaedy, Nizhniy Novgorod, Russian Federation, 3Radiology, VU Medical Centre, Amsterdam, The Netherlands, 4Lycalis sprl., Brussels, Belgium, 5Synthon BV, Nijmegen, The Netherlands, 6Medical University of Lodz, Lodz, Poland


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Poster Session 2, 21(S11) Background: GTR (Synthon BV) is a generic glatiramer acetate that was demonstrated to be clinically equivalent to brand glatiramer acetate (GA, Copaxone® Teva) in the 9-month double-blind (DB) part of the GATE trial in patients with relapsing-remitting multiple sclerosis (RRMS). Goals: The extension of the GATE trial aimed to show that GTR is continuously safe and effective over 2 years and that efficacy and safety is maintained when switching from GA to GTR. Methods: Ambulatory RRMS patients with ⩾1 relapse in the year prior to screening and 1-15 gadolinium-enhanced brain lesions were randomized to receive 20 mg GTR, 20 mg GA, or placebo (PLC) for 9 months. All patients completing the DB part could enter the 15-month open-label (OL) treatment part, and received daily injections of 20 mg GTR. Patients were monitored for relapses, progression of disability and by MRI (reported separately). Safety and tolerability were assessed through monitoring of adverse events (AE), injection site reactions, and routine blood laboratory tests. Results: Of the 794 patients treated in the DB part, 728 patients continued in the OL part: 324 (GTR/GTR), 323 (GA/GTR), or 81 (PLC/GTR). During the DB part the annualized relapse rate (ARR) was 0.31 (GTR), 0.40 (GA), and 0.38 (PLC), with 78.4% (GTR), 75.2% (GA) and 76.5% (PLC) of patients being relapsefree. During the OL part, ARRs were similar in all groups: 0.21 (GTR/GTR), 0.24 (GA/GTR), and 0.23 (PLC/GTR), with 79.2% (GTR/GTR), 75.3% (GA/GTR) and 76.3% (PLC/GTR) of the patients being relapse-free. Accordingly, analyses of the mean Expanded Disability Status Scale (EDSS) scores gave similar results in the treatment groups and remained stable. Switching from GA to GTR did not impact AE or local tolerability profiles. During DB part 51.0% (GTR), 54.3% (GA), and 56.0% (PLC) of patients experienced at least 1 AE; this was 33.3% (GTR/GTR), 36.5% (GA/GTR), and 43.2% (PLC/GTR) during the OL part. Overall, most frequent AEs were injection site reaction (17.1%), nasopharyngitis (8.2%), and immediate post-injection reaction (5.9%). During DB part 3.4% (GTR), 4.8% (GA), and 2.4% (PLC) of patients experienced at least 1 serious AE, this was 2.5% (GTR/GTR), 3.4% (GA/GTR), and 3.7% (PLC/GTR) during the OL part. Conclusions: With maintained efficacy and tolerability profiles over two-year treatment as well as following switching from branded to generic glatiramer, these results support GTR as a suitable alternative to branded glatiramer acetate. Disclosure J. Cohen: grants and personal fees (EMD Serono, Genentech, Genzyme, Innate Immunotherapeutics, Synthon BV, Vaccinex); A. Belova: personal fees (Synthon BV); F. Barkhof: personal fees (Bayer Schering Pharma, Sanofi Aventis, Biogen Idec, Teva, Merck Serono, Novartis, Roche, Synthon BV, Jansen Research, Genzyme), Data-analysis center (Biogen-Idec, TEVA, Merck Serono, Novartis, Roche, Synthon BV, Jansen Research); C. Wolf has received honoraria for serving as a consultant for toBBB, Desitin, Investitionsbank Berlin, Keyrus, Novartis, Synthon BV, and Teva; E. van den Tweel, J. Oberyé, N. Koper, and R. Mulder: employees of Synthon BV;

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K. Selmaj: grants and personal fees (Synthon BV, Roche, Biogen Idec, Novartis, TEVA, Merck, Genzyme, Neuron, Receptos).

P1051 Natural CD4+CD25+T regulatory cells (nTreg) cultured with antigen and Th2 cytokines, suppress induction of EAE S. Hodgkinson1, G. Tran2, C. Robinson2, P. Wilcox3, R. Hall4, B.M. Hall2 1Medicine, University of New South Wales, Strathfield, 2Medicine, University of New South Wales, Kensington, 3University of Sydney, Sydney, 4University of Newcastle, Newcastle, NSW, Australia T regulatory cells(Treg) prevent and can reverse autoimmune diseases. nTreg(CD4+CD25+FOXP3+T cells) are produced by the thymus, and present in peripheral lymphoid tissues at ratios of < 1:10 to effector CD4+CD25-FOXP3-T cells. nTreg suppress effector responses at >1:1, and when 5x106 are administered to Lewis rats with EAE have no effect. We induce more potent antigen specific Treg, by culture of nTreg with specific antigen (MBP) and Th2 cytokines and tested their capacity to inhibit EAE. nTreg from naïve Lewis rats were cultured with recombinant interleukin-4 (rIL-4)(200 units/ml) and MBP primed dendritic cells, for 4d. This produces Ts2 cells that express the specific receptor for IL-5(IL-5Ra) and suppress to specific antigen at 1:321:64. 5x106 Ts2 cells given to Lewis rats immunized with MBP/ CFA at 9d after immunization markedly suppressed clinical disease. Clinical score peaked at day 13 at 1.5±0.4 then recovered to 0 at15d, whereas controls peaked at 2.5±0.8 on 17d. Ts2 treated had significantly milder disease at 13 to 23d(p< 0.05). In vivo Ts2 cells can be further expanded by rIL-5 therapy, thus we re-cultured Ts2 cells with MBP and either rIL-5 or rIL-4. Re-culture with rIL-5 increased in vitro suppression to 1:1000; rIL-4 did not. Re-culture with rIL-5, but not rIL-4 induced expression of IL-4, IL-5 and IRF4 with continued expression of FOXP3, consistent with induction of Th2-like Treg. 106 Th2-like Treg given at 9d, delayed disease onset and severity. Peak disease was 2 at 17d vs 3 at14d in controls. Recovery was faster in Th2 like Treg treated, scores was 0 at 18d while controls sore was still 1.5 at 22d. These experiments show that antigen and Th2 cytokines can induce Treg with antigen specific increased potency that can markedly modify EAE clinical severity, and may provide a basis for expansion of human nTreg for treatment of MS. Disclosure Hodgkinson: nothing to disclose Tran: nothing to disclose Robinson: nothing to disclose Brcuce Hall: nothing to disclose Rachel Hall: nothing to disclose Wilcox: nothing to disclose P1052 Altered lymphocyte function in MS patients treated with immunomodulatory or immunosuppressive drugs Z. Fekete1, C. Malmeström2, M. Axelsson3, B.A. Andersson4,


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J. Lycke3 1Dept of Neurology, Borås Hospital, Borås, 2Dept of Neurology, Laboratory for Clinical Immunology, 3Dept of Neurology, 4Laboratory for Clinical Immunology, Sahlgrenska University Hospital, Gothenburg, Sweden Background: Lymphocyte function studies complement phenotyping and cytokine levels in our understanding of the immuneresponse in MS. We evaluated lymphocyte function with Flow Cytometric Assay for Specific Immune Response in Cellmediated Activated Whole Blood (FASCIA) before and after 6 months of treatments in relapsing-remitting (RR) MS patients. The aim was to evaluate the assay as a tool to monitor treatment response at a lymphocyte functional level. Materials and methods: 56 RRMS patients who started treatment with interferon beta or glatiramer acetate, IFN/GA, (n=19), natalizumab (NTZ), (n=22) or mitoxantrone (MTX), (n=15). Blood was obtained before and after 6 months. 41 matched blood donors served as controls. FASCIA is a functional assay, measuring specific cell mediated immunity in vitro. Whole blood was stimulated with antigens from varicella zoster virus , herpes simplex virus, influenza A, cytomegalovirus, Candida albicans, tuberculosis purified protein derivate, tetanus toxoid and control-stimulants phythohemeagglutinin and pokeweed mitogen. The result was based on flow cytometric readout of the number of CD4+ and CD8+ lymphoblasts. Results: There was a significant increase in proliferation in unstimulated cells of MS patients compared to controls (p< 0.001). Further increased responses after stimulation with antigens from Candida albicans (CD4+, p=0.02 and CD8+, p=0.049), HSV (CD4+, p=0.01 and CD8+, p=0.007) and from influenza A (CD4+, p=0.021). After 6 months of treatment there was a significant difference in response to Influenza A between treatment groups. NTZ showed 2-5-fold increased response compared to IFN/GA (CD4+, p=0.01 and CD8+ p=0,007) and 2-fold increased response compared to MTX (CD4+ p=0.013, and CD8+, p=0.042). There was further a significant increase in response to mitogen PHA (CD4+, p=0.031 and CD8+ p=0,002) compared to MTX. Adjusted for multiple comparisons there were no differences among the other antigens tested. Conclusion: The specific cell mediated immunity after stimulation with common antigens is increased in MS-patients compared to controls and MS-patients treated with natalizumab had increased response, particularly upon stimulation with Influenza A peptides. This might reflect that natalizumab don’t alter the reactivity of the T-cells. The study indicates that functional tests of lymphocytes can be of value and can be further developed for MS-candidate antigens and for studies of CSF cells. Disclosure Zoltan Fekete: nothing to disclose Clas Malmeström: Has received honoraria for lecturing, advisory board councils, and travel expenses for attending meetings from Biogen Idec, Merck-Serono, Novartis and Genzyme, and has received unconditional research support from Biogen Idec. Bengt Andersson: nothing to disclose Jan Lycke: has received travel support and/or lecture honoraria from Biogen, Novartis, Teva and Genzyme/SanofiAventis; has

served on scientific advisory boards for Almirall, Teva, Biogen, Novartis and Genzyme/SanofiAventis; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, Novartis and Teva.

P1053 Prospective, multicenter study of monthly pulsed methylprednisolone treatment in patients with primary progressive multiple sclerosis: clinical and magnetic resonance imaging results S. Ozakbas1, G. Kosehasanogullari2, B. Piri Cinar3, T. Kahraman1, H. Limoncu1 1Dokuz Eylul University, Izmir, 2Usak State Hospital, Usak, 3Giresun State Hospital, Giresun, Turkey There are currently no approved therapies for patients with primary progressive multiple sclerosis (PPMS) and treatments that have been shown to successfully modify disease course in patients with relapsing-remitting MS (RRMS) have not demonstrated benefit in PPMS. We aimed to evaluate the efficacy and safety of pulsed methylprednisolone given every month in patients with PPMS. This was a multi-center, examiner-blinded, prospective study. 47 (24 female) patients meeting diagnostic criteria of PPMS according to revised McDonald criteria were included in the study. Mean age was 44±4.6, mean disease duration was 4.7±5.1, and mean EDSS score was 5.9±3 (range 5.0-8.0). Mean progression at EDSS was 0.79 in the previous 2 year. All patients were submitted to magnetic resonance imaging (MRI). Patients were assessed for the full 24-month follow-up. Comparisons were done between previous 2 year before study begins and the end of year 2 of study based on clinical and MRI parameters. The patients didn’t use other immunosupressor or immunomodulating drugs. To maintain treatment blinding, we used the two-physician principle: a treating neurologist and an evaluating neurologist. The comparison between pre-and-post-treat¬ment EDSS scores was our reference points. Patients were given 1 g daily IV methylprednisolone (IVMP) for 5 days initially. Then, they were given 1 g IVMP once a month for 24 months. Mean EDSS score was decreased from 5.9 to 5.1 at the end of the second year (p=0.004). 33 out of 47 patients (70.2%) had at least 0.5 point decrease in EDSS. 9 patients (19.1%) had the same EDSS. A total of 42 patients (89.4%) became progression-free. Mean progression at EDSS decreased from 0.79 in the previous 2 year to - 0.11 at the end of the study (p=.0.0001). Female patients responded better than male patients (p=0.03). Patients with below EDSS 6.0 (n=21) had a better response to treatment than patients with EDSS 6.0 or higher (n=26) (p=0.002). 7 (14.2%) patients had sustained disability progression. In this group, mean progression in EDSS was also decreased from 1.2 in the previous 2 year to 0.5 at the end of the study (p=0.003). Total number of T2 lesions was decreased from 16 to 5 (p=0.007). Total number of Gd enhancing lesions was also decreased from 19 to 3 (p=0.0002). Our preliminary results indicated that treatment with IVMP prevented clinical and radiological worsening of MS in the majority of patients and it was safe and well tolerated by the patients with PPMS.


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Poster Session 2, 21(S11) Disclosure Serkan Ozakbas has nothing to disclose. Gorkem Kosehasanogullari has nothing to disclose. Bilge Piri Cinar has nothing to disclose. Turhan Kahraman has nothing to disclose. Hatice Limoncu has nothing to disclose.

P1054 Therapeutic management in the real life setting of Italian MS centers: when, why and how we switch therapy G.T. Maniscalco1, A. Signori2, F. Gallo2, P. Anovazzi3, L. Prosperini4, S. Lo Fermo5, A. Repice6, I.R. Zarbo7, R. Cerqua8, S. Bonavita9, A. Di Sapio10, L. Lavorgna9, M.P. Sormani2 1Multiple Sclerosis Centre, Neurological Clinic of ‘A. Cardarelli’ Hospital, Naples, 2Department of Health Sciences, Section of Biostatistics, Univerisity of Genova, Genova, 3Multiple Sclerosis Study Centre, AO S.Antonio Abate, Gallarate, (VA), 4Department of Neurology and Psychiatry, Sapienza University, Rome, 5Multiple Sclerosis Centre, AOU Policlinic Vittorio Emanuele, Catania, 6Neurosciences Department Careggi University Hospital, University of Florence, Florence, 7Department of Clinical and Experimental Medicine, University of Sassari, Sassari, 8Neurological Clinic, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, 9Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, 102nd Neurology Unit and CReSM (Regional Referral Multiple Sclerosis Centre), AOU San Luigi Gonzaga - Orbassano, Torino, Italy Background: Because of a rapidly changing MS therapeutic scenario, guidelines for treatment switch have not been clearly established and no broad consensus on therapeutic algorithms has been reached. Objectives: To provide a snapshot of switch patterns from first therapy prior to the introduction of new therapies in an Italian MS population. Methods: Newly diagnosed patients between Jan 2010 and Dec 2013 were included. Association of frequency and timing of switch with baseline demographic, clinical, MRI data were evaluated. KM survival curves and multivariate Cox model were used to test the association of baseline covariate with time to switch. Results: Data on 472patients (female=68.2%) from 9 Italian MS centres were collected. Mean age at diagnosis was 34 years (SD=11), median EDSS was 1.5 (range=0-6.5), median number of previous year relapses was 1 (range=0-4), 48% of patients showed active lesions at MRI. 134 patients (KM estimate=32%) switched from first therapy after 2 years, 183 (KM estimate=48%) after 3 years. Median time to switch was 1127 days (SE=100 days). Switching was 49.5% from IFNb1a-im, 44.3% from IFNb1a-sc, 50% from IFNb1b, 34.4% from glatiramer acetate (GA), 27.3% from fingolimod (FTY), 40.7% from natalizumab (NTZ) and 55.6% from other therapies.39.6% patients switched among IFNs and GA (lateral switch) and 48.8% escalated to a second line therapy (FTY, NTZ or immunosuppressant) (vertical switch). 66% patients switched for inefficacy, 21.6% for tolerability, 12.4% for other reasons.

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Younger age (HR=0.96;p< 0.001), baseline spinal cord lesions (HR=1.63;p=0.003), IFN or GA as first therapy (HR=2.30;p=0.02) and more recent diagnosis(HR=1.47;p=0.022)were associated with switches.Comorbidities (HR=1.91;p=0.009) and baseline EDSS under 2.5 (HR = 1.72; p = 0.08) were associated with a lateral switch, while presence of baseline spinal cord lesions (HR=1.98;p=0.003) and more recent diagnosis (HR=1.39;p=0.021) were associated with a vertical switch. Conclusions: These data are part of an ongoing study that will include also patients diagnosed in years 2014 to 2017, to evaluate the impact of new drugs on therapeutic choices. For the time being, our data show how almost half of patients have their treatment changed, mainly for inefficacy, after 3 years from treatment start. Patients on GA and FTY seem to have a higher drug persistence. Disclosure G.T. Maniscalco received speaking and advisory honoraria from Biogen, Novartis and Teva. P. Annovazzi received speaking and advisory honoraria from Almirall, Biogen, Novartis, Genzyme and Teva L. Lavorgna received honoraria from Bayer Shering, Almirall and Novartis for lectures or scientificboards. A. Di Sapio received speaking and advisory honoraria from Biogen, Merck Serono, Teva, Novartis and Bayer Schering. A. Repice recived speaking and advisory honoraria from Biogen, Teva, Novartis and Genzyme M.P.Sormani received consulting fees from Biogen, Novartis, TEVA, Genzyme, Roche, Merck Serono, Synthon L. Prosperini has received consulting and/or lecture fees and/ot travel grants from Bayer Schering, Biogen, Genzyme, Novartis and Teva. S. Lo Fermo received honoraria for consultancy from Merck Serono, Biogen and Novartis S. Bonavita received speaker and advisory board honoraria from Novartis, Merck-Serono and Biogen I.R. Zarbo received speaking and advisory honoraria from Biogen, Novartis and Teva. R Cerqua received speaking and advisory honoraria from Almirall, Biogen, Novartis, Genzyme and Teva. A. Signori and F. Gallo declares no disclosures related to this manuscript. P1055 IFNb enhances immunoregulatory features of mesenchymal stem cells T. Vigo1,2, C. Procaccini3, M. Ruggieri4, M. Salvetti5, D. Centonze6,7, G. Matarese8,9, N. Kerlero de Rosbo1,2, A. Uccelli1,2, MS RUN 1Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-infantili, Facoltà di Medicina e Chirurgia, Università di Genova, 2Center of Excellence for Biomedical Research (CEBR), Genova, 3Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Università di Napoli Federico II, Napoli, 4Dipartimento Scienze Mediche di Base, Neuroscienze ed Organi di Senso, Università degli Studi di Bari, Bari, 5Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental


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Health and Sensory Organs, Sapienza University, 6MS Clinical and Research Center, Tor Vergata University and Hospital, Rome, 7IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli, 8Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, Salerno, 9IRCCS MultiMedica, Milano, Italy

from Genentech, Roche, Allergan, Sanofi-Aventis, BiogenDompé, and Novartis; consulting honoraria and/or speaker fees and a basic science study grant from Merck-Serono. M. Salvetti received lecture fees from Biogen-Dompé, research support from Bayer-Schering, Biogen-Dompé, Merck-Serono, Sanofi-Aventis.

Background: Mesenchymal stem cells (MSC) have been proposed for the treatment of multiple sclerosis (MS) based on the results obtained in experimental autoimmune encephalomyelitis (EAE) where intravenous MSC administration resulted in a significant decrease of disease severity through the induction of immune tolerance. MSC immunomodulatory activity is remarkably enhanced by proinflammatory cytokines. Microarray analysis of MSC transcriptome upon exposure to activated T cells revealed the up-regulation of several immunomodulatory genes associated with the interferon pathway. IFNβ is routinely used for the treatment of MS and has pleiotropic effects, including anti-inflammatory function and the regulation ofglycolitic metabolism during the antiviral response. Aims: The aim of this study was to address the effect of IFNβ on mouse bone marrow-derived MSC. Materials and methods: MSC isolated from mouse bone marrow were subjected to AffymetrixGene Chip Mouse Genome 430 2.0 array. The effect of IFNβ on MSC was measured through co-culture experiments with T-cells. Gene expression analysis was carried out by real time PCR; pathway analysis was performed by western blot. Results: Microarray analysis of MSC transcriptome exposed to activated T cellsdemonstrated that secretory leukocyte peptidase inhibitor (Slpi), an anti-inflammatory molecule with anti-inflammatory, antimicrobial, and anti-protease properties, is significantly up-regulated.Exposure to IFNb strongly enhances the expression of Slpi in MSC in a STAT1- and STAT3-dependent manner.IFNβenhanced the ability of MSC to inhibit T cell activation and impaired self-renewal and differentiation through the inhibition of mTOR. As mTOR is a critical regulator of glucose metabolism, we analyzed the changes induced by IFNβon MSC glycolytic metabolism.Exposure to IFNβimpaired MSC glycolytic capacity and enhanced a compensatory oxydative metabolism, by increasing mitochondrial respiration. Conclusions: These data show that Slpi is a novel soluble factor involved in the immunomodulatory function of MSC and reveal a new role of IFNβ as modifier of MSC metabolism,suggesting that the subsequent metabolic switch could play a role in their immunoregulatory features. Discussion: The beneficial effect of IFNβ on MSC suggests that MSC couldconsidered as an add-on therapy to IFNβ treatment in individuals with MS and incomplete control of disease.

P1056 The effect of interferon beta 1a and polyphenolic extracts on autophagy, apoptosis and oxidative stress in patients with multiple sclerosis: an in vitro study M. Ruggieri1, L. Savino1, D. Centonze2, S. Scacco1, G. Matarese3, A. Uccelli4, R. Mechelli5, M. Salvetti5, D. Paolicelli1, M. Trojano1, on behalf of MS RUN Network 1University of Bari, Bari, 2Tor Vergata University and Hospital Rome, Rome, 3University of Salerno, Salerno, 4University of Genoa, Genoa, 5Sapienza University of Rome, Rome, Italy

Disclosure D. Centonze has received honoraria and/or consulting fees from Almirall, Bayer-Schering, Biogen Idec, Genzyme, GW Pharmaceuticals, Merck-Serono, Novartis, Sanofi-Aventis and Teva; research grants from Biogen Idec Merck-Serrono, Novartis, and Teva; and is Advisory Board Member of Bayer-Shering, Merck-Serono, and Teva. A. Uccelli has received consulting honoraria and/or speaker fees and a basic science study grant to support part of the work submitted from Biogen Idec; consulting honoraria and/or speaker fees

Objectives: Accumulation of aberrant proteins and inclusion bodies, hallmarks of neurodegenerative diseases such as Multiple Sclerosis (MS), have toxic effects, resulting in overproduction of reactive oxygen species and oxidative stress. Autophagy, considered an alternative apoptosis, is a significant intracellular mechanism that removes damaged organelles and misfolded proteins in order to maintain cell homeostasis. Excessive or insufficient autophagic and apoptotic activity leads to altered homeostasis causing neurodegeneration. In this study, we evaluated the “in vitro” effects of IFN-β 1a and polyphenolic extracts on the induction of apoptosis and autophagy, as well as their relation to oxidative stress. Materials and methods: Peripheral and cerebrospinal fluid lymphocytes of 50 RR-MS patients were included into the study. Autophagic (ATG5 and LC3b), apoptotic (Bax and Bcl2) molecules, and oxygen consumption were studied.Respirometric analysis, Western blot , flow cytometry, and cell culture were used. Results: Treatment of peripheral and CSF lymphocytes with IFN-β 1a and polyphenolic extracts induced significant levels of in vitro apoptosis induced in, while autophagy and oxidative stress were reduced by these treatments. Discussion and conclusions: These finding suggest that oxidative stress may not be a universal phenomenon in all forms of MS but may be a particular manifestation of inflammatory neurodegeneration. Apoptosis can play a protective role; the inhibition of this process can significantly enhance growth and perpetuate autoreactive T cells. This enhanced autophagy may play a role in the pathogenesis of MS. IFN-β 1a and polyphenolic extracts effects, alone or in combination, are able to restore basal oxidative stress as well as the apoptotic or autophagic mechanisms that are closely, associated with this process. This finding offers insights into a possible cure for MS.

References 1. Kamat PK, Kalani A, Kyles P, Tyagi SC, Tyagi N.Autophagy of mitochondria: a promising therapeutic target for neurodegenerative disease. Cell Biochem Biophys. 2014 Nov;70(2):707-19. doi: 10.1007/s12013-014-0006-5. 2. Ghavami S, Shojaei S, Yeganeh B, Ande SR, Jangamreddy JR, Mehrpour M, Christoffersson J, Chaabane W, Moghadam AR, Kashani HH, Hashemi M, Owji AA, Łos MJ. Autophagy


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Poster Session 2, 21(S11) and apoptosis dysfunction in neurodegenerative disorders. See comment in PubMed Commons belowProg Neurobiol. 2014 Jan;112:24-49. doi: 10.1016/j.pneurobio.2013.10.004. Epub 2013 Nov 6. Disclosure M. Ruggieri, L. Savino, S. Scacco and R. Mechelli have nothing to disclose. Maria Trojano received honoraria for consultancy or speaking from Biogen, Sanofi-Aventis, Merck Serono and Bayer-Schering and research grants from Merck Serono, Biogen and Novartis. Damiano Paolicelli received honoraria for consultancy and/or speaking from Biogen Idec, Novartis and Bayer-Schering and research grant from Serono Foundation. Marco Salvetti received lecture fees from Biogen-Dompé, research support from Bayer-Schering, Biogen-Dompé, MerckSerono, Sanofi-Aventis. Dr. Diego Centonze is an Advisory Board member of Almirall, Bayer Schering, Biogen, Genzyme, GW Pharmaceuticals, Merck-Serono, Novartis, Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen Idec, Genzyme, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi-Aventis, Teva. He is also an external expert consultant of the European Medicine Agency (EMA), and the principal investigator in clinical trials for Bayer Schering, Biogen Idec, Merck Serono, Mitsubishi, Novartis, Roche, Sanofiaventis, Teva. His preclinical and clinical research was supported by grants from Bayer, Biogen, Merck Serono, Novartis e Teva. Antonio Uccelli has received consulting honoraria and/or speaker fees and a basic science study grant to support part of the work submitted from Biogen; consulting honoraria and/or speaker fees from Genentech, Roche, Allergan, Sanofi-Aventis, BiogenDompè, and Novartis; consulting honoraria and/or speaker fees and a basic science study grant from Merck-Serono. Giuseppe Matarese: nothing to disclose. P1057 Teriflunomide safety in subsets of patients with relapsing MS: results from the TEMSO and TOWER studies G. Comi1, J. de Seze2, K. Thangavelu3, P. Truffinet4, M. Benamor4, P. Rufi4, L. Kappos5 1University Vita-Salute San Raffaele, Milan, Italy, 2Strasbourg University, Hôpital Civil, Strasbourg, France, 3Genzyme, a Sanofi company, Cambridge, MA, United States, 4Genzyme, a Sanofi company, Chilly-Mazarin, France, 5University Hospital Basel, Basel, Switzerland Background: Teriflunomide is a once-daily oral immunomodulator for treatment of relapsing-remitting MS (RRMS). In TEMSO (NCT00134563) and TOWER (NCT00751881), teriflunomide demonstrated efficacy on annualized relapse rate, disability progression and magnetic resonance imaging (MRI) parameters (MRI performed in TEMSO only). Study populations included patients with progressive forms of MS, although most patients had RRMS (TEMSO, 91%; TOWER, 97%). Objective: To report safety outcomes from the RRMS subpopulations in TEMSO and TOWER. Methods: All randomized patients exposed to medication were included in the safety population and analysed according to treatment received. Safety assessments were based on monitoring of

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adverse events (AEs), serious AEs, laboratory parameters, physical examinations and vital signs. Results: The RRMS safety populations comprised 993 patients in TEMSO (teriflunomide 14 mg, n=332; 7 mg, n=334; placebo, n=327) and 1134 patients in TOWER (teriflunomide 14 mg, n=365; 7 mg, n=394; placebo, n=375). In both studies, similar proportions of patients in all treatment groups reported AEs (TEMSO: 14 mg, 90.7%; 7 mg, 89.5%; placebo, 87.8%; TOWER: 14 mg, 86.3%; 7 mg, 84.5%; placebo, 83.7%) and serious AEs (TEMSO: 14 mg, 15.7%; 7 mg, 14.1%; placebo, 12.8%; TOWER: 14 mg, 12.1%; 7 mg, 12.9%; placebo, 12.3%). More patients receiving teriflunomide discontinued treatment due to AEs (TEMSO: 14 mg, 10.8%; 7 mg, 9.3%; placebo, 7.6%; TOWER: 14 mg, 15.9%; 7 mg, 12.7%; placebo, 6.1%), mainly due to a protocol requirement to discontinue treatment in the event of confirmed alanine aminotransferase (ALT) >3x ULN or confirmed neutrophil count < 1000 cells/µL. Four deaths were reported in TOWER, none considered related to study drug: 2 in the 14-mg group (suicide, and septicaemia due to Gram-negative infection complicated by disseminated intravascular coagulopathy); 1 in the 7-mg group (traffic accident); and 1 in the placebo group (respiratory tract infection). AEs reported more frequently with teriflunomide (⩾10% in either teriflunomide group, and ⩾2% greater than placebo) were diarrhoea, nausea (14 mg only), ALT increase, hair thinning and headache (7 mg only) in TEMSO; and ALT increase, hair thinning, diarrhoea and headache (7 mg only) in TOWER. CONCLUSIONS: Safety outcomes for teriflunomide in the RRMS patient subgroups of the TEMSO and TOWER studies were similar, and were consistent with those observed in the overall population with relapsing forms of MS. Disclosure Study supported by Genzyme, a Sanofi company. GC: Consulting fees (Almirall, Bayer, Chugai, Excemed, Genzyme, Merck Serono, Novartis, Receptos, Sanofi, Serono Symposia International Foundation [SSIF], Teva); fees from nonCME services (Almirall, Bayer, Biogen, Excemed, Genzyme, Merck Serono, Novartis, Receptos, Sanofi, SSIF, Teva). JS: Consulting services, advisory boards (Genzyme). KT: Employee of Genzyme. PT: Employee of Genzyme, with ownership interest. MB: Employee of Genzyme, a Sanofi company PR: Employee of Genzyme. LK: Author´s institution (University Hospital Basel) has received in the last 3 years and used exclusively for research support: steering committee, advisory board and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, Xenoport); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, Teva); support of educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva); royalties (Neurostatus Systems GmbH); grants (Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society, Swiss National Research Foundation).

P1058 Sigma - 1 receptor agonists: new drug-candidates targeting neurological and immune aspects of MS


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B. Oxombre Vanteghem1, C. Lee-Chang1, D. Lefranc1, M. Toussaint2, M. Donnier-Marechal3, P. Carato3, L. Prin1,4, P. Melnyk5, P. Vermersch1,6 1LIRIC - UMR 995, Lille Cedex, 2CNRS UMR 8161, 3UDSL EA 4481, 4CHRU Lille - Pôle Immunologie, 5JPArc - UMR S 1172, 6CHRU Lille - Pôle Neurologie - Service Neurologie D, Lille, France Background: Selective agonists of the sigma-1 receptor (S1R) are generally reported to protect against neuronal damage and modulate oligodendrocyte differentiation. Human and rodent lymphocytes possess saturable, high-affinity binding sites for compounds binding to the S1R and potential immunomodulatory properties have been described for sigma receptor ligands. Nevertheless, expression and function of S1R in autoimmune neuroinflammation remains unexplored. Objective: In the current study, we sought to evaluate the impact of a S1R protein agonist in experimental autoimmune encephalomyelitis (EAE), a valuable model of the inflammatory aspects of multiple sclerosis (MS). Methods: S1R expression was quantified in the central nervous system (CNS) of actively induced EAE mice by a western-blot multiplex analysis. Fused tetrahydroisoquinoline-hydantoin (TicH) were designed, synthesized and evaluated. A selected TicH agonist compound was injected i.p. at the time of immunization (5mg/kg, i.p.). Control mice received one administration of saline solution. Disease severity was assessed clinically for 35 days by a daily monitoring (subjective 0-5 point scale). An extensive histopathological evaluation of the CNS was performed. Phenotyping of B-cell subsets and regulatory T-cells were performed by flow cytometry in spleen and cervical lymph nodes. Results: Most efficient TicH compounds showed nanomolar S1R affinity, selectivity versus S2R, very low cytotoxicity and ADME properties compatible with therapeutic development. Prophylactic treatment of EAE mice with the S1R TicH agonist results in an overall reduction in the clinical progression of EAE, by preventing mononuclear cell accumulation and demyelination in brain and spinal cord, and by increasing T2 B-cells and regulatory T-cells. Preadministration of the S1R antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine (BD1047) blocked the S1R TicH agonist clinical effects. Conclusions: These findings demonstrate that this S1R agonist, containing the tetrahydroisoquinoline-hydantoin structure, decreased the magnitude of inflammation as well as demyelination in EAE. This effect was associated with increased proportions of B-cell subsets and regulatory T-cells with potential immunoregulatory functions. Targeting of the S1R protein might thus provide new therapeutic opportunities in MS. Disclosure Oxombre B: nothing to disclose. Lee-Chang C: nothing to disclose. Lefranc D: nothing to disclose. Toussaint M: nothing to disclose. Donnier-Maréchal M: nothing to disclose. Carato P: nothing to disclose. Prin L: nothing to disclose. Melnyk P: nothing to disclose.

Vermersch P: Honoraria and consulting fees from Biogen, Genzyme-Sanofi, Bayer, Novartis, Teva, Merck-Serono, GSK and Almirall. Research supports from Biogen, Bayer, Novartis and Merck-Serono. P1059 Natalizumab versus fingolimod in RRMS patients non-responder to first-line therapies: a 2 years, bicenter, retrospective, intention-to-treat cohort study D. Baroncini1, A. Ghezzi1, P.O. Annovazzi1, M. Zaffaroni1, V. Martinelli2, B. Colombo2, M.J. Messina2, G. Minonzio3, M. Rodegher2, M. Romeo2, L. Moiola2, F. Sangalli2, G. Comi4 1Multiple Sclerosis Study Center, Sant’Antonio Abate Hospital, Gallarate, 2Department of Neurology, San Raffaele Hospital, Milan, 3Neuroradiology Department, Sant’Antonio Abate Hospital, Gallarate, 4Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Hospital, Milan, Italy Background: No randomized, head-to-head, comparison studies of natalizumab (NAT) vs fingolimod (FTY) are yet available. Some groups tried to make a direct comparison in observational, open-label studies, with divergent findings. Objectives: To compare NAT vs FTY effectiveness in a real life, intention-to-treat (ITT) population of active RRMS patients failing first-line treatments (FLT), followed up to 2 years. Subjects and methods: Consecutive RRMS patients failing FLT according to EMA recommendations and naïve to secondline agents, who switch to FTY or NAT from June 2011 to February 2014, were enrolled in two Italian MS center. Exclusion criteria: immunosuppressors use in the last year. Clinical (relapses, 6-months confirmed EDSS score worsening/improvement) and MRI data (number of new/enlarging T2 lesions, Gd+ lesions). No evidence of disease activity (NEDA-3: absence of relapses, brain MRI activity and EDSS worsening) was evaluated. Propensity score (PS) 1:1 matching was used to obtain two comparable groups. Results: After PS matching, 196 patients (98 for each cohort) were included, and baseline demographic/clinical characteristics overlap. ITT populations: 192 (NAT=94, FTY=98) and 146 patients (NAT=70, FTY=76) with 1 and 2 years of follow-up. Treatment discontinuation rate was higher in NAT vs FTY (32% vs 8%; p< 0.001), mainly due to PML concern. Proportion of patients with disability worsening was similar between NAT and FTY (15 Vs 11%, p>0.1). A trend favouring NAT vs FTY for disability improvement (12 vs 5%, HR 2.99, p=0.062) was found. Proportion of relapse-free patients was higher in NAT vs FTY (82% vs 67%, HR 0.48, p=0.018). Brain MRI activity was lower in NAT vs FTY in 0-1 (12 vs 28%, p=0.007) and 0-2 years (18 vs 33%, p=0.016), while there was no significant difference in 1-2 years (6 vs 12%, p>0.1). The reduction of new T2 lesions formation was significantly higher in NAT vs FTY in 0-1 year (mean 0.21 vs 0.51, p=0.005), but not in 1-2 year (mean 0.13 vs 0.14, p>0.1). Reduction of Gd+ lesions was similar across treatment groups in the whole follow-up (p>0.1). Proportion of NEDA-3 patients was higher in NAT vs FTY cohort (70 vs 47%, HR 0.48, p=0.002) at 2 years. Discussion: In our study NAT dominated FTY for almost all outcome measures, especially in the first year. For JCV- patients with


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Poster Session 2, 21(S11) high disease activity NAT remains the best option, the major concern remaining the best way to manage its discontinuation in JCV+ patients. Disclosure Dr. Baroncini has no relevant disclosures for this abstract. He received personal compensation from Almirall for creation of editorial publications and travel grants for participation to National and International Congresses from Genzyme. Dr. Zaffaroni has served on scientific advisory boards for Teva, Medtronics, Aventis, Merck Serono and Novartis, and served as a consultant for Biogen Idec. Dr. Annovazzi received honoraria for speaking and travel grants from Biogen Idec, Teva, Genzyme, Novartis, Almirall and Wellspect healthcare. Dr. Minonzio reports no disclosures. Dr. Martinelli has received compensations for consulting and travel/accomodations/meeting expenses support from Novartis, Genzyme, Sanofi-Aventis, Merck Serono, Biogen Idec, Bayer Schering, and TEVA pharmaceuticals. Dr. Colombo has no relevant disclosures for this abstract. Dr. Messina has no relevant disclosures for this abstract. Dr. Rodegher has no relevant disclosures for this abstract. Dr. Romeo has no relevant disclosures for this abstract. Dr. Moiola has no relevant disclosures for this abstract. Dr. Sangalli has no relevant disclosures for this abstract. Prof. Giancarlo Comi received personal compensation from Bayer Schering, Serono Symposia International Foundation, Merck Serono International, TEVA Pharmaceutical Ind. Ltd, SanofAventis and Biogen Idec for consulting services, received personal compensation from TEVA Pharmaceutical Industries Ltd, Sanofi-Aventis, Serono Symposia Int. Foundation, Biogen Dompè and Bayer Schering for speaking activities. TEVA Pharmaceutical Industries Ltd, Sanofi-Aventis, Serono Symposia Int. Foundation, Biogen Dompè and Bayer Schering have provided prof. Comi for the costs of travelling and lodging related to speaking activities. Dr. Ghezzi received honoraria for speaking from Genzyme, BiogenIdec, Merck-Serono, Novartis, and Almirall, for consultancy from Merck-Serono, Novartis, Biogen-Idec, Genzyme, received support for participation to National and International Congresses from Biogen-Idec, Merck-Serono Novartis, Genzyme, Teva

P1060 Adaptive and innate immune cell phenotypes in the blood of fingolimod-treated MS-patients J.L. Talbot1, L. Börnsen1, J.R. Christensen2, B.R. Nielsen1, C. Ammitzbøll1, M.R. von Essen1, H.B. Søndergaard1, F. Sellebjerg2 1Danish Multiple Sclerosis Center, Copenhagen University Hospital Rigshospitalet, 2Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Introduction: Immune-mediated demyelination in relapsing remitting multiple sclerosis (RRMS) involves adaptive and innate immune cells. Treatment with fingolimod reduces disease-activity in patients with RRMS. Fingolimod induces internalization of the sphingosine-1-phosphate receptor, which is ubiquitously

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expressed on immune cells. Altered migration of distinct CD4+Tcell and B-cell subsets in secondary lymphoid tissue is believed to be a major, therapeutically relevant mode of action of fingolimod. Few data exist on how fingolimod affects other circulating immune cells. Aim: To examine fingolimod treatment effects on a broad panel of peripheral blood mononuclear cell (PBMC) subsets in vivo. Methods: A panel of cell surface markers on PBMCs from 18 untreated and 18 fingolimod-treated MS-patients was analyzed by flow cytometry. A total of 208 subsets were defined: 26 CD4+CD8T-cell-subsets, 25 CD4+CD8+, CD4-CD8+ or CD4-CD8- T-cell subsets, 24 B-cell subsets, 23 monocyte subsets, 23 myeloid dendritic cell (mDC) subsets, 23 plasmacytoid DC (pDC) subsets, and 14 natural-killer (NK)-cell subsets. Absolute cell counts were determined for all subsets (cells/µl blood). Statistics was by Mann-Whitney U-test and correction of multiple testing was by the false discovery rate (q< 0.05). Results: Fingolimod treated patients had significantly decreased cell counts of T and B-cells compared to untreated patients, while there were no significant differences in the cell counts of NK-cells, monocytes, pDCs and mDCs. Cell counts were significantly affected by treatment with fingolimod in 100% of the CD4+CD8T-cell subsets, 40% of the CD4+CD8+ T-cell subsets, 40% of the CD4-CD8+ T-cells subsets, 24% of the CD4-CD8- T-cell subsets, 88 % of the B-cell subsets, 17% of the monocyte-subsets, 13% of the mDc subsets, 4% of the pDC subsets and 14% of the NK-subsets. Conclusion: Treatment with fingolimod preferentially reduced the recirculation of a broad panel of CD4+CD8- T-cell and B-cell subsets. Compared to CD4+CD8- T-cells subsets, fingolimod treatment-effects on CD4+CD8+, CD4-CD8+, CD4-CD8- subsets were less pronounced and more differentiated. Fingolimod-treatment selectively altered the count of few monocyte, DC and NK-cell subsets within the blood-compartment. Fingolimod mostly affects the T- and B-cell cells pool in the blood, however, minor effects on monocyte, DC and NK-cell pools may also reflect a therapeutically relevant treatment-effect of fingolimod in MS. Disclosure Jacob Talbot: nothing to disclose. Lars Börnsen has had travel expenses reimbursed by Novartis and by Genzyme for congress participation. J. Romme Christensen has received speaker honoraria from Genzyme and TEVA, consultant honoraria from Biogen Idec and TEVA, and has had travel expenses reimbursed by Biogen Idec and Merck Serono. Birgitte Romme Nielsen has had travel expenses reimbursed by Biogen Idec and Merck Serono, and received support for congress participation from Merck Serono. Cecilie Ammitzbøll has had travel expenses reimbursed by Biogen Idec, Novartis, TEVA and Genzyme. Marina Rode von Essen: nothing to disclose. Helle Bach Søndergaard: nothing to disclose. Finn Sellebjerg has served on scientific advisory boards for Biogen Idec, Genzyme, Merck Serono, Novartis and TEVA, served as consultant for Biogen Idec and Lundbeck; has received support for congress participation from Biogen Idec, Novartis and TEVA; has received speaker honoraria from Biogen Idec, Genzyme, Merck Serono and Novartis. His laboratory has received research support from Biogen Idec and Novartis.


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P1061 Assessing the efficacy, tolerability, and safety of rituximab for the treatment of multiple sclerosis: experience in 313 patients at a large academic center E. Alvarez, J. Seibert, B. Vollmer, J. Blackburn, M. Strobel, J. Freeman, S. Sillau, J. Honce, J.L. Bennett, A. Miravalle, T. Schreiner, J. Corboy, T. Vollmer, K. Nair University of Colorado Denver, Aurora, CO, United States Objective: To assess the efficacy, tolerability, and safety of rituximab treatment of patients with multiple sclerosis (MS) in a real world clinical setting at a large academic center. Background: Phase II studies show efficacy of anti-CD20+ B-cell treatments like rituximab in MS. The safety and efficacy of rituximab beyond one year has not been described in MS. Methods: Retrospective chart review of MS patients at the University of Colorado Denver (UCD),Metro Community Providers Network (MCPN), and Children’s Hospital Colorado (CHC) who were prescribed rituximab. Clinical data collected included demographic information, laboratory data, clinical relapses, MRI lesions, and infusion reactions. Results: 285 patients received rituximab at UCD, including 200 with ⩾2 courses (median 18 months, range 6-72). Additionally 19 patients treated at MCPN (14 patients having ⩾2 courses) and 9 at CHC with rituximab were also examined. For the UCD patients, mean age was 46.3 years (15-79) with mean disease duration of 11 years; 67.5% were women; 83.2% were Caucasian. 66.2%, 20.3%, and 13.5%, had relapsing remitting, secondary progressive, and primary progressive MS, respectively. The majority of patients were treated with 1 gram initially with subsequent doses of 500 mg every 6 months. Two UCD patients experienced 3 clinical relapses and 3 patients at MCPN experienced 3 relapses. Seven patients out of 140 (5%) with follow up MRIs at UCD developed 10 new T2 lesions; no enhancing lesions were observed. 18 of 185(9.7%) patients reconstituted their CD20+cells early, which was related to dose and weight. 20% reported minor first dose infusion-related reactions (8% with follow-up courses). At UCD, 81.6% were JC+ prior to treatment with no cases of progressive multifocal leukoencephalopathy. 114 patients at UCD and MCPN were treated with natalizumab including 5 who had relapses on natalizumab prior to switching to rituximab and remained stable on rituximab. Ten pediatric patients (9 at CHC and 1 at UCD) did well on rituximab. Three patients had neutropenic fevers attributable to rituximab. Conclusions: Rituximab was well tolerated and safe for the treatment of MS. Although this is a retrospective study, rituximab was effective at reducing relapses in MS with minimal clinical relapses or new MRI activity. Disclosure Enrique Alvarez: Consulting: Teva Neuroscience, Genzyme, and Biogen IDEC. Clinical Research: Novartis, Biogen Idec, Rocky Mountain MS Center Julie Seibert: nothing to disclose Brandi Vollmer: nothing to disclose Jace Blackburn: nothing to disclose Molly Strobel: nothing to disclose Jessica Freeman: nothing to disclose Stefan Sillau: nothing to disclose

Justin Honce: Grant support: Novartis and Biogen IDEC. Consulting: Cortechs Labs. Jeff Bennett: Editorial board for Journal of Neuro-ophthalmology, Multiple Sclerosis, Neurology: Neuroimmunology & Neuroinflammation, holds patents for compositions and methods for the treatment of neuromyeltis optica, novel blocking monoclonal therapy for neuromyelitis optica, has consulted for EMDSerono, Questcor Pharmaceuticals, Alnaylam Pharmaceuticals, Medimmune, Abbvie, Novartis Pharmaceuticals, Chugai Pharmaceuticals, Genzyme, Genentech, received research support from Questcor Pharmaceuticals, Novartis Pharmaceuticals, NIH, Guth-Jackson Foundation, holds stock in Apsara Therapeutics, receives license fee and royalty payments from Aquaporumab. Augusto Miravalle: Consulting: Teva Neuroscience, Genzyme, Accelerated Cure Project, Questcor, Putnam Associates, Mallinckrodt, Biogen IDEC, Medscape. Clinical research: Roche, Biogen, NIH, Genentech, Teva Neuroscience, Osmotica, Accelerated Cure Projects Teri Schreiner: Clinical trials: Novartis, Biogen IDEC, NIH, MSDX. John Corboy: Consultant: Novartis (to design clinical trials and safety information processing), Celgene Therapeutics (to design clinical trials), Teva Neurosciences (advisory board), Biogen Idec (to answer a survey to identify consensus treatment statements in MS.Clinical trial: NIH, Novartis, Sun Pharma, Celgene Therapeutics, National Multiple Sclerosis Society (NMSS). Research grants: Juvenile Diabetes Research Foundation (Biomarker in MS), NMSS (MS Tissue Bank), Diogenix (adjudicator for diagnosis of MS). Honoraria:Pro CE, Rocky Mountain MS Center, via Genzyme, Grand Rounds at multiple academic institutions. Other: Medical-legal work, Editor, Neurology: Clinical Practice. Board Member on NMSS Colorado-Wyoming Chapter Timothy Vollmer: Consulting: Acorda, Biogen Idec, Consortium of MS Centers (CME presentation), DeltaQuest, Genentech, Novartis, Novartis Canada, Novartis, Japan, Teva, Teva Canada, Xenoport, Mylan, Medscape. Clinical Research: Accelerated Cure Project, Acorda, Avanir, Biogen Idec, EMD Serono, Genzyme, Jensen Research, MedImmune, NIH, Novartis Pharmaceuticals, Ono Pharmaceuticals, Rky Mnt MS Center, Teva, Neuroscience, Vaccinex, Roche Kavita Nair: Astellas, Eli Lilly, Gilead, Genentech, Biogen IDEC P1062 Characterization of vatelizumab, a novel antibody that binds VLA-2 W.M. Siders1, A. Attinger2, C. Voirol2, E. Havari1, M.J. Turner1, J.M. Kaplan1, I. Antonijevic3, S. Hou2 1Neuroimmunology Research, Genzyme, a Sanofi company, Framingham, MA, United States, 2Glenmark Pharmaceuticals S.A., La Chaux-de-Fonds, Switzerland, 3Translational Medicine, Genzyme, a Sanofi company, Cambridge, MA, United States Background: Integrins are a large family of heterodimeric cell surface receptors that interact with extracellular matrix proteins or cell adhesion molecules to mediate normal physiological, as well as pathological, processes. The α2β1 integrin (also known as Very Late Antigen [VLA]-2) is composed of an α2 subunit and a β1


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Poster Session 2, 21(S11) subunit. Vatelizumab is a humanized monoclonal immunoglobulin G (IgG)4 antibody directed against the α2 subunit I domain of VLA-2, a collagen-binding integrin. The mechanism of action of vatelizumab is not known, but it is hypothesized to block the interaction of VLA-2 expressed on activated lymphocytes with collagen, thus reducing the inflammatory cascade at sites of inflammation, such as MS lesions. Vatelizumab is being developed for the treatment of relapsing forms of MS. Objective: To characterize the in vitro biological activity of vatelizumab, a novel anti-VLA-2 antibody. Methods: The expression of VLA-2 on immune cells was characterized by flow cytometry. The in vitro activity of vatelizumab was analysed in both antibody-dependent cell-mediated cytolysis (ADCC) and complement-dependent cytolysis (CDC) assays. The ability of vatelizumab to block the binding of VLA-2 positive cells to collagen, and its potential effects on platelet function, were also evaluated. Results: Flow cytometry analysis indicated that, unlike VLA-4, VLA-2 is not constitutively expressed on all T lymphocytes. In vitro ADCC and CDC assays confirmed that, as expected from an IgG4 isotype, vatelizumab did not induce cell lysis following binding to VLA-2. Vatelizumab potently inhibited the binding of human α2-expressing cells to rat or human type I collagen. In addition, vatelizumab inhibited type I collagen-induced interferon γ release from anti-CD3 activated human T cells. Vatelizumab showed no effect on the activation of platelets, did not induce aggregation, and did not affect extrinsic or intrinsic coagulation pathways. Conclusions: Vatelizumab is an anti-VLA-2 antibody that inhibits the binding of VLA-2 positive cells to collagen. It does not trigger ADCC or CDC upon binding and has no effect on platelet function. Vatelizumab is currently being tested in a phase 2 study (NCT01659138) for the treatment of patients with relapsing MS. Disclosure WMS: Employee of Genzyme. AA: Employee of Debiopharm, but was employed by Glenmark when study conducted. CV: Employee of Glenmark. EH: Employee of Genzyme. MJT: Employee of Genzyme. JMK: Employee of Genzyme. IA: Employee of Genzyme. SH: Employee of Glenmark. P1063 Efficacy of delayed-release dimethyl fumarate vs glatiramer acetate on a novel composite outcome measure of inflammatory disease activity: post-hoc analysis of the CONFIRM study M. Kremenchutzky1, R.J. Fox2, J.T. Phillips3, M. Kita4, K.E. Peace5,6, J.B. Lewin7, A. Zhang7, M. Okwuokenye7, M.R. Edwards7, J.L. Marantz7 1London Health Sciences Centre, London, ON, Canada, 2Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, 3Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, 4Virginia Mason Multiple Sclerosis Center, Seattle, WA, 5Jiann-Pingg Hsu College of Public Health, Georgia Southern University,

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Statesboro, GA, 6Department of Biostatistics, School of Medicine, Virginia Commonwealth University, Richmond, VA, 7Biogen, Inc., Cambridge, MA, United States Background: Compared with placebo (PBO), delayed-release dimethyl fumarate (DMF) demonstrated efficacy and safety in relapsing-remitting multiple sclerosis (RRMS) in the Phase 3 DEFINE/CONFIRM studies. To more fully examine the effect of DMF on active inflammatory MS, we developed a novel composite endpoint combining relapse, gadolinium-enhancing (Gd+) lesions, and new/enlarging T2 lesions. Objectives: Compare the efficacy of DMF vs glatiramer acetate (GA) on inflammatory disease activity in a post-hoc analysis of the CONFIRM study. Methods: Eligibility criteria included age 18-55 years and EDSS score 0-5.0. Patients were randomized to receive DMF 240 mg twice (BID) or thrice daily, PBO, or subcutaneous GA (reference comparator) for up to 2 years (96 weeks). Brain MRI scans were performed in a subset of patients (MRI cohort). Inflammatory disease activity was defined as an event (relapse, Gd+ lesion, or new/enlarging T2 lesion) occurring within a specified interval (week 0−24, 24−48, or 48−96). Patients were considered free of inflammatory disease activity if they did not experience an event within a given interval or any preceding intervals, and were evaluated for inflammatory disease activity as long as they were known to be at risk. Estimate of an underlying proportional hazards model in continuous time was based on a complementary log-log model adjusted for baseline number of relapses (⩽1 vs ⩾2), EDSS score (⩽2.0 vs >2.0), presence or absence of Gd+ lesions, and T2 lesion volume (⩽median vs >median). Results are reported for DMF BID (approved dosing regimen in all regions). Results: The intent-to-treat population included 359, 350, and 363 patients receiving DMF, GA, or PBO, respectively; among them, 169, 175, and 167 were in the MRI cohort. Life-table estimates of the proportion (standard error) of patients receiving DMF vs GA who were free of inflammatory disease activity were 36% (4%) vs 29% (3%) during week 0−24, 34% (4%) vs 23% (3%) during week 24−48, and 21% (3%) vs 16% (3%) during week 48−96. The overall hazard ratio (HR) (95% confidence interval [CI]) for DMF vs GA was 0.77 (0.59−0.99; P=.0446). To confirm the efficacy of DMF on this novel endpoint, we also compared the effects of DMF vs PBO: the overall HR (95% CI) for DMF vs PBO was 0.60 (0.46−0.79; P=.0002). Conclusions: DMF significantly reduced the risk of inflammatory disease activity over 2 years compared with GA. The differential treatment effect was seen by 24 weeks. Disclosure This study is supported by Biogen, Inc. Marcelo Kremenchutzky: Research support/consulting fees from Biogen, Sanofi, Genzyme, Novartis, Bayer, Teva, and Serono. Robert J. Fox: consultant fees from Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Biogen, and Novartis; research grant funding from Novartis. J. Theodore Phillips: consulting fees from Acorda, Biogen, Genzyme, Merck Serono, and Sanofi; research support from Roche.


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Mariko Kita: served as PI on studies sponsored by Biogen, Novartis, Acorda and Serono; on the speaker´s bureau for Biogen; participated in advisory boards for Biogen and Novartis; honoraria and fees were paid directly to her employer and personal compensation was limited to travel/lodging reimbursement. Karl E. Peace: Biostatistical Consultant to Biogen. James B. Lewin: employee of and holds stock/stock options in Biogen, Inc. Annie Zhang: employee of and holds stock/stock options in Biogen, Inc. Macaulay Okwuokenye: employee of and holds stock/stock options in Biogen, Inc. Michael R. Edwards: employee of and holds stock/stock options in Biogen, Inc. Jing L. Marantz: employee of and holds stock/stock options in Biogen, Inc. P1064 A novel mechanism of action for teriflunomide by the induction of immunosuppressive gut CD39+FoxP3+Tregs in mice C. Kircher, E. Kasper, K. Telesford, S. Begum-Haque, A. Pant, L. Kasper, J. Ochoa-Reparaz Microbiology and Immunology, Dartmouth College, Hanover, NH, United States Terilunomide is an approved oral therapeutic to treat relapsing forms of multiple sclerosis (MS). The MOA is presumed to be the inhibition of de novo pyrimidine synthesis by acting as a reversible non-competitive inhibitor of the mitochondrial enzyme DHODH. Our laboratory has shown that alterations of the gut microbiome significantly affect EAE severity. Recent studies indicate the importance of gut microbes in the resistance to drugs and their influence on gut-mediated immune responses has been shown. Although the effect of teriflunomide on the proliferation of lymphocytes in MS is well established, we propose that, in addition, teriflunomide as an orally delivered treatment could affect the gut-associated lymphoid tissue (GALT) immune responses due to changes in the colonization of gut microbial populations. In this work, we hypothesized that oral treatment with teriflunomide would affect the phenotype and function of GALT immune cells. B6 mice were treated daily with 20 mg/kg of teriflunomide by oral gavage for 4 weeks, and the frequencies and phenotype of immune cells of GALT were compared weekly. Teriflunomide reduced the percentages of T cells, B cells, dendritic cells and monocytes/macrophages of Peyer’s patches (PPs) when compared to controls. Despite the reduction in T cell percentages, a significant increase of the relative frequencies of CD39+Tregs was observed. Further, the percentages of CD103+ cells in DCs, known to promote Treg conversion in the gut, were not reduced in PPs. No enhanced percentages of CD39+Tregs were observed in the spleens and cervical lymph nodes (CLN), suggesting a gut-restricted effect. In vitro, teriflunomide-sensitized Tregs reduced the proliferation of MOG-specific memory CD4+T cells isolated from EAE mice. Furthermore, although the exposure of total splenocytes from B6 mice and MOG-TCR specific transgenic mice stimulated with MOG to teriflunomide reduced the absolute frequencies of CD4+ T cells and CD39+Tregs, teriflunomide failed to reduce these populations when cells were isolated from PP and MLN. In vivo, the effect of

teriflunomide-induced CD39+Tregs was evaluated by adoptive transfer into recipient EAE mice. Our results identify specific gut CD39+Tregs that may contribute to the efficacy of teriflunomide as an oral therapeutic in relapsing MS. Disclosure This study was supported by Genzyme. Lloyd Kasper, Sakhina Begum-Haque and Javier Ochoa-Reparaz are funded by Genzyme. Christopher Kircher, Eli Kasper, Kiel Telesford and Anudeep Pant have nothing to disclose. P1065 Fingolimod treatment induces changes in NK and T-helper cell subpopulations and in T-cell co-stimulation markers F. Largey1, A. Czaplinski2, I. Jelcic1, M. Sospedra1, R. Martin1, I. Jelcic1 1Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital of Zurich, 2Neurozentrum Bellevue, Zurich, Switzerland Fingolimod is a functional sphingosine-1-phosphate (S1P) receptor antagonist approved for immunomodulatory treatment of relapsing-remitting multiple sclerosis (RRMS). It inhibits lymphocyte egress from secondary lymphoid organs by interfering with S1P signalling with the result of a marked peripheral lymphopenia. Fingolimod treatment may lead to rare, but sometimes severe or even fatal herpes viral infections, i.e. disseminated varicella zoster virus (VZV) infections, VZV encephalitis and herpes simplex virus type 1 encephalitis. In order to improve our understanding of fingolimod-induced changes in lymphocyte subpopulations and potential consequences for immune control of viruses, we characterized the blood cell composition during fingolimod treatment.We collected blood from RRMS patients prior to (V0) and after at least 3 months (V3) and 9 months (V9) of fingolimod treatment. We used ex vivo multicolour flow cytometry for detailed phenotypic analysis of peripheral blood lymphocytes and automated cell counting for absolute quantification of cell numbers.We corroborate previously reported findings, i.e. decrease in naïve and central memory T cells, increase in effector memory and terminally differentiated effector memory T cells as well as decrease in CD56bright NK cells by fingolimod treatment. Additionally, the frequency of NKT and gd T cells was increased. Absolute numbers of gd T cells were decreased by fingolimod, whereas absolute numbers of NKT cells were not altered. The proportion of T cells expressing co-stimulatory molecules CD27 and CD28 decreased, whereas CD137 expression relatively increased during fingolimod suggesting recent antigen-dependent activation of T cells. Concordantly, the percentage of cells expressing CD127 (IL-7Rα) decreased in all T cell subsets, along with a decrease in median IL-7Rα expression. Furthermore, Th1 cell frequencies increased during fingolimod, whereas CRTh2 and Th17 cell frequencies decreased. Importantly, absolute numbers of Th1 cells decreased at V3, but increased to V9, suggesting compensatory mechanisms.In conclusion, fingolimod treatment induces a variety of changes in T cell co-stimulation markers and relative and absolute numbers of peripheral blood lymphocytes, including


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Poster Session 2, 21(S11) cells suggested to play a role in herpes viral immunity, i.e. NK cells, gd T cells and T cells including Th1 cells. Whether these changes specifically affect anti-herpes viral immunity, is currently under investigation. Disclosure Neuroimmunology and MS Research receives unrestricted grant support from Biogen and Novartis, seminar support from Genzyme/Sanofi Aventis, Novartis, Biogen, Merck, Teva. F. Largey has nothing to disclose. A. Czaplinski received compensations for speaker or advisor activities from Biogen, Merck-Serono, Bayer-Schering, Teva, Genzyma, Novartis, Roche. IV. Jelcic has nothing to disclose. M. Sospedra has nothing to disclose. R. Martin has received personal compensation (advisory function) from Novartis, Biogen, Merck, Bionamics, CellProtect, Genzyme/ Sanofi Aventis. IL. Jelcic has received unrestricted grants from Biogen Idec and Novartis, and speaker honoraria from Novartis. P1066 Lack of evidence for T-cell expression of siglec-10 and suppressive interaction with soluble CD52 L. Azzopardi1, E. Havari2, M. Turner2, W. Brondyk2, D. Reczek2, Z. Georgieva1, W. Siders2, J. Kaplan2, B. Roberts2, A.J. Coles1, J. Jones1 1University of Cambridge, Cambridge, United Kingdom, 2Genzyme, a Sanofi company, Cambridge, MA, United States Background: Recently published observations have suggested that a population of T cells expressing high levels of CD52 may exert regulatory activity through the release of soluble CD52 and subsequent binding to the inhibitory Siglec-10 receptor on the surface of stimulated T cells. These findings may have relevance in the context of multiple sclerosis (MS) treatment with alemtuzumab (anti-CD52) antibody and were therefore investigated. Objective: Assess the expression of Siglec-10 by resting and activated T cells from healthy controls and autoimmune patients. Evaluate the suppressive potential of soluble CD52 on T cell activation. Methods: Surface Siglec-10 expression on peripheral blood mononuclear lymphocytes from 10 healthy controls, 5 individuals with relapsing-remitting (RR) MS and 5 individuals with type 1 diabetes (TID) was measured by flow cytometry, directly ex vivo and following 96 hours of activation with soluble anti-CD3 or anti-CD3/28 beads. T cell Siglec-10 mRNA expression was assessed by Taqman analysis of magnetically separated T cells directly ex vivo and following activation at 24, 48, 72, and 96 hours; B cells, known to express Siglec-10, were used as a positive control. The ability of CD52 to bind to Siglec-10 was assessed by Biacore, using a glycosylated soluble human CD52-Fc fusion construct expressed in HEK293 cells. To test the suppressive capacity of soluble CD52, PBMCs were activated with soluble anti-CD3 in the presence or absence of the CD52-Fc construct. Activation was assessed by measuring CD69 and CD25 expression by flow cytometry.

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Results: In contrast to the expression of Siglec-10 by B cells, Siglec-10 could not be detected on the surface of resting or activated T cells by flow cytometry, nor was it expressed at the mRNA level in T cells derived from healthy controls, TID and RRMS patients. In addition, binding of soluble CD52-Fc to Siglec-10 was undetectable by Biacore, and soluble CD52-Fc failed to suppress anti-CD3-mediated T cell activation, as measured by upregulation of CD69 and CD25 expression. Conclusion: Our findings failed to replicate previously published observations. In particular, the expression of Siglec-10 by T cells and a suppressive interaction between Siglec-10 and soluble CD52 could not be confirmed. Overall, our results are not supportive of an immune regulatory role for high CD52-expressing T cells through the release of soluble CD52. Disclosure LA: nothing to disclose. EH: Employee of Genzyme, a Sanofi Company. MT: Employee of Genzyme, a Sanofi Company. WB: Employee of Genzyme, a Sanofi Company. DR: Employee of Genzyme, a Sanofi Company. ZG: nothing to disclose. WS: Employee of Genzyme, a Sanofi Company. JK: Employee of Genzyme, a Sanofi Company. BR: Employee of Genzyme, a Sanofi Company. AJC: Consulting fees, lecture fees, and institutional grant support (Genzyme). JJ: Dr Joanne L Jones reports receiving consulting fees and lecture fees from Genzyme Sanofi. P1067 Key regulatory function of vitamin D for response to glucocorticosteroids in multiple sclerosis R. Hoepner1, S.M. Pittlik1, A. Salmen1, F. Arakrak1, X. Pedreiturria1, R. Gold1, H. Reichardt2, F. Lühder3, A. Chan1 1Neurology, Ruhr University Bochum, Bochum, 2Institute for Cellular and Molecular Immunology, 3Neuroimmunology, Georg-August-University, Göttingen, Germany Background: Glucocorticosteroids (GC) are the mainstay of MS-relapse treatment and GC-resistance may result in severe accumulation of disability. Alterations of the GC receptor (GR) complex may contribute to GC-resistance. We investigated in vitro and in vivo the potential of the secosteroid Vitamin D (VD) to modulate GR-dependent GC-resistance. Methods: Modulation of GC-induced apoptosis by VD was analysed in vitro by flow cytometry in human T-cells and human T-lymphoblastic Jurkat cells as well as in T-cells from Balb/c mice and GRdim-/- mice in which the GR is not able to dimerize. GR-concentration was quantified using a cell-based ELISA. Impact of VD on clinical GC-effects were investigated in MOG35-55 EAE. 25(OH)D3 serum levels in MS patients with stable disease (n=59), steroid-resistant relapse (n=22) and steroid-responsive relapse (n=28) were determined by immunoassay. Results: Both in steroid-resistant Jurkat T-cells (n=4) and primary human T-cells (n=5), co-incubation with VD led to a 1.41.7 fold increase of methylprednisolone-(MPS)-induced apoptosis (p< 0.05). VD increased total GR expression levels in


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primary human T-cells in a dose-dependent fashion (1.2-1.4 fold, p< 0.05). The same was observed in T-cells from wt mice, whereas in T-cells of GRdim-/- mice VD did not augment MPSinduced apoptosis, highlighting the functional relevance of the GR. In vivo, VD and MPS exerted synergistic therapeutic effects on EAE (p⩽0.001). VD serum levels were decreased in patients with steroid-resistant relapse compared to patients with steroidresponsive relapse (mean nmol/l (SD): 28 (23) vs. 49 (38); p=0.02). Discussion: Our data demonstrate that VD modulates GC signalling in vitro and in vivo via GR-dependent mechanisms. If prospectively validated in clinical studies, our findings may have therapeutic implications to overcome GC resistance in MS relapse and thus reduce persisting neurological deficits. Disclosure R Hoepner ([email protected]) received research and travel grants from Biogen Idec and Novartis. Anke Salmen ([email protected]) received personal compensation for activities with Novartis, Sanofi and Almirall Hermal GmbH. F Arakrak ([email protected]) reports no disclosures. X Pedreiturria ([email protected]) reports no disclosures. Ralf Gold ([email protected]) serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis. HM Reichardt ([email protected]) has nothing to disclose. F Lühder ([email protected]) received research grants from TEVA and Sanofi-Aventis and personal compensation for activities from Bayer Vital GmbH Andrew Chan ([email protected]) revieved consulting fees, speaker honoraria (Almirall, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi, Teva); research support (Biogen Idec, Genzyme, Novartis). P1068 Glatiramer acetate in patients with autoimmune diseases predominantly affecting the myelon R. Hoepner1, I. Ayzenberg2, I. Kleiter2, R. Gold2 1Neurology, St Josef Hospital, Ruhr University Bochum, 2Neurology, Ruhr University Bochum, Bochum, Germany Background: Glatiramer acetate (GA) is a well-established firstline multiple sclerosis (MS) medication. However its´ impact on autoimmune neuroinflammation predominantly affecting the spinal cord is unclear. Methods: We retrospectively analysed medical records of patients with myelitis who were treated with GA for at least 6

months (ethic approval no. 4573-13). Patients were stratified for neuromyelitis optica (NMO) fulfilling Wingerchuk criteria (n=8, aquaporin 4 antibodies (AQP4) positive 5/8; CSF oligoclonal bands (OCB) positive 0/8), MS patients with predominant optico-spinal (MSOS) involvement fulfilling Mc Donald criteria (n=9, OCB positive 6/9) and isolated autoimmune myelitis (AM) (n=10, OCB positive 9/10, visual evoked potentials normal 8/10, one missing value) with cerebral MRI not fulfilling Barkhof criteria. The annualized relapse rate (ARR) served as main measurement of GA efficacy. All data are presented as mean (standard error). Results: Mean duration of GA therapy was 2.2 years (0.3) and GA was withdrawn in 16 patients (NMO 6/8, OS 5/10, AM 5/10) of whom 8 withdraw GA due to disease progression (NMO 5/10, MSOS 3/10, AM 0/10). As demonstrated by mean ARR, GA was ineffective in NMO (prior GA 1.2 (0.3) vs. during GA 2.1 (0.7), p=0.2), especially in those with positive AQP4 status (ARR on GA: AQP4 pos. 3.4 (0.7) vs. neg. 0.33 (0.33)), and only partially effective in MSOS patients (prior GA 0.7 (0.1) vs. during GA 0.4 (0.2), p=0.2). In contrast, in patients with AM ARR decreased significantly (prior GA 0.8 (0.3) vs. during GA 0.1 (0.04), p=0.03). This finding also remained significant in the subgroup of AM patients with definite disease activity before GA, defined as clinical or radiological disease activity (prior GA 1 (0.3) vs. during GA 0.05 (0.05), p=0.03; n=8). Conclusion: We investigated a monocentrically treated patient population with predominant affection of the myelon. GA therapy was ineffective in NMO, especially in those patients with positive AQP4 antibodies, which might be due to the B-cell driven pathology of NMO. On contrast patients with MSOS and especially AM had a reduced relapse rate during GA therapy. Disclosure R Hoepner ([email protected]) received research and travel grants from Biogen Idec and Novartis. I Ayzenberg ([email protected]) received travel grands from International Headache Society. Ingo Kleiter has received honoraria for speaking/consultation and travel grants from Bayer Healthcare, Biogen Idec, Chugai, Merck Serono, and the Guthy Jackson Charitable Foundation, and research grants from the Mercator Foundation, Bayer Healthcare, Biogen Idec, Novartis Pharmaceuticals, and Teva as well as from the MERCUR Foundation. Ralf Gold ([email protected]) serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis. P1069 Targeting innate immune cells as a novel therapeutic approach for multiple sclerosis A. Edling1, A. Mahan1, L. Woodworth1, T. Garron1, A. Stockmann1, J.L. Kane Jr.2, M. Metz2, B. Roberts1, J. Kaplan1


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Poster Session 2, 21(S11) 1Neuroimmunology

Research, Genzyme, a Sanofi company, Framingham, 2LGCR SMRPD Chemical Research, Sanofi, Waltham, MA, United States Introduction: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) that causes intermittent relapses and progressive neurological deterioration. Activated microglial cells and macrophages contribute to CNS damage and play a significant role in disease progression and neurodegeneration in MS. These activated innate immune cells can participate in antigen presentation and produce inflammatory and neurotoxic mediators that are destructive to neurons and oligodendrocytes. Colony-stimulating factor-1 receptor (CSF-1R) is a receptor-tyrosine kinase expressed on macrophages, monocytes, and microglial cells and represents a potential target for therapeutic modulation of effector function. Methods: Potent CNS penetrant small molecule CSF-1R inhibitors were generated through an in-house medicinal chemistry program. Female C57BL/6 or NOD/ShlTJ mice were immunized with myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide to induce experimental autoimmune encephalomyelitis (EAE) and were treated therapeutically with a small molecule CSF-1R inhibitor. Cohorts were evaluated for progression and severity of disease symptoms. Flow cytometry and CNS tissue homogenates were utilized to evaluate the functional impact of CSF-1R inhibitor treatment on innate immune cells in the CNS and periphery. Histological analysis was conducted to evaluate the effect of treatment on demyelination and axonal loss within the CNS. Results: Therapeutic administration of a small molecule CSF-1R inhibitor in the MOG C57BL/6 EAE model resulted in significant disease inhibition accompanied by a reduction in the levels of circulating and CNS macrophage and microglia populations. In the murine MOG-induced NOD EAE model of secondary progressive MS, therapeutic treatment with a CNS penetrant CSF-1R inhibitor significantly decreased mean disease scores, disease progression, axonal damage/loss, and demyelination. This effect correlated with significantly reduced levels of innate immune cells and inflammatory/neurotoxic mediators in the CNS. Conclusions: These results support inhibition of CNS innate immune cells through CSF-1R receptor antagonism as a strategy to provide neuroprotection in MS by reducing inflammation, demyelination, and axonal loss.

Background: Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Objectives: Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (NR1A4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity. Methods: Murine and human macrophage responses were investigated in vitro and in vivo under homeostatic conditions, upon stimulation as well as during MOG-induced EAE. Results: In mice, pharmacologic FXR activation by the synthetic ligand GW4064 during MOG-induced experimental autoimmune encephalomyelitis (EAE) resulted in a profound reduction in disease severity - both, when treatment started before EAE-induction and after onset of disease. Importantly, amelioration of EAE by GW4064 was uneffective in FXR knockout mice, demonstrating receptor-specifity. FXR-mediated amelioration of EAE was accompanied by reduced immune cell infiltration and demyelination in the CNS and furthermore, we observed a decrease in numbers of pro-inflammatory MOG-reactive IL-17A and IFNg-producing T cells. Concomitantly, there was a significant increase in levels of IL-10, which we identified as the central mediator of FXR-mediated EAE amelioration as systemic neutralization of IL-10 completely abolished disease amelioration by GW4064. We identified FXR in myeloid cells to be important for induction of IL-10. In addition, FXR activation promoted a strong anti-inflammatory phenotype in macrophages, which is characterized by IL-10 production and the capacity to suppress T cell proliferation. In vivo, transfer of FXR-activated macrophages into EAE-diseased wildtype animals significantly ameliorated already ongoing disease, thus confirming the anti-inflammatory capacity of FXR-activated macrophages. Importantly, such amelioration was no longer observed when FXR-activated macrophages lacked IL-10, thus underlining the importance of IL-10 induction in macrophages during FXR-mediated EAE amelioration. Conclusions: Together, we propose an important role of FXR in control of T cell-mediated autoimmunity by promoting antiinflammatory macrophage responses. Disclosure

Disclosure Study supported by Genzyme, a Sanofi company. All authors are employees of Genzyme/Sanofi.

P1070 The bile acid receptor FXR controls CNS autoimmunity in an IL-10-dependent fashion M. Herold1, S. Hucke1, M. Liebmann1, D. Buck2, F. Lüssi3, S. Meuth1, F. Zipp3, B. Hemmer2, T. Kuhlmann4, H. Wiendl1, L. Klotz1 1Department of Neurology, University of Münster, Münster, 2Technische Universität München, Department of Neurology, München, 3Department of Neurology, University of Mainz, Mainz, 4Department of Neuropathology, University of Münster, Münster, Germany

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Stephanie Hucke: SH received speaker honoraria from Novartis. Martin Herold: MH has nothing to disclose. Marie Liebmann: ML has nothing to disclose. Dorothea Buck: DB received compensation for activities with Bayer HealthCare, BiogenIdec, MerckSerono, and Novartis, she was supported by the Abirisk and the PML Consortium. Felix Lüssi: FL received travel grants from Teva Pharmaceuticals and Merck Serono. Sven Meuth: SGM received honoraria for lecturing and travel expenses for attending meetings and financial research support from Bayer, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, MSD, Novartis, Omniamed, Novo Nordisk, SanofiAventis and Teva. Frauke Zipp: FZ has received research grants from Teva, Merck Serono, Novartis and Bayer as well as consultation funds from Teva, Merck Serono, Novartis, Bayer Healthcare, Biogen Idec


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Germany, ONO, Genzyme, Sanofi-Aventis and Octapharma, her travel compensation has been provided for by the aforementioned companies. Tanja Kuhlmann: TK received speaker honoraria from Novartis, Biogen Idec Canada,and Teva; she received compensation as a consultant from Genzyme. Heinz Wiendl: HW received compensation for serving on Scientific Advisory Boards/Steering Committees for Bayer Healthcare, Biogen Idec, Genzyme, Merck Serono, Novartis and Sanofi Aventis; he received speaker honoraria and travel support from Bayer Vital GmbH, Bayer Schering AG, Biogen Idec, CSL Behring, Fresenius Medical Care, Genzyme, Glaxo Smith Kline, GW Pharmaceuticals, Lundbeck, Merck Serono, Omniamed, Novartis and Sanofi Aventis; he received compensation as a consultant from Biogen Idec, Merck Serono, Novartis and Sanofi Aventis, has received research support from Bayer Vital, Biogen Idec, Genzyme Merck Serono, Novartis, Sanofi Aventis Germany, Sanofi US. Luisa Klotz: LK received compensation for serving on Scientific Advisory Boards for Genzyme and Novartis; she received speaker honoraria and travel support from Novartis, Merck Serono and CSL Behring; she receives research support from Novartis and Biogen Idec. P1071 T helper subsets changes in alemtuzumab multiple sclerosis treated patients: the recovery of immune system capacity as a possible indicator to treatment S.F. De Mercanti1, S. Rolla2, A. Cucci3, V. Bardina2, A. Vacca1, E. Cocco4, A. Vladic5, S. Soldo-Butkovic5, M. Habek6, I. Adamec6, D. Horakova7, P. Annovazzi8, G. Edan9, F. Novelli10, L. Durelli1, M. Clerico1 1Division of Neurology, Department of Clinical and Biological Sciences, 2Department of Clinical and Biological Sciences, University of Torino, 3Division of Neurology, Department of Clinical and Biological Sciences, University of AarhusTorino, Torino, 4Multiple Sclerosis Center, Department Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy, 5Department of Neurology, University of Zagreb, School of Medicine, 6Department of Neurology, University Hospital Center Zagreb, Zagreb, Croatia, 7Department of Neurology, University of Prague and Center of Clinical Neuroscience, Prague, Czech Republic, 8Multiple Sclerosis Study Center, AO S. Antonio Abate, Gallarate, Italy, 9Pole des Neurosciences, CHU Pontchaillou, Rennes, France, 10Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy

Background: Alemtuzumab is a humanized monoclonal antibody that targets the CD52 antigen, expressed at high levels on the surface of T and B lymphocytes. Alemtuzumab is effective in immunologically-mediated diseases and it was tested in two phase III trials (CARE-MS I and CARE-MS II) in relapsing-remitting (RR) multiple sclerosis (MS). Objectives: To investigate the changes in Th subsets, Treg percentages and function, and mRNA levels of a widespread pattern of immunologically relevant molecules during a 24 month followup after alemtuzumab treatment in RRMS patients.

Material and methods: Multicenter follow-up of 29 alemtuzumab-treated RRMS patients in the CARE-MS I and CARE-MS II trials. Peripheral blood samples were obtained at months 0, 6, 12, 18 and 24. We evaluated: (1) mRNA levels of 26 immunological molecules (cytokines, chemokines, chemokine receptors and transcriptional factors); (2) Th1, Th17 and Treg cell percentages; myelin basic protein (MBP) specific-Treg suppressor (3) activity. Results: Expression anti-inflammatory cytokines IL-10, IL-27 and TGFβ increased whereas expression of pro-inflammatory molecules related to the Th1 or Th17 subsets decreased after alemtuzumab administration and remained lower than baseline through the follow-up period. The percentage of CD4+ cells in PB remained significantly lower than baseline while the percentage of Th1 and Th17 cells did not significantly change. A significant increase in the percentage of Treg cells was observed at month 24 and was accompanied by an increase in Treg cell suppressive activity against MBP-specific Th1 and Th17 cells. Conclusion: The long-lasting therapeutic benefit of alemtuzumab in RRMS may involve a shift in the cytokine balance towards inhibition of inflammation associated with a reconstitution of the PB CD4+ T cell subsets that includes expansion of Treg cells with increased suppressive function. Disclosure Stefania De Mercanti: nothing to disclose Simona Rolla: nothing to disclose Angele Cucci: nothing to disclose Valentina Bardina: nothing to disclose Alessandro Vacca: nothing to disclose Eleonora Cocco: nothing to disclose Anton Vladic: nothing to disclose Silvia Soldo-Butkovic: nothing to disclose Mario Habek: nothing to disclose Ivan Adamec: nothing to disclose Dana Horakova: nothing to disclose Pietro Annovazzi: nothing to disclose Gilles Edan: nothing to disclose Franco Novelli: nothing to disclose Luca Durelli: nothing to disclose Marinella Clerico: nothing to disclose P1072 Sustained low rate of brain volume loss with longterm delayed-release dimethyl fumarate treatment in relapsing-remitting multiple sclerosis patients: results from the ENDORSE study D. Miller1, T. Yousry1, R.J. Fox2, R. Gold3, D.L. Arnold4,5, J. Potts6, J.L. Marantz6, L. Kappos7 1Institute of Neurology, University College London, London, United Kingdom, 2Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, United States, 3St. Josef Hospital, Ruhr University, Bochum, Germany, 4Montreal Neurological Institute, McGill University, 5NeuroRx Research, Montreal, QC, Canada, 6Biogen, Inc., Cambridge, MA, United States, 7University Hospital Basel, Basel, Switzerland


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Poster Session 2, 21(S11) Background: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated robust efficacy and an acceptable safety profile in relapsing-remitting multiple sclerosis (RRMS) in the Phase 3 DEFINE and CONFIRM studies and their extension study, ENDORSE. Objectives: Evaluate the long-term rate of brain volume loss in patients receiving continuous DMF treatment vs those switching from placebo (PBO) or glatiramer acetate (GA) in ENDORSE. Methods: Eligibility criteria include age 18-55 years and Expanded Disability Status Scale score 0-5.0. In ENDORSE, patients randomized to DMF 240 mg twice (BID) or three times (TID) daily in DEFINE/CONFIRM continued the same dosage. Patients randomized to placebo (PBO) or GA (CONFIRM only) were re-randomized 1:1 to DMF BID or TID. In a subset of patients (MRI cohort), normalized brain volume was determined at baseline and percentage brain volume change (PBVC) was calculated using the SIENA method for each post-baseline MRI visit relative to baseline. Data were analyzed (May 14, 2014 cutoff) by treatment in parent/extension study. BID dosing (approved dose) is reported for patients treated continuously with DMF; BID and TID dosing in ENDORSE were pooled for patients switching from PBO or GA to increase sample size. Data for Years 1 and 2 are from DEFINE/CONFIRM; data from Years 3, 4, and 5 are from ENDORSE and represent the first 3 years after the switch from PBO or GA to DMF. Results: Among patients in the MRI cohort of DEFINE/ CONFIRM who went on to participate in ENDORSE (n=211 [BID/BID], 206 [PBO/DMF], and 108 [GA/DMF] at DEFINE/ CONFIRM baseline), adjusted mean PBVC at Year 2 relative to DEFINE/CONFIRM baseline was significantly lower with DMF BID vs PBO (P=.0265) and DMF BID vs GA (P=.0388). Upon switching to DMF, adjusted mean PBVC at Years 3, 4, and 5 relative to ENDORSE baseline was not significantly different with BID/BID vs PBO/DMF or BID/BID vs GA/DMF. In the BID/BID arm, a low annualised PBVC was observed over the whole 5 years (mean [95% confidence interval]: -0.32/year [-0.37, -0.27]). Updated data (Year 6) will be presented. Conclusions: In DEFINE/CONFIRM, patients treated with DMF BID exhibited significantly reduced brain volume loss over 2 years vs PBO. Upon switching to DMF, the rate of brain volume loss was not substantially different in the PBO/DMF and GA/ DMF groups vs the BID/BID group. The findings are consistent with a sustained beneficial effect of DMF on brain atrophy.

Ludwig Kappos: Institution (University Hospital Basel) received and used exclusively for research support: steering committee, advisory board and consultancy fees from Actelion, Addex, Bayer Health Care, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, Xenoport; speaker fees from Bayer Health Care, Biogen, Merck, Novartis, Sanofi-Aventis, Teva; support of educational activities from Bayer Health Care, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva; royalties from Neurostatus Systems GmbH; grants from Bayer Health Care, Biogen, Merck, Novartis, Roche, Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations. Robert J. Fox: Consultant fees from Actelion, Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Actelion, Biogen, and Novartis; research grant funding from Novartis. Ralf Gold: Honoraria from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders. Douglas L. Arnold: Honoraria/revenue/consultancy: Acorda Therapeutics, Biogen, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, MedImmune, Mitsubishi, Novartis, Opexa Therapeutics, Receptos, Roche, Sanofi-Aventis, Teva; employee and stockholder of NeuroRx; research support from Novartis and Biogen. James Potts: Employee of and holds stock/stock options in Biogen, Inc. Jing L. Marantz: Employee of and holds stock/stock options in Biogen, Inc. P1073 Efficacy and safety of delayed-release dimethyl fumarate in relapsing-remitting multiple sclerosis patients with cardiovascular disease: integrated analysis of the phase 3 DEFINE and CONFIRM studies E. Havrdova1, R.J. Fox2, R. Gold3, J. Li4, A. Zhang4, J. Potts4, J.L. Marantz4 1First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, 2Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, United States, 3St. Josef Hospital, Ruhr University, Bochum, Germany, 4Biogen, Inc., Cambridge, MA, United States

Disclosure This study is supported by Biogen, Inc. David H. Miller: Honoraria through payments to my employer, UCL Institute of Neurology, for Advisory Committee and/or Consultancy advice in multiple sclerosis studies from Biogen, GlaxoSmithKline, Novartis, Merck, Chugai, Mitsubishi Pharma Europe and Bayer Schering Pharma; compensation through payments to my employer for performing central MRI analysis of multiple sclerosis trials from GlaxoSmithKline, Biogen, Novartis, Apitope and Merck; the Queen Square MS Centre at UCL Institute of Neurology is supported by the UK MS Society and UCLUCLH Biomedical Research Centre. Tarek Yousry: Research support from Biogen, GlaxoSmithKline, Novartis, and Schering AG; honoraria from Biogen, Bayer Schering, and Novartis.

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Background: In multiple sclerosis (MS) patients presenting with certain comorbidities, treatment options can be limited. For example, fingolimod is contraindicated in patients with a history of cardiovascular (CV) conditions due to a potential for bradycardia, AV block, and prolongation of the QT interval upon initiation of treatment. Hence, it is important to determine the efficacy and safety of other MS disease-modifying therapies (DMTs) in these patients. Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated efficacy and safety in relapsing-remitting MS (RRMS) in the Phase 3 DEFINE and CONFIRM studies. Objectives: Assess the efficacy and safety of DMF in RRMS patients with CV disease in a post-hoc integrated analysis of DEFINE and CONFIRM.


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Methods: Eligibility criteria included age 18-55 years and Expanded Disability Status Scale (EDSS) score 0-5.0. Patients were randomized to receive DMF 240 mg twice (BID) or thrice daily, placebo, or subcutaneous glatiramer acetate (reference comparator; CONFIRM only) for up to 2 years. Brain MRI scans were performed in a subset of patients (MRI cohort). Patients with CV disease were identified from baseline medical history (reported medical condition in the category of CV disease). Results are reported for placebo and DMF BID (approved dosing regimen in all regions). Results: The integrated intent-to-treat (ITT) population included 771 and 769 patients receiving placebo or DMF BID, respectively; among them, 148 and 139 had CV disease (eg, hypertension, hypercholesterolemia, coronary artery disease, and/or arrhythmias). Baseline characteristics of patients with CV disease were generally similar to those of the overall ITT population. In patients with CV disease, at 2 years, DMF BID demonstrated a significant reduction compared with placebo on annualized relapse rate (ARR; rate ratio [95% confidence interval, CI]: 0.597 [0.377, 0.946]; 40% reduction; P=.028) and number of new or enlarging gadolinium-enhancing lesions (80% reduction; P=.0101), T2 lesions (82% reduction; P< .0001), and T1 lesions (66% reduction; P=.0016). Safety data will be presented. Conclusions: This analysis indicates that DMF demonstrates consistent efficacy on clinical (ARR) and MRI endpoints in RRMS patients with CV disease. However, due to the small sample size, the results should be interpreted with caution. A safety summary of DMF in these patients will be presented. Disclosure This study is supported by Biogen, Inc. Eva Havrdova: honoraria from Bayer, Biogen, Genzyme, GlaxoSmithKline, Merck Serono, Novartis, Sanofi, and Teva; research support from Biogen; supported by PRVOUK-P26/ LF1/4, program of Ministry of Education, Czech Republic. Robert J. Fox: consultant fees from Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Biogen, and Novartis; research grant funding from Novartis. Ralf Gold: honoraria from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders. Jie Li: employee of and holds stock/stock options in Biogen, Inc. Annie Zhang: employee of and holds stock/stock options in Biogen, Inc. James Potts: employee of and holds stock/stock options in Biogen, Inc. Jing L. Marantz: employee of and holds stock/stock options in Biogen, Inc. P1074 Natalizumab-associated PML in Dutch MS patients M.T. Wijburg1,2, A. Vennegoor1, C.E. Leurs1, B.M. Uitdehaag1, M.P. Wattjes2, J. Killestein1, on behalf of the Dutch Natalizumab-Associated PML Study Group 1Department of Neurology, 2Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands

Background: Natalizumab, an effective treatment for relapsingremitting MS, increases the risk to develop progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the central nervous system (CNS) caused by the JC virus (JCV). The presence of anti-JCV antibodies, treatment duration longer than two years and immunosuppressant use prior to treatment, are associated with an increased risk for PML. Its incidence is estimated at 3.87 per 1000 treated patients in general and 11.2 per 1000 treated patients in the highest risk category (anti-JCV antibody positive, treatment > 2 years and prior immunosuppressant use). Objective: To report natalizumab-associated PML from a national registry in The Netherlands (NL). Methods: In agreement with the MS task force of the Netherlands Society of Neurology (NVN), we established the Dutch natalizumab-associated PML database, pooling all natalizumab associated PML patients in NL. Results: As of May 13, 2015, there are 27 MS patients registered who are considered to have natalizumab-associated PML (19 confirmed and 8 high suspect cases). To define the risk of PML the denominator consists of about 790 MS patients who are currently being treated with natalizumab in NL. However, the proportion of Dutch MS patients on natalizumab who are JCV positive, their JCV-index and the duration of treatment for more than 12-24 months is not exactly known. Also, the exact number of patients who received at least one infusion of natalizumab, but have stopped the drug is unknown. Conclusion: These preliminary data suggest that in Dutch natalizumab-treated MS patients, the risk of developing PML may be higher than in previously reported patient groups. However, determining the exact incidence in patients at risk depends on exact numbers of patients on natalizumab categorized for duration of treatment and level of JCV indexes in blood. Further study is needed to corroborate our observation. If confirmed, the questions remains whether this distinctive high incidence of PML in NL is due to specific circumstances in our country or underestimations of the risk in other populations. Disclosure M.T. Wijburg: nothing to disclose. A. Vennegoor: has received speaking fees from Teva. VU Medical Center has received financial support for research activities from Bayer Schering Pharma, Biogen-Idec, GlaxoSmithKline, Merck Serono, Novartis, and Teva. C.E. Leurs: nothing to disclose. B.M.J. Uitdehaag: received personal compensation for consulting from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche en TEVA. M.P. Wattjes: received consultancy fees from Biogen Idec and Roche. J. Killestein: accepted speaker and consulting fees from MerckSerono, Biogen Idec, Teva, Genzyme and Novartis. P1075 Diagnostic performance of brain MRI in pharmacovigilance of natalizumab-treated MS patients M.P. Wattjes1, M.T. Wijburg1,2, A. Vennegoor2, B.I. Witte3, S.D. Roosendaal1,4, E. Sanchez1, Y. Liu1,5, C.O. Martins Jarnalo1,6, N.D. Richert7, B.M. Uitdehaag2, F. Barkhof1, J. Killestein2 1Department of Radiology and Nuclear Medicine, 2Department of Neurology, 3Department of Epidemiology and Biostatistics,


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Poster Session 2, 21(S11) VU University Medical Center, Amsterdam, 4Department of Radiology, Erasmus Medical Centre, Rotterdam, The Netherlands, 5Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing, China, 6Department of Radiology, Medical Center Haaglanden, The Hague, The Netherlands, 7Multiple Sclerosis Clinical Development Group, Biogen, Cambridge, MA, United States Background: In natalizumab-treated multiple sclerosis (MS) patients, magnetic resonance imaging (MRI) is considered as a sensitive tool in detecting both MS disease activity and progressive multifocal leukoencephalopathy (PML). However, the detection of new pathology and the correct differentiation of new pathology (new PML lesion versus new MS lesion) during natalizumab pharmacovigilance can be rather challenging. Objective: The primary aim of this study was to investigate the performance of trained neuro-radiologists using brain MRI in detecting new MS lesions and asymptomatic PML lesions and in differentiating between MS and PML lesions in natalizumabtreated MS patients. The secondary aim was to investigate interrater agreement among readers with experience in the field of MRI in MS disease and treatment monitoring. Methods: In this retrospective diagnostic study, we included four readers who were blinded for all demographic and (para)clinical information and who had different levels of experience. They assessed reference and follow-up brain MRI scans of 48 natalizumab-treated MS patients with either new asymptomatic PML lesions (n=21), or new MS lesions (n=20) or no new lesions (n=7). Sensitivity and specificity for detection of new lesions in general (MS and PML lesions), MS and PML lesion differentiation and PML detection were determined. Inter-rater agreement among the readers was calculated. Results: Overall sensitivity and specificity for the detection of new lesions regardless whether MS or PML lesions were 77.4% (range per rater 58.5-92.7%) and 89.3% (range 85.7-100%), respectively; for PML/MS lesion differentiation, 74.2% (range 60.0-93.8%) and 84.7% (range 50.0-100%), respectively; and for asymptomatic PML lesion detection, 59.5% (range 42.976.2%) and 91.7% (range 70.4-100%), respectively. Inter-rater agreement for the tested diagnostic categories was fair to moderate. Conclusion: The diagnostic performance of trained neuro-radiologists using brain MRI in pharmacovigilance in natalizumabtreated MS patients is moderately good. Inter-rater agreement among trained readers is fair to moderate. These findings suggest that MRI reading in natalizumab pharmacovigilance is challenging even in specialized centres. Disclosure M.P. Wattjes: received consultancy fees from Biogen Idec and Roche. M.T. Wijburg: nothing to disclose. A. Vennegoor: has received speaking fees from Teva. VU Medical Center has received financial support for research activities from Bayer Schering Pharma, Biogen-Idec, GlaxoSmithKline, Merck Serono, Novartis, and Teva. B.I. Witte: nothing to disclose. S.D. Roosendaal: nothing to disclose. E. Sanchez: served as a consultant for F. Hoffmann-La Roche.

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Y. Liu: is supported by the ECTRIMS-MAGNIMS Fellowship from The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). C.O. Martins Jarnalo: nothing to disclose. N.D. Richert: is an employee of Biogen Idec. B.M.J. Uitdehaag: received personal compensation for consulting from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche en TEVA. F. Barkhof: serves on the editorial boards of Brain, Neurology, Neuroradiology, Multiple Sclerosis Journal and Radiology, and serves as a consultant for Bayer-Schering Pharma, Sanofi-Aventis, Genzyme, Biogen-Idec, Teva, Novartis, Roche, Synthon BV and Jansen Research. J. Killestein: accepted speaker and consulting fees from MerckSerono, Biogen Idec, Teva, Genzyme and Novartis. P1076 MR imaging characteristics of early PMLIRIS in natalizumab-treated MS patients M.P. Wattjes1, M.T. Wijburg1,2, A. Vennegoor2, B.I. Witte3, M. de Vos1, N.D. Richert4, B.M. Uitdehaag2, F. Barkhof1, J. Killestein2, on behalf of the Dutch-Belgian NatalizumabAssociated PML Study Group 1Department of Radiology and Nuclear Medicine, 2Department of Neurology, 3Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands, 4Multiple Sclerosis Clinical Development Group, Biogen, Cambridge, MA, United States Background: The early detection of magnetic resonance imaging (MRI) findings suggestive of immune reconstitution inflammatory syndrome (IRIS) in natalizumab-associated progressive multifocal leukoencephalopathy (PML) is of crucial clinical relevance in terms of treatment decision making and clinical outcome. Objective: The aim of this study was to investigate the earliest imaging characteristics of PML-IRIS manifestation in natalizumab-treated MS patients and describe an imaging pattern that might aid in early and specific diagnosis of PML-IRIS. Methods: This was a retrospective study assessing brain MRI of 26 natalizumab-associated PML patients presenting with lesions suggestive of PML-IRIS during follow-up by two readers in consensus. MRI findings suggestive of PML-IRIS were evaluated considering characteristics such as mass effect, edema, contrastenhancement, new perivascular T2-lesions and signs of meningeal inflammation. These imaging criteria for defining PML-IRIS were developed according to previously described PML-IRIS imaging findings that were confirmed by histopathology. Results: Contrast-enhancement was the most common sign, present in 92.3% of the patients, followed by new T2 lesions clustered in a perivascular distribution pattern (33.3%). In patients with contrast-enhancement, the enhancement was present in the lesion periphery in 95.8% of the patients. Contrast-enhancing lesions with a perivascular distribution pattern outside of the PML lesion were observed in 33.3% of the patients. The pattern of the enhancement was patchy in 70.8% of the patients and punctate in 45.8% of the patients. The most common pattern was contrastenhancement in the border of the PML lesion with either a patchy or punctate appearance in 88.5% of all patients.


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Conclusion: Although our in vivo PML-IRIS imaging findings were not confirmed by histopathology we found a typical imaging pattern of early PML-IRIS in natalizumab-treated MS patients. Contrast-enhancement was the most common early sign of natalizumab-associated PML-IRIS. The most frequent enhancement pattern was a patchy or punctuate appearance at the lesion border. Disclosure M.P. Wattjes: received consultancy fees from Biogen Idec and Roche. M.T. Wijburg: nothing to disclose. A. Vennegoor: has received speaking fees from Teva. VU Medical Center has received financial support for research activities from Bayer Schering Pharma, Biogen-Idec, GlaxoSmithKline, Merck Serono, Novartis, and Teva. B.I. Witte: nothing to disclose. M. de Vos: nothing to disclose. N.D. Richert: is an employee of Biogen Idec. B.M.J. Uitdehaag: received personal compensation for consulting from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche en TEVA. F. Barkhof: serves on the editorial boards of Brain, Neurology, Neuroradiology, Multiple Sclerosis Journal and Radiology, and serves as a consultant for Bayer-Schering Pharma, Sanofi-Aventis, Genzyme, Biogen-Idec, Teva, Novartis, Roche, Synthon BV and Jansen Research. J. Killestein: accepted speaker and consulting fees from MerckSerono, Biogen Idec, Teva, Genzyme and Novartis.

P1077 Safety, tolerability and pharmacodynamic characterization of vatelizumab, a monoclonal antibody targeting very-late-antigen (VLA)-2: a randomized, double-blind, placebo-controlled phase 1 study I.A. Antonijevic1, M.N. Patekar2, G. Gudi2, M.A. Panzara1 1Genzyme, a Sanofi company, Cambridge, MA, United States, 2Glenmark Pharmaceuticals, SA, La Chaux-de-Fonds, Switzerland Background: Vatelizumab is a humanized monoclonal antibody that targets very-late-antigen (VLA)-2, a collagen-binding integrin. The mechanism of action of vatelizumab is not known, but it is hypothesized to block the interaction of VLA-2 expressed on activated lymphocytes with collagen, thus reducing the inflammatory cascade at sites of inflammation, such as MS lesions. Objectives: To investigate the safety and tolerability of vatelizumab in healthy human subjects in a first-in-human, randomized, double-blind, placebo-controlled study. Pharmacodynamic (PD) parameters were also assessed. Methods: The study was conducted in 3 parts at a single US site. In Part 1, subjects received ascending single intravenous (iv) doses of placebo or vatelizumab. In Parts 2 and 3, subjects received 2 iv doses of placebo or vatelizumab separated by 14 days. PD parameters, including C-reactive protein and serum cytokines, were assessed. Changes in lymphocyte subpopulations (e.g. CD4, CD8, CD19) and CD34+ progenitor cells were assessed in Parts 2 and 3 only.

Results: In total, 68 subjects, aged 18 to 55 years, were enrolled (Part 1/2/3: n=36/17/15); 63 (93%) and completed the dosing per protocol. There were no deaths and no serious adverse events (SAEs). A total of 16 (44%) subjects in Part 1, and 22 (69%) subjects in Parts 2 and 3, experienced at least 1 adverse event (AE); all AEs were mild or moderate in intensity, resolved by study completion, and were not dose-dependent. The most frequent AE was headache (Part 1: 11 AEs in 8 subjects; Parts 2/3: 19 AEs in 16 subjects). One AE (mild anaemia) led to withdrawal, and 1 subject discontinued due to underlying paroxysmal atrial fibrillation; neither event was considered treatment-related, and both resolved prior to study completion. There were no consistent effects on pre-specified PD parameters. Conclusions: Vatelizumab appeared well tolerated with a favourable safety profile in healthy volunteers. The ongoing phase 2 EMPIRE study (NCT02222948) is evaluating the efficacy and safety of vatelizumab in patients with relapsing-remitting MS. Disclosure Study supported by Glenmark Pharmaceuticals. IA: Employee of Genzyme. MNP: Employee of Novartis, but was employed by Glenmark when study conducted. GG: Employee of Glenmark. MP: Employee of Genzyme. P1078 Alemtuzumab use in neuromyelitis optica spectrum disorders - a brief case series L. Azzopardi, A.L. Cox, C. Mccarthy, J.L. Jones, A.J. Coles Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom Background: Alemtuzumab is an anti-CD52 monoclonal antibody recently licensed for use in relapsing-remitting multiple sclerosis (MS). Here we report our experience of its use in neuromyelitis optica (NMO) spectrum disorders. Objective: To investigate retrospectively whether alemtuzumab was a useful therapy in NMO. Methods: Retrospective case review of patients treated with alemtuzumab in Cambridge, UK, who fulfil the criteria for NMO spectrum disorder under the revised Wingerchuk criteria and the consensus criteria drawn up by the International Panel for NMO Diagnosis convened in 2011. Results: Three cases of NMO were identified. Case 1, 9Y female, presented in 1998 with protracted vomiting, transverse myelitis and bilateral optic neuritis, with one lower medullary and several longitudinally extensive cord lesions. Despite intensive immunosuppression including two cycles of alemtuzumab, she continued to relapse, was wheelchair bound and registered blind by age 12, and died at age 18. Case 2, 41Y female, presented in 2004 with bilateral optic neuritis and transverse myelitis with longitudinally extensive cervical cord lesions. Despite three cycles of alemtuzumab given 12 months apart, she had 5 relapses with visual impairment and new cord lesions within 21 months of first cycle. She later developed tumefactive white matter lesions, biopsy confirming active demyelination, and died aged 51.


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Poster Session 2, 21(S11) Case 3, 31Y female, presented in 2007 with transverse myelitis with longitudinally extensive cervical cord lesions and positive AQP4-IgG antibody. After one cycle of alemtuzumab, she relapsed with 4 episodes of myelitis within 18 months, with new enhancing lesions and accumulating disability. She became relapse-free after rituximab followed by mycophenolate mofetil. Conclusions: From this small case series we conclude that, in contrast to MS, alemtuzumab failed to prevent disabling relapses and poor outcome in NMO. Case 3 stabilised with rituximab, the important mechanistic difference being prolonged B lymphocyte depletion, which is only depleted for 1-2 months after alemtuzumab. Other drugs effective in MS also fail to suppress or may even exacerbate NMO, while two published cases similarly demonstrated alemtuzumab is ineffective as a treatment of NMO. We therefore caution against the use of alemtuzumab in NMO. Disclosure Azzopardi, L: nothing to disclose. Cox, AL: nothing to disclose. McCarthy, C: nothing to disclose. Jones, JL: reports receiving consulting fees and lecture fees from Genzyme Sanofi. Coles, AJ: reports receiving consulting fees, lecture fees, and institutional grant support from Genzyme Sanofi. P1079 Superior efficacy and tolerability of rituximab as compared to fingolimod for MS patients switching from natalizumab due to positive JC virus serology P. Alping1, P. Islam-Jakobsson2, L. Novakova3, J. Salzer2, A. Björck1, M. Axelsson3, C. Malmeström3, K. Fink1, T. Frisell4, J. Lycke3, A. Svenningsson2, F. Piehl1 1Clinical Neuroscience, Karolinska Institutet, Stockholm, 2Pharmacology and Clinical Neuroscience, Umeå University, Umeå, 3Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, 4Medicine Solna, Karolinska Institutet, Stockholm, Sweden Background: In order to avoid PML, JC virus antibody positive (JCV+) patients switch from natalizumab (NTZ) to other disease modulatory therapies. In Sweden, the most frequently used options have been fingolimod (FGL) and rituximab (RTX). However, no formal clinical trial has been conducted mirroring this situation. Rituximab (RTX) has shown promising phase II data in relapsing-remitting MS (RRMS), but lacks formal approval in MS. Objective: To compare measures of efficacy and tolerability for JCV+ patients switching from NTZ to RTX or FGL in a non-randomized cohort with prospective follow up. Methods: We collected data on all RRMS patients switching from NTZ to either FGL or RTX due to JCV+ at three Swedish MS centres. The number of patients and relative allocation to either FGL or RTX were in Stockholm n=170, FGL 51%; Göteborg n=72, FGL 85%; Umeå n=40, FGL 18%, and in the total cohort n=282; FGL 55%. Outcome data was derived from the Swedish MS registry (SMSreg) and medical chart reviews.

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Results: In the Stockholm data set (n=170) 37 and 3 patients ended treatment with FGL and RTX, respectively, over 1.5 years, yielding a hazard ratio (HR) for drug termination of 0.16 (0.050.54) for RTX compared to FGL. The HR for a clinical relapse (19 vs 2) or an adverse event (AE; 16 vs 2) within 1.5 years was 0.07 (0.01-0.52) and 0.10 (0.01-0.74), respectively, for RTX compared to FGL. Furthermore, 9 vs 1 patient had ⩾1 gadolinium enhancing lesion (Gd+) on magnetic resonance imaging (MRI) and 12 vs 1 patient Gd+ or new T2 lesions compared to a prior scan within 1 year after switch, corresponding to an odds ratio (OR) of 0.11 (95% CI 0.01-0.71) and 0.08 (0.00-0.41), respectively, for MRI activity with RTX compared to FGL. In contrast, first dosing events were more common for RTX than FGL. Significances remained after correction for differences in age, sex, EDSS, suspected conversion to SPMS and follow-up time. In the preliminary analyses of the two other data sets the main results were replicated. Conclusions: We found a relatively high rate of treatment cessation among JCV+ NTZ patients switching to FGL, due both to recurrence of disease activity and AEs. In contrast, these risks, except for first dosing events, were much smaller for patients switching to RTX. These findings provide preliminary evidence for superior efficacy and tolerability of RTX compared to FGL in this patient population and a strong rationale for a formal randomized controlled study. Disclosure Peter Alping: nothing to disclose. Protik Islam-Jakobsson: nothing to disclose. Lenka Novakova: nothing to disclose. Jonatan Salzer has received lecture honoraria from BiogenIdec, Teva Pharmaceuticals and Sanofi-Genzyme and has received travel support from Biogen Idec. Anna Björck: nothing to disclose. Markus Axelsson has received compensation for lectures and/or advisory boards from Biogen, Sanofi-Genzyme and Novartis. Clas Malmeström has received honoraria for lecturing, advisory boards, and travel expenses from Biogen, Merck-Serono, Novartis and Sanofi-Genzyme, and has received unconditional research support from Biogen. Katharina Fink has received an unrestricted research grant from Biogen. Thomas Frisell: nothing to disclose. Jan Lycke has received travel support and/or lecture honoraria from Biogen, Novartis, Teva and Sanofi-Genzyme; has served on scientific advisory boards for Almirall, Teva, Biogen, Novartis and Sanofi-Genzyme; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, Novartis and Teva. Anders Svenningsson has served on advisory boards for SanofiGenzyme and has received travel funding and/or speaker honoraria from Biogen, Sanofi-Genzyme, Novartis and Baxter Medical Fredrik Piehl has received unrestricted academic research grants and travel support from Biogen and Novartis, and compensations for lectures and/or participation in advisory boards from Biogen, Merck Serono, Novartis, Sanofi-Genzyme, Roche and Teva, which have been exclusively used for the support of research activities. Academic research funding from the Swedish MRC and the County of Stockholm.


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P1080 Preliminary results of a phase 2 trial of autologous mesenchymal cell therapy in MS (STREAMS) R. Ali1, R. Nicholas2, S. Marley3, S. Mallik4, R. Palanicawandar2, B. Zamarreno2, F. Dazzi3, D. Miller4, P. Muraro1 1Imperial College London, 2Imperial College Healthcare NHS Trust, 3Kings College London, 4University College London Institute of Neurology, London, United Kingdom Objectives: The objectives of the STREAMS (Stem Cells in Rapidly Evolving Active Multiple Sclerosis) trial are to evaluate the safety of intravenously-administered autologous mesenchymal stem/stromal cells (MSCs) and to detect their potential treatment effect in patients with inflammatory-active MS. Background: Several clinical trials aim to exploit the potent immunomodulatory, neuroprotective and potentially reparative properties of MSCs however STREAMS is distinctive in design, recruiting only patients with evidence of recent inflammatory MS activity. Design and methods: 12 patients were enrolled to this Phase 2 randomized double-blind, crossover study in London, which is also part of the international consortium, MESEMS, which aims to recruit ~160 patients in total. Criteria for MS activity required at least 1 relapse in RRMS/SPMS or disability progression of ⩾1 EDSS point (if baseline EDSS ⩽5.0) or ⩾0.5 EDSS point (if baseline EDSS was ⩾5.5) in PPMS/SPMS occurring in the preceding 18 months; and detection of at least one gadolinium enhancing lesion (GEL) on MRI brain within 6 months of the bone marrow harvest. The patients received 1-2x106 MSCs/kg or placebo at Week 0 with treatment reversed at Week 24; the allocation was randomised and double blinded. Clinical assessments and MRIs were performed at weeks 0, 4, 12, 24, 28, 36 and 48. The co-primary outcomes were safety and the number of GELs on sequential MRIs between treatment groups. Secondary outcomes included combined MRI activity, number of relapses, disease progression and changes in the Multiple Sclerosis Functional Composite (MSFC) score. Exploratory work included an extensive fresh ex-vivo analysis of immune cell populations by 12-color flow-cytometry, mantoux tests, and in vitro mechanistic work to understand the immunomodulating action of MSCs. Results: Culture duration varied from 19-36 days. The mean yield of all 12 successful harvests was 3.10x106 cells/kg with only one harvest below target (0.44x106 cells/kg). All trial visits have been concluded. No serious adverse events have been recorded. Treatment allocation will be unblinded after all analyses have been completed. Conclusion: The initial results of the trial support both the safety and feasibility of mesenchymal stem cell therapy. Disclosure Dr Rehiana Ali: Funded by the UK MS Society and UK Stem Cell foundation (UKSCF) Dr Richard Nicholas: Has received honorarium for speaking (Bayer, Biogen, Genzyme, Merck Serono, Novartis), is a principal investigator for Biogen, Novartis and TEVA, has received funds for staff (Biogen) and research (Biogen, Teva), organising education (Biogen, Genzyme) and is a member of advisory boards (Biogen, Genzyme, Merck Serono, Novartis and Roche).

Dr Steve Marley: Nothing to disclose Dr Shahrukh Mallik: Funded by the UK MS Society and UKSCF Dr Renuka Palanicawandar: Nothing to disclose Dr Belen Zamarreno: Nothing to disclose Professor Francesco Dazzi: Funded by Leukaemia and Lymphoma Research (LLR), Medical Research Council (MRC) and the EU. Professor David Miller: Has received honoraria through payments to his employer, UCL Institute of Neurology, for Advisory Committee and/or Consultancy advice in multiple sclerosis studies from Biogen Idec, GlaxoSmithKline, Novartis, Merck, Chugai, Mitsubishi Pharma Europe and Bayer Schering Pharma. He has also received compensation through payments to his employer for performing central MRI analysis of multiple sclerosis trials from GlaxoSmithKline, Biogen Idec, Novartis, Apitope and Merck. The Queen Square MS Centre at UCL Institute of Neurology is supported by the UK MS Society and UCL-UCLH Biomedical Research Centre. Dr Paolo Muraro: Funded by the MS Society (Ref 944/10), UKSCF and the Italian MS Society (FISM) P1081 Switching from natalizumab to fingolimod: recurrence of disease activity is closely related to duration of wash out and alpha-4 integrin desaturation - a prospective study in RRMS Y. Naegelin1, M. Rasenack1,2, C. Blatti3, C. Sievers2, M. Meira2, N. Sanderson2, M. Mehling1,2, B. Fischer-Barnicol1, M. Andelova1,4, M. Amann1,4,5, C. Stippich4, E.W. Radue5, B. Engelhardt3, R.L. Lindberg2, L. Kappos1,2, T. Sprenger1,4,5, T. Derfuss1,2 1Neurology, Departments of Medicine, Biomedicine, Clinical Research and Biomedical Engineering, 2Laboratory of Clinical Neuroimmunology, Department of Biomedicine, University Hospital Basel, Basel, 3Theodor Kocher Institute, University of Bern, Bern, 4Division of Diagnostic and Interventional Neuroradiology, Radiology, 5Medical Image Analysis Center, University Hospital Basel, Basel, Switzerland Background: There is still no consensus on the optimal washout period when switching from Natalizumab (NTZ) to Fingolimod (FTY), balancing risks of disease activity against potential adverse effects on the immune system. Objective: To study clinical and MRI activity as well as immunological measures in patients switching from NTZ to FTY (0.5mg daily) after a washout of 4 (cohort 1) and 8 (cohort 2) weeks (w). Methods: In this prospective, observational study patients with relapsing-remitting MS (RRMS) were switched from NTZ to FTY after a 4 or 8 weeks washout. Clinical visits and standardized MRI assessments were performed at baseline (last NTZ infusion) and w 4, 8, 12, 16, 20, 32, 56* and 108* (*only cohort 2). Immunological measures (only cohort 2) included alpha4-integrin saturation, anti-viral T cell response, and the migratory capacity of peripheral blood mononuclear cells (PBMCs). Results: Cohort 1 included 9 patients (7 females, mean age 46.1 years, mean EDSS 3.4, mean NTZ exposure 62.1 months) and cohort 2 included 16 patients (13 females, mean age 38.2 years, mean EDSS 3.4, mean NTZ exposure 42.4 months). Both cohorts were not free of disease activity before switching, having an annualized relapse rate of 0.22 (cohort 1) and 0.46 respectively. After a washout period of 8 weeks clinical and/or MRI activity occurred


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Poster Session 2, 21(S11) in 62.5% of patients with first evidence of disease activity appearing w 16. After a 4 week washout clinical and/or MRI activity occurred in 44.5% of patients with first signs of disease activity emerging w 32. There was a clear pattern of increasing disease activity after alpha4-integrin desaturation. Migratory capacity of lymphocytes increased over the study period. Conclusions: Patients switching from NTZ to FTY with a washout period of 4 weeks appear to have less clinical and MRI activity than those with a washout of 8 weeks. Recurrence of disease activity is closely related to alpha4-integrin desaturation. This investigator initiated and led study was supported by Novartis Disclosure Naegelin Y has nothing to disclose Rasenack M has nothing to disclose Blatti C has nothing to disclose Sievers C has nothing to disclose Meira M has nothing to disclose Sanderson N has nothing to disclose Mehling M has nothing to disclose Fischer-Barnicol B has nothing to disclose Andelova M has nothing to disclose Amann M has nothing to disclose Stippich C has nothing to disclose Radue E-W served on advisory boards for Novartis, Biogen, Merk-Serono and Bayer Engelhardt B has received support from the Swiss National Science Foundation and the Swiss MS Society. Lindberg RLP has received research support from Swiss MS Society, Swiss National Science Foundation, European FP6 and IMI JU programs, Roche Postdoc Fellowship Program (RPFprogram), unrestricted research grants from Novartis and Biogen Kappos L (Institution University Hospital Basel) received in the last 3 years and used exclusively for research support: steering committee/consulting fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; royalties from Neurostatus Systems GmbH; grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis, Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society, and the Swiss National Research Foundation. Sprenger T served on advisory boards for Genzyme, Novartis, Mitsubishi Pharma, Eli Lilly, Biogen, Actelion, ATI, Electrocore and Allergan. He received travel support from Genzyme, Pfizer, Bayer Schering, Eli Lilly and Allergan. He receives research support from the Swiss MS Society, EFIC, Novartis Pharmaceuticals and the Swiss National Foundation. Derfuss T serves on scientific advisory boards for Novartis Pharma, Merck Serono, Biogen Idec, Genzyme, Mitsubishi Pharma, TEVA Pharma, GeNeuro, and Bayer Schering Pharma; has received funding for travel and/or speaker honoraria from Biogen Idec, Novartis, Merck Serono, and Bayer Schering Pharma; and receives research support from the Swiss National Research Foundation, Biogen Idec, Novartis Pharma, the European Union, and the Swiss MS Society.

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P1082 Skin adverse events occurring during treatment with new oral drugs for multiple sclerosis J.L. Ruiz Peña, G. Navarro Mascarell, M.D. Paramo Camino, S. Perez, S. Eichau, E. Pacheco, F. Damas, G. Izquierdo Ayuso MS Clinic (Department of Neurology), Hospital Virgen Macarena, Sevilla, Spain Background and objective: Treatments of multiple sclerosis (MS) have undergone a revolution over the past 2 decades. Classical MS treatments using first-line injectable drugs remain of major concern in terms of therapeutic adherence and efficacy. The new orally administered drugs approved for MS treatment represent significant therapeutic advances. However they may also have safety and tolerability issues. We report two cases of skin serious adverse events. Method: Case report of a 41-year-old woman treated with Fingolimod with a facial pilomatrix carcinoma and a case report of a 29-year-old woman treated with oral fumarate (BG12) with a wells syndrome. Results: We report a case of a 41-year-old woman with a relapsing Remitting MS treated with Fingolimod for 18 months that developed a nodular lesion in the right part of her mouth. Histological evaluation demonstrated a cystic lesion lined by a basaloid epithelium at the periphery and filled with eosinophilic cornified material containing shadow cells in upper part of the tumor, and multilobular proliferation of basaloid cells in association with small foci of shadow cells in the remaining part. Based on these findings, the diagnosis of proliferating pilomatricoma was made. A 29-year-old woman with a relapsing remitting ms treated with oral fumarate (BG12) that alter four years of treatment presented with a severely itching rash, consisting of urticaria-like, infiltrating, red-violet plaques on the upper and middle back, abdomen, arms, thighs, and submammary region. A skin biopsy revealed a deep perivascular infiltration of lymphocytes and innumerable eosinophils. Collections of eosinophils with eosinophilic granules (flame figures) among collagen bundles were noted. On the basis of the clinical and histological findings, a diagnosis of Wells Syndrome was established. Conclusions: To the authors’ knowledge this is the first reported case of drug-induced Wells syndrome from oral fumarate and the first case of pilomatrix carcinoma in a fingolimod treated patient. A high degree of clinical suspicion must be exercised to diagnose these rare conditions. Self-examination of the skin in each visit and dermatologic examination annually may be the best risk management strategy during new oral therapy. Disclosure JLRP has received speaking honoraria from Novartis GIA has received honoraria or consultation fees from Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis, Teva, Novartis, Genzyme, and Almirall. The rest have nothing to declare. P1083 Fingolimod every-other-day as a possible strategy to overcome fingolimod-induced severe lymphopenia in MS patients


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A. Merlini1, M. Rodegher1, P. Perrone2, F. Patti3, M.J. Messina1, M. Romeo1, G. Comi1, V. Martinelli1 1Department of Neurology, San Raffaele Scientific Institute -Institute of Experimental Neurology, Milan, 2Department of Neurology, Legnano Hospital, Legnano, 3Department of Neurosciences, University of Catania, Catania, Italy

P1084 Fumaric acid esters do not reduce T-cell adhesiveness of inflamed human brain microvascular endothelium A. Haarmann, M. Nehen, A. Deiß, G. Stoll, M. Buttmann Department of Neurology, University of Würzburg, Würzburg, Germany

Background: A rare side-effect of fingolimod (FTY), a recently approved treatment for relapsing-remitting multiple sclerosis (MS), is severe lymphopenia (< 0,2*10^9/L). If severe lymphopenia is persistent, FTY discontinuation is recommended, depriving patients of an effective treatment option. Aims: We investigated whether FTY administered every-otherday (FTY-EOD), either transiently or chronically, was successful in overcoming severe lymphopenia in at risk patients, while at the same time maintaining effective control of clinical and neuroradiological disease activity. Materials and methods:  Multicenter retrospective consecutive case series. Results: So far we have collected 12 patients (age 39,3 +/- 8,5), who underwent off-label FTY-EOD due to severe lymphopenia, from three Italian MS centers. All patients were female. Mean disease duration was 141,3 months, mean EDSS at FTY start was 2,7+/-1,9. All patients had previously undergone immunomodulatory treatment; seven patients had also undergone immunosuppressive or natalizumab treatment. Mean BMI was 21,0 +/-2,5. Lymphopenia occurred variedly after FTY start (IQR= 11 months), with mean value of lymphocyte count of 0,21*10^9/L +/-0,04. No correlation could be observed between BMI and lymphocyte counts. Expanded disability status scale (EDSS) at FTY-EOD start was 2,6 +/-1,9. The mean number of relapses in the previous year was 0,92 +/-1,24. Three months after FTY-EOD start, lymphocyte values increased in all patients (0,54*10^9/L +/-0,34). Ten patients continued FTY-EOD for further 3 months with mean lymphocyte count of 0,65*10^9/L +/-0,66. In this group, at the six-month follow up, 2 patients had had 1 clinical relapse and 1 patient had experienced 2 clinical relapses. Discussion and conclusion: In our small case series FTY-EOD was able to prevent FTY-induced severe lymphopenia, while maintaining lymphocyte counts below the normal threshold. Nevertheless, 3 patients experienced clinical relapses during the following 6 months. Further investigation is warranted to assess FTY-EOD long-term safety and efficacy in controlling clinical and neuroradiological disease activity.

Background and objective: Dimethyl fumarate (DMF) is approved for disease-modifying treatment of patients with relapsing-remitting multiple sclerosis. Putative anti-inflammatory mechanisms include an inhibition of endothelial NF-kappaB activation, decreased ICAM-1 upregulation and reduced leucocyte adhesion under inflammatory conditions. Here we studied these mechanisms, previously demonstrated in non-CNS endothelial cell types, in single donor human brain microvascular endothelial cells (HBMEC) at early passages. Methods and results: In static adhesion assays, neither pretreatment of HBMEC monolayers with DMF nor with its primary metabolite monomethyl fumarate (MMF) reduced the adhesion of activated Jurkat T cells to resting or inflammatorystimulated HBMEC. Accordingly, basal expression or IL-1betainduced up-regulation of ICAM-1 on HBMEC, as measured by flow cytometry, was neither decreased by DMF nor by MMF. Furthermore, neither DMF nor MMF reduced the IL-1betainduced nuclear translocation of NF-kappaB p65 or the activation of p38 MAP kinase in HBMEC. In contrast, DMF reduced the IL-1beta-driven p65 translocation in human umbilical vein endothelial cells cultured in parallel, which were used as a positive control. Conclusions: Fumaric acid esters probably do not directly target the highly specialized endothelial cells at the human blood-brain barrier to reduce immune cell infiltration into the CNS under inflammatory conditions. Disclosure This study was funded by local research funds from the University of Würzburg. The authors have nothing to disclose.

Disclosure

P1085 Postpartum relapse rate in multiple sclerosis and intravenous immunoglobulines in the postpartum period S. Raunegger, J. Haas Neurology, Jewish Hospital Berlin, Berlin, Germany

Arianna Merlini: nothing to disclose. Mariaemma Rodegher: received personal compensation for speaking from Novartis Farma, Merck Serono and Biogen-Dompè. Patrizia Perrone: nothing to disclose. Francesco Patti: nothing to disclose Maria Josè Messina: nothing to disclose. Marzia Romeo: nothing to disclose. Vittorio Martinelli: received speaker honoraria or funding for travels from Biogen-Dompé, Merck Serono, Bayer Schering Pharma, Novartis Farma and Sanofi-Aventis. Giancarlo Comi: received personal compensation for speaking and consultancy activities from Bayer Schering Pharma, Merck Serono, Sanofi-Aventis, Biogen-Dompè, Novartis Farma and TEVA Pharmaceutical Ind. Ltd.

Background: There is a high risk for exacerbations within the postpartum period. During pregnancy and breastfeeding period licensed drugs for immunotherapy in Multiple Sclerosis (MS) are not recommended or contradictory. Immunoglobuline was used for prevention of exacerbations in different studies and probably seem to lower the risk for disease activity. Since 1996 we documented pregnancies and longterm postpartum course of MS in our data base MDOC. Objective: There is an ongoing discussion concerning the treatment recommendation after delivery. To get information about the disease course during breastfeeding with and without intravenous immunglobilines (IVIg) or with immunmodulatory drugs after delivery the data base MDOC was analysed.


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Poster Session 2, 21(S11) Methods: 249 patients with multiple sclerosis and with 365 pregnancies were identified out of 6015 (female: 72.05%, male: 27.95%) documented MS patients between 1996 and 2014. Age, duration of disease, Expanded Disability Status Scale (EDSS), relapse rate, treatment with immunmodulatory drugs, before and after pregnancy were documented and analysed by statistical methods. Results: The average age at first pregnancy was 31.0 (range 17.642.9) years, the average age at MS manifestation was 23.9 (range 9.7-69.4). 64.5% of the patients had an immunomodulating therapy before pregnancy. The average EDSS before pregnancy was 1.7. At the end of the first year after delivery the average EDSS of all patients was 1.8, after 2 years 1.9 (n= 134), after 5 years 2.3 (n= 91), after 10 years 3.5 (n= 47). The relapse rate the year before pregnancy was 0.43, during pregnancy 0.23. 61.8 % of the patients were treated with 10g IVIg per month during the breastfeeding period. The relapse rate in the first six month postpartum of patients who received IVIg and nursed was 0.47, without IVIg treatment 0.55. Conclusions: Compared to the PRIMS study with an increase of relapse rate of 70% after delivery we observed only 9% for IVIg and 13% for no therapy. High percentage of immunomodulatory therapy before pregnancy may have lowered the risk for postpartum relapses.

factors, and baseline normalized brain volume as a covariate. Analysis of variance (ANOVA) models, with treatment and study as factors, were employed as sensitivity analyses of the difference in PBVC between treatment groups, with and without MI of missing values. MI by treatment, without stratification of other covariates, was used to generate 500 complete data sets for each study interval. Variances were calculated within and between data sets. Results: By rank ANCOVA, fingolimod 0.5 mg (N=783) reduced BVL significantly compared with placebo (N=773) during each interval examined (months 6-12, p=0.033; all other intervals p< 0.001). By ANOVA, the size and significance of this treatment effect was unaffected by MI of missing values. The mean between-group differences (fingolimod 0.5 mg minus placebo) in PBVC, with and without MI, respectively, were: months 0-6, 0.133 and 0.133 (p=0.003, both); months 6-12, 0.077 (p=0.071) and 0.075 (p=0.081); months 0-12, 0.195 and 0.194 (p< 0.001, both); months 12-24, 0.342 and 0.348 (p< 0.001, both); months 0-24, 0.369 and 0.352 (p< 0.001, both). The proportion of imputed values ranged from 1.8% (months 0-6) to 18.3% (months 0-24). Conclusions: Estimates of the treatment effect of fingolimod on BVL made using MI of missing values, were consistent with results obtained from observed case analyses.

Disclosure J. Haas got compensation by Biogen, Bayer, Teva, Sanofi Aventis, Allergan, Genzyme, CSL Behring, Octapharma. S. Raunegger has nothing to disclose

Neuroprotection P1086 Estimation of brain volume loss with multiple imputation of missing values in the placebo-controlled FREEDOMS trials of fingolimod G. Cutter1, X. Meng2, M.Z. Islam2, B. Brown2 1Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, 2Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States Background: Over 2 years in the phase 3 FREEDOMS and FREEDOMS II trials, fingolimod reduced brain volume loss (BVL) in patients with relapsing-remitting multiple sclerosis (RRMS) by approximately one third compared with placebo. During the trials 15-30% of patients missed at least one magnetic resonance imaging (MRI) assessment of brain volume, which may bias estimates of the treatment effect on BVL. Such estimates may be improved by applying statistical methods to handle missing values, and among these methods, multiple imputation (MI) has the advantage of using trends among like patients in the data set to estimate results. Objective: To examine the impact of missing values on BVL estimates, in patients with RRMS treated with fingolimod 0.5 mg or placebo during the two FREEDOMS trials. Methods: In a population combined from the two FREEDOMS trials, and reflecting pre-planned analyses conducted in each trial, percentage brain volume changes (PBVC) during different study intervals were compared among treatment groups using a rank analysis of covariance (ANCOVA), with treatment and study as

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Disclosure Gary Cutter has participated in Data and Safety Monitoring Boards: Apotek, Biogen-Idec, Cleveland Clinic (Vivus), Glaxo Smith Klein Pharmaceuticals, Gilead Pharmaceuticals, Horizon Pharmaceuticals, Modigenetech/Prolor, Merck/Ono Pharmaceuticals, Merck, Merck/ Pfizer, Neuren, Sanofi-Aventis, Teva, Washington University, NHLBI (Protocol Review Committee), NINDS, NICHD (OPRU oversight committee); Consulting or Advisory Boards: Consortium of MS Centers (grant), D3 (Drug Discovery and Development), Genzyme, Genentech, Jannsen Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, Novartis, Opexa Therapeutics, Receptos, Roche, EMD Serono, Somalution, Teva pharmaceuticals, Transparency Life Sciences. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. Xiangyi Meng, Zahur Islam and Brandon Brown are employees and stock holders of Novartis Pharmaceuticals Corporation. P1087 MESEMS: a randomized, double blind placebo-controlled cross-over study to evaluate safety and efficacy of intravenous administration of autologous mesenchymal stem cells in patients with multiple sclerosis A. Uccelli1, L. Brundin2, M. Clanet3, O. Fernandez4, A. Laroni1, P. Muraro5, R. Oliveri6, E.-W. Radue7, P. Soelberg Sorensen6, M.P. Sormani1, M.S. Freedman8 1University of Genova, Genova, Italy, 2Karolinska Insitutet, Stockholm, Sweden, 3University of Toulouse, Toulouse, France, 4Hospital Regional Universitario Carlos Haya, Malaga, Spain, 5Imperial College London, London, United Kingdom, 6University of Copenhagen, Copenhagen, Denmark, 7Medical Image Analysis Center, Universitätsspital Basel, Basel, Switzerland, 8Ottawa Hospital, Ottawa, ON, Canada


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Background: Mesenchymal stem cells (MSC) have been demonstrated to ameliorate experimental autoimmune encephalomyelitis through the induction of immune tolerance and promotion of tissue repair. Based on this rationale the International Mesenchymal Stem Cells Transplantation Study Group generated a scientific consensus through a shared approach devising a protocol for a potential phase II trial. Aims: To describe the protocol for a phase II trial assessing safety and efficacy of MEsenchymal StEm cells for the treatment of Multiple Sclerosis (MESEMS). Methods: The MESEMS network is a group of independent clinical trials, following the same protocol and sharing key centralized procedures: analysis of MRI data (Basel, Switzerland); central randomization and collection of safety and clinical data (Genoa, Italy). The design will permit pooled analysis of data for the evaluation of primary and secondary objectives. Funding was obtained nationally through foundations and MS Societies, while the Italian MS Foundation, MSIF and ECTRIMS have financially supported coordination and centralized activities. Results: MESEMS is being investigated in 8 countries, with an anticipated enrollment of 160 MS patients. The MESEMS protocol is a double-blind, randomized, sham-controlled cross-over trial. The main inclusion criteria are: relapsing-remitting, secondary progressive or primary progressive MS displaying disease activity by clinical and MRI parameters, age 18-50, EDSS 3.0-6.5 and disease duration 2-10 years. The primary endpoints are safety and efficacy of autologous MSC in MS patients by measuring the total number of gadolinium enhancing lesions on MRI at week 4, 12 and 24 in the MSC vs. sham treatment groups. Secondary outcomes aim to gather preliminary information of the efficacy on other MRI metrics, clinical, immunological, neuropsychological and neuro-ophthalmological parameters. Two trial treatments, one with 1-2 millions of autologous bone marrow-derived MSC/Kg body weight and one with sham (media), are administered at week 0 and week 24 according to randomization. The total follow up is 48 weeks. Conclusion: A novel network approach has permitted us to overcome financial and logistic issues and to start an International academic trial with stem cells for MS. Results of the MESEMS trial will permit us to evaluate the safety and efficacy of MSC in MS and provide the rationale for designing a phase III program that will center on proving repair.

Disclosure Fundings for the study Fondazione Italiana Sclerosi Multipla ECTRIMS MSIF UK Multiple Sclerosis Society UK Stem Cell Foundation UK Clinical Trials Network The Danish Multiple Sclerosis Society ARSEP Association pour la Recherche sur la Sclérose En Plaques Vetenskapsrådet, Sweden Theme Center for Regenerative Medicine, Karolinska Institute, Sweden Neurology Clinic, Karolinska University Hospital, Stockholm Institute of Health Carlos III (Badalona) FIMABIS (Andalusian Public Foundation for Health and Biomedicine Research in Malaga)

Andalusian Initiative for Advanced Therapies - Health and Progress Foundation MS society of Canada Antonio Uccelli: nothing to disclose about the topic of this abstract Lou Brundin: nothing to disclose about the topic of this abstract Michel Clanet: nothing to disclose about the topic of this abstract Oscar Fernandez: nothing to disclose about the topic of this abstract Alice Laroni: nothing to disclose about the topic of this abstract Paolo Muraro: nothing to disclose about the topic of this abstract Roberto Oliveri: nothing to disclose about the topic of this abstract Ernst-Wilhelm Radue: nothing to disclose about the topic of this abstract Per Sorensen-Solberg: nothing to disclose about the topic of this abstract Maria Pia Sormani: nothing to disclose about the topic of this abstract Mark Freedman: nothing to disclose about the topic of this abstract P1088 Switching from subcutaneous interferon beta-1a to alemtuzumab further decreases new lesion activity and slows brain volume loss in treatment-naive patients with active relapsingremitting multiple sclerosis: CARE-MS I extension study A. Rovira1, F. Barkhof2, B. Kieseier3, X. Montalban1, D.H. Margolin4, K. Thangavelu4, D.L. Arnold5,6, on behalf of the CARE-MS I Investigators 1Vall d’Hebron University Hospital, Barcelona, Spain, 2VU University Medical Centre, Amsterdam, The Netherlands, 3Heinrich-Heine-University, Düsseldorf, Germany, 4Genzyme, a Sanofi company, Cambridge, MA, United States, 5NeuroRx Research, 6Montréal Neurological Institute, McGill University, Montreal, QC, Canada Background: In the CARE-MS I study (NCT00530348) of treatment-naive patients with active relapsing-remitting multiple sclerosis (RRMS), alemtuzumab significantly improved many magnetic resonance imaging (MRI) outcomes, including an increased proportion of patients free of MRI activity compared with subcutaneous interferon beta-1a (SC IFNB-1a), and a slowing of brain volume loss. Goals: To examine 2-year MRI outcomes in patients who switched to alemtuzumab after receiving SC IFNB-1a. Methods: In the 2-year, phase 3, head-to-head, rater-blinded CARE-MS I study, SC IFNB-1a-treated patients received 44 µg 3 times/week for 2 years. These patients were eligible for the extension study (NCT00930553); upon enrolment, they received 2 annual courses of alemtuzumab 12 mg (infused on 5 consecutive days at extension study baseline and on 3 consecutive days 12 months later). MRI outcomes were assessed at baseline and yearly thereafter and included: gadolinium (Gd)-enhancing, new/enlarging T2 hyperintense and new T1 hypointense lesion activity/ counts; MRI activity-free (absence of new Gd-enhancing and new/enlarging T2 lesions); and brain volume loss measured by brain parenchymal fraction (BPF) change. Results: Most SC IFNB-1a-treated patients in CARE-MS I (144/173 [83%]) enrolled in the extension. Mean lesion number per patient decreased after switching to alemtuzumab and stayed low through extension Year 2 (new Gd-enhancing: 0.31 [before alemtuzumab] to 0.04 [after]; new/enlarging T2: 1.60 to


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Poster Session 2, 21(S11) 0.68; new T1: 0.47 to 0.11). Of those with new Gd-enhancing, T2, and T1 lesion activity after 2 years on SC IFNB-1a (17.9%, 39.3%, and 18.4%), 91.7%, 76.0%, and 95.7% of patients were lesion-free in Year 2 after switching to alemtuzumab. Similarly, of those with MRI activity after 2 years on SC IFNB-1a (40.0%), 76.5% were MRI activity-free in Year 2 of the extension study, following alemtuzumab treatment at Month 0 and Month 12. Median yearly BPF loss declined from -0.50% in Year 2 on SC IFNB-1a to -0.13% in Year 2 after switching to alemtuzumab. Conclusion: The majority of SC IFNB-1a-treated patients who had MRI activity on SC IFNB-1a in the core study and switched to alemtuzumab was MRI activity-free. Alemtuzumab also markedly reduced the yearly rate of brain volume loss. These findings demonstrate that alemtuzumab further improves outcomes after switching from SC IFNB-1a and support the superior efficacy of alemtuzumab in patients who received prior disease-modifying therapy. Disclosure Study supported by Genzyme, a Sanofi company and Bayer Healthcare Pharmaceuticals. AR: Scientific advisory boards (Biogen Idec, Novartis, Genzyme, OLEA Medical); editorial boards (American Journal of Neuroradiology, Neuroradiology); speaker honoraria (Bayer, Genzyme, Sanofi, Bracco, Merck Serono, Teva, OLEA Medical, Stendhal, Novartis, Biogen Idec); research support (Bayer); research agreements (Siemens AG). FB: Consultancy fees or honoraria (Bayer Schering Pharma, Biogen Idec, Genzyme, Janssen Research, Merck-Serono, Novartis, Roche, Sanofi, SynthonBV, and Teva); compensation for speaker bureau participation (Serono Symposia Foundation, MedScape); research support paid to his institution (Biogen Idec, Dutch MS Society, Janssen Research, Merck-Serono, Novartis, Roche, SynthonBV, and Teva). BK: Consulting fees (Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi, Teva Neuroscience); contracted research (Bayer Schering, Biogen Idec, Merck Serono, Teva Neuroscience). XM: Speaking honoraria and travel expenses for participation in scientific meetings, steering committee member of clinical trials or participation in advisory boards of clinical trials in the past years (Almirall, Bayer, Biogen Idec, EMD, Genentech, Geneuro, Genzyme, Merck, Neurotec, Novartis, Roche, Sanofi, Teva Pharmaceuticals). DHM and KT: Compensation as employees of Genzyme. DLA: Compensation for serving as a speaker, consultant, and advisory board participant, and receiving research support (Acorda, Bayer, Biogen Idec, Canadian Institutes of Health Research, Eli Lilly, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, MedImmune, Merck Serono, MS Society of Canada, NeuroRx Research, Novartis, Opexa Therapeutics, Receptos, Roche, Sanofi, and Teva); holds stock in NeuroRx Research. P1089 Laquinimod reduces CNS pathology and demyelination induced by B lymphocytes from multiple sclerosis patients in a novel brain slice model of MS

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D.E. Harlow1, S. Selva2, K.E. Saul1, L.J. Jackson2,3, W.B. Macklin1, T.L. Vollmer2,4 1Cell & Developmental Biology, 2Neurology, University of Colorado School of Medicine, Aurora, CO, United States, 3TEVA Pharmaceutical Industries Ltd, Petach Tikva, Israel, 4Rocky Mountain Multiple Sclerosis Center, Aurora, CO, United States Background: Laquinimod is a compound under development for the treatment of multiple sclerosis (MS). Results from phase 3 studies have revealed a unique protective effect on the loss of brain volume in relapsing-remitting MS patients, relative to placebo. Laquinimod has been reported to have effects on multiple cell types including astrocytes, myeloid derived cells, and lymphocytes. Using a novel B lymphocyte-induced demyelination brain slice model of MS, we have previously found that B cells from MS patients induce astrocyte and microglia reactivity, damage to oligodendrocytes, and demyelination. This study examined if laquinimod has direct effects on interactions of B cells with CNS cell types, particularly astrocytes, in the context of B cell-mediated CNS damage. Methods: CD19+ B cells were isolated from treatment-naíve MS patients and healthy controls and added to mouse cerebellar slice cultures to induce demyelination in the presence or absence of laquinimod. A subset of unstimulated B cells was incubated in medium or in medium with laquinimod, and analyzed by flow cytometric acquisition and analysis. Slices were fixed and stained for markers of astrocyte or microglia reactivity, demyelination, and axonal pathology. Slice culture media was saved for both human (B cell) and murine (CNS cells) cytokine analysis. Results: In the absence of laquinimod, B lymphocytes from treatment-naïve MS patients, but not from controls, induced alterations in astrocyte morphology, oligodendrocyte loss, and demyelination of cerebellar slices. In the presence of laquinimod, there was reduced astrogliosis, reduced microglial activation, and preservation of myelinated nerve axons. No changes in the overall or subset B cell populations (naíve, memory, activated) were seen after incubation with laquinimod. Analysis of human versus murine cytokines in slice media and B cell-astrocyte co-culture experiments are underway to determine the mechanisms(s) by which B cell-CNS cell interactions are altered in response to laquinimod and how that leads to myelin preservation. Conclusions: In a cerebellar slice demyelination model, laquinimod reduced astrocyte and microglia reactivity and prevented myelin damage induced by B cells from MS patients. Thus, laquinimod may affect cross talk between the CNS and adaptive immune system. Disclosure This study was funded by the Investigator Sponsored Studies Program at Teva and the Rocky Mountain Multiple Sclerosis Center. P1090 Laquinimod is protective to oligodendrocytes during lysolecithin-induced demyelination in a murine brain slice model D.E. Harlow1, K.E. Saul1, W.B. Macklin1, T.L. Vollmer2,3 1Cell & Developmental Biology, 2Neurology, University of Colorado School of Medicine, 3Rocky Mountain Multiple Sclerosis Center, Aurora, CO, United States


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Background: Laquinimod is a compound under development for the treatment of multiple sclerosis (MS). In phase 3 studies, laquinimod had a protective effect against the loss of brain volume in relapsing-remitting MS patients, relative to placebo. Cell culture studies have shown that laquinimod has a direct effect on CNS cells, namely astrocytes and microglia. We set out to examine the protective effects of laquinimod on CNS cell types in the lysolecithin model of demyelination using murine cerebellar slices. Methods: Cerebellar slice cultures were generated from P10 mice and grown for 12 days to allow for robust myelination. Slices were pretreated with 5µM laquinimod for 1 hour prior to lysolecithin treatment. Demyelination was then induced by exposure to 0.25% lysolecithin for 17 hours, after which slices were returned to normal medium to study recovery and remyelination. Laquinimod was kept in the medium throughout the lysolecithin treatment and recovery period. Slices were then fixed at different time points of recovery and analyzed by immunohistochemistry for oligodendrocyte survival, degree of myelination, and astrogliosis. Cytokine analysis was also performed on slice medium at various time points. Results: Lysolecithin induced rapid loss of Olig2+ oligodendrocytes, changes in GFAP immunohistochemistry, and myelin destruction during the first 48 hours after lysolecithin removal. In contrast, in the presence of laquinimod, Olig2+ cells were preserved after lysolecithin beginning at early time points suggesting protection of oligodendrocytes. Additionally, demyelination was reduced, and GFAP reactivity was more similar to untreated slices. Interestingly, while IL-10 levels in media from demyelinated slices were greatly reduced after lysolecithin, IL-10 levels were >2-fold higher in media from laquinimod-treated demyelinated slices. Current studies are investigating the effect of laquinimod on the expression of other cytokines, as well as the effect of laquinimod during different phases of demyelination and remyelination. Conclusions: Laquinimod protects oligodendrocytes from toxininduced demyelination by lysolecithin, either directly or indirectly through effects on other CNS cell types (astrocytes, microglia). These results suggest that laquinimod may have beneficial effects in recovery from demyelination, including in contexts of noninflammation-mediated demyelination. Disclosure This study was funded by the Investigator Sponsored Studies Program at TEVA Pharmaceutical Industries Ltd . P1091 Adult bone marrow mesenchymal stem cells suppress the inflammation-induced increase of Ccl2 and Ccl5 mRNA levels in vitro and in vivo and promote reparative responses by astrocytes in vitro A. Voulgari-Kokota1, A. Buffo2, N. Kerlero de Rosbo1, A. Uccelli1 1Department of Neuroscience, Ophthalmology and Genetics, University of Genoa, Genoa, 2Department of Neuroscience Rita Levi-Montalcini-University of Turin, Neuroscience Institute of Turin (NIT), Neuroscience Institute Cavalieri Ottolenghi (NICO), Turin, Italy Bone marrow mesenchymal stem cells (MSC) have a beneficial effect on the disease course of experimental autoimmune encephalomyelitis (EAE)-affected mice due to their neuroprotective and

immunomodulatory properties and are currently used in a number of clinical trials in multiple sclerosis (MS) patients. We chose to study the potent effect of MSC administration on the functions of reactive astrocytes, which are known to be involved in neuroinflammation and neurodegeneration in MS and EAE. Firstly, MSC were co-cultured with cortical mouse astrocytes in the presence of IFNγ, one of the major cytokines produced by infiltrating T cells in brain parenchyma during EAE. Then, total RNA was isolated from MSC-treated and untreated astrocytes and the mRNA levels of several inflammatory mediators were examined using Real Time RT-PCR. Astrocytic genes found to be regulated by MSC in vitro were also examined in EAE brain after MSC administration, at the peak of the disease. Moreover, the neuroprotective ability of MSC-treated astrocytes was assessed in vitro against glutamate excitotoxicity, a mechanism for tissue damage in MS. After co-culturing astrocytes and MSC, astrocyte conditioned medium was used to treat embryonic cortical neurons previously exposed to NMDA. Our results showed that MSC downregulate the IFNγ-induced increase of Ccl2 mRNA and protein levels and Ccl5 mRNA levels in astrocytes in vitro. Also, MSC administration reduces the mRNA levels of Ccl2 and Ccl5 in EAE brain. Due to the function of CCL2 as a mediator of acute excitotoxic injury and the role of CCL5 in presynaptic cortical defects during EAE, we decided to compare the neuroprotective ability of MSC-treated and untreated astrocytes. We found that secreted factors from MSC-treated astrocytes significantly protect embryonic cortical neurons from excitotoxic death, promote neurite outgrowth after injury and increase synaptophysin mRNA levels. MSC were found to decrease the transcriptional levels of two chemokines which have a well-established role in EAE and MS pathology. Furthermore, MSC-secreted factors were shown to induce reparative responses by astrocytes enhancing their ability to restore neuronal function after injury. These findings reveal an unknown aspect of MSC beneficial effect in inflamed CNS. Disclosure There are no conflicts of interest This study was partly supported by an ECTRIMS postdoctoral fellowship

Long-term treatment monitoring P1092 Progression to disability milestones in multiple sclerosis with long-term natalizumab treatment M. Trojano1, H. Butzkueven2,3, L. Kappos4, H. Wiendl5, T. Spelman2, F. Pellegrini6, Y. Chen6, Q. Dong6, H. Köndgen6, S. Belachew6, on behalf of the TOP Investigators 1University of Bari, Bari, Italy, 2University of Melbourne, Melbourne, 3Monash University, Box Hill, VIC, Australia, 4University Hospital Basel, Basel, Switzerland, 5University of Münster, Münster, Germany, 6Biogen, Cambridge, MA, United States Background: The TYSABRI® (natalizumab) Observational Program (TOP) is an ongoing, global, open-label, 10-year prospective study of natalizumab-treated relapsing-remitting multiple sclerosis patients.


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Poster Session 2, 21(S11) Objectives: To assess the risk of confirmed disability accumulation and of attaining specific Expanded Disability Status Scale (EDSS) milestones at 288 weeks in TOP. Methods: Analyses included patients with ⩾24 months of data. Confirmed disability progression was defined as an increase in EDSS score of ⩾1.0 point sustained for 24 or 48 weeks. Cumulative probabilities of 24- and 48-week confirmed EDSS progression and transition to milestone EDSS scores ⩾3.0, ⩾4.0, and ⩾6.0 by baseline EDSS subgroup were evaluated overall and in patients with and without on-treatment relapses. Sensitivity analyses excluded patients whose progression was not confirmed at the last available EDSS assessment. A separate analysis performed in patients who discontinued natalizumab treatment within the first 24 months will also be presented. Results: As of 1 May 2014, 3253 patients with baseline EDSS scores had completed ⩾24 months in TOP, receiving a median (range) of 40 (4-90) natalizumab doses; 908 of 4161 potential 24-month completers (21.8%) had discontinued treatment. The baseline mean EDSS score was 3.4. An estimated 18.5% and 13.5% of patients had 24- and 48-week confirmed EDSS progression, respectively. Cumulative probabilities of 24- and 48-week confirmed EDSS progression were higher in patients with on-treatment relapses than in those without relapses (23.6% vs 15.0% for 24-week confirmed progression; 17.7% vs 10.8% for 48-week confirmed progression [both P< 0.0001]). Probabilities of 48-week confirmed transition from EDSS scores of 0.0-2.0 to ⩾3.0, 2.0-3.0 to ⩾4.0, and 4.0-5.0 to ⩾6.0 were 11.1%, 11.8%, and 9.5%, respectively, in the primary analysis and 9.9%, 9.6%, and 9.1%, respectively, in the sensitivity analysis. The risk of transitioning differed significantly between patients with and without residual relapses in the lower EDSS score ranges (0.0064⩽P⩽0.0171) but not in patients with EDSS scores ⩾4.0. Conclusions: After approximately 5.5 years of natalizumab treatment in TOP, the probability of 48-week confirmed EDSS progression remained low but was significantly increased by the presence of residual relapses. Results of the sensitivity analysis suggest that progression events confirmed at 48 weeks may capture mostly irreversible worsening of disability. Disclosure Supported by Biogen. MT: scientific advisory boards for Biogen, Merck Serono, Novartis; speaker honoraria from Biogen, Merck Serono, Novartis, Sanofi, Teva; research grants from Biogen, Merck Serono, Novartis. HB: compensation for consulting from Biogen, Merck Serono, Novartis; research support from Biogen, Merck Serono. LK: Institution (University Hospital Basel) has received research support from Actelion, Addex, Bayer Health Care, Biogen, Biotica, CSL Behring, Genzyme, Lilly, Merck, Mitsubishi, Neurostatus Systems, Novartis, Ono Pharma, Pfizer, Receptos, Roche, Sanofi, Santhera, Siemens, Teva, UCB, Xenoport, the European Union, the Roche Research Foundation, the Swiss MS Society, the Swiss National Research Foundation. HW: honoraria from Bayer, Biogen, Medac, Merck Serono, Novo Nordisk, Sanofi, Schering, Teva; consultant for Bayer Vital/ Schering, Biogen, Medac, Merck Serono, Novartis, Novo Nordisk, Sanofi, Teva; research support from Bayer, Biogen, Medac, Merck Serono, Novo Nordisk, Sanofi, Schering, Teva.

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TS: honoraria for consultancy and funding for travel from Biogen, Novartis. FP, YC, QD, HK, SB: employees of Biogen. P1093 Characteristics of continued tecfidera Use in the NARCOMS registry S.S. Cofield1, M. Mann2, T. Tyry3, A.R. Salter1, S. McNeal1, R.J. Fox4, R.A. Marrie5, G.R. Cutter1 1Biostatistics, University of Alabama at Birmingham, Birmingham, AL, 2Biogen, Inc., Cambridge, MA, 3Dignity Health, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, 4Neurology, Cleveland Clinc, Cleveland, OH, United States, 5University of Manitoba, Winnipeg, MB, Canada

Background: Oral disease modifying therapies (DMT) are a new option for treating relapsing forms of multiple sclerosis. Dimethyl fumarate (DMF; Tecfidera®) was approved in April 2013. Changes in disability, relapse activity, and healthcare utilization after switching to DMF have not been well-described. Objective: Characterize changes in Patient Determined Disease Steps (PDDS), recent relapse activity, and health care utilization among DMF users in the NARCOMS registry from Fall 2013 to Spring 2014. Method: Respondents who completed the Fall 2013 and Spring 2014 updates, indicated current or past use of DMF, and PDDS were included. Nonparametric Wilcoxon Rank and McNemar’s tests were conducted as applicable; p-value ⩽ 0.05 was considered meaningful. Results: 449/8242 (5.4%) of Fall 2013 respondents reported DMF use between April-October 2013. In Spring 2014, 203/449 (45.2%) indicated current DMT use: 188 (92.6%) continued DMF use, 3.0% switched to an injectable therapy, 2.0% to natalizumab, 1.5% to fingolimod or teriflunomide, and 1.0% to another DMT. Of the 188 participants who reported continued DMF use: 87.2% were Female, 98.8% had health insurance (67.6% private), median age 53.5 years, median disease duration 13.5 years. The median PDDS (median 3=Gait Disability) did not change from Fall 2013 to Spring 2014 (median change 0, p=0.80) for continuous DMF users, nor for those who did not continue DMF use (median change 0, p=0.06). Excluding those who did not answer (n=11) or were unsure if they had had a relapse (n=22), the proportion with any relapse was similar: 15 (9.7%) reported a relapse on both surveys, while 14 (9.0%) reported only in Fall 2013, 25 (16.1%) had a relapse only on the Spring 2014 survey while 101 (65.2%) reported no relapse in either update (p=0.08). Similarly the proportion hospitalized did not change (n=186): 1.6% reported admissions on both surveys, 2.7% reported admissions only in Fall 2013, 6.5% only in Spring 2014, while 89.2% reported no admissions on either update (p=0.09). Emergency department use did not change. 100% of those with a visit in Fall 2013 reported one in Spring 2014 (26), but none of those without a visit in 2013 had a visit in the Spring 2014 (0%, n=160). Conclusions: Respondents continuing DMF use over at least six months reported similar disability, relapse or healthcare utilization as compared to those who discontinued DMF. Longer followup of continuous users is needed.


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Disclosure Dr. Cofield has received support for consulting services from the American Shoulder and Elbow Society, DSMB service from MedImmune, and/or grant support for various entities; no direct conflicts. Dr. Salter has received support for consulting services and grant support; no direct conflicts. Dr. Fox has received support for consulting fees from Actelion, Biogen, MedDay, Novartis, Questcor, Teva, and XenoPort; no direct conflicts. Dr. Marrie has conducted clinical trials for sanofi-aventis; no direct conflict. Ms. Mann is an employee of Biogen, Idec. Dr. Tyry has nothing to disclose. Ms. McNeal has nothing to disclose. Ms. Crowe has nothing to disclose. Dr. Cutter has consulting and/or DSMB commitments in Past 12 months. Participation of Data and Safety Monitoring Committees: All of the below organizations are focused on medical research: Apotek, Biogen-Idec, Cleveland Clinic(Vivus), Glaxo Smith Klein Pharmaceuticals, Gilead Pharmaceuticals, Horizon Pharmaceuticals, Modigenetech/Prolor, Merck/Ono Pharmaceuticals, Merck, Merck/Pfizer, Neuren, Sanofi-Aventis, Teva, NHLBI (Protocol Review Committee), NINDS, NICHD (OPRU oversight committee). Consulting, Speaking fees & Advisory Boards: Consortium of MS Centers (grant), D3 (Drug Discovery and Development), Genzyme, Genentech Jannsen Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, Novartis, Opexa Therapeutics, Receptos, Roche, EMD Serono, Spiniflex Pharmaceuticals, Somahlution, Teva pharmaceuticals, Transparency Life Sciences. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. Sources of funding: NARCOMS is supported by the CMSC and the Foundation of the CMSC.

P1094 No evidence of an increased risk for malignancy associated with natalizumab therapy in 9 years of postmarketing surveillance C. Carrillo-Infante, S. Gheuens, M. Wenten, P.R. Ho, I. Koulinska, S. Richman Biogen, Cambridge, MA, United States Background: Natalizumab has been commercially available for almost a decade, with approximately 140,000 patients exposed and 400,000 patient-years (PYs) of exposure. The large exposure to natalizumab, especially compared with more recently approved multiple sclerosis (MS) disease-modifying therapies, provides the opportunity to assess postmarketing data for evidence of rare and/ or latent events such as malignancies. Objective: To compare cumulative malignancy rates in natalizumab-treated patients to rates in the Surveillance Epidemiology and End Results (SEER) program in the general US population from 2000 to 2011. Methods: A search of the natalizumab global safety database was conducted from 23 November 2004 through 07 February 2015

using the MedDRA 17.1 System Organ Class of neoplasms. Cumulative rates of healthcare professional (HCP)-confirmed malignancies in natalizumab-treated patients were compared with SEER incidence rates. For a subset of malignancies, epidemiological analyses based on US health claims data and literature review were conducted to estimate incidence in MS patients versus non-MS controls. Patient demographics, natalizumab disposition, risk factors, histology, treatment, outcomes, and causality were also assessed. Results: The overall cumulative reporting rate of HCP-confirmed malignancies was 363.88 (95% CI: 345.55-382.91) per 100,000 PYs, which is lower than the overall SEER rate of 468.19 per 100,000 PYs. Overall, malignancies in natalizumab-treated patients were similar in type and frequency to those in the general population, with breast cancer the most frequently reported malignancy in women and prostate cancer in men, followed by lung cancer in both genders. Although a few cancers had higher reporting rates in natalizumab-treated patients than in SEER, these rates were similar to those in the general MS population based on an epidemiologic database analysis and literature review. In addition, many malignancy cases had risk factors or confounders. Conclusions: Because natalizumab has been on the market for almost 10 years, we were able to study events with long latencies, such as malignancies. Cumulative postmarketing reporting rates for malignancies in natalizumab-treated patients were generally similar to rates in either SEER or the MS population, and they have remained stable for the past few years. While some biologics carry an increased cancer risk, this does not appear to be the case with natalizumab, based on current data. Disclosure Supported by Biogen. CCI, SG, MW, PRH, IK, SR: Employees of Biogen. P1095 Disability improvement with alemtuzumab is associated with durable improvement on functional assessment in multiple sclerosis scores over 4 years in CARE-MS II patients with RRMS though most were treatment-free after year 1 T. Moreau1, R. Arroyo González2, H.-P. Hartung3, R.M.M. Hupperts4, M. Kita5, D.H. Margolin6, L. Kasten7, G. Giovannoni8, on behalf of the CARE-MS II Investigators 1Burgundy University, Dijon University Hospital, Dijon, France, 2Hospital Clinico San Carlos, Madrid, Spain, 3Heinrich-Heine University, Düsseldorf, Germany, 4Orbis Medisch Centrum, Maastricht University Medical Center, Sittard, The Netherlands, 5Virginia Mason Hospital and Medical Centre, Seattle, WA, 6Genzyme, a Sanofi company, 7PROMETRIKA, LLC, Cambridge, MA, United States, 8Queen Mary University of London, Barts and The London School of Medicine, London, United Kingdom Background: In CARE-MS II, alemtuzumab-treated patients were significantly more likely to achieve a 6-month sustained reduction in preexisting disability (SRD) and had greater qualityof-life (QoL) improvements than those treated with subcutaneous interferon beta-1a. Improvements in disability and QoL were evident through 4 years, despite most patients not receiving any


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Poster Session 2, 21(S11) treatment since Month 12. Previous work has demonstrated correlation between disability and QoL scores. Goals: To examine the relationship between QoL measured by Functional Assessment of Multiple Sclerosis (FAMS) and SRD over 4 years in alemtuzumab patients. Methods: CARE-MS II (NCT00548405) was a 2-year, phase 3, rater-blinded study in which patients with active relapsingremitting multiple sclerosis and inadequate response to prior therapy (⩾1 relapse) received alemtuzumab 12 mg at baseline and Month 12. As-needed retreatment after relapse or magnetic resonance imaging activity, or other DMT, was permitted in the extension (NCT00930553). QoL was assessed using the 6 scales of FAMS. SRD was ⩾1-point Expanded Disability Status Scale decrease over 6 months (baseline score ⩾2.0). QoL change from baseline was determined in patients with/ without SRD by an unstructured covariance model (time by group interaction). Results: 393 (93%) alemtuzumab-treated patients entered the extension; 68% did not receive alemtuzumab since Month 12 and 5% received another DMT. At Year 4, FAMS total score was significantly improved from baseline for patients who achieved 6-month SRD (13.5; P< 0.0001); this improvement was significantly greater in patients with 6-month SRD than without SRD (group difference: 11.76; P< 0.0001). Patients with 6-month SRD had significant improvements from baseline on 5 of 6 FAMS scales: mobility, symptoms, general contentment, thinking and fatigue, and emotional well-being (all P< 0.01). On those 5 scales, scores were improved to a significantly greater extent in patients with 6-month SRD than without SRD at Year 4 (all P⩽0.05). Conclusion: Improvement in preexisting disability was associated with significantly improved QoL measured by the FAMS questionnaire. SRD-associated QoL gains in alemtuzumab-treated patients were maintained through Year 4, despite most patients receiving their last treatment course 3 years prior. These data provide evidence that SRD is a clinically meaningful outcome measure and demonstrate the impact of disability improvement on QoL from the patient perspective. Disclosure Study supported by: Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. GG: Compensation for consulting, serving on a scientific advisory board, speaking, or other activities (Biogen Idec, Five Prime Therapeutics, Genzyme, GW Pharma, Merck-Serono, Novartis, Roche, Synthon, Teva, and Vertex Pharmaceuticals); compensation for serving as a journal editor (Multiple Sclerosis and Related Disorders); and research support (Serono). H-PH: Honoraria for consulting and speaking at symposia (Bayer Healthcare, BiogenIdec, CSL Behring, Genzyme, Merck Serono, Novartis, Octapharma, Roche, Teva, and Sanofi, with approval by the Rector of Heinrich Heine-University). MK: Personal compensation for serving as speaker or consultant (Genzyme, Biogen Idec, and Novartis). TM: Consulting and speaking fees (Biogen Idec, Sanofi Aventis, Genzyme, Teva Pharma, Bayer Schering, Merck Serono, Novartis, Roche, and Almirall). RAG: Compensation for serving as advisory board participant and speaker (Biogen, Novartis, Teva, Merck, Genzyme, Bayer, Almirall, and Roche).

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RH: Research grants, speaker´s fees and honoraria for advisory boards (BIOGEN, Genzyme-Sanofi,TEVA,Novartis and Merck). DHM: Employee of Genzyme. LK: Provides statistical support as a consultant for Genzyme. P1096 Durable improvement in clinical outcomes with alemtuzumab following switch from subcutaneous interferon beta-1a in treatment-naive patients with active RRMS: three-year follow-up of the CARE-MS I extension study H.-P. Hartung1, D.L. Arnold2,3, J.A. Cohen4, A.J. Coles5, E.J. Fox6, E. Havrdova7, K.W. Selmaj8, D.H. Margolin9, L. Kasten10, M.A. Panzara9, D.A.S. Compston5, on behalf of the CARE-MS I Investigators 1Heinrich-Heine University, Düsseldorf, Germany, 2NeuroRx Research, 3Montréal Neurological Institute, McGill University, Montréal, QC, Canada, 4Cleveland Clinic, Cleveland, OH, United States, 5University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom, 6Central Texas Neurology Consultants, Round Rock, TX, United States, 7First Medical Faculty, Charles University in Prague, Prague, Czech Republic, 8Medical University of Łódź, Łódź, Poland, 9Genzyme, a Sanofi company, 10PROMETRIKA, LLC, Cambridge, MA, United States Background: In the 2-year CARE-MS I study (NCT00530348) in treatment-naive patients with active relapsing-remitting multiple sclerosis (RRMS), alemtuzumab significantly reduced annualised relapse rate (ARR) over subcutaneous interferon beta-1a (SC IFNB-1a), with manageable and consistent safety. In an extension study (NCT00930553), SC IFNB-1a-treated patients from the core study switched to receive alemtuzumab at extension study baseline and at Month 12, and had reduced ARR and reduced magnetic resonance imaging (MRI) activity 2 years after switching. Goals: To examine efficacy and safety of alemtuzumab 3 years after switching from SC IFNB-1a. Methods: Patients who received SC IFNB-1a 44 µg 3 times/week in CARE-MS I received 2 annual courses of alemtuzumab 12 mg in the extension, infused on 5 consecutive days at extension study baseline and on 3 consecutive days 12 months later, then asneeded retreatment based on evidence of disease activity (eg, relapse or MRI activity). Endpoints included ARR, 6-month sustained accumulation of disability (SAD; ⩾1-point Expanded Disability Status Scale [EDSS] increase over 6 months [⩾1.5point if baseline EDSS=0]), improved/stable/worsened EDSS score (⩾0.5-point decrease [improvement] or increase [worsening] from core baseline), and 6-month sustained reduction in preexisting disability (SRD; ⩾1-point EDSS decrease from baseline over ⩾6 months [patients with baseline score ⩾2.0]). Results: The extension study enrolled 144 (83%) SC IFNB-1atreated patients from CARE-MS I; 84% of patients did not receive treatment since Month 12 after switching. ARR decreased after switching to alemtuzumab by 69% in Years 0-2 (0.12) and 72% in Years 0-3 (0.11) versus the 2-year core study (0.39). In Years 0-2 and 0-3 after switching to alemtuzumab, 93% and 86% of patients were free from 6-month SAD, 73% and 70% had stable or improved EDSS scores, and 17% and 18% achieved 6-month SRD, respectively. The safety profile of alemtuzumab 3 years


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after switching from SC IFNB-1a was similar to that observed in core study alemtuzumab patients. Conclusion: Durable improvement in clinical outcomes was observed 3 years after switching from SC IFNB-1a to alemtuzumab in patients with active RRMS, even though most patients had not received alemtuzumab treatment for 2 years. These data highlight that patients who switch from SC IFNB-1a to alemtuzumab have increased benefits with a safety profile consistent with that observed in the core study alemtuzumab arm. Disclosure Study supported by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. H-PH: Honoraria for consulting and speaking at symposia (Bayer Healthcare, BiogenIdec, CSL Behring, Genzyme, Merck Serono, Novartis, Octapharma, Roche, Teva, and Sanofi, with approval by the Rector of Heinrich Heine-University). DLA: Compensation for serving as a speaker, consultant, and advisory board participant, and receiving research support (Acorda, Bayer, Biogen Idec, Canadian Institutes of Health Research, Eli Lilly, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, MedImmune, Merck Serono, MS Society of Canada, NeuroRxResearch, Novartis, OpexaTherapeutics, Receptos, Roche, Sanofi, and Teva); holds stock in NeuroRxResearch. JAC: Personal compensation for serving as a consultant or speaker (EMD Serono, Genentech, Innate Immunotherapeutics, and Vaccinex). AJC: Consulting fees, lecture fees, and institutional grant support (Genzyme). EJF: Consultancy fees, honoraria, travel, and research support (Bayer Healthcare, BiogenIdec, Eli Lilly, EMD Serono, Genzyme, Novartis, Ono, OpexaTherapeutics, Pfizer, Sanofi, and Teva). EH: Honoraria and consulting fees (Bayer, GlaxoSmithKline, Genzyme, Biogen Idec, Sanofi-Aventis, Merck Serono, Roche, Teva, and Novartis); consulting services, speaking and serving on scientific advisory boards and research support (Czech Ministry of Education). KWS: Consulting fees (Biogen Idec, Genzyme, Novartis, and Roche); lecture fees (Bayer Healthcare Pharmaceuticals, Biogen Idec, Merck Serono, and Novartis), and financial compensation for scientific presentations (Genzyme). DHM: Employee of Genzyme. LK: Provides statistical support as a consultant for Genzyme. MAP: Employee of Genzyme. DASC: Consulting fees and grant support (Genzyme) and lecture fees (Bayer Schering Pharma) on behalf of the University of Cambridge; and personal remuneration for lecture fees (Genzyme) from July 2014. P1097 First dose time effects of fingolimod on the autonomic nervous system J. Zwierzanska1, K. Thomas2, J. Eisele2, M. Reimann2, S. Prieur2, K. Haink2, H. Rüdiger2, T. Ziemssen2 1Neurology, Städtisches Klinikum Görlitz, 2Center for Clinical Neuroscience, Neurological Clinic, Carl Gustav Carus University Dresden, University of Technology, Dresden, Germany

Background: Fingolimod (FTY), an oral drug for the treatment of highly active relapsing multiple sclerosis, exerts its effects as functional modulator of sphingosin-1-phosphat (S1P) receptors which are present in the autonomic nervous system as well. Because of its effects on heart rate modulation, first dose monitoring have been implemented. Question: The aim of our study was to investigate short time effects of FTY on the cardiovascular autonomic nervous system using innovative methods to measure autonomic outflow. Methods: 84 patients with highly active relapsing multiple sclerosis were investigated before and at 2, 4 and 6 hours after the first FTY dose. The detailed examination of the autonomic nervous system included tilt table test with continuous measurement of SBP (systolic pressure), DBP (diastolic pressure), HR (heart rate), CO (cardiac output), TPR (total peripheral resistance), EF (ejection fraction) by Finometer®. Spectral analysis and calculation of baroreflex sensitivity (BRS) and heart rate variability during deep metronomic breathing (main parameter: E/I ratio, BRS) was performed as well. Outcome: We observed the already known maximal HR reduction in the 4. hour after the FTY first dose (-17,2% in supine, -18,4% in tilted position). In supine position, this was associated with a decrease of CO (-9,5%) and a compensatory increase of SV (+9,6%) and EF (+6%). Due to increase of BRS (+72,5%) SBP stayed nearly stable (-1,5%). The increase of TPR (+5.7%) was prolonged over 6h. At no time point, orthostatic hypotension or syncope could be induced by tilt table testing. The cardiac sensitive patients (>20% decrease of HR) showed an augmented reduction of CO (-13%) and increase of TPR (+12%) and BRS (+157%). The HR increase during tilted position increased from +10% before FTY up to +16,7% at 4h for cardiac sensitive patients. There was also a significant negative correlation between time since MS diagnosis and BRS (over whole study). The E/I ratio and BRS did not demonstrate any significant modulation during deep metronomic breathing. Conclusion: Fingolimod as a S1P receptor modulator has different effects on the autonomic nervous system which are different between patients. These effects are not clinically symptomatic and are at maximum 4 hours after FTY first dose. Modulation of the autonomic nervous system may be responsible for the slight increase of blood pressure over time. Support: Novartis Deutschland Disclosure Professor Ziemssen has received personal compensation for participating on advisory boards, trial steering committees and data and safety monitoring committees, as well as for scientific talks and project support from: Bayer HealthCare, Biogen Idec, Elan, Genzyme, Merck Serono, Novartis, Roche, Sanofi-Aventis, Synthon and Teva P1098 Peginterferon beta-1a dosed every 2 weeks maintained efficacy over 3 years in patients with relapsing-remitting multiple sclerosis S.D. Newsome1, B. Sperling2, S. Liu2, S. Shang2, S. Hung2, V. Evilevitch2 1Johns Hopkins University, Baltimore, MD, 2Biogen, Cambridge, MA, United States


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Poster Session 2, 21(S11) Background: ATTAIN is a 2-year extension study of the Phase 3, 2-year ADVANCE study, to evaluate long-term safety, tolerability, and disease outcomes of peginterferon beta-1a in patients with RRMS. This analysis examines, on a yearly basis, long-term efficacy of peginterferon beta-1a dosed every 2 weeks over 3 years of treatment (ADVANCE Years 1, 2 and the first year of ATTAIN [Year 3]). Objective: To investigate efficacy of peginterferon beta-1a over 3 years in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: RRMS patients aged 18-65 received peginterferon beta1a dosed subcutaneously every 2 or 4 weeks, or delayed treatment (placebo for Year 1 followed by peginterferon beta-1a every 2 or 4 weeks for Years 2 and 3). The analysis population of interest in this study included all patients treated with peginterferon beta-1a every 2 weeks starting from ADVANCE Year 1 who had available data for the specific year and endpoint evaluated. In the every 2 weeks arm, annualised relapse rate (ARR), mean number of gadoliniumenhanced lesions (Gd+), new/newly enlarging T2 lesions, and new T1 hypointense lesions were evaluated in each study year. Results: In total, 512, 438, and 376 patients receiving peginterferon beta-1a every 2 weeks from the ADVANCE intent-to-treat population were included in the analysis for Years 1, 2, and 3, respectively. The adjusted ARR in Years 1, 2 and 3 was 0.282 (0.256, based on relapses confirmed by an independent neurology evaluation committee [INEC]), 0.201 (0.178 confirmed by INEC), and 0.215 (confirmation by INEC is not available in ATTAIN), respectively. The mean number of Gd+ lesions remained a consistent 0.2 in each year. In Years 1, 2, and 3, the mean number of new/newly enlarging T2 lesions was 4.1, 1.9, and 1.9, respectively, and mean number of new T1 lesions was 1.8, 0.7, and 0.8, respectively. Conclusions: In patients with RRMS, peginterferon beta-1a dosed every 2 weeks showed maintained efficacy on clinical and imaging outcomes over 3 years of treatment. Further, mean number of new/newly enlarging T2 lesions and new T1 lesions were greatly reduced in years 2 and 3 compared with Year 1. Disclosure This study was sponsored by Biogen (Cambridge, MA, USA). SN has participated in scientific advisory boards for Biogen, Genzyme, and Novartis; research support from Biogen and Novartis (paid directly to institution). BS, SL, SS, SH and VE are all employees and stockholders of Biogen. P1099 Teriflunomide efficacy on annualized relapse rate and expanded disability status scale scores: 2.5-year follow-up in the TOWER extension study in patients with relapsing MS L. Kappos1, M.S. Freedman2, G. Comi3, A.E. Miller4, J.S. Wolinsky5, K. Thangavelu6, P. Truffinet7, P. Rufi7, P.W. O’Connor8 1University Hospital Basel, Basel, Switzerland, 2University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada, 3University Vita-Salute San Raffaele, Milan, Italy, 4Icahn School of Medicine at Mount Sinai, New York, NY, 5University of Texas Health Science Center at Houston, Houston, TX, 6Genzyme, a Sanofi company, Cambridge, MA, United

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States, 7Genzyme, a Sanofi company, Chilly-Mazarin, France, 8University of Toronto, Toronto, ON, Canada Background: Teriflunomide is a once-daily, oral immunomodulator for the treatment of relapsing-remitting MS. In the randomized, controlled phase 3 TOWER study (NCT00751881), patients with relapsing forms of MS (RMS, n=1165) received teriflunomide 14 mg, 7 mg, or placebo, for ⩾48 weeks. Teriflunomide. 14 mg significantly reduced annualized relapse rate (ARR) and the risk of disability progression confirmed for ⩾12 weeks; 7 mg significantly reduced ARR. Patients completing the TOWER core study were eligible to enroll in an open-label extension. Objective: To report interim clinical efficacy data from patients with RMS treated for up to 5.5 years in TOWER and the extension. Methods: All patients entering the extension received teriflunomide 14 mg once daily, regardless of treatment allocation in the core study. Efficacy evaluations reported here focus on ARR and mean change from baseline in Expanded Disability Status Scale (EDSS) score by year of the extension. Results: In total, 750 patients (91% of core study completers) entered the extension (14 mg/14 mg, n=232; 7 mg/14 mg, n=265). Baseline characteristics of patients enrolled in the extension were similar to the core study population. As of July 31, 2014, cumulative duration of teriflunomide exposure for patients across both the core study and extension were 899 and 1023 patient-years for 14 mg/14 mg, and 7 mg/14 mg, respectively. In patients who enrolled in the extension, adjusted ARRs were 0.257 (14 mg/14mg), and 0.305 (7 mg/14 mg) in the core study. These decreased through the extension in both treatment groups (0.260, 0.193 [14 mg/14 mg]; 0.295, 0.188 [7 mg/14 mg]; for years 1 and 2, respectively). After 96 weeks of the extension, change in EDSS scores from core study baseline were small and similar among treatment groups (mean change [95% CI]: 0.015 [0.0141, 0.171]; and 0.008 [-0.151, 0.166]; for 14 mg/14 mg, and 7 mg/14 mg respectively). The probability of disability progression according to early vs delayed treatment in the randomized population will be presented separately. The adverse event profile in the extension was consistent with the core study. Conclusions: ARR was low and EDSS score remained stable in this interim analysis of the TOWER extension. Together with the safety results, these data highlight the clinical benefits of continuing teriflunomide over the long term in patients with RMS. Disclosure Study supported by Genzyme, a Sanofi company. LK: Author´s institution (University Hospital Basel) has received in the last 3 years and used exclusively for research support: steering committee, advisory board, and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, Xenoport); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, Teva); support of educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva); royalties (Neurostatus Systems GmbH); grants (Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society, Swiss National Research Foundation).


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MSF: Consulting fees (Bayer HealthCare, Biogen Idec, Chugai, EMD Canada, Genzyme, Novartis, Sanofi, Teva Canada Innovation); member of company advisory boards/board of directors/other similar group (Bayer HealthCare, Biogen Idec, Hoffman La-Roche, Merck Serono, Novartis, Opexa, Sanofi); speaker bureau (Genzyme). GC: Consulting fees (Almirall, Bayer, Chugai, Excemed, Genzyme, Merck Serono, Novartis, Receptos, Sanofi, Serono Symposia International Foundation [SSIF], Teva); fees from nonCME services (Almirall, Bayer, Biogen, Excemed, Genzyme, Merck Serono, Novartis, Receptos, Sanofi, SSIF, Teva). AEM: Consulting fees (Accordant Health Services, Alkermes, Biogen Idec, EMD Serono, Genentech, Genzyme, GSK, Mallinckrodt Pharmaceuticals [Questcor], Novartis, Teva); contracted research (Acorda Therapeutics, Biogen Idec, Genentech, Novartis, Questcor, Roche, Sanofi). JSW: Consulting fees (AbbVie, Actelion, Alkermes, Athersys, EMD Serono, Forward Pharma, Genentech, Genzyme, Novartis, Roche, Teva, Teva Neuroscience, to-BBB, XenoPort); contracted research (Genzyme, National Institutes of Health, National MS Society through the University of Texas Health Science Center at Houston, Sanofi); royalties (University of Texas Health Science Center at Houston for monoclonal antibodies out-licensed to Chemicon International). KT: Employee of Genzyme, a Sanofi company PT: Employee of Genzyme, a Sanofi company PR: Employee of Genzyme, a Sanofi company PWO: Consulting fees (Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, Sanofi, Teva, all related to MS clinical trials); contracted research (Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, Sanofi, Teva, for clinical trials work). P1100 Alemtuzumab demonstrates durable reduction of MRI activity over 5 years in CARE-MS I with the majority of patients treatment-free for 4 years D.L. Arnold1,2, A. Traboulsee3, J.A. Cohen4, A.J. Coles5, E.J. Fox6, G. Giovannoni7, H.-P. Hartung8, E. Havrdova9, K.W. Selmaj10, D.H. Margolin11, K. Thangavelu11, M.A. Panzara11, D.A.S. Compston5, on behalf of the CARE-MS I Investigators 1NeuroRx Research, 2Montréal Neurological Institute, McGill University, Montréal, QC, 3The University of British Columbia, Vancouver, BC, Canada, 4Cleveland Clinic, Cleveland, OH, United States, 5University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom, 6Central Texas Neurology Consultants, Round Rock, TX, United States, 7Queen Mary University of London, Barts and The London School of Medicine, London, United Kingdom, 8Heinrich-Heine University, Düsseldorf, Germany, 9First Medical Faculty, Charles University in Prague, Prague, Czech Republic, 10Medical University of Łódź, Łódź, Poland, 11Genzyme, a Sanofi company, Cambridge, MA, United States Background: In the CARE-MS I trial (NCT00530348) in treatment-naive patients with active relapsing-remitting multiple sclerosis (RRMS), alemtuzumab had superior efficacy versus subcutaneous interferon beta-1a (SC IFNB-1a), including a

significantly greater proportion of patients free from magnetic resonance imaging (MRI) activity over 2 years. Efficacy of alemtuzumab was durable over 4 years, despite most patients not receiving alemtuzumab retreatment since Month 12, or other disease-modifying therapy (DMT). Goals: To examine the effect of alemtuzumab on MRI outcomes over 5 years in patients who participated in CARE-MS I and the ongoing extension study. Methods: The CARE-MS I study enrolled patients with active RRMS (⩾1 relapse in the past year and ⩾2 in the past 2 years). Patients randomised to alemtuzumab received 12 mg/day intravenously on 5 consecutive days and on 3 consecutive days 12 months later. In the extension study (NCT00930553), as-needed alemtuzumab retreatment was available ⩾1 year apart based on evidence of disease activity (eg, relapse or MRI activity). Patients could receive another DMT at investigators’ discretion. MRI scans were acquired at baseline and yearly thereafter. MRI assessments included gadolinium (Gd)-enhancing, new/enlarging T2 hyperintense and new T1 hypointense lesion activity, and MRI activity (absence of new Gd-enhancing and new/enlarging T2 lesions). Results: 349 (95%) CARE-MS I alemtuzumab patients entered the extension study. At the end of Year 5, 68% of patients had not received alemtuzumab treatment since Month 12, and 2% received another DMT. In each of Years 3, 4 and 5, the proportions of patients free of Gd-enhancing (87.2%-90.2%), new/enlarging T2 (70.1%-72.3%), or new T1 lesions (85.4%-89.2%) were similar to those in Year 2. Most patients were free of MRI activity in each of Years 3, 4, and 5 (69.6%-72.1%). The proportions with ⩾2 new lesions were similar in Year 4 and Year 5 for Gd-enhancing (5.2% vs 6.9%), new/enlarging T2 (20.5% vs 20.4%), and new T1 lesions (10.0% vs 8.5%). Conclusion: The majority of patients remained free of new lesions and MRI activity in Year 5 after receiving alemtuzumab, despite most patients not receiving retreatment over the previous 4 years. The durable reduction of new lesion formation may be the result of immunomodulatory effects following the distinct pattern of lymphocyte repopulation after treatment with alemtuzumab, which represents a novel treatment approach for RRMS. Disclosure Study supported by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. DLA: Compensation for serving as a speaker, consultant, and advisory board participant, and receiving research support (Acorda, Bayer, Biogen Idec, Canadian Institutes of Health Research, Eli Lilly, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, MedImmune, Merck Serono, MS Society of Canada, NeuroRx Research, Novartis, Opexa Therapeutics, Receptos, Roche, Sanofi, and Teva); holds stock in NeuroRx Research. AT: Consulting fees (Biogen, Chugai, Genzyme, MedImmune, Novartis, Roche, Serono, and Teva Innovation); principal investigator on clinical trials (Genzyme, Roche). JAC: Personal compensation for serving as a consultant or speaker (EMD Serono, Genentech, Innate Immunotherapeutics, and Vaccinex). AJC: Consulting fees, lecture fees, and institutional grant support (Genzyme). EJF: Consultancy fees, honoraria, travel, and research support (Bayer Healthcare, Biogen Idec, Eli Lilly, EMD Serono, Genzyme, Novartis, Ono, Opexa Therapeutics, Pfizer, Sanofi, and Teva).


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Poster Session 2, 21(S11) GG: Compensation for consulting, serving on a scientific advisory board, speaking, or other activities (Biogen Idec, Five Prime Therapeutics, Genzyme, GW Pharma, Merck Serono, Novartis, Roche, Synthon, Teva, and Vertex Pharmaceuticals); compensation for serving as a journal editor (Multiple Sclerosis and Related Disorders); and research support (Serono). H-PH: Honoraria for consulting and speaking at symposia (Bayer Healthcare, Biogen Idec, CSL Behring, Genzyme, Merck Serono, Novartis, Octapharma, Roche, Teva, and Sanofi, with approval by the Rector of Heinrich Heine-University). EH: Honoraria and consulting fees (Bayer, GlaxoSmithKline, Genzyme, Biogen Idec, Sanofi, Merck Serono, Roche, Teva, and Novartis); consulting services, speaking and serving on scientific advisory boards and research support (Czech Ministry of Education). KWS: Consulting fees (Biogen Idec, Genzyme, Novartis, and Roche); lecture fees (Bayer Healthcare Pharmaceuticals, Biogen Idec, Merck Serono, and Novartis), and financial compensation for scientific presentations (Genzyme). DHM, KT and MAP: Compensation as employees of Genzyme. DASC: Consulting fees and grant support (Genzyme) and lecture fees (Bayer Schering Pharma) on behalf of the University of Cambridge; and personal remuneration for lecture fees (Genzyme) from July 2014. P1101 Durable improvement in clinical outcomes with alemtuzumab following switch from subcutaneous interferon beta-1a in patients with active RRMS: three-year follow-up of the CARE-MS II extension study J.A. Cohen1, D.L. Arnold2,3, A.J. Coles4, E.J. Fox5, H.-P. Hartung6, E. Havrdova7, K.W. Selmaj8, D.H. Margolin9, L. Kasten10, M.A. Panzara9, D.A.S. Compston4, on behalf of the CARE-MS II Investigators 1Cleveland Clinic, Cleveland, OH, United States, 2NeuroRx Research, 3Montréal Neurological Institute, McGill University, Montréal, QC, Canada, 4University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom, 5Central Texas Neurology Consultants, Round Rock, TX, United States, 6Heinrich-Heine University, Düsseldorf, Germany, 7First Medical Faculty, Charles University in Prague, Prague, Czech Republic, 8Medical University of Łódź, Łódź, Poland, 9Genzyme, a Sanofi company, 10PROMETRIKA LLC, Cambridge, MA, United States Background: In the 2-year CARE-MS II study (NCT00548405) in patients with active relapsing-remitting multiple sclerosis (RRMS) and an inadequate response (⩾1 relapse) to prior therapy, alemtuzumab significantly reduced annualised relapse rate (ARR) and 6-month sustained accumulation of disability (SAD) over subcutaneous interferon beta-1a (SC IFNB-1a), with manageable and consistent safety. In an extension study (NCT00930553), core study SC IFNB-1a-treated patients switched to alemtuzumab at extension baseline and at Month 12, and had reduced ARR and magnetic resonance imaging (MRI) activity 2 years after switching. Goals: To examine efficacy and safety of alemtuzumab 3 years after switching from SC IFNB-1a.

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Methods: Patients who received SC IFNB-1a 44 µg 3 times/week in CARE-MS II received 2 annual courses of alemtuzumab 12 mg in the extension, infused on 5 consecutive days at extension baseline and on 3 consecutive days 12 months later, then as-needed retreatment based on evidence of disease activity (eg, relapse or MRI activity). Endpoints included ARR, SAD (⩾1-point Expanded Disability Status Scale [EDSS] increase over 6 months [⩾1.5-point if baseline EDSS=0]), improved/stable/worsened EDSS score (⩾0.5-point decrease [improved] or increase [worsened] from core baseline), and 6-month sustained reduction in preexisting disability (SRD; ⩾1-point EDSS decrease from baseline over ⩾6 months [baseline score ⩾2.0]). Results: The extension enrolled 146 (83%) SC IFNB-1a-treated patients from CARE-MS II; 86% did not receive treatment since Month 12 after switching. ARR decreased after switching to alemtuzumab by 71% in Years 0-2 (0.15) and 73% in Years 0-3 (0.14) versus the 2-year core study (0.52). In Years 0-2 and 0-3 after switching to alemtuzumab, 89% and 81% of patients were free from 6-month SAD, 69% and 61% had stable/improved EDSS scores, and 15% and 21% achieved 6-month SRD. The safety profile of alemtuzumab 3 years after switching from SC IFNB-1a was similar to that observed in core study alemtuzumab patients. Conclusion: Durable improvement in clinical outcomes was observed 3 years after switching from SC IFNB-1a to alemtuzumab in patients with active RRMS and inadequate response to prior therapy, even though most patients had not received alemtuzumab for 2 years. These findings demonstrate that patients who switch from SC IFNB-1a to alemtuzumab have increased benefits with a safety profile consistent with that observed in the core study alemtuzumab arm. Disclosure Study supported by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. JAC: Personal compensation for serving as a consultant or speaker (EMD Serono, Genentech, Innate Immunotherapeutics, and Vaccinex). DLA: Compensation for serving as a speaker, consultant, and advisory board participant, and receiving research support (Acorda, Bayer, Biogen Idec, Canadian Institutes of Health Research, Eli Lilly, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, MedImmune, Merck Serono, MS Society of Canada, NeuroRxResearch, Novartis, OpexaTherapeutics, Receptos, Roche, Sanofi, and Teva); holds stock in NeuroRxResearch. AJC: Consulting fees, lecture fees, and institutional grant support (Genzyme). EJF: Consultancy fees, honoraria, travel, and research support (Bayer Healthcare, BiogenIdec, Eli Lilly, EMD Serono, Genzyme, Novartis, Ono, OpexaTherapeutics, Pfizer, Sanofi, and Teva). H-PH: Honoraria for consulting and speaking at symposia (Bayer Healthcare, BiogenIdec, CSL Behring, Genzyme, Merck Serono, Novartis, Octapharma, Roche, Teva, and Sanofi, with approval by the Rector of Heinrich Heine-University). EH: Honoraria and consulting fees (Bayer, GlaxoSmithKline, Genzyme, Biogen Idec, Sanofi-Aventis, Merck Serono, Roche, Teva, and Novartis); consulting services, speaking and serving on scientific advisory boards and research support (Czech Ministry of Education).


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KWS: Consulting fees (Biogen Idec, Genzyme, Novartis, and Roche); lecture fees (Bayer Healthcare Pharmaceuticals, Biogen Idec, Merck Serono, and Novartis), and financial compensation for scientific presentations (Genzyme). DHM: Employee of Genzyme. LK: Provides statistical support as a consultant for Genzyme. MAP: Employee of Genzyme. DASC: Consulting fees and grant support (Genzyme) and lecture fees (Bayer Schering Pharma) on behalf of the University of Cambridge; and personal remuneration for lecture fees (Genzyme) from July 2014. P1102 Durable efficacy of alemtuzumab on clinical outcomes over 5 years in CARE-MS II with most patients free from treatment for 4 years E.J. Fox1, D.L. Arnold2,3, J.A. Cohen4, A.J. Coles5, H.-P. Hartung6, E. Havrdova7, K.W. Selmaj8, D.H. Margolin9, L. Kasten10, M.A. Panzara9, D.A.S. Compston5 1Central Texas Neurology Consultants, Round Rock, TX, United States, 2NeuroRx Research, 3Montreal Neurological Institute, McGill University, Montreal, QC, Canada, 4Cleveland Clinic, Cleveland, OH, United States, 5University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom, 6HeinrichHeine University, Dusseldorf, Germany, 7First Medical Faculty, Charles University in Prague, Prague, Czech Republic, 8Medical University of Lodz, Lodz, Poland, 9Genzyme, a Sanofi company, 10PROMETRIKA, LLC, Cambridge, MA, United States Background: In CARE-MS II (NCT00548405), alemtuzumab significantly reduced annualised relapse rate (ARR) and 6-month sustained accumulation of disability (SAD) versus subcutaneous interferon beta-1a over 2 years, with a manageable and consistent safety profile, in patients with relapsing-remitting multiple sclerosis (RRMS) and an inadequate response to a prior therapy (⩾1 relapse). Alemtuzumab’s efficacy was durable through 4 years, despite most patients not receiving alemtuzumab or other diseasemodifying therapy (DMT) since Month 12. Goals: To examine 5-year efficacy and safety in patients who received alemtuzumab in CARE-MS II. Methods: In CARE-MS II, patients with active disease (⩾1 relapse in the past year and ⩾2 in the past 2 years) received 2 annual courses of alemtuzumab 12 mg. In the ongoing extension (NCT00930553), as-needed alemtuzumab retreatment was available ⩾1 year apart based on evidence of disease activity (relapse or magnetic resonance imaging activity). Endpoints included ARR, SAD (⩾1-point Expanded Disability Status Scale [EDSS] increase over 6 months [⩾1.5-point if baseline EDSS=0]), EDSS score improvement or worsening (⩾0.5-point decrease or increase from baseline), and sustained reduction in preexisting disability (SRD; ⩾1-point EDSS decrease from baseline over 6 months [baseline score ⩾2.0]). Results: 393 (93%) alemtuzumab-treated patients completing CARE-MS II enrolled in the extension. Through 5 years, 367 (93%) remained on study, 60% did not receive alemtuzumab since Month 12, and 8% received another DMT. The low ARR was maintained from Year 3 (0.22) to Year 5 (0.18). Through Years 0-5, 75% of patients were free from 6-month SAD, and 65% had stable/improved EDSS. An additional 14% of patients achieved

6-month SRD from Years 2-5 (43% total Years 0-5). Incidences of infusion-associated reactions and infections during the extension were reduced versus core study, and serious adverse event (AE) incidence was low. Thyroid AE incidence peaked at Year 3 and declined thereafter. Conclusion: Alemtuzumab’s efficacy was maintained for 5 years, despite most patients not receiving additional treatment over the previous 4 years. Incidence of most AEs during the extension study was comparable or reduced compared with core study, and thyroid AEs declined after Year 3. Durable efficacy may result from immunomodulatory effects of the distinct pattern of lymphocyte repopulation following treatment, representing a novel treatment approach for RRMS. Disclosure Study supported by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. EJF: Consultancy fees, honoraria, travel, and research support (Bayer Healthcare, BiogenIdec, Eli Lilly, EMD Serono, Genzyme, Novartis, Ono, OpexaTherapeutics, Pfizer, Sanofi, and Teva). DLA: Compensation for serving as a speaker, consultant, and advisory board participant, and receiving research support (Acorda, Bayer, Biogen Idec, Canadian Institutes of Health Research, Eli Lilly, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, MedImmune, Merck Serono, MS Society of Canada, NeuroRxResearch, Novartis, OpexaTherapeutics, Receptos, Roche, Sanofi, and Teva); holds stock in NeuroRxResearch. JAC: Personal compensation for serving as a consultant or speaker (EMD Serono, Genentech, Innate Immunotherapeutics, and Vaccinex). AJC: Consulting fees, lecture fees, and institutional grant support (Genzyme). H-PH: Honoraria for consulting and speaking at symposia (Bayer Healthcare, BiogenIdec, CSL Behring, Genzyme, Merck Serono, Novartis, Octapharma, Roche, Teva, and Sanofi, with approval by the Rector of Heinrich Heine-University). EH: Honoraria and consulting fees (Bayer, GlaxoSmithKline, Genzyme, Biogen Idec, Sanofi-Aventis, Merck Serono, Roche, Teva, and Novartis); consulting services, speaking and serving on scientific advisory boards and research support (Czech Ministry of Education). KWS: Consulting fees (Biogen Idec, Genzyme, Novartis, and Roche); lecture fees (Bayer Healthcare Pharmaceuticals, Biogen Idec, Merck Serono, and Novartis), and financial compensation for scientific presentations (Genzyme). DHM: Employee of Genzyme. LK: Provides statistical support as a consultant for Genzyme. MAP: Employee of Genzyme. DASC: Consulting fees and grant support (Genzyme) and lecture fees (Bayer Schering Pharma) on behalf of the University of Cambridge; and personal remuneration for lecture fees (Genzyme) from July 2014. P1103 Alemtuzumab demonstrates durable reduction of MRI activity over 5 years in CARE-MS II with most patients free from treatment for 4 years A. Traboulsee1, J.A. Cohen2, A.J. Coles3, D.A.S. Compston3, E.J. Fox4, G. Giovannoni5, H.-P. Hartung6, E. Havrdova7, K.W. Selmaj8, D.H. Margolin9, K. Thangavelu9, M.A. Panzara9, D.L.


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Poster Session 2, 21(S11) Arnold10,11, on behalf of the CARE-MS II Investigators 1The University of British Columbia, Vancouver, BC, Canada, 2Cleveland Clinic, Cleveland, OH, United States, 3University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom, 4Central Texas Neurology Consultants, Round Rock, TX, United States, 5Queen Mary University of London, Barts and The London School of Medicine, London, United Kingdom, 6Heinrich-Heine University, Düsseldorf, Germany, 7First Medical Faculty, Charles University in Prague, Prague, Czech Republic, 8Department of Neurology, Medical University of Łódź, Łódź, Poland, 9Genzyme, a Sanofi company, Cambridge, MA, United States, 10NeuroRx Research, 11Montréal Neurological Institute, McGill University, Montréal, QC, Canada Background: In the CARE-MS II trial (NCT00548405) in patients with active relapsing-remitting multiple sclerosis (RRMS) who had an inadequate response (⩾1 relapse) to prior therapy, alemtuzumab had superior efficacy versus subcutaneous interferon beta-1a (SC IFNB-1a), including significantly more patients free from magnetic resonance imaging (MRI) activity over 2 years. Efficacy of alemtuzumab was durable through 4 years, despite most patients not receiving alemtuzumab retreatment since Month 12, or other disease-modifying therapy (DMT). Goals: To examine the effect of alemtuzumab on MRI outcomes over 5 years in patients who participated in CARE-MS II and the ongoing extension study (NCT00930553). Methods: In CARE-MS II, RRMS patients with active disease (⩾1 relapse in past year and ⩾2 in past 2 years) randomised to alemtuzumab received 12 mg/day intravenously on 5 consecutive days and on 3 consecutive days 12 months later. In the extension, as-needed retreatment or permitted use of approved DMT was available, based on evidence of disease activity (eg, relapse or MRI activity). Baseline and yearly MRI scans were acquired for assessment of gadolinium (Gd)-enhancing, new/enlarging T2 hyperintense and new T1 hypointense lesion activity, and MRI activity (absence of new Gd-enhancing and new/enlarging T2 lesions). Results: 393 (93%) CARE-MS II alemtuzumab patients entered the extension study. Through 5 years, 367 (93%) remained on study, 60% of patients had not received alemtuzumab since Month 12, and 8% received another DMT. In each of Years 3, 4 and 5, the proportions of patients free of Gd-enhancing (86.5%89.7%), new/enlarging T2 (67.9%-70.3%), or new T1 lesions (86.3%-87.5%) were similar to those in Year 2 (end of core study). Most patients were free of MRI activity in each of Years 3, 4 and 5 (67.7%-69.9%). Proportions with ⩾2 new lesions were similar in Years 4 and 5 for Gd-enhancing (4.5% vs 5.8%), new/ enlarging T2 (22.3% vs 21.6%), and new T1 lesions (6.0% vs 6.6%). Conclusion: The majority of patients who had inadequate response to prior therapy at entry into CARE-MS II remained free of new lesions and MRI activity in Year 5 after receiving alemtuzumab, despite most patients not receiving retreatment over the previous 4 years. The durable reduction of new lesion formation may be the result of immunomodulatory effects following the distinct pattern of lymphocyte repopulation after alemtuzumab treatment, which represents a novel treatment approach for RRMS.

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Disclosure Study supported by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. AT: Consulting fees (Biogen, Chugai, Genzyme, MedImmune, Novartis, Roche, Serono, and Teva Innovation); principal investigator on clinical trials (Genzyme, Roche). JAC: Personal compensation for serving as a consultant or speaker (EMD Serono, Genentech, Innate Immunotherapeutics, and Vaccinex). AJC: Consulting fees, lecture fees, and institutional grant support (Genzyme). DASC: Consulting fees and grant support (Genzyme) and lecture fees (Bayer Schering Pharma) on behalf of the University of Cambridge; and personal remuneration for lecture fees (Genzyme) from July 2014. EJF: Consultancy fees, honoraria, travel, and research support (Bayer Healthcare, Biogen Idec, Eli Lilly, EMD Serono, Genzyme, Novartis, Ono, Opexa Therapeutics, Pfizer, Sanofi, and Teva). GG: Compensation for consulting, serving on a scientific advisory board, speaking, or other activities (Biogen Idec, Five Prime Therapeutics, Genzyme, GW Pharma, Merck Serono, Novartis, Roche, Synthon, Teva, and Vertex Pharmaceuticals); compensation for serving as a journal editor (Multiple Sclerosis and Related Disorders); and research support (Serono). H-PH: Honoraria for consulting and speaking at symposia (Bayer Healthcare, Biogen Idec, CSL Behring, Genzyme, Merck Serono, Novartis, Octapharma, Roche, Teva, and Sanofi, with approval by the Rector of Heinrich Heine-University). EH: Honoraria and consulting fees (Bayer, GlaxoSmithKline, Genzyme, Biogen Idec, Sanofi, Merck Serono, Roche, Teva, and Novartis); consulting services, speaking and serving on scientific advisory boards and research support (Czech Ministry of Education). KWS: Consulting fees (Biogen Idec, Genzyme, Novartis, and Roche); lecture fees (Bayer Healthcare Pharmaceuticals, Biogen Idec, Merck Serono, and Novartis), and financial compensation for scientific presentations (Genzyme). DHM, KT and MAP: Compensation as employees of Genzyme. DLA: Compensation for serving as a speaker, consultant, and advisory board participant, and receiving research support (Acorda, Bayer, Biogen Idec, Canadian Institutes of Health Research, Eli Lilly, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, MedImmune, Merck Serono, MS Society of Canada, NeuroRx Research, Novartis, Opexa Therapeutics, Receptos, Roche, Sanofi, and Teva); holds stock in NeuroRx Research. P1104 Durable improvement in expanded disability status scale functional systems scores over 4 years with alemtuzumab despite a majority of patients not receiving treatment since year 1 G. Giovannoni1, R. Berkovich2, O. Fernandez3, E.J. Fox4, H. Wiendl5, D.H. Margolin6, L. Kasten7, C. LaGanke8, on behalf of the CARE-MS II Investigators 1Queen Mary University of London, Barts and The London School of Medicine, London, United Kingdom, 2Keck School of Medicine, University of Southern California, Los Angeles, CA, United States, 3Fundacion IMABIS, Hospital Universitario


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Carlos Haya, Malaga, Spain, 4Central Texas Neurology Consultants, Round Rock, TX, United States, 5University of Münster, Münster, Germany, 6Genzyme, a Sanofi company, 7PROMETRIKA LLC, Cambridge, MA, 8North Central Neurology Associates, Cullman, AL, United States Background: Alemtuzumab, approved in >40 countries for relapsing multiple sclerosis (MS), had superior efficacy versus subcutaneous interferon beta-1a on Expanded Disability Status Scale (EDSS)-based disability outcomes in the 2-year CARE-MS II study (NCT00548405). A durable effect on disability outcomes was maintained in an ongoing extension study (NCT00930553), with 66% of patients having improved or stable EDSS scores over 4 years even though most did not receive any treatment since Month 12. The EDSS score is derived from component scores across 7 functional systems measuring different aspects of disability. Goals: To analyse the impact of alemtuzumab treatment on EDSS functional system scores over 4 years in CARE-MS II. Methods: CARE-MS II was a phase 3 study in which patients with active relapsing-remitting MS and an inadequate response to prior therapy (⩾1 relapse) received alemtuzumab 12 mg at baseline and Month 12, with as-needed retreatment after relapse or magnetic resonance imaging activity in the extension study. EDSS was determined quarterly by blinded raters. Improvement and worsening were defined as a ⩾0.5-point decrease or increase in EDSS score, respectively, from core baseline. Results: 393 (93%) patients from the alemtuzumab 12 mg arm of CARE-MS II entered the extension; 368 (94%) remained on study, 68% did not receive alemtuzumab since Month 12, and 5% received another disease-modifying therapy. At Year 4, scores were improved from baseline or remained stable in 78%-86% of patients for each functional system. Functional systems with the greatest proportion of patients with improved scores at Year 4 were cerebellar (28.4%), pyramidal (28.3%), sensory (27.2%), and cerebral (23.2%); mean (SD) changes from baseline were −0.12 (0.84), −0.12 (0.97), −0.06 (1.02), and −0.14 (0.87), respectively. Conclusion: In patients with an inadequate response to prior therapy, all 7 EDSS functional systems were improved/stable in most patients for 4 years, and thus contributed to overall EDSS improvement/stability. The greatest improvements were observed in the cerebellar, pyramidal, sensory, and cerebral systems. These findings support the durability of improvement in preexisting disability with alemtuzumab as most patients were treatment-free for 3 years. Durable disability reduction may stem from the immunomodulatory effects of the distinct pattern of lymphocyte repopulation after alemtuzumab treatment, representing a novel treatment approach for RRMS. Disclosure Study supported by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. GG: Compensation for consulting, serving on a scientific advisory board, speaking, or other activities (Biogen Idec, Five Prime Therapeutics, Genzyme, GW Pharma, Merck-Serono, Novartis, Roche, Synthon, Teva, and Vertex Pharmaceuticals); compensation for serving as a journal editor (Multiple Sclerosis and Related Disorders); and research support (Serono).

RB: Compensation for consulting, or serving on a scientific advisory board (Acorda, Avanir, Bayer, Biogen Idec, Genzyme, Novartis, Questcor, and Teva). OF: Compensation for consulting in advisory boards, chairman or lecturer in meetings, and research support (Biogen-Idec, BayerSchering, Merck-Serono, Teva, Novartis, Genzyme, Almirall, and Allergan). EJF: Consultancy fees, honoraria, travel, and research support (Bayer Healthcare, BiogenIdec, Eli Lilly, EMD Serono, Genzyme, Novartis, Ono, OpexaTherapeutics, Pfizer, Sanofi, and Teva). HW: Honoraria for lecturing, travel expenses for attending meetings (Bayer Healthcare, Biogen Idec/Elan Corporation, Lilly, Lundbeck, Merck Serono, Novartis, Sanofi Aventis, and Teva); compensation for serving as a consultant (Biogen Idec, Merck Serono, Novartis Pharma, and Sanofi Aventis); research support (Bayer Schering Pharma, Biogen Idec/Elan Corporation, Merck Serono, Novartis, Novo Nordisk, and Sanofi Aventis). DHM: Employee of Genzyme. LK: Provides statistical support as a consultant for Genzyme. CL: Compensation for consulting (AcordaTherapeutics, Bayer, Biogen Idec, Cephalon, EMD Serono, Genzyme, Novartis, Pfizer, Questcor, Strativa, Teva, and UCB). P1105 Efficacy and safety of fingolimod in relapsing-remitting multiple sclerosis: results from a retrospective French cohort E. Nerrant1, P. Labauge2, B. Brochet3, E. Thouvenot1, J.-C. Ouallet3, X. Ayrignac2, C. Carra-Dallière2, G. Castelnovo1 1Department of Neurology, Hôpital Carémeau, Nîmes, 2Department of Neurology, Hôpital Gui de Chaulliac, CHRU, Montpellier, 3Department of Neurology, CHU Pellegrin, Bordeaux, France Background: Fingolimod (FTY), a sphingosine-1-phosphatereceptor modulator, showed a clinical and radiological efficacy with safety in multiple sclerosis (MS) patients. Thus, FTY is an established oral drug as a second-line treatment of relapsingremitting (RR) MS. Objectives: To evaluate the clinical and radiological efficacy, and the safety profile of FTY in a large French cohort. Methods: This retrospective multicentre study enrolled MS patients under FTY treatment in Bordeaux, Montpellier and Nîmes, France. Clinical and radiological disease activity was assessed compared to baseline: Expanded Disease Scale Score (EDSS), annualized relapse rate (ARR), no evidence of disease activity (NEDA) defined by absence of relapses, no sustained EDSS progression, and absence of active magnetic resonance imaging (MRI) characterized by new T2 or T1 gadoliniumenhancing lesions. FTY therapy discontinuation and adverse events were recorded for safety and tolerability evaluation. Results: Up to November 2014, 234 MS patients (169 women and 65 men, mean age 40.9 (18-67) years-old) were enrolled. The course of disease was RR in 85% and secondary progressive for others, with disease duration of 9.5 (0.3-40) years. The mean exposition to FTY was 21.8 months (1 day to 72 months). EDSS at baseline was 3.1 ± 1.7. With FTY, EDSS stabilization or improvement was observed in 74.2%. The ARR before starting FTY was 1.21 and decreased to 0.29 after treatment. At baseline, MRI was considered as active in 45.1% of patients and decreased to 9.8%


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Poster Session 2, 21(S11) under FTY therapy. NEDA was obtained in 42.6% of patients with FTY treatment. FTY was discontinued in 25.2% of patients, due to inefficacy in 45.8% of cases, side effects (40.0%), pregnancy (5.1%), or patient choice (1.7%). Side effects leading to cessation included macular oedema (n=3), arterial hypertension (n=1), bradycardia (n=2), second-degree atrioventricular block (n=1), herpes recurrence (n=1), headaches and asthenia (n=4). After discontinuation, FTY was switched by natalizumab in 22.0%, immunosuppressive drugs in 16.9%, dimethyl-fumarate in 15.2%, interferon or glatiramer acetate in 6.7% and others in 60.8%. Conclusion: In this French cohort, FTY is effective on ARR reduction, MRI stabilization with 2/3 of patients with NEDA. This clinical practice cohort is consistent with efficacy data from phase 3 trials. The frequency of side effects leading to cessation of treatment, was higher in clinical practice than in clinical trials. Disclosure Dr Nerrant reports no disclosures. Pr Labauge reports no disclosures. Pr Brochet or its institution received research grants and/or consulting fees from Biogen, Bayer, Novartis, Genzyme, Roche, Medday, Merck-Serono, and Teva. Dr Thouvenot reports no disclosures. Dr Ouallet reports no disclosures. Dr Ayrignac reports no disclosures. Dr Carra-Dallière reports no disclosures. Dr Castelnovo reports no disclosures.

P1106 Durable efficacy of alemtuzumab in CARE-MS II patients with highly active relapsing-remitting multiple sclerosis: 4-year outcomes S. Krieger1, M.S. Freedman2, T. Moreau3, E. Havrdova4, K.W. Selmaj5, D.H. Margolin6, L. Kasten7, on behalf of the CARE-MS II Investigators 1Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY, United States, 2Ottawa Hospital Ontario, Ottawa, AB, Canada, 3Burgundy University, Dijon University Hospital, Dijon, France, 4First Medical Faculty, Charles University in Prague, Prague, Czech Republic, 5Medical University of Lodz, Lodz, Poland, 6Genzyme, a Sanofi company, 7PROMETRIKA, LLC, Cambridge, MA, United States Background: In CARE-MS II (NCT00548405), alemtuzumab significantly reduced annualised relapse rate (ARR), 6-month sustained accumulation of disability (SAD), and magnetic resonance imaging (MRI) lesions versus subcutaneous interferon beta-1a over 2 years in patients with highly active relapsing-remitting multiple sclerosis (RRMS) and an inadequate response (⩾1 relapse) to prior therapy. Efficacy in these patients was durable through 3 years, despite most receiving no therapy since Month 12. GOALS: To examine 4-year efficacy in patients with highly active disease who received alemtuzumab in CARE-MS II. Methods: Patients received alemtuzumab 12 mg at baseline and Month 12. As-needed retreatment after relapse or MRI activity or another disease-modifying therapy (DMT) was permitted in an extension study (NCT00930553). Highly active disease was

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defined as ⩾2 relapses in year prior to randomisation and ⩾1 baseline gadolinium (Gd)-enhancing lesion. Improved Expanded Disability Status Scale (EDSS) score is ⩾0.5-point decrease from baseline. SAD is ⩾1-point EDSS increase over 6 months (⩾1.5point if baseline EDSS=0). No evidence of disease activity is defined as absence of MRI (new Gd-enhancing and new/enlarging T2 lesions) and clinical (SAD or relapse) disease activity. Brain volume loss was assessed by brain parenchymal fraction (BPF) change. Results: The extension enrolled 92 of 103 (89%) highly active alemtuzumab-treated patients who completed CARE-MS II. Through 4 years, 67% received only the initial 2 courses; 98% did not receive another DMT. Low ARR was maintained in Year 4 (0.2). From core study baseline to end of Year 4, 71% of patients had stable or improved EDSS scores and 76% were free from 6-month SAD. As in Years 2 and 3, most patients were free from Gd-enhancing (86%), new/enlarging T2 (68%), and new T1 hypointense (84%) lesions in Year 4. Annual median percent BPF change was -0.263% in Year 2, -0.006% in Year 3, and -0.199% in Year 4. Proportion of patients achieving no evidence of disease activity was similar in Years 2 (59%), 3 (54%), and 4 (52%). Conclusion: Efficacy was durable through Year 4 in patients with highly active disease, despite most not receiving additional treatment since Month 12. These findings demonstrate a benefit of alemtuzumab in RRMS patients with highly active disease and inadequate response to prior therapy, and may result from immunomodulatory effects due to the distinct pattern of lymphocyte repopulation following treatment. Disclosure Study supported by: Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. SK: Compensation for consulting and advisory board work (Acorda Therapeutics, Bayer, Biogen Idec, EMD Serono, Genentech, Genzyme, Novartis, Questcor Pharmaceuticals, and Teva Pharmaceutical Industries) and has given non-promotional lectures (Biogen Idec and Genzyme). MSF: Honoraria or consulting fees (Actelion, Bayer Healthcare, Biogen Idec, Chugai, EMD Canada, Genzyme, Merck Serono, Novartis, Hoffman La-Roche, Sanofi-Aventis, Teva and Canada Innovation; serving on advisory boards, board of directors or other similar group (Actelion, Bayer Healthcare, Biogen Idec, Hoffman La-Roche, Merck Serono, Novartis, Opexa, and SanofiAventis); participation in speaker’s bureau (Genzyme). TM: Consulting and speaking fees (Almiral, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Sanofi Aventis, and Teva). EH: Honoraria and consulting fees (Bayer, Biogen Idec, Genzyme, GlaxoSmithKline, Merck Serono, Novartis, Roche, Sanofi-Aventis, and Teva); consulting services, speaking and serving on scientific advisory boards and research support (Czech Ministry of Education). KWS: Consulting fees (Biogen Idec, Genzyme, Novartis, and Roche); lecture fees (Bayer Healthcare Pharmaceuticals, Biogen Idec, Merck Serono, and Novartis), and financial compensation for scientific presentations (Genzyme). DHM: Employee of Genzyme. LK: Provides statistical support as a consultant for Genzyme.


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P1107 Increased relapses in patients switching from natalizumab to dimethylfumarate, fingolimod and teriflunomide N. Vu, H. Moses, S. Sriram, S. Pawate Vanderbilt University Medical Center, Nashville, TN, United States The use of natalizumab is limited by the risk of progressive multifocal leukoencephalopathy (PML) due to reactivation of the John Cunningham virus (JCV) in the brain. Therefore in patients that are positive for the JCV antibody, many patients and physicians choose to switch to a different therapy after 12-24 months of natalizumab. Cessation of natalizumab therapy has been shown to be poorly tolerated, with increased numbers of MS relapses, typically occurring after 3 months of suspension. We report here our experience with the FDA approved oral medications dimethylfumarate, fingolimod and teriflunomide in patients that discontinued natalizumab, almost always because of the risk of PML. Switch from natalizumab to fingolimod: The ARR was 0.09 for the 38 patients during the last 2 years on natalizumab. In the first year on fingolimod, the ARR was 0.38, a 4.2 fold increase .There was also an increase in MRI activity from 18% over 2 years on natalizumab to 23.5% in 1 year on fingolimod. EDSS and 25 foot walk times did not change significantly. Switch from natalizumab to dimethylfumarate: The ARR was 0.145 for the 24 patients during the last 2 years on natalizumab. In the first year on dimethyl fumarate, the ARR was 0.48, a 3.3 fold increase (Table 3). There was also an increase in MRI activity from 19% over 2 years on natalizumab to 37% in 1 year on dimethyl fumarate. EDSS and 25 foot walk times did not change significantly. Switch from natalizumab to teriflunomide: The ARR was 0.045 for the 12 patients during the last 2 years on natalizumab. In the first year on teriflunomide, the ARR was 0.36, an 8 fold increase. There was also an increase in MRI activity from 9% over 2 years on natalizumab to 80% in 1 year on teriflunomide. EDSS and 25 foot walk times did not change significantly. Limitations of our study include the retrospective nature of chart review, and the small numbers especially for teriflunomide (n=11). In addition, MRI relapses are high (80%) in teriflunomide patients because only 5 patients have had MRIs at study time, prompted by concerns for relapse, thus they are not a representative sample. Our study suggests that selection of an oral agent in patients switching from natalizumab should be based on factors such as tolerability and contraindications specific to the patients, and not necessarily their efficacy in preventing relapses. Disclosure Dr. Moses has consulted for Biogen. Drs. Pawate, Sriram, Vu have nothing to disclose. P1108 Rituximab in multiple sclerosis, a long term safety and efficacy study P. Islam-Jakobsson1, P. Alping2, J. Salzer1, A. Björck2, K. Fink2, T. Frisell3, F. Piehl2, A. Svenningsson1 1Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, 2Department of Clinical Neuroscience,

3Department

of Medicine, Karolinska Insitutet, Stockholm,

Sweden Background: Rituximab (RTX) is a monoclonal antibody, which depletes B-cells bearing the CD20 antigen. To date two randomized studies in MS have been performed; one in relapsing remitting MS (RRMS) with 104 patients and one in primary progressive MS (PPMS) with 439 patients. While promising short term effects on inflammatory features in RRMS have been demonstrated, long term safety and efficacy issues are uncertain. Objective: To collect and analyse long term safety and efficacy data for MS patients treated with RTX at two specialized MS centres (Umeå University Hospital and Karolinska University Hospital). Methods: All patients treated off label with RTX are prospectively followed up in the Swedish MS register (SMSreg). Thus, data on safety and efficacy was retrieved from SMSreg and through medical chart review for all patients ever treated with RTX at the two MS centres. Adverse events (AE) were graded according to “Common Terminology Criteria for Adverse Events”, CTCAE, v4.03: June 2010. Results: We identified a total of n=753 MS patients, the majority with RRMS, treated with RTX over at total of >1000 patient years. A majority of patients displayed positive JC virus serology. Approximately 2000 doses of 100-2000 mg RTX was administered. Notably, most patients have been treated with a single dose of 500 or 1000 mg every 6 months, rather than with repeated infusions two weeks apart. Less than 15 serious adverse events (SAEs, grade ⩾3) were detected, including generalized arthralgia, palmoplantar pustulosis, bilateral non-infectious pulmonary infiltrates and infusion-related hypersensitivity reactions. All cases had a full recovery. Data on total AEs, drug survival, number of contrast enhancing MRI lesions, annualized relapse rates and clinical worsening measured with EDSS before and during RTX treatment will be presented. However, preliminary analyses indicate a one year drug survival >90%. Conclusions: We here report the largest cohort of MS patients treated with RTX over an extended period of time. RTX demonstrates a high degree of drug survival, with few treatment interruptions due to inadequate treatment response and a good tolerability profile. It is also the first larger study to support the use of single infusions of RTX rather than two infusions two weeks apart. The results support further clinical development of RTX for MS. Disclosure Protik Islam-Jakobsson, Peter Alping, Anna Björck, Katharina Fink and Thomas Frisell have nothing to disclose. Jonatan Salzer has received lecture honoraria from BiogenIdec, Teva Pharmaceuticals and Genzyme/Sanofi and has received travel support from BiogenIdec. A. Svenningsson has served on advisory board for SanofiGenzyme and has received travel funding and/or speaker honoraria from Biogen, Sanofi-Genzyme, Novartis and Baxter Medical Fredrik Piehl has received unrestricted academic research grants from BiogenIdec and Novartis, and compensation for lectures and/or participation in advisory boards from Biogen, Merck Serono, Novartis, Sanofi, Roche and Teva, which have been exclusively used for the support of research activities.


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Poster Session 2, 21(S11) P1109 Predictive value of EDSS worsening and relapse/ active T2 lesions on outcomes among patients receiving IFN β-1a SC tiw for RRMS: post hoc analyses of PRISMS data over 4 years M. Cascione1, J. Fang2, F. Dangond2 1South Tampa Multiple Sclerosis Center, Tampa, FL, 2EMD Serono, Inc., Rockland, MA, United States Background: In PRISMS-2, interferon beta-1a (IFN β-1a) 44 and 22 µg subcutaneously (SC) three times weekly (tiw) reduced relapse rates, T2 lesion number and time to disability progression after 2 yrs. In a 2-yr extension, outcomes were superior for patients (pts) who continued on IFN β-1a SC vs pts who switched from placebo (pbo) to IFN β-1a SC. Goals: To examine the effect of early EDSS worsening and relapse/active T2 lesions at 6 months (mo) on sustained EDSS progression at Yrs 1, 2, 3 and 4. Methods: In PRISMS-2, pts with EDSS 0-5.0 and ⩾2 relapses in the past 2 yrs were randomized to IFN β-1a 44 or 22 µg or pbo for 2 yrs. In the 2-yr extension, pts either continued on IFN β-1a SC or switched from pbo to IFN β-1a SC for Yrs 3 and 4 (delayed treatment [DT]). In these post hoc analyses we examined the impact of consistent EDSS worsening and relapse/active T2 lesions at 6 mo on subsequent sustained EDSS progression. Increased EDSS on two consecutive exams was defined as change from baseline of ⩾1 or ⩾0.5 points at either Mo 3 or 6; consistent stability/improvement was defined as change of ⩽0 at Mo 3 and 6. Results: Pts were randomized to IFN β-1a 44 (n=184) or 22 µg (n=189) SC tiw or pbo (n=187). Early increased EDSS was associated with subsequent EDSS progression in all treatment groups at 1 (p< 0.0001), 2 (p< 0.0001), 3 (p⩽0.0001) and 4 (p⩽0.0002) yrs. Odds ratios (ORs) for lack of EDSS progression strongly favoured the early EDSS stable/improved group vs early EDSS worsening group at Yrs 1-4 (OR ⩽0.03 for all treatment groups). Relapse at 6 mo was significantly associated with EDSS progression in IFN β-1a SC tiw-treated pts at 1 (OR < 0.42; p< 0.05), 2 (OR < 0.42; p< 0.05), 3 (OR< 0.41; p< 0.01) and 4 (OR< 0.46, p< 0.05) yrs; no significant association was seen in the DT group (OR < 0.76, Yrs 1-4). Similar results were obtained for presence of both relapses and active T2 lesions at 6 mo in the IFN β-1a SC group (OR < 0.44; p< 0.05, Yrs 1-4); in the DT group, a significant association with EDSS progression was seen only at Yr 4 (OR 0.28; p< 0.05). No notable differences in the proportion of pts with EDSS progression in the ⩾1 relapse + ⩾1 active T2 group, compared with the ⩾1 relapse group, were seen across 4 yrs. Conclusions: In this post hoc analysis of 2-yr PRISMS data, increased EDSS on two consecutive early measurements in IFN β-1a SC tiw-treated pts shows stronger association with subsequent EDSS progression than relapse and/or active T2 lesions. Disclosure MC received funding/honoraria for research, consultation, and/or speakers bureau participation from Acorda, Bayer HealthCare, Biogen, EMD Serono, Inc., Genentech, Sanofi-Genzyme, Novartis, Pfizer, Roche, and Teva Pharmaceuticals.

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JF and FD are employees of EMD Serono, Inc., Rockland, MA, USA (a subsidiary of Merck KGaA, Darmstadt, Germany). Study supported by EMD Serono, Inc., Rockland, MA, USA (a subsidiary of Merck KGaA, Darmstadt, Germany) and Pfizer Inc, New York, NY, USA.

Risk management for disease modifying treatments P1110 The evolution of the anti-JCV antibody index value post-natalizumab: switching to fingolimod or dimethyl fumarate L. Bellengier, M. Cambron, A. Lacour, A. Chouraki, E. Duhin, P. Vermersch Neurology, Hopital Roger Salengro, Lille University, CHU Lille, Lille, France Introduction: Although natalizumab is a very potent drug to treat relapsing-remitting multiple sclerosis (MS), there is on major downside to this treatment. Patients with index values of anti-JCV antibodies higher than 1.5 and having received natalizumab for more than 2 years are at increased risk for developing a progressive multifocal leucoencephalopathy (PML). Consequently neurologists often decide to switch to another disease modifying therapy. Methods: In a cohort of 73 patients followed in the University Hospital of Lille (France) natalizumab treatment was withdrawn and switched for dimethyl fumarate (DMF) (N=41) of fingolimod (N=32) because of this increased risk for PML. Patients were randomized 1:1 to one of the oral therapies unless there was a contraindication for one treatment. Anti-JCV antibodies index values were dosed at the moment of natalizumab withdrawal, and after 3 months (M3) and 6 months (M6). Results: We did not observed significant changes of the mean JCV index value after stopping natalizumab in the whole group (2.9 ± 0.74, 2.7 ± 0.64 and 2.8 ± 0.76) at time of the last infusion, at M3 and M6, respectively), and neither in the fingolimod arm (2.9 ± 0.78, 2.7 ± 0.66 and 2.7 ± 0.87, respectively) nor in the DMF arm (2.9 ± 0.75, 2.8 ± 0.62 and 2.8 ± 0.63, respectively). None of these changes was significant. Conclusion: Shortly after stopping natalizumab, there are only minor changes in the mean JCV index value after switching to fingolimod or DMF. A longer follow-up is needed to confirm theses preliminary results. Disclosure Bellengier L.: congress fees and travel expenses from MerckSerono and GSK. Cambron M.: congress fees and travel expenses from Biogen Idec, Novartis, Genzyme, Merck-Serono, Bayer, consulting fees from Novartis. Lacour A.: consulting fees from LFB, Pfizer and Merz, honoraria from Biogen-Idec, Serono, TEVA, Novartis, Pharnext, LFB, Octapharma, Alexion and Alnylam. Chouraki A.: congress fees and travel expenses from Biogen Idec. Duhin E.: nothing to disclosure. Vermersch P.: honoraria and consulting fees from Biogen Idec, Sanofi-Genzyme, Bayer, Novartis, Teva, Merck-Serono, GSK and Almirall, research supports from Biogen Idec, SanofiGenzyme, Bayer, and Merck-Serono.


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P1111 JCV (John Cunningham virus) index: follow-up of a French cohort S. Mathais1, A. Gayou2, X. Moisset1, J.C. Ouallet2, B. Pereira1, A. Ruet2, F. Taithe1, K.-K. Kounkou2, E. Dumont1, B. Brochet2, P. Clavelou1 1CHU de Clermont Ferrand, Clermont-Ferrand, 2CHU de Bordeaux, Bordeaux, France

Kounkou: nothing to disclose Dumont: nothing to disclose Brochet: received research grants and/or consulting fees from Biogen, Bayer, Novartis, Genzyme, Roche, Medday, MerckSerono, and Teva Clavelou: received honoraria and travel expenses to conferences from and is a consultant to Teva-Pharma, Merck-Serono, Novartis, Biogen-Idec, LFB, Genzyme, Bayer, Almirall and Lundbeck

Objectives: Patients receiving natalizumab (NTZ) are at risk of PML (Progressive Multifocal Leukoencephalopathy) due to JCV reactivation. In order to predict that risk we currently use the JCV index. Recently, cut-off values for the JCV index have been published. The risk of PML seems to be very low under 0.9, low between 0.9 and 1.5 and high above 1.5. We wanted to better characterize the JCV index and its evolution and check whether the suggested thresholds were applicable to our cohort. Methods: This study was conducted in two French University Hospitals (Bordeaux and Clermont-Ferrand) until the 31/12/2014. We included 352 patients over 18 years with a relapsing-remitting multiple sclerosis and at least one JCV index. We got 908 samples. Three subjects developed a PML. We evaluated the seropositivity for JCV, the potential modifying factors of JCV index (before and under NTZ), its evolution under NTZ and particularly in case of PML. Results: 63.2% of NTZ-naïve patients were positive for JCV. At this stage the JCV index is statistically related with the age but independent from sex, disease duration or anterior exposure to immunosuppressive agents. Among the patients finally treated with NTZ 39.7% were positive for JCV at baseline and 55% at the last JCV index. On NTZ only the treatment duration was statistically related to the evolution of the JCV index. 84.5% of subjects remained stable during the follow-up specially if they were initially positive for JCV (45.4%). 6.7% seroconverted and 1.5% seroreverted. Our three cases of PML presented two risk factors (over 2 years of NTZ and seropositivity for JCV). Their indexes were above 1.5 for at least 3 months prior PML. Conclusions: JCV index seems to remain fairly constant over time and the published threshold for high PML risk (1.5) was confirmed in our cohort.

P1112 Novel oral MS treatments: one-year real-life experience with 128 patients treated with dimethyl-fumarate T. Sejbaek, Z. Illes Department of Neurology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark

Disclosure Mathais: nothing to disclose Gayou: nothing to disclose Moisset: received travel expenses from Merk-Serono, BiogenIdec, Sanofi-Pasteur-MSD and Genzyme and received honoraria from Astellas and Institut UPSA de la douleur. Ouallet: received consultancy fees, speaker fees, research grants (non-personal), and honoraria from Novartis, Biogen-Idec, Merck-Serono, Bayer Schering, Roche, Almirall, Teva and Genzyme Pereira: nothing to disclose Ruet: received research grants and/or consulting fees from Novartis, Biogen-Idec, Merck-Serono, Bayer Healthcare, Roche, and Teva. Taithe: received travel expenses from Bayer HealthCare SAS, Biogen-Idec, Merck-Serono and Genzyme and received honoraria from Astellas and Institut UPSA de la douleur.

Background: Real-life experience with dimethyl-fumarate (Tecfidera), a recently introduced oral MS treatment is limited. Objective: We examined if treatment of MS patients with dimethyl-fumarate in real-life setting reflects expectations based on the approved label. Methods: Side effects and laboratory abnormalities were examined in 128 patients treated with dimethyl-fumarate. Results: Treatment with dimethyl-fumarate was initiated in March 2014 in Denmark: 128 patients were enrolled and followed with a mean duration 258 days±97 days (17-421). The mean age of patients was 40 years±10.5 years (21-67): 43 male and 85 female people with MS were included. Forty-three patients were treatment-naïve, 80 patients received one or more 1st line treatment and 5 were treated with a 2nd line treatment before dimethylfumarate. We observed adverse events (AEs) in 74% of cases. Most frequent was transient flushing and gastrointestinal side effects. In 7 cases (5 %), the AEs were associated with discontinuation of treatment (flushing, gastrointestinal, pruritus, urticaria). Six patients (4.6 %) were concomitantly treated with low-dose aspirin (max 75mg a day). Twenty-five patients (19.5%) developed lymphocytopenia grade I or grade II. We observed grade III lymphocytopenia in 3 cases, no grade IV occurred. Both transient and persisting lymphocytopenia were present. Mild liver enzyme elevation was seen in 6 cases. Conclusion: Adverse events with dimethyl-fumarate were frequent but usually mild and well tolerated. Less than 5% were treated with concomitant low-dose aspirin. Only 5% of patients discontinued treatment due to side effects during the first year. Surprisingly, more than 20% of patients developed lymphocytopenia, however only grade I or II. Adherence seems stronger with dimethyl-fumarate than 1st line injectables. Disclosure Z. Illes has received research support from Biogen Idec and travel grants and speaking fees from Bayer Healthcare, Biogen Idec, Merck Serono, Sanofi-aventis/Genzyme, Teva Pharmaceuticals, and Novartis, research grants from Biogen Idec, Lundbeckfonden and Scleroseforeningen (Denmark). T. Sejbaek received received travel grants and speaking fees from Biogen Idec, Merck Serono, Sanofi-aventis/Genzyme, Teva Pharmaceuticals and Novartis.


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Poster Session 2, 21(S11) P1113 Exploring the clinical course of hair thinning associated with teriflunomide: an update to the teriflunomide real-world case series L. Hendin Travis1, A. Okai2, S. Jackson3, L. Farnett4, S. Cavalier4, D. Stam4, K. Liu4, K.R. Edwards5 1Phoenix Neurological Associates Ltd, Phoenix, AZ, 2Multiple Sclerosis Treatment Center of Dallas, Dallas, TX, 3Baton Rouge Clinic, Baton Rouge, LA, 4Genzyme, a Sanofi company, Cambridge, MA, 5Multiple Sclerosis Center of Northeastern New York, Latham, NY, United States Background: Teriflunomide is an oral immunomodulator approved for the treatment of relapsing-remitting MS. The safety profile of teriflunomide has been well characterized in phase 2 and 3 trials, where hair thinning occurred in 14% of teriflunomide 14mg patients vs 5% of placebo patients. Almost all cases were mild to moderate, and resolved without corrective treatment while patients continued to receive teriflunomide. Only 6% of patients who received teriflunomide 14mg and experienced hair thinning discontinued study treatment. Objective: To illustrate the clinical course of hair thinning in patients who experience this adverse event (AE) during treatment with teriflunomide. Methods: Patients who reported hair thinning during teriflunomide treatment were eligible. At onset and follow-up, healthcare professionals (HCPs) and patients completed hair thinning questionnaires ranking severity as mild/moderate/severe or from 0 to 10, respectively. A standardized protocol and camera were used to photograph patients’ hair from 5 standard views (anterior, posterior, left lateral, right lateral, anterior superior) and an optional manipulated view with hair pulled back. Results: At data cut off (14 May 2015), 38 patients had completed follow-up visits. Most were female (97%), Caucasian (84%), with no history of hair loss (89%). Mean age at onset was 51 years, and mean time from starting teriflunomide to onset of hair thinning was 77 days (< 3 months). HCPs classified most cases as mild (63%) or moderate (34%), with a single severe case in a 33-year-old female with a prior history of drug-induced hair loss. Mean patient-perception of severity was 5.1/10. On average, follow-up visits took place 9 months after onset. Complete/near-complete resolution or marked improvement was reported by 79% of patients at followup; only 1 patient described minimal improvement (hair thinning rated mild by HCP and 2/10 by patient at both visits). Teriflunomide was discontinued in 5 patients: 3 permanently (1 hair thinning, 1 rash, 1 GI upset) and 2 temporarily (1 hair thinning, 1 GI upset). Photographs of patients at onset and follow-up will be presented. Conclusions: Although hair thinning in these patients was consistent with observations from the clinical trial programme, this case series provides patients’ own perspectives and brings cases to life with pictorial evidence. As with any possible AE, patient education in advance of treatment is important to ensure appropriate treatment expectations. Disclosure Study supported by Genzyme, a Sanofi company. LHT: Consulting services (Acorda, Biogen Idec, EMD Serono, Genzyme, Novartis, Pfizer, Mallinckrodt); research support (Biogen Idec, EMD Serono, Genzyme).

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AO: Consulting services (Bayer, Biogen Idec, EMD Serono, Genzyme, Questcor, Teva Neuroscience); research support (Genzyme, Novartis, Sun Pharma). SJ: Nothing to disclose. LF, SC, DS, and KL: Employees of Genzyme, a Sanofi company. KRE: Consulting services (Biogen Idec, Genzyme, Novartis); research support (Actelion, Biogen Idec, Eisai, Eli Lilly, Genentech, Genzyme, Novartis, TauRx Therapeutics, Vaccinex). P1114 ALLOW - a phase 3b trial characterising flu-like symptoms in patients transitioning to pegylated interferon beta-1a: interim analysis of all patients R.T. Naismith1, B. Hendin2, S. Wray3, X. You4, G. Sabatella4, J. Zambrano4 1Washington University School of Medicine, St Louis, MO, 2Phoenix Neurological Associates, Phoenix, AZ, 3Hope Neurology MS Center, Knoxville, TN, 4Biogen, Cambridge, MA, United States Background: ALLOW is a Phase 3b open-label, randomised study designed to evaluate patients with relapsing-remitting multiple sclerosis (RRMS) transitioning from non-pegylated interferon (IFN) treatment to peginterferon beta-1a for incidence of new or worsening flu-like symptoms (FLS); including the duration and severity of FLS, as well as the effects of prophylactic naproxen treatment for FLS in these patients. Objective: To evaluate the proportion of the first (approximately) 200 patients enrolled who experienced new or worsening FLS (defined as a ⩾2.0 increase in FLS score), when transitioning from non-pegylated IFN beta to peginterferon beta-1a, as well as the impact of the various FLS treatments versus a naproxen-based FLS treatment. Methods: Eligible patients had received a stable regimen of a nonpegylated IFN for ⩾4 months for RRMS, immediately prior to screening. During the 4-week run-in period, patients remained on their IFN treatment to evaluate FLS (influenza-like illness (ILI), myalgia, pyrexia and/or asthenia) on that regimen. Patients were then randomised (1:1) to continue their current FLS-management or specifically to a regimen of naproxen 500 mg twice daily, starting 24 hours before peginterferon beta-1a treatment and continuing for 48 hours after, for the first 8 weeks of treatment. All patients could then switch to the FLS-management regimen of their preference and were followed for a total of 48 weeks. Results: In total, 201 patients were enrolled and received treatment, and were included in this interim analysis. Baseline demographics between the two FLS treatment groups were similar. For the primary endpoint, the majority of patients reported no new/ worsening FLS events following transition to peginterferon beta1a during the first 8 weeks (89.6% [172/192]). For all patients, reported ILI events were mild (3.0%) or moderate (2.5%). Patients on a structured naproxen regimen showed a numerical improvement in new/worsening FLS versus those continuing on the current FLS regimen (7.4% [7/94] versus 13.3% [13/98], respectively). Only 2.48% [5/201] of dosed patients withdrew due to FLS. Conclusions: Patients transitioning from non-pegylated IFN to peginterferon beta-1a in this study did not experience any additional FLS. Scheduled naproxen may be a beneficial pre-emptive


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strategy in these patients. This second interim analysis confirmed the findings of the first interim analysis. Full results of this study are expected in 2016. Disclosure This study is sponsored by Biogen (Cambridge, MA, USA). RTN has received honoraria for consulting with Acorda, Bayer, Biogen, EMD Serono, Genentech, Genzyme, Novartis, Questcor. BH has been involved in Speaker Bureaus with Acorda, Biogen, Novartis, Genzyme and Teva, Mallinkrodt; Research with Biogen, Teva, and Genentech; Advisory to EMD Serono, Biogen, Genzyme and Novartis. SW has received consulting fees from Acorda, Biogen Idec, EMD Serono, Genzyme/Sanofi Aventis, Novartis, Questcor, Teva; Speaker’s fees from Acorda, Bayer, Biogen Idec, EMD Serono, Genzyme/Sanofi Aventis, Novartis, Questcor, Teva; contracted research from Biogen Idec, EMD Serono, Genzyme, Novartis, Roche, Receptos. XY, GS and JZ are employees and stockholders in Biogen.

P1115 Gastrointestinal tolerability of dimethyl fumarate improves with a four-week titration in multiple sclerosis A. Orviz-García1, I. González-Suárez1, F. López-Pérez2, V. López-De Velasco1, J. Matías-Guiu1, C. Oreja-Guevara1 1Neurology, 2Fundación de Investigación, University Hospital San Carlos, Madrid, Spain Introduction: Dimethyl fumarate (DMF) was approved in Europe in 2014 as first-line treatment for relapsing-remitting multiple sclerosis (RRMS). The technical data-sheet specifies a seven-day titration to reduce starting adverse effects (AEs). Clinical trials have shown that DMF efficacy starts around 10-12 weeks from the beginning of treatment. Methods: The study included patients with RRMS who started DMF on May 2014. Some patients were randomized to receive a short up-titration period (full dose reached in seven days) while the others were provided with an extended period of four weeks (beginning from 120mg once a day). Neurological examination and 3-Teslas MRI was performed at baseline. The follow-up involved first month tolerability interview and quarterly laboratory and neurological assessment. Results: 38 RRMS-patients were analysed with a mean of 37 years-old and 80% of females. Baseline EDSS scored 2.0 and median disease duration was 5 years. 76% of patients were switched from another treatment (nine were naive), 70% from injectable DMT. 18 patients were included in fast titration group while 20 in the slower one. Despite administration with fat diet, gastrointestinal (GI) events occurred in 58% of all patients, 41% of them with stomach cramps and diarrhea associated. 76% experimented flushing reaction, which lasted less than 30 min but a third of them had it spreaded out of the face and neck. It appeared in more than 50% of the takes. One patient from seven-days titration group stopped DMF due to GI events, even decreasing the dose and going on with slower rise. None patients gave up taking DMF because of flushing. With fast titration, the incidence of GI events was higher than with slow one, 72% versus 45% (p=0,09), but no differences were found about flushing (74 vs 75%). Five

cases from the DMF slow titration group experimented one relapse within the first six weeks of treatment. Conclusion: Slow titration of DMF in four weeks instead of one, could reduce GI events and consequently treatment discontinuation rate. DMF efficacy starts with a delay of about 10 weeks so it justifies the increase of relapse rate in the four-weeks titration group and it has to be taken into account to define washout periods between treatments if this titration is implemented. Disclosure Aida Orviz-García received honoraria for speaking from Novartis Ines González-Suárez received honoraria for speaking for Novartis and BiogenFrancisco López-Pérez: nothing to disclosure Victoria López-De Velasco: nothing to disclosure Jorge Matias-Guiu: nothing to disclosure Celia Oreja-Guevara received honoraria for speaking and/or consultancy from Biogen, Genzyme, Bayer, Merck-Serono, Roche, Teva and Novartis. P1116 Reduced risk of relapses in the switch between natalizumab and fingolimod in 91 patients Y.D. Fragoso1, T. Adoni2, S.V. Alves-Leon3, S.L. ApostolosPereira4, Y.R. Araujo5, J. Becker6, J.B. Brooks1, E.C. Correa7, A. Damasceno8, C.A. Damasceno9, M.L. Ferreira10, P.D. Gama11, R.A. Gama11, S. Gomes12, M.V. Goncalves13, A.K. Grzesiuk14, S.C. Machado15, A.P. Matta16, M.F. Mendes17, T.A. Ribeiro18, C.F. Rocha19, H.H. Ruocco20, H. Sato21, R.F. Simm22, C.B. Tauil23, C.C. Vasconcelos24 1Universidade Metropolitana de Santos, Santos, 2Hospital Sirio Libanes de Sao Paulo, Sao Paulo, 3Universidade Federal do Rio de Janeiro, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, 4Hospital das Clinicas Universidade de Sao Paulo, Sao Paulo, 5Hospital de Base do Distrito Federal, Brasilia, 6Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, 7CLINEN de Brasilia, Brasilia, 8Universidade Estadual de Campinas, Campinas, 9Universidade Federal de Juiz de Fora, Juiz de Fora, 10Hospital da Restauracao de Recife, Recife, 11Pontificia Universidade Católica Campus Sorocaba, Sorocaba, 12Hospital Beneficencia Portuguesa, Hospital Paulistano, Sao Paulo, 13Hospital Regional Hans Dieter Schimidt, Joinville, 14Centro de Reabilitação Integral Dom Aquino Correa, Cuiaba, 15Hospital de Caridade de Florianópolis, Florianópolis, 16Universidade Federal Fluminense, Niteroi, 17Faculdade de Medicina da Santa Casa de Sao Paulo, Sao Paulo, 18Universidade Federal de Goias, Goiania, 19Neurologia Clinica Belo Horizonte, Belo Horizonte, 20Faculdade de Medicina de Junidiaí, Jundiai, 21Instituto de Neurologia de Curitiba, Curitiba, 22Hospital das Clínicas da Universidade de Sao Paulo, Sao Paulo, 23Hospital de base do Distrito Federal, Brasilia, 24Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, Brazil Background: Natalizumab (NTZ) is a good therapeutic option for patients with multiple sclerosis (MS). However, long-term use of NTZ increases the risk of developing progressive multifocal leukoencephalopathy (PML), a potentially fatal disease. Withdrawal of NTZ may be necessary in order to minimise the risks of PML,


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Poster Session 2, 21(S11) but acute reactivation of MS has been described as a frequent complication of NTZ withdrawal. Most researchers have concerns regarding the safety of an early switch to fingolimod (FTY) after NTZ withdrawal and recommend a long washout period between the two drugs. Consequently, the risk of disease reactivation when FTY is started after the washout is high. The present study presents alternatives for the washout period that lead to reduced incidence of relapses. Methods: This was a prospective observational study carried out in 24 Brazilian MS units. Data were collected on 91 patients. This was an open observational study, and each participating physician took his/her own decision on how to proceed with the drug switch, according to his/her best judgment. The alternatives were “no washout” (switch to FTY done 4 to 8 weeks after NTZ withdrawal) or “corticosteroids during washout” (monthly pulses of methylprednisolone (MP) 1 g per day, for 3 days until starting FTY). Results: There were 20 males and 71 females, with a median age of 39 years. The main reason for switching from NTZ to FTY was the risk of PML. Thirty-two patients had no washout period (first dose of FTY between 4 and 8 weeks after last NTZ infusion), while all others used monthly pulses of MP for 3 to 12 months between drugs. The median follow-up period was 6 months (range: 3 to 27 months). Ten patients (11%) presented relapses up to seven months after changing from NTZ to FTY. Five patients (out of 74) presented new lesions on magnetic resonance imaging, but 17 patients did not undergo repeated imaging after switching drugs. Regarding adverse events (other than relapses), there were five cases of headache, two of lymphopenia and two of increased hepatic enzymes. There were no significant changes in these patients’ degree of disability, as assessed using EDSS. Conclusion: The literature reports on very high relapse rates with this drug switch. The relapse rate observed during and after the switch between NTZ and FTY can be reduced by using MP pulses during the washout period or through administration of FTY without washout after NTZ.

Disclosure Yara D Fragoso - nothing to disclose, Tarso Adoni - nothing to disclose, Soniza V Alves-Leon - nothing to disclose, Samira L Apostolos-Pereira - nothing to disclose, Yuna R Araújo - nothing to disclose, Jefferson Becker - nothing to disclose, Joseph BB Brooks - nothing to disclose, Eber C Correa - nothing to disclose, Alfredo Damasceno - nothing to disclose, Carlos AA Damasceno - nothing to disclose, Maria Lucia B Ferreira - nothing to disclose, Paulo D Gama - nothing to disclose, Rodrigo A Gama - nothing to disclose, Sidney Gomes - nothing to disclose, Marcus VM Goncalves - nothing to disclose, Anderson K Grzesiuk - nothing to disclose, Suzana CN Machado - nothing to disclose, Andre PC Matta - nothing to disclose, Maria Fernanda Mendes - nothing to disclose, Taysa AGJ Ribeiro - nothing to disclose, Cristiane F Rocha - nothing to disclose,

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Heloisa H Ruocco - nothing to disclose, Henry Sato - nothing to disclose, Renata F Simm - nothing to disclose, Carlos B Tauil - nothing to disclose, Claudia CF Vasconcelos - nothing to disclose. P1117 Detection of thyroid malignancies in alemtuzumab-treated patients in the multiple sclerosis clinical development program B. Lecumberri1, D.L. Arnold2,3, J.A. Cohen4, A.J. Coles5, E.J. Fox6, H.-P. Hartung7, E. Havrdova8, K.W. Selmaj9, D.H. Margolin10, L. Kasten11, M.A. Panzara10, D.A.S. Compston5, on behalf of the CAMMS223, CARE-MS I, and CARE-MS II Investigators 1La Paz University Hospital, Autonoma University of Madrid, Madrid, Spain, 2NeuroRx Research, 3Montréal Neurological Institute, McGill University, Montréal, QC, Canada, 4Cleveland Clinic, Cleveland, OH, United States, 5University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom, 6Central Texas Neurology Consultants, Round Rock, TX, United States, 7Heinrich-Heine University, Düsseldorf, Germany, 8First Medical Faculty, Charles University in Prague, Prague, Czech Republic, 9Medical University of Łódź, Łódź, Poland, 10Genzyme, a Sanofi company, 11PROMETRIKA, LLC, Cambridge, MA, United States Background: Thyroid function was monitored quarterly in multiple sclerosis (MS) clinical trials as alemtuzumab was associated with increased risk of thyroid adverse events (AEs). Patients with thyroid AEs had further screening. Greater surveillance via modern imaging and fine-needle biopsy has coincided with increased thyroid cancer incidence. This is further illustrated by the elevated incidence in patient cohorts benefitting from close medical follow-up. Goals: To summarise the cases, and detection of thyroid malignancies in alemtuzumab-treated patients in MS clinical studies. Methods: In the phase 2 CAMMS223 (NCT00050778) and phase 3 CARE-MS I and II (NCT00530348; NCT00548405) studies, alemtuzumab-treated patients received annual courses of 12 or 24 mg (only 12 mg in CARE-MS I). Patients could enter an extension study (NCT00930553) for ongoing follow-up and as-needed retreatment. Standardized incidence ratios (SIRs) were estimated based on comparison of observed cases in the MS clinical studies with that in a retrospective MS cohort (Clinformatics Data Mart [N=32,348]). After calculating ageand gender-specific incidence rates, the expected number of events was estimated to determine SIR (95% CIs including 1.0 suggest no increased risk). Results: As of 1 May 2015, 6 of 1486 (0.4%) alemtuzumabtreated patients had thyroid malignancies. All were stage 1 and of a papillary type (3 were microcarcinomas) and discovered 10-41 months after last dose through additional safety follow-up in patients with thyroid disorders. One patient had a preexisting lymph node at baseline that was subsequently found to contain papillary thyroid cancer. All 6 patients underwent thyroidectomy and received thyroxine; 4 were treated with radioactive iodine. Thyroid cancer rate in the studies was 0.073/100 person-years and the SIR was 1.25 (95% CI: 0.56-2.79).


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Conclusion: This analysis suggests no increased risk of thyroid cancer in alemtuzumab patients versus a larger MS cohort. Thyroid malignancy incidence should be considered in the context of a potential ascertainment bias resulting from work-up of existing thyroid conditions and a possible preexisting tumour in 1 patient. Thyroid malignancy risk with alemtuzumab will continue to be assessed long term. Disclosure Study supported by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. BL: Nothing to disclose. LA: Compensation for serving as a speaker, consultant, and advisory board participant, and receiving research support (Acorda, Bayer, Biogen Idec, Canadian Institutes of Health Research, Eli Lilly, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, MedImmune, Merck Serono, MS Society of Canada, NeuroRxResearch, Novartis, OpexaTherapeutics, Receptos, Roche, Sanofi, and Teva); holds stock in NeuroRxResearch. JAC: Personal compensation for serving as a consultant or speaker (EMD Serono, Genentech, Innate Immunotherapeutics, and Vaccinex). AJC: Consulting fees, lecture fees, and institutional grant support (Genzyme). EJF: Consultancy fees, honoraria, travel, and research support (Bayer Healthcare, BiogenIdec, Eli Lilly, EMD Serono, Genzyme, Novartis, Ono, OpexaTherapeutics, Pfizer, Sanofi, and Teva). H-PH: Honoraria for consulting and speaking at symposia (Bayer Healthcare, BiogenIdec, CSL Behring, Genzyme, Merck Serono, Novartis, Octapharma, Roche, Teva, and Sanofi, with approval by the Rector of Heinrich Heine-University). EH: Honoraria and consulting fees (Bayer, GlaxoSmithKline, Genzyme, Biogen Idec, Sanofi-Aventis, Merck Serono, Roche, Teva, and Novartis); consulting services, speaking and serving on scientific advisory boards and research support (Czech Ministry of Education). KWS: Consulting fees (Biogen Idec, Genzyme, Novartis, and Roche); lecture fees (Bayer Healthcare Pharmaceuticals, Biogen Idec, Merck Serono, and Novartis), and financial compensation for scientific presentations (Genzyme). DHM: Employee of Genzyme. LK: Provides statistical support as a consultant for Genzyme. MAP: Employee of Genzyme. DASC: Consulting fees and grant support (Genzyme) and lecture fees (Bayer Schering Pharma) on behalf of the University of Cambridge; and personal remuneration for lecture fees (Genzyme) from July 2014. P1118 A functional scale for progressive multifocal leukoencephalopathy: the NIH PML scale G. von Geldern1, B. Smith2, D. Reich2, A. Nath2, I. Cortese2 1Neurology, University of Washington, Seattle, 2National Institute of Neurological Disorders and Stroke, Bethesda, WA, United States Background: Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by reactivation of JC virus. PML can be seen in

patients with multiple sclerosis (MS) as a complication of disease modifying therapy, such as natalizumab and other medications. Despite being a predominantly white matter disease, PML presents with a combination of cortical and subcortical symptoms. While general functional scales have been used to assess patients with PML, a tool permitting sensitive quantification of PMLspecific deficits would be of great value for validation of imaging and biological biomarkers and as an outcome in trials studying therapeutic interventions in PML. Objective: To develop a sensitive clinical scale to accurately characterize neurological impairment in patients with PML and to assess changes in neurological dysfunction over time. Methods: Fifteen patients participating in the NIH natural history study of PML underwent detailed analysis of the patterns of clinical impairment. Eleven domains of neurological function relevant to PML were identified. Patients were followed longitudinally for up to 24 months with clinical and neuropsychological assessment, biological sampling, and MR imaging. Based on the evolution of symptoms over time in our cohort, a rational weighting of each domain is proposed that sensitively captures biologically relevant worsening and improvement in a 100-point scale. Results: The NIH PML Scale incorporates eleven clinical domains commonly and characteristically affected by PML including cognitive dysfunction, motor symptoms, and higher order visual dysfunction, not otherwise found in one comprehensive scale. Findings were compared to and validated against existing disability scales and clinical-radiological correlation was performed. Conclusions: The NIH-PML scale provides a comprehensive functional assessment of the neurological status of this patient population. A specific clinical scale for PML will be a valuable tool when evaluating future treatment strategies. Disclosure Gloria von Geldern: nothing to disclose. Bryan Smith: nothing to disclose. Daniel Reich: nothing to disclose. Avindra Nath: nothing to disclose. Irene Cortese: nothing to disclose. P1119 Fingolimod first-dose effects in patients with RRMS concomitantly receiving SSRIs on day 1: pooled analysis of the real-world phase 4 PREFERMS and EPOC studies E. Fox1, M. Cascione2, B. Hughes3, X. Meng4, B. Brown4 1Central Texas Neurology Consultants, Round Rock, TX, 2Tampa Neurology Associates, Tampa, FL, 3Mercy Ruan Neuroscience Center, Des Moines, IA, 4Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States Background: Phase 3 fingolimod treatment initiation data demonstrated that symptomatic bradycardia and atrioventricular block (AVB) are uncommon, typically do not require intervention and that the majority of patients are discharged from first-dose monitoring 6h post-dose. First-dose evidence from the real-world, phase 4, open-label, 6-month EPOC (Evaluating Patient OutComes) and 12-month PREFERMS (Prospective, Randomized, active-controlled, open-label study to Evaluate patient retention of Fingolimod versus approved first-line disease modifying therapies in adults


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Poster Session 2, 21(S11) with Relapsing-remitting Multiple Sclerosis [RRMS]) studies support these findings. Selective serotonin-reuptake inhibitors (SSRIs) are commonly administered for depression and anxiety in patients with MS. Pooled phase 3 data show that concomitant use of SSRIs does not affect cardiac outcomes associated with fingolimod treatment initiation. Objective: To investigate the first-dose effect of fingolimod in patients concomitantly receiving SSRIs on day 1 on cardiac outcomes in a pooled analysis of the real-world phase 4 EPOC and PREFERMS studies. Methods: Patient data were pooled from EPOC and from PREFERMS. A subgroup of patients received fingolimod and concomitant SSRIs on day 1 and underwent first dose observation. Patients underwent ECG monitoring at baseline and 6-hours after first dose of fingolimod, with vital signs recorded hourly. Results: Baseline demographics in patients receiving SSRIs on day 1 (n=313) were similar to those of patients in the overall study population (n=1420). Consistent with the overall population, the lowest mean heart rate in the subgroup of patients received fingolimod and SSRIs on day 1, was reached by 5h post dose (mean change from baseline, overall: -7.8 bpm; SSRIs: -7.2 bpm) and began to recover by 6h. In both the overall population and SSRI subgroup, most patients were discharged at 6h (overall: 95.1%; SSRI: 97.1%), few patients had extended monitoring after 6h (overall: 4.5%; SSRI: 2.6%). No patients in the SSRI subgroup required hospitalization (overall: 0.2%), had symptomatic bradycardia (overall: 0.6%) or reported SAEs (overall: 0.1%). Conclusions: Concomitant use of SSRIs does not affect cardiac outcomes associated with fingolimod treatment initiation. Results of this pooled analysis of real-world studies are consistent with previous controlled fingolimod trials. Disclosure Edward Fox has received consultancy fees, honoraria, travel and/ or research support from Acorda Therapeutics, Bayer, Biogen, Eli Lilly, EMD Serono, Genzyme, GlaxoSmithKline, Novartis, Ono, Opexa Therapeutics, Roche, Sanofi and Teva Neuroscience. Mark Cascione has received research support, speaker fees, and/ or consulting fees from Acorda Therapeutics, Bayer Health Care Pharmaceuticals, Biogen, EMD Serono, Genzyme, Novartis, Pfizer, Sanofi-Aventis, and Teva. Bruce Hughes has received research support, served as an advisory board member, or been involved in a speaker´s bureau for Acorda, Bayer, Biogen, EMD Serono, Gen- zyme, Questcor, Novartis, and Teva. Xiangyi Meng and Brandon Brown are employees of Novartis Pharmaceuticals Corporation. P1120 Pregnancy outcomes in patients with active RRMS who received alemtuzumab in the clinical development program A. Achiron1, C. Chambers2, E.J. Fox3, P. Mc Combe4, S. Otero5, D.H. Margolin6, L. Kasten7, D.A.S. Compston8, on behalf of the CAMMS223, CARE-MS I, and CARE-MS II Investigators 1Chaim Sheba Medical Center, Tel Hashomer, Israel, 2University of California San Diego, La Jolla, CA, 3Central Texas Neurology Consultants, Round Rock, TX, United States, 4The University of Queensland, Brisbane, QLD, Australia, 5Vall d’Hebron University Hospital, Barcelona, Spain, 6Genzyme, a

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Sanofi company, 7PROMETRIKA, LLC, Cambridge, MA, United States, 8University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom Background: Because many individuals with multiple sclerosis (MS) are women of childbearing age, it is important to assess the effects of disease-modifying therapy on pregnancy. In murine studies of alemtuzumab, lymphocyte counts were altered in exposed pups, but physical development was not affected. There are no clinical studies of alemtuzumab in pregnant women. Women of childbearing potential should use effective contraception for 4 months after receiving alemtuzumab. Goals: To report pregnancy outcomes in alemtuzumab-treated female patients in the clinical development programme. Methods: In the phase 2 CAMMS223 (NCT00050778), phase 3 CARE-MS I (NCT00530348) and CARE-MS II (NCT00548405) studies, alemtuzumab-treated patients received annual courses of 12 or 24 mg (only 12 mg in CARE-MS I). Patients could enter an extension study (NCT00930553) for ongoing follow-up and asneeded retreatment based on evidence of disease activity (relapse or magnetic resonance imaging activity). Alemtuzumab is low or undetectable in serum within 30 days. If pregnancy occurs, retreatment is suspended but the patient can remain in the study for safety follow-up. Results: As of 5 February 2015, 1486 patients (8053 patient-years; 64.8% female) were exposed to alemtuzumab; 179 pregnancies occurred in 131 alemtuzumab-treated female patients (n=157 completed; n=14 ongoing; n=8 unknown outcome). Of completed pregnancies, 104 (66%) were live births. To date, no congenital abnormalities or birth defects have been observed in delivered infants. Excluding pregnancies with unknown outcomes, there were 36 (21%) spontaneous abortions, 16 (9%) elective abortions, and 1 (0.6%) stillbirth. Elective abortions were due to anembryonic gestation (n=2), extrauterine pregnancy (n=2), foetal defects (n=1; cystic hygroma and hypoplastic heart), or personal choice (n=6); 5 had no information available. Reported rates of spontaneous abortions in the general population vary (11%-22%). Conclusion: Based on cumulative experience in the MS clinical programme, the most common outcome was full-term live birth. Available data on pregnancies are not suggestive of an emerging adverse pattern. The rate of spontaneous abortion is similar to rates observed in the general population. Disclosure Study supported by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. AA: Personal compensation for activities (Novartis and Teva Neuroscience); research support (Bayer-Schering Pharma, Biogen Idec, and Teva Neuroscience). CC: Grant funding (GlaxoSmithKline, Novartis and CSL Limited). EJF: Consultancy fees, honoraria, travel, and research support (Bayer Healthcare, BiogenIdec, Eli Lilly, EMD Serono, Genzyme, Novartis, Ono, OpexaTherapeutics, Pfizer, Sanofi, and Teva). PM: Travel grants and honoraria (Biogen, Novartis, and Sanofi). SO: Speaker honoraria (Serono Symposia International Foundation). DHM: Employee of Genzyme. LK: Provides statistical support as a consultant for Genzyme.


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DASC: Consulting fees and grant support (Genzyme) and lecture fees (Bayer Schering Pharma) on behalf of the University of Cambridge; and personal remuneration for lecture fees (Genzyme) from July 2014. P1121 Disparities and challenges to oral disease modifying MS therapies and the potential of individualized patient coaching Y. Begus-Nahrmann1, G. Niemczyk2, B. Schmid2, M. Mäurer3 1Konzept Pharma Service GmbH, Elze, 2Biogen GmbH, Ismaning, 3Caritas Krankenhaus, Bad Mergentheim, Germany Background: The benefit of patient programs for injectable therapies is widely accepted. Oral therapies lack the barrier of selfinjection and patient programs seem not mandatory. Yet, various studies for oral drugs have shown that efficient therapy handling and adherence to therapy is not guaranteed. Oral medications like delayed-release dimethyl fumarate (DMF; gastro-resistant) have their own challenges. The objective of this retrospective cohort study is to evaluate a real-life cohort of DMF patients in the time course of up to 15 months of therapy experience. Furthermore, the potential benefit of individual patient coaching is analysed. Methods: From February 2014 patients were recruited. All patients signed a written consent form and received the code for a smartphone application with reminder function. Coached patients were in contact by phone at least 2 times with the personal coach in the first month. Afterwards contents and coaching frequency were adapted according to patient needs including motivational interviewing and compliance coaching. The control cohort of not coached patients was contacted 1-2 times per year. Results: As of April 2015, 7518 patients taking DMF have been recruited. In total, data for 6573 DMF patients including 1123 dropouts could be analyzed. More than 50% of the dropouts have discontinued DMF therapy in the first three months. Gastrointestinal issues were reported as the most frequent dropout reason (38.8%) of the discontinuers. While gastrointestinal issues were most frequent in the first two therapy months, incidence is constantly decreasing in the ongoing months. Patients further reported flushing/pruritus (12.1%), ongoing disease activity (11.7%) and changes in blood counts (7.9%) as reasons for therapy discontinuation. Dropout reason and time to therapy discontinuation were differentiated for coached and not coached patients. 3.5%, 6.2% and 9.6% of coached patients stopped therapy after 3, 6 and 12 months compared to 7.8%, 13.2% and 25% of the controls, respectively. Patients in the control cohort tended to quit therapy more often because of partly manageable side effects like gastrointestinal problems and flushing/pruritus. Conclusion: Side effects reported in the phase III studies are also the main reasons for discontinuing DMF therapy in the real-world setting. Patient coaching provides an essential contribution to overcome preventable or manageable side effects, leading to therapy continuation and treatment satisfaction. Disclosure Y. Begus-Nahrmann has nothing to disclose. M. Mäurer has received honoraria from Biogen, Boehringer Ingelheim, Bayer Healthcare, Merck Serono, Genzyme, Sanofi Aventis, Talecris, Teva, Novartis

G. Niemczyk and B. Schmid are employees of Biogen. Study was supported by Biogen. P1122 The importance of low JC virus copy numbers in CSF in the diagnosis of progressive multifocal leukoencephalopathy in MS patients G. von Geldern1, C. Ryschkewitsch2, M.C. Monaco2, P. Jensen2, E.O. Major2 1Neurology, University of Washington, Seattle, WA, 2Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States Background: Multiple sclerosis (MS) patients treated with disease modifying therapy, esp natalizumab are at risk of developing Progressive Multifocal Leukoencephalopathy (PML), a demyelinating disease of the central nervous system due to reactivation of JC virus (JCV). Diagnosis of PML can be challenging in MS patients with who have baseline neurological deficits and MRI lesions due to their MS. Detection of JCV DNA in cerebrospinal fluid (CSF) is therefore an important component of diagnosing PML. Commercially available JCV testing has a detection limit of several hundred copies per mL. The significance of low copy numbers of JCV DNA in CSF needs further investigation. Objective: Assessing the significance of low copy JCV in the CSF for the diagnosis of PML in MS patients. Methods: CSF of MS patients on natalizumab from multiple centers was analyzed. JCV DNA copy number was detected by quantitative real-time polymerase chain reaction (qPCR) with a detection limit of 10 copies/mL (c/mL). 118 patients with < 500 copies/mL were identified. Clinical and magnetic resonance imaging (MRI) findings were reviewed. A subset of patients underwent repeat CSF analysis after discontinuation of natalizumab. Results: Repeat CSF revealed high copy numbers of JCV in 38%, 29% continued to have low copies, and 33% had undetectable JCV on repeat sampling. Only three patients had no typical MRI findings and six patients lacked clinical features concerning for MS. Discussion: Only a third of PML patients with low copy numbers cleared the virus and this included patients with atypical clinical or MRI findings. Another third have persistent low virus in CSF and a third have high copy numbers. While detection of JCV DNA in CSF by itself is not sufficient for diagnosis, attention should be paid even to low copy numbers. Disclosure Gloria von Geldern: nothing to disclose. Caroline Ryschkewitsch: nothing to disclose. Maria C. Monaco: nothing to disclose. Peter Jensen: nothing to disclose. Eugene O. Major: nothing to disclose. P1123 Alemtuzumab related Listeria infections - a growing concern? S. Ohm, A. Borchert, B.-M. Mackert Neurology, Vivantes Auguste-Viktoria Klinikum, Berlin, Germany


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Poster Session 2, 21(S11) Background: Alemtuzumab is a new highly efficacious humanized monoclonal antibody therapy for active relapsing-remitting multiple sclerosis. The antibody targets the CD 52 antigen of circulating B and T lymphocytes which results in a rapid and prolonged depletion and repopulation. Despite this profound and effective modulation of the adaptive immune system severe opportunistic infections seem to occur very rarely in patients with multiple sclerosis. However, there is a very small but growing number of Listeria infections related to alemtuzumab in Germany, to our knowledge two since approval. Listeriosis may be severe. Presenting these cases might help to complement guidelines and eventually lower the risk of infections. We report the third case of a Listeria infection after the first cycle of alemtuzumab. Case report: A 33-year-old women with high fever and chills was readmitted to our clinic ten days after her final alemtuzumab infusion. According to the current national guidelines she didn´t consume any potentially Listeria-contaminated food after she was released. However, she ingested raw milk products up to a few days before commencing the therapy. She received several cycles of methylprednisolone during the washout period due to a high disease activity. Results: Blood tests on admission showed a typical constellation of a bacterial infection with elevated leukocyte count and C-reactive protein level as well as a very high increase in procalcitonin level. Blood cultures revealed the presence of Listeria monocytogenes (LM). As a result of the Listeria sepsis the patient developed a temporary moderate thrombocyto- and leukopenia. Two weeks therapy of ampicillin resulted in clinical remission and normal leukocyte and platelet count. Cerebral magnetic resonance imaging, chest X-ray and transesophageal echocardiogram revealed no further involvement of any other organs. Conclusions: Current guidelines for the treatment of alemtuzumab 1. should consider the long and variable incubation time (3-70 days) of LM and recommend an abstinence of concerned food up to two and a half months before therapy. 2. As LM infection after alemtuzumab therapy is increasingly reported, special attention should be given to this possible infection and early adequate diagnostic investigation and therapy should be initiated. Disclosure Sascha Ohm: nothing to disclosure.

P1124 Peripheral lymphocyte subsets and JCV antibody index in MS patients treated with natalizumab: a longitudinal analysis A. Carotenuto1, R. Lanzillo1, L. Del Vecchio2,3, G. Scalia2,3, F. Ausiello1, M. Moccia1, C.V. Russo1, V. Brescia Morra1 1Neurosciences, Reproductive Science and Odontostomatology, 2Unita’ Operativa Complessa Citometria, Immunologia Cellulare e dei Trapianti, Federico II University, 3CEINGE Biotecnologie Avanzate, Naples, Italy Background: Natalizumab (NAT) acts reducing extravasation of inflammatory immune cells across the blood-brain barrier into the central nervous system (CNS). Quantification of anti-JCV

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antibody index has increased stratification of progressive multifocal leukoencephalopathy (PML) risk in course of treatment. Objective: To evaluate lymphocyte subsets modification during NAT and their correlation with anti-JCV antibody index in order to identify alternative, reliable immunological markers of PML risk. Methods: This is a 24 months prospective longitudinal study on RR MS patients treated with NAT. Demographic and clinical data were collected. The assessment of immune cell subsets in peripheral blood was performed by flow cytometry at month 0, 1, 3, 12 and 24. The ratio between T Helper lymphocytes CD4+ and T Suppressor lymphocytes CD8+ was calculated. Anti JCV antibodies index was evaluated at month 0, 12 and 24. Linear regression and Pearson chi2 tests were used for statistical analysis. Results: 51 MS patients were enrolled (33 F) with a mean age of 39 y (SD 1,41) and a median disease duration of 10 y (range). Median EDSS was 3,5 (range 2 - 7). Nineteen patients were naïve to any disease modifying treatment. After 2 years, natalizumab induced an increase of white blood cell count (p=0,001), total lymphocytes (p< 0,001), B lymphocytes CD19+ (p=0,008) and a decrease of T lymphocytes CD3+ (p=0,005) and T Helper lymphocytes CD4+(p=0,01), as such as CD4/CD8 ratio (p=0,01). At month 24 CD3+ and CD8+ count inversely related to anti-JCV antibodies index (p=0,01 and p=0,001 respectively), while CD4+ levels were directly related (p=0,02). CD4/CD8 ratio was positively correlated to anti-JCV antibodies index at month 0 (p=0,04), 12 ( p=0,007) and 24 (p=0,001). Conclusion: Our study confirms that lymphocytes subsets modify on NAT therapy and suggests that CD4/CD8 ratio could be an alternative biomarker to improve the estimate of PML risk. Implications of lymphocytes subset alterations in the pathogenesis of PML are under analyses. Disclosure A. Carotenuto: nothing to disclose. R. Lanzillo: received honoraries for public speaking and advisory from, Biogemn, Bayer shering, Teva, Genzyme, Almirall, Novartis, Merck Serono. G. Scalia: nothing to disclose. L. Del Vecchio: nothing to disclose. F. Ausiello: nothing to disclose. M. Moccia: nothing to disclose. C.V. Russo: nothing to disclose. V. Brescia Morra: received honoraries for public speaking and advisory from, Biogemn, Bayer shering, Teva, Genzyme, Almirall, Novartis, Merck Serono. P1125 The pharmacogenetics of interferon beta induced liver injury in multiple sclerosis K. Kowalec1,2, C. Ross2, E. Kingwell3, A. Traboulsee3, E. Yoshida4, R.A. Marrie5, M. Kremenchutzky6, T. Campbell7, P. Duquette8, B. Carleton2, H. Tremlett3 1Neuroscience, University of British Columbia Hospital, 2Pharmaceutical Outcomes Programme, University of British Columbia, 3Neurology, University of British Columbia Hospital, 4Gastroenterology, University of British Columbia, Vancouver, BC, 5Medicine, University of Manitoba, Winnipeg,


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MB, 6Neurology, Western University, London, ON, 7Neurology, Dalhousie University, Halifax, NS, 8Neurology, University of Montreal, Montreal, QC, Canada Background: Drug-induced liver injury is a common cause of acute liver failure. Approximately 1-2% of interferon-beta (IFNβ) exposed multiple sclerosis (MS) patients experience druginduced liver injury. Pharmacogenomic biomarkers that predict drug-induced liver injury would be of high clinical utility to mitigate toxicity concerns, support risk management strategies and enhance the understanding of liver injury due to biologics. Objectives: To identify genetic factors associated with IFN-β induced liver injury. Methods: People with MS exposed to IFN-β (cases and controls) were recruited from five Canadian MS clinics. Extensive demographic and clinical data were collected. Severe cases of liver injury were defined as alanine or aspartate aminotransferase (ALT or AST) levels ⩾ 5x upper limit of normal. Controls were those with >2 years IFN-β exposure and no biochemical evidence of liver injury. IFN-β product, age at IFN-β start, MS disease course and sex were priority parameters used to compare cases and controls. DNA samples were genotyped using an Illumina 1.7M SNP array. We will analyze genetic variants in high priority genes identified by previous genetic studies of either drug induced liver injury or IFN-β effectiveness for an association with IFN-β induced liver injury and then follow this initial targeted analysis with a genome-wide analysis. Results: We have enrolled 172 Canadian patients (40 cases, 132 controls). Cases were similar to controls with respect to mean (±SD) ages (in years) at IFN-β start and MS onset (39.3±11.6 vs. 40.0±9.4 and 31.8±10.1 vs. 32.9±8.1, respectively), and self-reported ancestry (European ancestry: 77.8% cases vs. 86.4% controls). Across all patients, there was preponderance of female sex (80.6%) and relapsing remitting course (91.7%), neither of which differed between cases and controls. Cases were exposed to IFN-β for a median 5 months (range: 1-163 months) and were followed for a median 9 years (range: 0-17 years). Analysis of the genomic data is underway and will be presented. Conclusions: Severe cases of liver injury due to IFN-β were similar to controls with respect to clinical and demographic characteristics. The current study represents a step towards personalized therapy for MS and will help determine the contribution of genetic variation to this severe adverse drug reaction.

consultancy for Biogen, Chugai, EMD Serono, Hoffman la Roche, Medimmune, Sanofi Genzyme, Teva Neuroscience. EY is an investigator of clinical trials sponsored by Gilead Inc, Merck Inc, Vertex Inc, Hoffman LaRoche Inc, Abbvie Inc, Janssen Inc, Boeringher Ingelheim Inc. He has received honoraria for CME lectures from Merck Canada, Gilead Canada. He has been a speaker at Advisory Board Meetings of Boeringher Ingelheim Canada, Hoffman LaRoche Canada, Abbvie Canada for which he received an honorarium. He is a member of the Gilead Canada compassionate release program adjudication committee for which he has received an honorarium. RAM has conducted clinical trials for sanofi-aventis. She receives research funding from CIHR, the MS Society of Canada, the NMSS, Rx & D Health Research Foundation and Research Manitoba. MK No actual or potential conflict of interest in relation to this work, however, in the last two years MK or MK’s institution has received consulting fees, research support or grants from CIHR, MS Society of Canada, Bayer, Biogen, Genzyme, Novartis, Sanofi-Aventis, Serono, and Teva. TC was a principle investigator for a research study for Biogen Idec Canada; has received honoraria for lectures from EMD Merck Serono Canada, Biogen Idec Canada, Teva Canada Innovation, and Genzyme; has participated/spoken at Advisory Board Meetings of EMD Merck Serono, Teva Canada Innovation, Biogen Idec Canada, Genzyme, and Novartis for which an honorarium and travel support was received to attend the meeting. PD has received support as a consultant, membership on advisory councils, and grants from the pharmaceutical industry. He is funded by the MS Society of Canada, and by the CIHR. HT is funded as a Canada Research Chair and has received research support from the National Multiple Sclerosis Society, the Canadian Institutes of Health Research, and the UK MS Trust and travel expenses to attend meetings or conferences from the Consortium of MS Centres (2013), the National MS Society (2012, 2014), Bayer Pharmaceuticals (2010), Teva Pharmaceuticals (2011), ECTRIMS (2011, 2012, 2013, 2014), UK MS Trust (2011), the Chesapeake Health Education Program, US Veterans Affairs (2012), Novartis Canada (2012), Biogen Idec (2014), American Academy of Neurology (2013, 2014, 2015). BC The Pharmaceutical Outcomes Programme has received Financial support for its pharmacogenomics research to be presented from: Canada Foundation for Innovation, Canadian Institutes of Health Research, Genome Canada, Genome British Columbia and the Provincial Health Services Authority, the University of British Columbia and the Child & Family Research Institute, and Pfizer Canada (unrestricted).

Disclosure KK receives funding from the Canadian Institutes of Health Research (Banting and Best Canada Graduate Scholarship), the Multiple Sclerosis Society of Canada and the University of British Columbia. CR receives funding support from the Canadian Institutes of Health Research, Canadian Foundation for Innovation, Canadian Hearing Foundation, BC Children´s Hospital Foundation, Child & Family Research Institute, Canadian Gene Cure Foundation, Teva Pharmaceutical Industries Inc., Genome BC, CIHR Drug Safety & Effectiveness Network. EK has no disclosures. AT has received grant support from Hoffman la Roche and Sanofi Genzyme; steering committee membership for Hoffman la Roche;

P1126 Influence of ethyl hydrogen fumarate vs. dimethylfumarate on the development of lymphopenia R. Hoepner, S. Faissner, A. Salmen, G. Ellrichmann, K. Strassburger-Krogias, R. Gold, A. Chan Neurology, Ruhr University Bochum, Bochum, Germany Background: Different fumaric acid esters (FAE) are used in the treatment of MS (dimethylfumarate, DMF) or psoriasis (DMF/ ethyl hydrogen fumarates, EHF. FAE treatment leads to reduction of lymphocyte counts. Relative contribution of DMF vs. EHF to reduction of lymphocytes are not investigated.


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Poster Session 2, 21(S11) Methods: This retrospective data analysis was approved by the local ethic committee 4797-13. We investigated white blood cell counts (WBC) and lymphocyte subpopulations from predominantly progressive MS patients (n=38) monocentrically treated with DMF/EHF (Fumaderm®, Bochum cohort) and compared them with respective data from pivotal phase III trials of DMF in MS (DEFINE/CONFIRM cohort). 16/38 patients had a medication history for an immunosuppressive therapy. Seven patients were subsequently swithed to DMF (Tecfidera®). To assess relative contribution of DMF/EHF we calculated a lymphopenia index (LI; lymphocyte count during DMF/EHF- lymphocyte count pre DMF/EHF divided by DMF in mg). Results: Whereas baseline lymphocyte count did not differ between DMF/EHF (Bochum cohort) and DMF treated patients (DEFINE/CONFIRM-cohort), the Bochum cohort demonstrated a stronger lymphocyte reduction within the 1st year starting at week 12 (range: 311-818/µl, each p< =0.05). In the 1st year of DMF/EHF therapy 9/31 patients demonstrated a lymphopenia ⩾ grade 1 (grade2 1/31; grade3 2/31), which increased in the 2nd treatment year (14/20; grade2 7/20; grade3 1/20). Immunosuppressive pre-treatment did not affect lymphocyte counts in DMF/EHF-treated patients. DMF/EHF treatment preferentially affected CD8+ cells with an increased median CD4/ CD8 ratio (baseline 1.4 (interquartile range 1.6), 1st year 2.5 (1.8), 2nd year 3.2 (1.9). LI increased in all patients who switched from DMF/EHF to DMF-monotherapy (median (IQR): -3.17 (5.2) vs. -1 (3.29)). Discussion: FAE appear to differentially affect lymphocyte populations with stronger effects observed with EHF as compared to DMF. Disclosure R Hoepner ([email protected]) received research and travel grants from Biogen Idec and Novartis. Simon Faissner ([email protected]) Simon Faissner received travel grants from Biogen Idec and Genzyme. Anke Salmen ([email protected]) received personal compensation for activities with Novartis, Sanofi and Almirall Hermal GmbH. G Ellrichmann ([email protected]) received speakers or scientific grant support from Biogen, TEVA Pharma, Novartis and Almirall Hermal. K Strassburger-Krogias ([email protected]) reports no disclosures. Ralf Gold ([email protected]) serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis. Andrew Chan ([email protected]) received Consulting fees, speaker honoraria (Almirall, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi, Teva); research support (Biogen Idec, Genzyme, Novartis). Biogen provided mean WBC and lymphocyte counts (SD) from DEFINE and CONFIRM trials.

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P1127 Progressive multifocal leukoencephalopathy presenting with posterior fossa radiological features in the context of natalizumab therapy in relapsing-remitting multiple sclerosis R. Nicholas1, J. Raffel2, O. Malik3 1Neurosciences, Imperial College Healthcare NHS Trust, 2Imperial College, 3Imperial College Healthcare NHS Trust, London, United Kingdom Background: Natalizumab (NTL) is a disease modifying therapy for relapsing-remitting MS. Its use is complicated by the risk of progressive multifocal leukoencephalopathy (PML) secondary to JC virus (JCV) reactivation. Early cases of PML presented as a clinical syndrome in the context of NTL use with high subsequent fatality. The development of a risk management plan based on risk stratification combined with planned MRI scanning allowed early diagnosis. In this context PML presents as an initial change on MRI but the outcome is significantly improved. There is an emerging spectrum of presentations and we present two cases that presented with posterior fossa radiological findings. Case 1: A 48 year old female had received 91 doses of NTL and had an EDSS of 6.0. She had a high JCV index. She presented with a brainstem relapse responding to steroids. MRI brain was stable. She experienced a further brainstem relapse 4 months later. NTL was stopped and Alemtuzumab was being considered. Repeat MRI 5 months later showed cerebellar atrophy with high T2 signal. CSF confirmed 3800 copies of JCV. Case 2: A 38 year old male who had received 48 infusions of NTL with an EDSS of 1.5. He had a high JCV index. He presented with a new brainstem lesion on routine scanning. Neuroradiology review felt this was an MS lesion. NTL was stopped and an LP was normal. 3 months later repeat imaging showed a further enhancing lesion in the brainstem and new characteristic PML changes in the left frontal lobe. Repeat LP showed 350 copies of JCV. Conclusions: We present two cases of posterior fossa presentation of PML. Heightened awareness of the wide variety of presentations of PML radiologically is required to ensure PML is picked up early with a subsequent improvement in clinical outcome. Disclosure Dr Nicholas: Bayer - honorarium for speaking. Biogen - principal investigator, funds for staff, research, organising education, honorarium for speaking, advisory boards. Genzyme - honorarium for speaking, organising education, advisory boards. Merck Serono honorarium for speaking, advisory boards. Novartis - principal investigator, honorarium for speaking, advisory boards. Roche advisory boards. TEVA - principal investigator, funds for research. Dr Raffel: nothing to disclose. Dr Malik: Biogen - funds for staff, research, organising education, honorarium for speaking, advisory boards. Novartis - honorarium for speaking, advisory boards.

P1128 Longitudinal analyses of anti-JCV antibody index as risk assessment for progressive multifocal leukoencephalopathy A. Salmen1, N. von Ahsen2, A.-K. Trampe1, R. Hoepner1, T. Plavina3, M. Subramanyam3, G. Kuesters3, R. Gold1, A. Chan1


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St Josef Hospital, Ruhr University Bochum, Bochum, 2Medizinisches Labor Bremen, Bremen, Germany, 3Biogen, Cambridge, MA, United States Background and objective: Anti-JC-virus (JCV) antibody level (antibody index, AI) has been proposed to further define the risk of natalizumab-associated progressive multifocal leukoencephalopathy (Nat-PML). To validate these results, we investigated longitudinal stability of anti-JCV AI in a natalizumab-treated MS cohort and anti-JCV AI in PML of different etiology. Methods: Anti-JCV AI was determined by STRATIFY JCVTM DxSelectTM in an independent longitudinal German cohort of natalizumab-treated MS patients (Nat-MS, n=468), in samples prior to Nat-PML (pre-PML, n=8), longitudinal Nat-PML (before/ at PML diagnosis, n=5) and in PML of other etiology (at diagnosis - 3.8 months after diagnosis, n=4). All data are presented as median [25.-75. percentile]. Results: Anti-JCV AI showed moderate fluctuation over time (intra-individual coefficient of variation 9.8% [4.8-17.6]) with median AI of 0.9 [0.2-2.9] at the first timepoint. Serostatus change (negative, 36.1% at first time point, to positive) was observed in 11% of this cohort over 7.6 [4.7-12.1] months, however with the majority of patients (n=12 of 19) with an AI ⩽0.9. Seroreversion (positive, 63.9% at first time point, to negative, highest positive AI 0.83) occurred in 4% over 4.6 [2.8-7.1] months, in 9 of 12 patients determined by confirmatory testing after detection of an indeterminate AI (i.e. ⩾0.2, but ⩽0.4). Pre-treatment of any kind was associated with the risk of change in serostatus (OR 4.5 [1.217.2], n=390, p< 0.05, Fisher’s exact 2-sided test). In pre-PML samples (27.5 [18.2-34.4] months prior to PML diagnosis), AI was higher (3.4 [3.1-3.6]) than in seropositive non-PML patients (2.4 [1.0-3.4], n=298, p=0.031). Longitudinal Nat-PML samples before and at diagnosis demonstrated a persistently high AI ⩾3.0. AI remained ⩾3.0 in all but one sample at and after NatPML diagnosis and 3 of 4 PML cases of different etiology. Conclusions: Determination of anti-JCV AI may be superior to mere serostatus in PML risk stratification with persistently high AIs preceeding PML diagnosis over an interval of up to 3 years. However, the best discriminating threshold for a high-risk group still needs to be defined. Although anti-JCV AI shows only moderate fluctuation longitudinally, this may be considered specially in determination of serostatus in patient groups with low AI. Disclosure A. Salmen received personal compensation for activities with Novartis, Sanofi and Almirall Hermal GmbH. N. von Ahsen and A.-K. Trampe report no disclosures. R. Hoepner received research and travel grants from Biogen Idec and Novartis. T. Plavina, M. Subramanyam and G. Kuesters are employees of and/ or hold equity in Biogen. R. Gold received personal compensation for activities with Bayer Healthcare, Biogen Idec and Teva Neuroscience and in an editorial capacity from Therapeutic Advances in Neurological Disorders, and also received patent payments from Biogen Idec and research support from Bayer Healthcare, Biogen Idec, Merck Serono, Teva Neuroscience, Novartis and from the German Ministry for Education and Research (BMBF, “German Competence Network Multiple Sclerosis” (KKNMS), CONTROL MS, 01GI0914).

A. Chan received consulting fees, speaker honoraria (Almirall, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi, Teva); research support (Biogen Idec, Genzyme, Novartis); and research grants from the German Ministry for Education and Research (BMBF, “German Competence Network Multiple Sclerosis” (KKNMS), CONTROL MS, 01GI0914). P1129 Lessons learned from eighteen non-fatal outcomes in natalizumab-associated PML: an evolving therapeutic approach in settings of varied presentations D. Stefoski1, R. Balabanov1, M. Ko1, J. Strong1, A. Javed2 1Rush University Multiple Sclerosis Center, 2Department of Neurology, University of Chicago, Chicago, IL, United States Objective: To analyze the varied presentation, diagnosis, immunostimulation, and management of natalizumab-associated progressive multifocal leukoencephalopathy (na-PML) and subsequent immune reconstitution inflammatory syndrome (IRIS). Patients: We diagnosed and treated 16 patients with na-PML and multiple sclerosis (MS), and diagnosed but not managed another. All were JCV antibody seropositive. Two had prior immunosuppressants. PML was variably suspected by brain MRI or clinical presentation (in 2 patients MRI trailed symptoms), and confirmed in most by JCV PCR in the CSF. In 2 patients diagnosis was by brain biopsy, and in 1 by MRI alone. Method: Patient management was based on the following assumptions for better outcome: 1) early (preclinical) diagnosis of PML by tri-annual brain MRI, 2) immune stimulatory G-CSF accelerates restitution of immune surveillance in and JCV elimination from the CNS, 3) cautious non-immunosuppressing management of IRIS, variably including plasma exchange (PLEX), mefloquin, mirtazapine, corticoids, maraviroc, mannitol and anticonvulsants. Results: At PML diagnosis 4/17 patients were asymptomatic and 13/17 presented with various degrees of impairment including, dysarthria, hemiparesis and ataxia. Sixteen patients received G-CSF with desired leuko- and lymphocytosis, without activating MS. There were no fatal outcomes, but the patient managed elsewhere was lost to detailed follow-up. Recoveries to pre-PML baseline ensued in all 4 asymptomatic and in 3 symptomatic patients. Substantial recoveries evolved in 2 symptomatic patients, resuming their pre-PML activities. The outcomes in 7 remaining symptomatic patients were worse. Follow-up CSF showed viral clearance. Favorable recoveries were associated with asymptomatic/early diagnosis, low viral copies in CSF, effective/early IRIS, and uncomplicated course. They were independent of PLEX, maraviroc, mefloquin and mirtazapine. Conversely, poor recoveries were associated with delayed diagnosis, suppressed and ineffective IRIS, and complicated course. Conclusion: Early, frequent MRIs, administration of G-CSF, and cautious management likely contributed to favorable resolutions of PML/IRIS in 9/17 patients leading to their resuming pre-PML functionality, and likely prevented fatal outcomes in all patients, including those with delayed diagnoses. This approach warrants further exploration.


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Tools for detecting therapeutic response

Disclosure Dusan Stefoski: is a compensated consultant to Biogen. Roumen Balabanov: is a compensated consultant to Biogen. Michael Ko: is a compensated consultant to Biogen. Jennifer Strong: nothing to disclose. Adil Javed: is a compensated consultant to Biogen.

P1130 Real world experience of lymphopenia in MS patients treated with dimethyl fumarate M. Romba1, D. Gallaro2, A. Wundes1, G. von Geldern1 1Neurology, 2University of Washington, Seattle, WA, United States Background: Oral dimethyl fumarate (DMF) was approved for the treatment of relapsing-remitting multiple sclerosis (MS) in the United States in March 2013. Grade 3 lymphopenia (absolute lymphocyte count below 500) developed in about 5 % of patients in the pivotal trials at one point during the study but prolonged lymphopenia over more than 2 years was only seen in 0.6%. Lymphopenia resulting from a fumaric acid ester preparation of DMF used to treat psoriasis has been associated with rare cases of progressive multifocal leukoencephalopathy (PML), an opportunistic central nervous system infection caused by JC virus. A recent case of Progressive Multifocal Leukoencephalopathy (PML) in a MS patient on DMF with sustained lymphopenia raised the concern about lymphopenia in DMF treated MS patients. No data is available to assess if dose reduction of DMF can lead to improvement in lymphocyte counts and it is unclear, if re-challenging a patient after DMF interruption for lymphopenia is safe. Objectives: To assess the prevalence of lymphopenia in patients treated with DMF in a real world setting and to assess the effect of DMF dose reduction on lymphopenia. Methods: We conducted a retrospective chart review of all patients prescribed DMF at our center from and identified 245 patients treated with DMF. Lymphocyte counts and when available CD4 and CD8 subsets were reviwed in addition to clinical history, neurological exams and duration of DMF. Results: In our cohort, 83/245 (34%) MS patients treated with DMF were found to have a reduced lymphocyte count (below 1000). 21/245 (8.5%) patients had lymphocyte counts less than 600 and 14/245 (5.6%) had grade 3 lymphopenia (below 500). Dose reduction of DMF from 480mg to 240mg a day did not lead to significant improvement in lymphocyte counts in our cohort and DMF was eventually discontinued in a large percentage of our patients developing lymphopenia. Conclusions: Lymphopenia poses a problem in the treatment of MS patients with DMF and more studies need to assess the clinical significance and optimal managment of lymphopenia in DMF.

P1131 Predicting treatment response to teriflunomide in the TEMSO study using the modified Rio score M.P. Sormani1, K. Thangavelu2, P. Rufi3, N. DeStefano4 1Biostatistics Unit, University of Genoa, Genoa, Italy, 2Genzyme, a Sanofi company, Cambridge, MA, United States, 3Genzyme, a Sanofi company, Chilly-Mazarin, France, 4Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy Background: TEMSO (NCT00134563) was a 108-week randomized, double-blind, placebo-controlled, parallel-group phase 3 study that assessed the efficacy and safety of teriflunomide, a once-daily oral immunomodulator approved for the treatment of relapsing-remitting MS. In the TEMSO extension (NCT00803049), patients receiving teriflunomide remained blinded and on their original dose while those previously receiving placebo were randomized 1:1 to receive teriflunomide 14 mg or 7 mg. Predictors of long-term disability can be an important disease management tool for a disabling disease such as MS. The modified Rio (mRIO) score system is used to predict treatment response to injectable disease-modifying therapies according to relapse and magnetic resonance imaging outcomes during the first year of treatment. Objective: To predict treatment response to teriflunomide in the TEMSO population using the mRIO score analysis. Methods: In TEMSO, 1086 patients with relapsing forms of MS were randomized and treated with teriflunomide 14 mg, 7 mg, or placebo. After 1 year of teriflunomide, study patients were classified into an mRIO score category for their risk of disease progression: 0=low, 1=intermediate, or 2 or 3=high. Risk of disability progression sustained for 12 weeks was assessed in each category, with a median total follow-up time of 292 weeks. Results: Patients receiving teriflunomide with a computable mRIO score after 1 year of treatment in TEMSO (14-mg and 7-mg groups combined; n=552) were categorized as 0, 63.4% (n=350); 1, 25.9% (n=143); and 2 or 3, 10.7% (n=59) compared with 48.8% (n=139), 32.6% (n=93), and 18.6% (n=53) of patients treated with placebo, respectively. Over 384 weeks from study initiation, the risk of disability progression sustained for 12 weeks in teriflunomide patients in the score 0 category was significantly reduced compared with patients in the score 2 or 3 category (hazard ratio, 2.055; P=0.0021) and showed a trend toward reduction compared with patients in the score 1 category (hazard ratio, 1.351; P=0.0696). The Kaplan Meier estimates of the proportion of patients progressing at end of Year 7 were 39% (score 0), 51.8% (score 1), and 52.2% (score 2 or 3). Conclusions: Results of the mRIO score analysis applied to the TEMSO study population were predictive of long-term treatment effect. Up to 89% of patients receiving teriflunomide were at a lower risk of disability progression over 7 years of follow-up in the TEMSO extension. Disclosure

Disclosure Meghan Romba: Nothing to disclose Deborah Gallaro: Nothing to disclose Annette Wundes: Nothing to disclose Gloria von Geldern: Nothing to disclose

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Study supported by Genzyme, a Sanofi company. MPS: consulting fees from Biogen, Genzyme, Novartis, Merck Serono, Roche, Synthon, and Teva. KT: Employee of Genzyme. PR: Employee of Genzyme.


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ND: has received honoraria from Schering, Biogen-Idec, Teva, Novartis, Genzyme, and Merck Serono S.A. for consulting services, speaking and travel support. He serves on advisory boards for Merck Serono S.A. and Novartis. He has received research grant support from the Italian MS Society. P1132 Alemtuzumab improves disability outcomes versus subcutaneous interferon beta-1a in CARE-MS I and II patients with active relapsing multiple sclerosis using the novel SAD-plus endpoint X. Montalban1, G. Giovannoni2, H.-P. Hartung3, E. Havrdova4, D.H. Margolin5, L. Kasten6, on behalf of the CARE-MS I and CARE-MS II Investigators 1Vall d’Hebron University Hospital, Barcelona, Spain, 2Queen Mary University of London, Barts and The London School of Medicine, London, United Kingdom, 3Heinrich-Heine University, Düsseldorf, Germany, 4First Medical Faculty, Charles University in Prague, Prague, Czech Republic, 5Genzyme, a Sanofi company, Cambridge, MA, United States, 6PROMETRIKA, LLC, Cambridge, MA, United States Background: In the CARE-MS studies with active relapsing-remitting multiple sclerosis (RRMS) patients who were treatment-naive (CARE-MS I; NCT00530348) or had an inadequate response (⩾1 relapse) to a prior therapy (CARE-MS II; NCT00548405), alemtuzumab significantly reduced relapses over subcutaneous interferon beta-1a (SC IFNB-1a). In CARE-MS II, alemtuzumab significantly reduced the risk of 6-month sustained accumulation of disability (SAD) compared with SC IFNB-1a by 42%. In CARE-MS I, alemtuzumab reduced risk of 6-month SAD by 30% versus SC IFNB-1a, but the treatment difference was not statistically significant. Other disability assessments in the CARE-MS studies were the Multiple Sclerosis Functional Composite and Sloan visual acuity. Goals: To examine alemtuzumab efficacy on disability in CARE MS I and II patients using a novel composite endpoint, ‘SADplus’, which may be more sensitive for detecting changes in neurological function than SAD alone. Methods: In the 2-year, phase 3, head-to-head, rater-blinded CARE-MS studies, patients were randomised to receive alemtuzumab 12 mg/day via intravenous infusions on 5 consecutive days at baseline and 3 consecutive days at Month 12 or SC IFNB-1a 44 µg 3 times/week. SAD-plus was defined as 6-month sustained worsening by 20% on Timed 25-Foot Walk or 9-Hole Peg Test, by 7 letters on 2.5% Sloan low-contrast visual acuity, or by SAD (⩾1.0-point Expanded Disability Status Scale [EDSS] increase; ⩾1.5-point if baseline EDSS=0). Results: In this post-hoc analysis, alemtuzumab significantly reduced the risk of disability measured using SAD-plus over 2 years versus SC IFNB-1a in both CARE-MS I (33% risk reduction, P=0.0210) and CARE-MS II (37% risk reduction; P=0.0013). In CARE-MS II, alemtuzumab also significantly reduced the risk of each SAD-plus component outcome versus SC IFNB-1a at Year 2: 6-month SAD (42% risk reduction; P=0.0084), and worsening on Timed 25-Foot Walk (38% risk reduction; P=0.0401), 9-Hole Peg Test (47% risk reduction; P=0.0450) and Sloan (49% risk reduction; P=0.0068). In CARE-MS I, treatment differences for each SAD-plus component favoured alemtuzumab but were not statistically significant.

Conclusion: Analysis using SAD-plus provides further support for alemtuzumab’s superior effect on MS-related disability versus SC IFNB-1a in patients with active RRMS. For treatment-naive patients, SAD-plus and SAD found treatment effects of similar magnitude, but only SAD-plus reached statistical significance. Disclosure Study supported by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. XM: Speaking honoraria and travel expenses for participation in scientific meetings, steering committee member of clinical trials or participation in advisory boards of clinical trials in the past years (Almirall, Bayer, Biogen Idec, EMD, Genentech, Geneuro, Genzyme, Merck, Neurotec, Novartis, Roche, Sanofi, Teva Pharmaceuticals). GG: Compensation for consulting, serving on a scientific advisory board, speaking, or other activities (Biogen Idec, Five Prime Therapeutics, Genzyme, GW Pharma, Merck-Serono, Novartis, Roche, Synthon, Teva, and Vertex Pharmaceuticals); compensation for serving as a journal editor (Multiple Sclerosis and Related Disorders); and research support (Serono). H-PH: Honoraria for consulting and speaking at symposia (Bayer Healthcare, BiogenIdec, CSL Behring, Genzyme, Merck Serono, Novartis, Octapharma, Roche, Teva, and Sanofi, with approval by the Rector of Heinrich Heine-University). EH: Honoraria and consulting fees (Bayer, GlaxoSmithKline, Genzyme, Biogen Idec, Sanofi-Aventis, Merck Serono, Roche, Teva, and Novartis); consulting services, speaking and serving on scientific advisory boards and research support (Czech Ministry of Education). DHM: Employee of Genzyme. LK: Provides statistical support as a consultant for Genzyme. P1133 Fampridine in multiple sclerosis patients: activity on upper limb function evaluated by kinematic analysis C. Solaro1, E. Trabucco1, M. Cella1, C. Proietti1, M. Casadio2, P. Tanganelli1, V. Sanguineti2 1Neurology Unit, Head and Neck Dept., ASL 3 ‘Genovese’, 2Dept. Informatics, Bioengineering, Robotics, Systems Engineering, University of Genoa, Genova, Italy Background: Fampridine (4-aminopyridine) is a potassium channel blocker that can increase action potential duration and amplitude, The medication is able to improve speed walking velocity in a subgroup of Multiple Sclerosis (MS) patients. Objective: The aim of the study is to assess the activity on upper limb function evaluated with a kinematics analysis of Fampridine (FA) in patients with MS. Materials and methods: 29 patients received fampridine (10 mg twice daily) for 2 weeks. Subjects generated isometric force steps with their dominant hand, in one of 6 randomly selected directions on the horizontal plane, and under two conditions: (i) VISION, i.e. subjects could see on a computer screen both the target force and NO VISION, i.e. no monitoring of the instantaneous force. In a second series of experiments, subjects performed planar arm movements (amplitude 10 cm) with an identical experimental design (6 different


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Poster Session 2, 21(S11) directions, two conditions); hand trajectories were sampled by a digitizing tablet. We then estimated the following indicators: reaction time (time between target onset and movement start); path curvature (percent increase of the length of the actual path, relative to the straight line); trajectory smoothness (integral of the norm of the jerk of the hand/force path); movement duration (total, acceleration and deceleration phase) and degree of asymmetry of the speed profile (ratio between the durations of deceleration and acceleration phases); aiming error (difference between target and starting trajectory direction). Kinematic and clinical evaluation at baseline (T0), at the end of treatment (T1) and 2 weeks later (T2). Results: Out of 29 subjects were 13 female and 16 male. Mean age was 51 years, mean disease duration 14 years, 13 (44.8 %) subjects had relapsing remitting, 8 (27.6 %) secondary progressive and 8 (27.6 %) had primary progressive disease course. Regarding kinematic indicator : trajectory smoothness and movement duration were significantly affected by the administration of Fampridine overtime (p < 0.05) both considering the all group and the responders group when evaluating at walking speed. We found a correlation of 9HPT variation and kinematic scores. Conclusion: The study showed an activity of fampridine on upper limb motor performance when evaluated with kinematic analysis. Further studies are needed in order to demostratea efficacy of FA on upper limb function.

Gait Velocity (cm/s), Ambulation time (AT)(s), Distance (cm), Cadence (step/min), Step Lengh Difference (cm), Step Time Difference (s) and Functional Ambulation Profile (FAP). Results: We analysed the data from 38 patients (27 females and 11 males) with an average age of 40,03 years (DS 10,54) at the onset of Fingolimod treatment, the mean duration of MS was 13,42 years (DS 6,89). The mean EDSS before treatment was 4,14 and the EDSS 6 months after the onset of Fingolimod was 3,82. The prior annualized relapse rate was 0,82 and 0,05 after having been administered this drug. We found some STPs that improved with Fingolimod therapy. The mean AT before treatment was 8,55 s and 6 months later it was 7, 52 (p=0,025), mean velocity also improved in 3 months from 91,87 cm/s to 100,97 (p=0,009). The mean FAP at 3 months of therapy was 85,71 and 93,2 at 6 months (p=0,008). We did not find any significant statistical difference between before and after treatment in the rest of STPs nor in any STPs after 3 months of treatment with Fingolimod. Conclusions: This is the first time that a DMT for MS shows an improvement in gait parameters measured by Gaitrite®. In our experience Fingolimod could be an effective therapy for improving the gait profile in our MS patients after 6 months of treatment. Our data shows that we could use some STPs, like velocity, AT y FAP as a markers for disability and disease progression. Gaitrite® is a valid system to evaluate the efficacy of MS therapies in gait disturbances.

Disclosure

Disclosure

Dr. Solaro served as advisory board the following companies: Biogen Idec, Merck Serono. He received speaking honoraria from Bayer Schering, Biogen Idec, Merck Serono, Teva, Almirall, Sanofi Genzyme. He received research grants and support by the FISM (Fondazione Italiana Sclerosi Multipla) Dr. Trabucco, Dr. Cella, Dr, Proietti, Dr Casadio, Dr Tanganelli and Dr. Sanguineti: nothig to disclose

- Eichau, S.: I received speaking and Advisory Board honoraria from Bayer,Biogen Idec, Novartis, Genzyme, Merck Sorono, Almirall and Teva. I also received research projects from all these pharmaceutical companies. - Perez-Sánchez, S.: She received speaking and Advisory Board honoraria from Bayer,Biogen Idec, Novartis, Genzyme, Merck Sorono, Almirall and Teva. She also received research projects from all these pharmaceutical companies. - Escudero-Uribe, S.: He received research projects from Bayer, Biogen Idec, Novartis, Genzyme, Merck Sorono, Almirall and Teva. - Horchsprung A.: She received research projects from Bayer, Biogen Idec, Novartis, Genzyme, Merck Sorono, Almirall and Teva. - Geniz MA.: She received research projects from Bayer,Biogen Idec, Novartis, Genzyme, Merck Sorono, Almirall and Teva. - Navarro-Mascarell G.: He received speaking and Advisory Board honoraria from Bayer,Biogen Idec, Novartis, Genzyme, Merck Sorono, Almirall and Teva. He also received research projects from all these pharmaceutical companies. - Izquierdo-Ayuso, I.: He received speaking and Advisory Board honoraria from Bayer,Biogen Idec, Novartis, Genzyme, Merck Sorono, Almirall and Teva. He also received research projects from all these pharmaceutical companies.

P1134 Gait improvement in multiple sclerosis patients treated with fingolimod S. Eichau, S. Pérez-Sánchez, S. Escudero-Uribe, A. Hochsprung, M.A. Geniz, G. Navarro-Mascarell, G. Izquierdo-Ayuso Multiple Sclerosis Unit at Virgen Macarena Hospital, Sevilla, Spain Background: Gait impairment is one of the most common and disabling symptoms in Multiple Sclerosis (MS) patients. There are many methods to quantify gait disabilities, but we are now using Gaitrite Electronic System® to study the spatiotemporal gait parameters (STPs). Gaitrite is an established and portable gait analysis tool that automatically provides gait data within seconds. Our aim is to analyse the efficacy of Fingolimod treatment improving STPs in MS patients, considering that any disease modifying therapy (DMT) has shown an improvement in gait parameters measured by Gaitrite®. Methods: Retrospective review of Relapsing Remiting MS patients on Fingolimod treatment at the Multiple Sclerosis Unit at Virgen Macarena Hospital, in Seville, Spain. The collected data included baselines and MS characteristics and STPs that were obtained using Gaitrite System® 3 times (before treatment, 3 and 6 months after the onset of treatment). The STPs measured were

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P1135 Antibodies against interferon beta and natalizumab in European multiple sclerosis patients J. Link1, R. Ramanujam1, M. Auer2, S. Hässler3, D. Bachelet3, C. Sievers4, P.E. Hyldgaard Jensen5, C. Warnke6, K. Ingenhoven6, D. Buck7, B. Hemmer7, V. Grummel7, B. Kieseier6, H.P. Hartung6, P. Soelberg Soerensen5, N. Fissolo8, M. Comabella8,


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X. Montalban8, R. Lindberg4, T. Derfuss4, F. Deisenhammer2, C. Mbogning3, P. Broët3, A. Lawton9, J. Davidsson9, P. Dönnes10, A. Fogdell-Hahn1 1Karolinska Institutet, Stockholm, Sweden, 2Innsbruck Medical University, Innsbruck, Austria, 3INSERM, Paris, France, 4University Hospital Basel, Basel, Switzerland, 5Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, 6University of Düsseldorf, Düsseldorf, 7Technische Universität München, Munich, Germany, 8Hospital Universitari Vall d’Hebron, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Barcelona, Spain, 9GlaxoSmithKline R&D, Middlesex, United Kingdom, 10SciCross AB, Skövde, Sweden

Anti-drug antibodies (ADA) are a consequence of the immune systems reaction against biopharmaceuticals and result in a loss of treatment efficacy. The consortium “Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the risk” (ABIRISK) enables access to large cohorts of patients with chronic inflammatory diseases treated with a range of biopharmaceutical products and their anti-drug antibody status. For multiple sclerosis patients, ADA data from 6 countries and 7 sites were gathered by local curators, anonymized, cross-checked by other curators and uploaded into the data base analytics platform TranSMART in collaboration with the EU-consortium eTRIKS. This upload contained 20 696 patients and ADA data from 43 713 samples together with treatment data, treatment duration, ADA assay methods, age and gender. Patients had an average of 2.68 samples analyzed for ADA with a median time of 15 months between the first and last tests. The longest follow up time between the first and last sample in a single patient was 16 years, enabling investigation of ADA fluctuations over time. Women were slightly more likely to be persistently ADA negative (74.6%, n=10,203) when compared with men (72.4%, n=4240). The immunogenicity of the different interferon beta preparations showed agreement with previous findings and confirmed that interferon beta 1a intra muscular was the least immunogenic. A decline in the use of the more immunogenic drugs was observed in three of the larger cohorts and might be a consequence of increased awareness of ADA and greater access to routine ADA analysis methods. Disclosure J Link, D. Bachelet, P. Broët, S. Hässler, P. Dönnes, C. Mbogning, N. Fissolo, K. Ingenhoven: have received funding from ABIRISK. J. Davidson: belong to EFPIA (European Federation of Pharmaceutical Industries and Association) member companies in the IMI JU and costs related to their part in the research were carried by the respective companies as in kind contributions under the IMI JU scheme A. Fogdell-Hahn: have received funding from ABIRISK, Biogen Idec and Pfizer Dr. Deisenhammer: participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Bayer Healthcare, Biogen Idec, Genzyme-Sanofi, Merck, Novartis Pharma, and Teva-Ratiopharm.

A. Lawton, R. Ramanujam, P.E. Hyldgaard Jensen, C. Sievers: Have nothing to disclose D. Buck: has received compensation for activities with Bayer HealthCare, BiogenIdec, MerckSerono, and Novartis and she is supported by the Abirisk Consortium. T. Derfuss serves on scientific advisory boards for Novartis Pharmaceuticals, Merck Serono, Biogen Idec, Genzyme, GeNeuro, Mitsubishi Pharma, Teva Pharmaceuticals and Bayer Schering Pharma; has received funding for travel and/or speaker honoraria from Biogen Idec, Genzyme, Novartis, Merck Serono and Bayer Schering Pharma; and receives research support from Biogen Idec, Novartis Pharma, the European Union, the Swiss National Foundation and the Swiss MS Society. X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall and Roche. M Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, and Novartis. B. Hemmer has served on scientific advisory boards for Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GSK, Chugai Pharmaceuticals, Micromet, Genentech and Genzyme Corporation; serves on the international advisory board of Archives of Neurology and Experimental Neurology; has received speaker honoraria from Bayer Schering, Novartis, Biogen Idec, Merck Serono, Roche, and Teva Pharmaceutical Industries Ltd; and has received research support from Biogen Idec, Bayer Schering, Merck Serono, Five prime, Metanomics, Chugai Pharmaceuticals and Novartis. He has been filed a patent for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and genetic determinants of neutralizing antibodies to interferon-beta. P. S. Sørensen has served on scientific advisory boards for Biogen Idec, Merck Serono, Novartis, Genzyme, Teva Pharmaceutical Industries Ltd., GlaxoSmithKline, medDay Pharmaceuticals and Forward Pharma; has been on steering committees or independent data monitoring boards in clinical trials sponsored by Merck Serono, Teva Pharmaceutical Industries Ltd., and GlaxoSmithKline; and has received speaker honoraria from Biogen Idec, Merck Serono, Teva Pharmaceutical Industries Ltd., Genzyme, and Novartis. His department has received research support from Biogen Idec, Bayer Schering, Merck Serono, TEVA, Baxter, Sanofi-Aventis, BioMS, Novartis, Bayer, RoFAR, Roche, Genzyme, from the Danish Multiple Sclerosis Society, the Danish Medical Research Council, and the European Union Sixth Framework Programme: Life sciences, Genomics and Biotechnology for health. R. Lindberg has received research support from the Swiss MS Society, Swiss National Science Foundation, European FP6 and IMI JU programs, Roche Postdoc Fellowship Program (RPFprogram), unrestricted research grants from Novartis and Biogen. C. Warnke: consultancy, grant support: Novartis, Bayer Schering, ABIRISKK. H.-P. Hartung, B. C. Kieseier: board membership, consultancy, speaking fees, grant support: Novartis, Teva, Biogen, Merck Serono, Bayer Schering, Sanofi-Aventis, Genzyme, ABIRISK The study is supported by ABIRISK.


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Poster Session 2, 21(S11) P1136 Disease activity on individual components of “no evidence of disease activity” (NEDA-4) in young adult patients with relapsing-remitting multiple sclerosis J. Gärtner1, D. Pohl2, A. Ghezzi3, W. Brück4, D. Häring5, G. Karlsson5, N. Putzki5, T. Chitnis6 1Dept. of Pediatrics and Adolescent Medicine, University Medicine, Göttingen, Germany, 2Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada, 3Centro Studi Sclerosi Multipla, Gallarate, Italy, 4Dept. of Neuropathology, University Medicine, Göttingen, Germany, 5Novartis Pharma AG, Basel, Switzerland, 6Partners Pediatric Multiple Sclerosis Centre, Massachusetts General Hospital, Boston, MA, United States Background: Disease activity differs in young patients with relapsing-remitting MS (RRMS) compared with the overall RRMS population. NEDA-4, defined as; 1) no MRI lesion activity, 2) no clinical relapses, 3) no confirmed disability progression (CDP), 4) annual brain volume loss (BVL) < 0.4% (proposed threshold distinguishing RRMS patients from healthy people), provides a comprehensive assessment of disease activity and worsening. Previously, pooled analysis of the FREEDOMS and FREEDOMS II trials favoured fingolimod over placebo in achieving NEDA-4 in young adults aged ⩽30 yrs (15.7% vs 2.8%,odds ratio 6.37;p< 0.001). Understanding drivers of disease activity in young patients was elementary for planning the ongoing paediatric MS study PARADIGMS (fingolimod vs intramuscular interferon β-1a). Objective: To explore drivers of disease activity on individual NEDA-4 components in young adults vs all patients in the placebo arm of the combined FREEDOMS studies. Methods: Post-hoc analysis was performed on the pooled placebo data from FREEDOMS/FREEDOMS II (N=773), and separately in a subset of patients aged ⩽30 years (young adults, N=147). Proportions of patients with T2 lesion activity (new/newly enlarging), relapse, CDP (6-month sustained increase in EDSS score by 1.5 points if baseline score is 0; 1.0 point if baseline score is ⩾1.0 and 0.5 points if baseline score is >5.0) and annualized BVL >0.4% at 24 months were calculated. Results: At 24 months, less than 5% in both the young and overall placebo group achieved NEDA-4. Proportion of placebo patients with T2 lesion activity (86.4% vs 71.9%) and relapses (57.1% vs 48.3%) was higher in young adults vs overall. For annualized BVL the proportions were similar (60.5% vs 60.4%), while CDP was somewhat less frequent in young adults (11.6% vs15.3%). The most frequent mutually exclusive combinations of disease activity in young patients were (⩽30 yrs vs overall): A) T2 lesion activity, relapses and BVL (25.9% vs 20.2%), B) T2 lesion activity and BVL ( 21.1% vs 19.4%) and C) T2 lesion and relapse activity (18.4% vs 9.6%). Conclusion: Disease activity in young patients on placebo was primarily driven by the inflammatory NEDA-4 components. Disability progression tended to be lower in young patients, potentially indicating relatively higher plasticity and regeneration. More than half the patients encountered BVL exceeding rates reported in healthy people suggesting an irreversible disease impact on the CNS irrespective of age.

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Disclosure Funding source: These studies were funded by Novartis Pharma AG. Jutta Gärtner received honoraria and consultancy fees from Bayer Vital, Biogen, Merck Serono, Teva, and Novartis and has received research grant support from Novartis and Biogen Daniela Pohl received personal compensation for activities with Bayer Schering, Merck Serono, and Teva. Angelo Ghezzi received honoraria for speaking from BayerSchering, Biogen Idec, Merck Serono, Novartis, and SanofiAventis; and for consultancy from Merck Serono, Biogen Idec, Teva and Novartis Pharmaceuticals. Wolfgang Brück received personal compensation for lectures by Bayer Vital, Biogen Idec, Merck Serono, Teva Pharma, Genzyme, Sanofi-Aventis and Novartis. He is a member of scientific advisory boards for Teva Pharma, Biogen Idec, Novartis and Genzyme. He receives research support from Teva Pharma, Biogen Idec, Genzyme and Novartis. He serves on the editorial boards of Neuropathology and Applied Neurobiology, Multiple Sclerosis International and Therapeutic Advances in Neurological Disorders Tanuja Chitnis received personal compensation for advisory boards/consulting for Alexion Pharmaceuticals, Biogen Idec and Novartis Pharmaceuticals and financial support for research activities from Merck Serono and Novartis Pharmaceuticals. Goeril Karlsson, Dieter Häring, and Norman Putzki are employees of Novartis Pharma AG. P1137 Relevance of time 25 foot walk test to assess the effectiveness of dalfampridine C. Donzé1, M.-A. Guyot1, O. Agnani1, P. Hautecoeur2, H. Khenioui1 1Physical Medecine and Rehabilitation Departement-CH Saint Philibert-Lille France, 2Physical Medecine and Neurology Department-CH Saint Philibert-Lomme, France, GH-ICL, Lomme, France Introduction: Dalfampridine ® is indicated in gait disorders for patients with multiple sclerosis (MS). In princeps studies, number of patients “responders” on the walk test was 42.9%. Objective: Determine the relevance of Time 25 Foot Walk Test (T25 FWT) to assess the effectiveness of treatment. Methods: A retrospective review of prospectively collected data was conducted in patients with MS. The effect of Dalfampridine was evaluated after 14 days of treatment with T25FWT. Fatigue was measured using the EMIF -SEP questionnaire and spasticity with digital validated scale (NRS). The differences between responders (R) (T25FWT> = 20%) and non-responders (NR) have been studied. (Student t test, p < 0.05). Results: Between April and October 2013, 134 patients (age: 54 ± 18, 6; median EDSS 6) who take Dalfampridine were evaluated and divided into 2 groups: R: 91 (67.9%); NR: 44 (32.6%). T25FWT Non-responders have a fatigue score (EMIF-MS) significantly lower (52.4 ± 21.8% vs 61.3 ± 18.7%; p < 0.05), a less spasticity score (NRS) [5 (min: 0, max: 10) vs 7 (min: 0, max 10)] and lower EDSS (p < 0 .001).


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Discussion: Variability in EDSS scores corresponding to the treatment indication (4-7) significantly varies speed walking. Patients with less disability (less than 5.5) can’t improve their rate of 20%. Other more sensitive tests could be offered such as the 2 minutes walk test and / or analysis of spatiotemporal gait parameters. Conclusion: The choice of walking assessments in MS patients is paramount to objectively assess the effect of this treatment and depends on the level of disability. Disclosure All authors have nothing to disclose

P1138 Cross-reactivity of anti-interferon beta antibodies against different interferons beta and interference of their presence in the JAK-STAT signalling pathway in multiple sclerosis patients I. Hurtado-Guerrero1, M.J. Pinto-Medel1, C. Marin-Bañasco1, A. Gallardo2, M. Suardiaz1, F. Diez de Baldeón2, O. Fernández2, B. Oliver-Martos1 1Research Laboratory, Institute of Clinical Neurosciences, HRU de Málaga, 2Department of Neurology, Institute of Clinical Neurosciences, HRU de Málaga, Malaga, Spain Introduction and objective: The occurrence of neutralizing antibodies (NAbs) against administered IFNβ has been reported. Their assessment during IFNβ therapy is recommended since it allows early identification of a subset of non-responders patients. Our research laboratory has more than 15 years experience in determining NAbs in Spain and Portugal. It is known that cross-reactivity of NAbs against different IFNβ preparations occurs due to the great structural similarity. Our aim was to analyze the cross reactivity of NAbs titers in a cohort of NAbs positive MS patients and to corroborate if these NAbs are able to interfere in the JAK-STAT signalling pathway. Methods: NAbs were detected by a cytopathic effect test, following the WHO recommendations. A subset of 88 patients NAbs+ were selected from our serum bank, comprising more than 900 samples from MS patients under IFNβ treatment, to analyze cross-reactivity against two IFNβ-1a and one IFNβ-1b. Aditionally, peripheral blood mononuclear cells from 8 patients were in vitro stimulated with three different IFNβ, in the presence of their autologous NAbs+ serum and in presence of a NAbs- serum, to assess phosphorylated STAT1 by flow cytometry in T cells and monocytes. Results: Of the 88 NAbs+ patients, 33% had low titers of NAbs (< 100 TRU), 10.2% had intermediate titers (>100 and < 300 TRU) and 56.8% had high titers (>300 TRU). Cross-reactivity between the different IFNβ was observed in 100% of patients with high titers, in 88% of intermediate titers and in 37% of low titers (p< 0.0001). The mean fluorescence intensity (MFI) of pSTAT1 in T cells and monocytes after stimulation with different IFNβ in presence of NAbs+ serum was significantly lower than after stimulation with IFNβ and without serum (p= 0.029). This inhibition of pSTAT1 was not observed in the presence of NABs- serum. Moreover, we have observed a significant decrease of the percentage of pSTAT1expressing cells proportional to NAbs titers.

Conclusion: A strong cross-reactivity was observed in all the patients with high titer of NAbs. NAbs developed against one IFNβ preparation are able to react with other IFNβ preparations not used in the therapy and to inhibit the activation of pSTAT1 in vitro. Disclosure O. Fernández: has received honoraria as consultant in advisory boards, and as chairman or lecturer in meetings, and has also participated in clinical trials and other research projects promoted by Almirall, Actelion, Allergan Bayer-Schering; Biogen-Idec, Novartis, Merck-Serono, Roche and Teva. I. Hurtado-Guerrero: nothing to disclose. M.J. Pinto-Medel: nothing to disclose. C. Marin-Bañasco: nothing to disclose. A. Gallardo: nothing to disclose. M. Suardiaz: nothing to disclose. F. Diez de Baldeón: nothing to disclose. L. Leyva: nothing to disclose. B. Oliver-Martos: nothing to disclose.

P1139 Baseline MxA expression as a biomarker of treatment response in multiple sclerosis patients treated with interferon β E. Matas1, L. Bau1, M. Martínez-Iniesta2, L. Romero-Pinel1, M.A. Mañé-Martínez1,3, A. Cobo-Calvo1, S. Martínez-Yélamos1 1Multiple Sclerosis Unit, Neurology Department, Hospital Universitari de Bellvitge-IDIBELL, 2Translational Research Laboratory, Institut Català d’Oncologia-IDIBELL, L’Hospitalet de Llobregat, 3Department of Neurology, Hospital Universitari Joan XXIII, Universitat Rovira i Virgili, Tarragona, Spain Background: Myxovirus resistance protein A (MxA) is a molecule induced after interferon β injection, mostly used to evaluate its bioactivity. Previous results show that baseline MxA mRNA expression could predict relapses in multiple sclerosis patients treated with interferon β. The objective of the study is to investigate whether differences depending on the type of interferon used could be found. Methods: Baseline blood samples were obtained before the first interferon β dose was administered to evaluate MxA mRNA expression using real-time polymerase chain reaction (PCR). Demographic and clinical variables were prospectively recorded to define treatment responder and non responder groups. Patients were pooled in two groups depending on the type of interferon β used: β-1a and β-1b. Results: 104 patients were included in the study. Previously reported results determined a threshold of 1.096 for baseline MxA mRNA expression using Receiver Operating Characteristic analysis to differentiate between responders and non responders (sensitivity 73.9%, specificity 69.0%). Survival analysis of the whole population of the study using this threshold showed that time to next relapse was significantly higher in patients with lower MxA titers (percentile 75, low-MxA 2.14 vs high-MxA 0.4; p< 0.0001). No differences were found depending on the type of interferon used: time to next relapse was longer in low-MxA patients treated with interferon β-1a (62 patients) (percentile 75, low-MxA 0.94 vs high-MxA 0.35; p=0.007) and interferon β-1b


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Poster Session 2, 21(S11) (42 patients) (percentile 75, low-MxA undefined vs high-MxA 0.63; p< 0.0001). Conclusion: The results suggest that baseline MxA mRNA levels may be useful for predicting whether multiple sclerosis patients will respond or not to interferon β treatment, independently of the type of interferon used. Disclosure E. Matas received honoraria from speaking engagements from Biogen, Teva and Merck Serono, research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer Schering Pharma and Merck Serono. L. Bau received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer Schering Pharma and Merck Serono. M. Martínez-Iniesta: nothing to disclosure. L. Romero-Pinel received honoraria from speaking engagements from Biogen, Teva and Merck Serono, research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer Schering Pharma and Merck Serono. MA. Mañé-Martínez received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer Schering Pharma and Merck Serono. A. Cobo-Calvo, received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Novartis, Bayer Schering Pharma and Merck Serono. S. Martínez-Yélamos received honoraria from speaking engagements, served on a scientific advisory board, collaborates as a consultant and scientific communications and received funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries LTD, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma. P1140 The regulatory/activated CD4+ T-cell ratio in peripheral blood predict response to fingolimod in multiple sclerosis patients L.M. Villar Guimerans1, C. Picon1, S. Sainz de la Maza1, E. Rodriguez-Martin1, M. Espiño1, A. Bermejo1, C. de Andres2, Y. Aladro3, J.C. Alvarez-Cermeño1 1Hospital Ramon y Cajal, 2Gregorio Marañon Hospital, 3Hospital de Getafe, Madrid, Spain Background: Multiple sclerosis (MS) is an heterogeneous disease and the response to different therapies varies in individual patients. Our aim was exploring the cell subsets that could identify optimal responders to Fingolimod, an oral therapy for MS, which inhibits cell expression of Sphingosine-1-PhosphateReceptor 1 and thereby inhibits the egress of lymphocytes from lymph nodes. Methods: We prospectively studied 62 patients treated with fingolimod in three university hospitals. Peripheral blood was collected before treatment and 6 months later. We studied different T, B, NK, and monocyte subsets at the two time points by flow

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cytometry . We monitored response to treatment by measuring clinical and radiological activity during 2 years. No evidence of disease activity (NEDA) was defined as not having new relapses or disability worsening during follow-up, or new lesions on annual MRI scans. Results: 32 patients (51,6%) showed NEDA during follow-up. Before treatment, they had higher percentages of NKT+ perforin + cells (p=0.01). After 6 months of therapy, all patients showed a decrease in T and B cells. However, those that were going to have NEDA showed an increase in the proportion of regulatory T cells (p=0.01). Differences were higher when we compared the ratio between regulatory and activated CD4+ T cells. It was elevated in NEDA patients compared to those with suboptimal response (0.28 ± 0.02 vs 0.14 ±0.03, mean±SEM, p=0.001.). We established a cut-off of 0.17 for this ratio that allowed us to identify patients with a high probability of remain with NEDA upon Fingolimod treatment (OR=7.8; CI:2.3-25.47;p=0.0005). Conclusions: Our results suggest that regulatory/activated CD4 ratio can identify patients who will develop an optimal response to fingolimod. Disclosure Luisa Maria Villar received payment for speaking, research, travel expenses or grants from Merck Serono, Biogen, Genzyme, Teva, Novartis Carmen Picón: nothing to disclose Susana Sainz de la Maza received payment for speaking, research, travel expenses or grants from Merck Serono, Biogen, Genzyme, Teva, Novartis Eulalia Rodriguez-Martin: nothing to disclose Mercedes Espiño: nothing to disclose Aida Bermejo: nothing to disclose Clara de Andrés: received payment for speaking, research, travel expenses or grants from Merck Serono, Biogen, Genzyme, Teva, Novartis Yolanda Aladro:received payment for speaking, research, travel expenses or grants from Merck Serono, Biogen, Genzyme, Teva, Novartis Jose Carlos Alvarez-Cermeño:received payment for speaking, research, travel expenses or grants from Merck Serono, Biogen, Genzyme, Teva, Novartis P1141 Lymphocyte subsets changes as biomarker of therapeutic response in Fingolimod treated relapsing MS M. D’Onghia1, D. Paolicelli1, C. Tortorella1, V. Direnzo1, P. Iaffaldano1, S. Zoccolella1, A. Manni1, V. Di Lecce1, G. Specchia2, M. Trojano1 1Basic Medical Sciences, Neurosciences and Sense Organs, 2University of Bari, Bari, Italy Background: The scenario of Multiple Sclerosis (MS) therapies is constantly evolving. Therefore the identification of potential biomarkers for therapeutic response can be useful in clinical practice. Objectives: To correlate lymphocyte count (LC) and changes in lymphocyte subsets with treatment response in a cohort of 119 Fingolimod (FTY) treated relapsing MS patients.


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Methods: LC and lymphocyte subsets (CD3+, CD4+, CD8+, CD56+, CD19+) were assessed at the start of FTY treatment (T0) and after 6 and 12 months of therapy (T6 and T12, respectively) by flow cytometry. Brain and spinal cord MRI and neurological examination were performed at baseline and every 6 months. Occurrence of relapses, new T2- or Gadolinium positive (Gd+) lesions were recorded during the first and the second semester of treatment. Simple and multivariate logistic regression models, adjusted for age and sex, were used for the analyses. Results: One-hundred and nineteen patients (69% female; mean age: 38.3±9 years) were followed-up for six months, and 89 of them for 12 months. During the first 6 months of therapy, a higher number of CD3+ (OR 1.003 IC 95% 1-1.005, p=0.04) and CD8+ (OR 1.005 IC 95% 1-1.010, p=0.06) and a lower number of CD56+ (OR 0.99 IC 95% 0.98-1, p=0.04) were predictive of a higher incidence of relapses, a lower change (Δ) of CD4+ between T0-T6 was associated with an increased risk of new T2-lesions (OR -1.002 IC 95% 1-1.004, p=0.04) and a lower Δ of total LC (OR 1.005 IC 95% 1.001-1.008, p=0.007), CD3+ (OR 1.006 IC 95% 1.002-1.011, p=0.005) and CD8+ (OR 1.007 IC 95% 1.0021.012, p=0.009) were associated with the occurrence of Gd+ lesions. Moreover in the subgroup of patients followed-up to 12 months, the Δ of total LC (OR 1.004 IC 95% 1-1.008, p< 0.05) and CD8+ (OR 1.009 IC 95% 1.001-1017, p=0.02) between T6-T12 predicted the occurrence of Gd+ lesions. ROC curves (Area under the curve, AUC>0.7) enabled to identify cut-off values of CD3+ and CD8+ (262/ul and 123/ul, respectively, p< 0.05) predicting a higher risk of relapses during the first 6 months and a cut-off value of total LC (571/ul, p< 0.05) predicting the occurrence of MRI Gd+ lesions at 12th month of therapy. Conclusion: Our study demonstrated the potential role of lymphocyte subsets changes as biomarker to early identify FTYtreatment response. Further studies will be necessary to verify the accuracy and reproducibility of our results. Disclosure D’Onghia M. received personal compensation for activities by TEVA. Paolicelli D. received honoraria for consultancy and/or speaking from Biogen Idec, Merck-Serono, Bayer - Schering, SanofiAventis, TEVA, Novartis and Genzyme. Tortorella C. received honoraria for consultancy and/or speaking from Biogen Idec, Merck-Serono, BayerSchering, SanofiAventis, TEVA, Novartis and Genzyme. Direnzo V. received personal compensation for activities by TEVA. Iaffaldano P. has served on scientific advisory boards for Biogen Idec, and has received funding for travel and/or speaker honoraria from Sanofi-Aventis, Biogen Idec, Teva and Novartis Trojano M. received honoraria for consultancy or speaking from Biogen, SanofiAventis, Merck Serono, Novartis, Genzyme, TEVA, and Bayer-Schering and research grants from Merck Serono, Biogen, and Novartis. Zoccolella S, Specchia G, Manni A and Di Lecce V have nothing to disclose. P1142 Predictive value of early MRI measures for long-term disease activity in patients with relapsing-remitting

multiple sclerosis receiving IFN β-1a SC tiw or IFN β-1a IM qw: post hoc analyses of the EVIDENCE study P.K. Coyle1, M.S. Freedman2, F. Dangond3, J. Fang3, A.T. Reder4 1Stony Brook University Medical Center, Stony Brook, NY, United States, 2University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada, 3EMD Serono, Inc., Rockland, MA, 4University of Chicago, Chicago, IL, United States Background: In EVIDENCE, patients with relapsing-remitting multiple sclerosis (RRMS) were randomly assigned to interferon beta-1a (IFN β-1a) 44 µg subcutaneously (SC) three times weekly (tiw; n=339) or IFN β-1a 30 µg intramuscularly (IM) once weekly (qw; n=338). Goals: To examine the early differences in magnetic resonance imaging (MRI) results between IFN β-1a treatments and the predictive value of early MRI lesions for later ‘disease activity free’ outcomes in patients with RRMS. Methods: T2 and pre-/post-contrast T1 scans were performed at screening, Study Day 1, and every 4 weeks through Week 24, with additional T2 scans at Weeks 48 and 72. This post hoc analysis assessed whether early lesions predicted no evidence of disease activity (NEDA) status at Week 48 (clinical activity free [CAF], defined as no relapses or 12-week confirmed disability worsening [⩾1 point increase in Expanded Disability Status Scale score]) by Week 48 and no new/enlarging T2 lesions from Week 24-48) and Week 72 (CAF by Week 72 and no new/enlarging T2 lesions from Week 48-72). Results: Compared with IFN β-1a IM qw, IFN β-1a SC tiw was associated with significantly fewer mean gadolinium enhancing (Gd+) lesions/patient/scan by Week 8 (1.34 vs 0.79, respectively; p=0.002). A greater proportion of patients receiving IFN β-1a SC tiw versus IFN β-1a IM qw had NEDA at Week 48 (44% vs 32%, respectively; p=0.003) and Week 72 (34% vs 19%, respectively). Absence (vs presence) of baseline Gd+ lesions was associated with higher percentages of patients reaching NEDA at Week 48 both in the IFN β-1a SC tiw (54.4% vs 34.1%; p=0.005) and IFN β-1a IM qw (43.4% vs 22.4%; p< 0.001) groups. Similarly, absence (vs presence) of Gd+ lesions at Week 8 was associated with higher percentages of patients reaching NEDA at Week 48 both in the IFN β-1a SC tiw (49.5% vs 22.5%; p< 0.001) and IFN β-1a IM qw (38.5% vs 19.0%; p=0.004) groups; absence (vs presence) of Gd+ lesions at Week 8 was also associated with a higher proportion of patients reaching NEDA at Week 72 both in the IFN β-1a SC tiw (38.8% vs 18.5%; p=0.008) and IFN β-1a IM qw (24.7% vs 9.6%; p=0.019) groups. Conclusions: Patients treated with IFN β-1a SC tiw had significantly fewer lesions versus those treated with IFN β-1a IM qw as early as Week 8 and also had a higher likelihood of achieving future NEDA status. Early MRI disease activity was predictive of long-term NEDA status. Disclosure P.K. Coyle: has received consulting fees from AbbVie, Accordant, Acorda, Bayer, Biogen, EMD Serono, Inc., Genentech/Roche, Genzyme/Sanofi, Mylan, Novartis, and Teva Pharmaceuticals, and has received fees for contracted research with Actelion, Genzyme/Sanofi, Novartis, and Opexa.


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Poster Session 2, 21(S11) M.S. Freedman: has received personal compensation from Novartis, Teva Canada Innovation, Sanofi-Aventis, Bayer HealthCare, Biogen, EMD Serono (Canada), Genzyme, and Opexa, and has received research support from Bayer HealthCare. F. Dangond and J. Fang: are employees of EMD Serono, Inc., Rockland, MA, USA (a subsidiary of Merck KGaA, Darmstadt, Germany). A.T. Reder: has received consulting fees from Acorda, Bayer, Biogen, EMD Serono, Inc., Genzyme, Novartis, Pfizer, Malinkrodt, Sanofi, and Teva Pharmaceuticals. Study supported by EMD Serono, Inc., Rockland, MA, USA and Pfizer Inc, New York, NY, USA.

Disclosure

Others

Background: Plasmapheresis is recommended treatment of multiple sclerosis (MS) relapse not responding to corticosteroid therapy. Low number of cohorts of patients with relapse remitting MS has been published. Therefore we present data from clinical experience of our centre. Objectives: To present a cohort consisting of relapse remitting MS patients who received course of plasmapheresis as treatment for acute MS relapse not responding to corticosteroids. Methods: All patients treated with plasmapheresis for acute MS relapse or clinically isolated syndrome (CIS) after corticosteroids and cyclophosphamide failure in MS Centre of General University Hospital in Prague, Czech Republic, between July 2008 and February 2015 were included in this retrospective study. Demographic and clinical data were obtained from patient records. Results: 19 patients (17 patients with relapse remitting MS and 2 patients with CIS) were included into the study, 14 (74%) were females. Mean age was 31.1 years (range 18.2-62.2), mean disease duration was 6.6 years (range 0.6-15.6). Mean Expanded Disability Status Score (EDSS) before relapse was 2.66 (range 0-6.5) and 4.77 (range 2-7) during relapse. Relapse types were represented as follows: 7 pyramidal, 6 optic neuritis and 6 multisymptomatic. Mean dose of corticosteroids administered was 4.55 g, 3 patients also received 1 g of cyclophosphamide. Mean time between relapse onset and plasmapheresis course initiation was 43.9 days (range 7-161), number of plasmapheresis cycles performed in every patient was 6.1 (range 4-7). According to treating physician evaluation plasmapheresis course was moderately or markedly efficient in 13 (68%) cases, 1 patient worsened. None or mild effect was achieved in 7 (37%) cases, including 3 patients that had received cyclophosphamide. However, improvement of EDSS by the end of plasmapheresis course was only achieved in 9 (47%) cases. 7 of these patients remained stable or further improved during 6 months following plasmapheresis. No serious adverse event of plasmapheresis was observed. Conclusions: We present a coherent cohort consisting of relapse remitting MS patients that were treated with plasmapheresis for acute MS relapse not responding to corticosteroids treatment. Based on our data, we consider plasmapheresis to be efficient and safe treatment of acute MS relapse nonresponsive to corticosteroids.

P1143 Demonstration of equivalence between Glatopa™ and Copaxone® J. Anderson, T. Ganguly, I. Capila, C. Bell, J. Prescott, J. Lansing, J. Glajch, R. Sachleben, M. Iyer, J. Bishop, G. Kaundinya Momenta Pharmaceuticals, Cambridge, MA, United States Objectives: To summarize the comprehensive evaluation of equivalence between Copaxone® 20 mg and a generic version, Glatopa™. Background: Glatopa is the first FDA-approved, substitutable generic version of Copaxone 20 mg (glatiramer acetate [GA] injection). GA is a mixture of synthetic polypeptides manufactured from 4 amino acids: alanine, lysine, glutamic acid, and tyrosine. It is produced entirely through chemical processes with standard starting materials in a predictable and reproducible reaction. This presentation summarizes the framework Momenta utilized to evaluate equivalence between the products as part of the Abbreviated New Drug Application to the US FDA. Design and methods: Equivalence between Glatopa and Copaxone was evaluated in several categories: 1) starting materials and basic chemistry; 2) manufacturing process (polymerization, depolymerization, and purification); 3) physicochemical properties (e.g., multiple methods for amino acid composition, molar mass distribution, N- and C-terminal analysis, peptide/acetate ratio, potency, etc.); biological and immunological properties (e.g., multiple 4) molecular, cell based, and in vivo assays for T cell, B cell, and APC biology; experimental autoimmune encephalitis [EAE] models; gene expression profile; etc.). Results: No differences were observed in the structure and function of Glatopa and Copaxone. Equivalence of physicochemical properties was demonstrated across >45 tests using a variety of methods for characterization (e.g., amino acid analysis, NMR, SEC, ELISA, HPLC, LC-MS, CD, Western Blot, etc.). Equivalence of biological properties was demonstrated across >15 assays including efficacy in three EAE models, immunogenicity studies, and gene expression profiling. Conclusions: Momenta showed Glatopa and Copaxone to be equivalent using a comprehensive set of physicochemical (structural) and biological (functional) assays.

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All authors are employees of Momenta Pharmaceuticals, Inc. P1144 Plasmapheresis as relapse treatment in relapse remitting multiple sclerosis: single centre experience P. Kleinova, J. Pavlickova, D. Horakova, E. Havrdova Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, First Faculty of Medicine and General University Hospital, Praha, Czech Republic

Acknowledgmets The project was supported by Czech Ministry of Education, PRVOUK-P26/LF1/4.


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Disclosure

Disclosure

Dr. Kleinova received travel compensation and speakers honoraria from Biogen Idec, Merck Serono, Novartis and Teva. Dr. Pavlickova received travel compensation from Biogen Idec. Dr. Horakova received compensation for travel, speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck Serono, Bayer Shering, Genzyme, and Teva, as well as support for research activities from Biogen Idec. Dr. Havrdova received speaker honoraria and consultant fees from Biogen Idec, Merck Serono, Novartis, Genzyme and Teva, as well as support for research activities from Biogen Idec and Merck Serono.

Study supported by Genzyme, a Sanofi company. TZ: Compensation for consulting services (Almirall, Bayer, Biogen Idec, Genzyme, GlaxoSmithKline, MSD, Merck Serono, Novartis, Sanofi, Synthon, and Teva); financial support for research activities (Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi, and Teva). AL: Compensation as an employee (Sanofi Aventis). SJ: Compensation as an employee (Genzyme). RK: Compensation for consulting services (Teva, Bayer Healthcare, Genzyme, Biogen Idec, and Novartis). UE: Compensation as an employee (Genzyme).

P1145 TREAT-MS: design and baseline characteristics of a noninterventional study to establish effectiveness, quality of life, cognition, health-related, and work capacity data on alemtuzumab in multiple sclerosis patients in Germany T. Ziemssen1, A. Leptich2, S. Jahn3, R. Kern1, U. Engelmann3, on behalf of the TREAT-MS Study Group 1Center of Clinical Neuroscience, Carl Gustav Carus University Hospital, Dresden, 2Clinical Study Unit, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, 3Medical Affairs, Genzyme GmbH, Neu-Isenburg, Germany

P1146 MS Italian patients manifesting natalizumabrelated PML between 2009 and 2014. Report of the Italian group for MS-PML study N. De Rossi1, C. Cordioli1, S. Gerevini2, M.P. Amato3, F. Bandini4, P. Cavalla5, M. Clerico6, M. Capobianco7, L. Deotto8, M.A. De Riz9, E. Ferrari10, C. Scarpazza1, M.L. Fusco11, A. Ghezzi12, L. Grimaldi13, A. Lugaresi14, L. Moiola15, P. Perrone16, L. Prosperini17, M. Rezzonico18, M. Rovaris19, G. Salemi20, M. Salvetti21, G. Santuccio22, C. Solaro23, C. Tortorella24, R. Capra1 1Regional Multiple Sclerosis Center, Presidio di Montichiari, Spedali Civili di Brescia, Brescia, 2Dipartimento Testa Collo Servizio di Neuroradiologia Ospedale San Raffaele, Milano, 3Department NEUROFARBA Section Neurosciences, Firenze, 4S.C. Neurologia Ospedale San Paolo, Savona, 5Centro SM, Dipartimento di Neuroscienze A.O.U. Città della Salute e della Scienza di Torino V, 6Torino University Researcher AOU San Luigi Gonzaga Orbassano, Torino, 7CRESM, c/0 AOU, Orbassano, 8Azienda Ospedaliera Universitaria Integrata di Verona Dipartimento ad attività integrata di Neuroscienze Unità Operativa Complessa di Neurologia A, Verona, 9Centro Sclerosi Multipla Padiglione Monteggia-IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, 10Centro Ospedaliero Cremonese, Divisione di Neurologia, Cremona, 11Department of Neurology, S.Gerardo Hospital and DNTB, University of Milano Bicocca, Monza, 12Direttore Neurologia 2 - Centro Studi Sclerosi Multipla, Azienda Ospedaliera ‘S. Antonio Abate’, Gallarate, 13Fondazione Istituto San Raffaele ‘G. Giglio’, Contrada Pietrapollastra s.n.c., Cefalù, 14Dipartimento di Neuroscienze, Università G. D’Annunzio, Imaging e Scienze Cliniche, Chieti, 15Dipartimento di Neurologia, Ospedale San Raffaele, 16Direttore Dipartimento Neuroscienze e U.O. Neurologia-Stroke Unit A.O. Ospedale Civile di Legnano via Papa Giovanni Paolo II, Legnano, Milano, 17Department of Neurology and Psychiatry, Sapienza University, Roma, 18AO S.Anna Como è in via Ravona 2 S.Fermo della Battaglia, Como, 19UO Riabilitazione Neuromotoria - Centro Sclerosi Multipla, IRCCS Santa Maria Nascente, Fondazione Don Carlo Gnocchi, Milano, 20Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche Università di Palermo, Palermo, 21Centre for Experimental Neurological Therapies (CENTERS), Neurology and Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University S. Andrea Hospital-site Rome, 22UO Neurologia, Ospedale Civile via Stelvio, Roma, 23Department of Head and Neck Neurology Unit ASL3 Genovese, Genova, 24Department of Basic Medical

Background: Alemtuzumab, a humanised monoclonal antibody, is licensed in Germany since October 2013 as treatment for patients with active relapsing-remitting multiple sclerosis (RRMS). In 2-year phase 3 studies, alemtuzumab had superior efficacy as compared to subcutaneous interferon beta-1a and durable efficacy over 4 years in an extension study with manageable safety in RRMS patients. Goals: To report on the study design and baseline characteristics of enrolled patients in TREAT-MS: a non-interventional longTerm study foR obsErvAtion of Treatment with LEMTRADA® in active RRMS. Methods: This noninterventional effectiveness study is a prospective treatment with alemtuzumab in approximately 3000 RRMS patients from neurological clinics and practices. Planned recruitment is until end of 2016. The study comprises a 5-year observation period. The following instruments will be used: Patient-Reported Outcome Indices for Multiple Sclerosis (PRIMUS), EuroQoL EQ-5D™, Work Productivity and Activity Impairment (WPAI), and Symbol Digit Modalities Test (SDMT). The Multiple Sclerosis Documentation System (MSDS) Project Development Group in Dresden adapted the patient-management software, MSDS3D, for use in this study. TREAT-MS will also fulfil a quality assurance function. Risk-management plan (RMP) measures such as monitoring for thyroid disorders, immune thrombocytopenia and nephropathies, and regular laboratory tests/urinalyses are represented in TREAT-MS and integrated into MSDS3D. Results: Study enrolment began in October 2014 and 80 patients have been enrolled to date. First baseline characteristic data will be presented. Conclusion: Implementation of RMP and perspective documentation of efficacy/safety data are combined in the TREAT-MS study.


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Poster Session 2, 21(S11) Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy Objective: To describe the progressive multifocal leukoencephalopathy (PML) and immune reconstitution inflammatory syndrome (IRIS) course, treatment and outcomes and to describe the features of epileptic seizures. Design and methods: clinical and neuroradiological data of 34 MS patients who manifested natalizumab-related PML from November 2009 to December 2014 were obtained from 25 Italian Multiple Sclerosis (MS) Centres and analyzed in the current work. Results: 29/34 patients survived to PML. 3 patients died within 6 months from the PML insurgence due to JC virus (JCV) brain infection and 2 patients died within 3 years due to long term bed immobility. PML disability peak was observed at the 6th month (mean EDSS increases of 1.2 points compared to the time of PML insurgence) and, at one year follow up, the mean EDSS still was 0.7 points higher compared to the time of insurgence. 29 patients were positive to JCV antibodies (the data is not available yet for 5 patients); higher number of CSF virus copies was related to the worse clinical course or death. Lower MRI lesion widening and monofocal presentation were related to a better clinical evolution, except for the subtentorial lesion locations. 19/34 patients manifested IRIS and a subacute clinical worsening in the first 5 months after PML onset; 15 out of the above 19 patients were treated with intravenous steroids with clinical improvement. Epileptic seizures were observed in 10/34 patients (29.5%), 2 of them at PML onset, 5 during IRIS and 3 after PML recovery. 2 patients were presenting with generalized tonic-clonic seizures, 1 with status epilepticus and 7 with focal attacks. Drugs showed poor efficacy during the acute phase of epilepsia, however their efficacy improved over time. Conclusions: Most of patients survived to PML but manifested a slightly long term worsening of their clinical condition. Steroid treatment of IRIS might reverse the IRIS-related disability increment. Epileptic seizures were commonly observed in PML and a progressive improvement of pharmacological response can be expected during the follow-up. Disclosure Nicola de Rossi: nothing to disclose. Cinzia Cordioli: nothing to disclose. Simonetta Gerevini: nothing to disclose. Maria Pia Amato has received research Grants and honoraria as a speaker and member of advisory boards by Biogen Idec Merk Serono, Bayer, Novartis, Teva, Sanofi, Genzyme and Almirall. Fabio Bandini: nothing to disclose. Paola Cavalla: nothing to disclose. Marinella Clerico: nothing to disclose. Marco Capobianco received consultancy fees or speaker compensations from Biogen-Idec, Sanofi-Genzyme, Novartis, MerckSerono, TEVA. Luciano Deotto: partecipation in clinical trisals of Bayer, Merk Serono, Teva, Novartis, Biogen idec, Almirall. Milena De Riz: nothing to disclose. Ernesta Ferrari: nothing to disclose. Cristina Scarpazza: nothing to disclose. Maria Letizia Fusco: nothing to disclose.

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Angelo Ghezzi has served on scientific advisory boards for Merck Serono, Novartis, Biogen Idec, Teva, Pharmaceutical Industries Ltd.; has received speaker honoraria from Merck Serono, Biogen Idec, Bayer Schering Pharma, Sanofi-Genzyme, Novartis, Serono Symposia International, Almirall. Luigi Grimaldi: nothing to disclose. Alessandra Lugaresi è Consulente di Bayer Schering, Biogen Idec, Merck Serono e Genzyme. Ha ricevuto rimborso spese di viaggio e onorari da Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis e Teva; inoltre sono stati erogati finanziamenti all’Università di afferenza e assegni di ricerca da parte di Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis e Teva. La Prof.ssa Lugaresi ha anche ricevuto sovvenzioni di viaggio e di ricerca della Associazione Italiana Sclerosi Multipla ed è stata consulente della “Fondazione Cesare Serono”. Lucia Moiola: honoraria for speaking from Biogen Idec, Sanofi Aventis e Merck Serono Patrizia Perrone: nothing to disclose. Luca Prosperini has received consulting fees and/or fees, and/or travel grants from Bayer Schering, Biogen Idec, Genzyme, Novartis, and Teva. Monica Rezzonico: ha parlato con retribuzione da parte di IMS Health e Mc CANN Complete Medical srl e sono stata sponsorizzata a congressi da dompè, biogenidec, serono, bayer, teva, novartis, aventis, baxter. Marco Rovaris: Travel grants and fees for scientific consultancies from Almirall, Bayer-Schering, Biogen Italia, Novartis, TEVA Italia. Giuseppe Salemi received grants from Merck Serono, BiogenIdec, Teva, Novartis, Bayer, and Sanofi-Aventis. Marco Salvetti: M. Salvetti receives research support and has received fees as speaker from Sanofi-Aventis, Biogen, Bayer Schering, and Merck Serono. He also receives research support from the Italian MS Foundation (FISM). Santuccio: nothing to disclose. Claudio Solaro: served as advisory board the following companies: Biogen Idec, Merck Serono. He received speaking honoraria from Bayer Schering, Biogen Idec, Merck Serono, Almirall, Teva, Genzyme. He received research grants and support by the FISM (Fondazione Italiana Sclerosi Multipla). Carla Tortorella: nothing to disclose. Ruggero Capra: lecture and consulting fees from Biogen-Idec, Sanofi Aventis and Novartis. P1147 COMPARE: a phase 1 pharmacokinetic study of subcutaneous peginterferon beta-1a vs subcutaneous interferon beta-1a over 2 weeks in healthy subjects X. Hu, S. Shang, I. Nestorov, K. Dawson, B. Sperling, B. Werneburg Biogen, Cambridge, MA, United States Background: Interferon (IFN) beta-1a and peginterferon beta-1a (PEG-IFN) are commonly prescribed subcutaneous (SC) medications for relapsing-remitting multiple sclerosis (RRMS). PEGIFN every 14 days and IFN beta-1a three times per week (TIW) have demonstrated efficacy in RRMS Phase 3 pivotal trials. While PEG-IFN is dosed less frequently, well-controlled head-to-head trials comparing drug exposure and tolerability have yet


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to be conducted. Since previously utilised markers of IFN e.g. neopterin are not linked to IFN-treatment efficacy, direct drug exposure may be a more appropriate endpoint for non-clinical comparisons. Objective: COMPARE is an open-label, crossover, Phase 1 study evaluating drug exposure, as measured by cumulative area under the concentration time curve (AUC) over 2 weeks, maximum observed serum concentrations (Cmax), and the safety and tolerability of SC PEG-IFN and SC IFN beta-1a over 2 weeks in healthy subjects. Methods: A total of 30 healthy subjects were assigned to receive either one 125 mcg SC dose of PEG-IFN or six SC doses of 44 mcg IFN beta-1a over 2 weeks, and then, following a 2-week washout period, received the alternate treatment. Drug concentration was measured by an enzyme-linked immunosorbent assay (ELISA) and the PK parameters were estimated using a non-compartmental analysis. A mixed-effect model with repeated measures including factors for treatment, sequence and period was used to analyse AUC over 2 weeks. Results: The analysis population for PK consisted of 26 subjects for each treatment. Drug exposure (2-week AUC0-336hr) was 37.7% higher for SC PEG-IFN than for SC IFN beta-1a (117.4 hr*ng/mL vs 73.1 hr*ng/mL respectively, p< 0.0001). Mean Cmax for SC PEG-IFN was 1121 pg/mL, and 141, 278 and 293 pg/mL for SC IFN beta-1a at 1st, 4th and 6th dose, respectively. The overall incidence of adverse events (AE) in this study was consistent with those reported in the approved labels, while a numerically greater frequency (rate) of injection site AE, headache, myalgia, and chills were observed during SC IFN beta-1a TIW dosing. Conclusions: One dose of SC PEG-IFN delivers significantly greater drug exposure than SC IFN beta-1a TIW measured by serum concentration over a 2-week dosing period with detectable drug levels throughout the dosing period. These findings demonstrate that pegylation of IFN beta-1a provides for continuous 2 week drug exposure after one injection and fewer AE compared to non-pegylated IFN beta-1a TIW.

injection management: non-interventional study on PDAsupported effects on adherence to long-term injection therapy”) was to evaluate whether the use of a PDA improves persistence and adherence of outpatients to interferon-beta-1b therapy. In total, 669 patients (194 males, 475 females, aged 38.4 years on average) who had started a treatment with interferon-beta-1b (injected subcutaneously every other day) participated in the BETAPATH study, which was a prospective, open-label study conducted in Germany. The patients were split into two groups to assess the utility of a PDA (n=339 patients) in comparison to a classical paper patient diary (non-PDA, n=330 patients). One cohort used a PDA with injection reminder function (PDA+, n=173 patients), and one cohort used a PDA without reminder function (PDA-, n=166 patients). The patients were followed for 2 years after the initial visit and asked to document each drug administration. Treatment persistence was in the range of observational studies, with roughly 40% of both PDA and non-PDA users discontinuing the therapy. For male patients, the drop-out rate was 10% lower in the PDA group compared to the non-PDA group. Around 15% of patients admitted that they skipped injections, most frequently due to forgetfulness. The PDA+ increased adherence to the injection schedule by a mean of 24.5 injections over 24 months in comparison to the PDA-. A logistic regression model identified the use of a PDA+ to be associated with a lower likelihood of non-adherence. In addition, pre-treatment as well as younger age and depression were risk factors for lowered adherence. In conclusion, we found that a PDA with reminder function increased the number of injections in the daily-life setting of MS patients. Our data suggest that electronic diaries reminding patients of upcoming injections improve treatment regularity of MS patients, especially in the first year after therapy initiation. Missing records in the second study year were partly attributable to patients´ tiredness of documentation, which should be prevented in the long run.

Disclosure

Disclosure

This study was sponsored by Biogen (Cambridge, MA, USA). HX, SS, NI, DK, SB and WB are all employees and stockholders of Biogen.

MH received speaking fees and travel support from Bayer HealthCare, Biogen Idec, Novartis and Teva. UB-S is an employee of Bayer Vital GmbH. TG is an employee of Bayer Vital GmbH. JC is an employee of Bayer Pharma AG. KH declares no conflicts of interest. VL received speaking fees and financial support for research activities from Bayer HealthCare, Biogen, Genzyme, Novartis and Sanofi. UKZ received speaking fees and financial support for research activities from Bayer HealthCare, Biogen, Merck Serono, Novartis, Sanofi, Almirall and Teva.

P1148 Evaluation of the impact of an electronic diary on adherence to long-term interferon-beta-1b therapy M. Hecker1, U. Bauer-Steinhusen2, T. Glaser2, J. Czekalla3, K. Hechenbichler4, V. Limmroth5, U.K. Zettl1, BETAPATH Study Group 1Department of Neurology, University of Rostock, Rostock, 2Neurology, Immunology and Ophthalmology, Bayer Vital GmbH, Leverkusen, 3Bayer Pharma AG, Berlin, 4Institute Dr. Schauerte, München, 5Clinic for Neurology and Palliative Medicine, Municipal Hospital Köln-Merheim, Köln, Germany Due to the chronic nature of multiple sclerosis (MS), patients are confronted with lifelong disease-modifying treatments. Adherence to self-applicable therapies is a common problem. Personal Digital Assistants (PDA) as electronic diaries can support recording medications taken. The aim of the BETAPATH study (“Betaferon®

P1149 Dalfampridine positive sensory and painful side effects C. Solaro, E. Trabucco, M. Cella, P. Tanganelli Neurology Unit, Head and Neck Department, ASL 3 ‘Genovese’, Genova, Italy Background: Oral extended release dalfampridine (FA) is a recently approved medication acting on voltage gate potassium channel able


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Poster Session 2, 21(S11) to improve in a subgroup of multiple sclerosis (MS) patients the ability of the action on such channel should enhance electrical conduction through demyelinated fibers leading to a gain of function. Paroxysmal symptoms are due to abnormal electrical discarges through demyelinated fibers including sensory paroxysms such trigeminal neuropathy associated to MS (TN) or motor paroxysms such as paroxysmal tonic spasms. Hypothesis: If the medication enhances the conduction in sensory fiber, it possible to increase positive symptoms related to sensory fibers damage such as parestesia or pain. Aim: We reported the experience of the occurrence of positive phenomena in patients treated with FA prospectively observe in last 18 month. Materials and methods: 44 patients received fampridine (10 mg twice daily) for 2 weeks. Results: A total of 44 patients with a mean age of 51 years (range 35-76 yrs) were considered: 22 (50%) were female and 22 (50%) are male. 13 (29.5%) patients had relapsing remitting MS (RR), 20 (45.5%) had secondary progressive MS (SP), 11 (25%) had primary progressive MS course (PP) The mean EDSS was 5.9 (range 3-7) with a median disease duration of years 14.2 ( range 3-30 yrs). 12 Patients were in therapy with Disease modifying drugs (DMD): 6 patients took Interferon, 3 Copolymer and 3 Natalizumab. Out of 44 patients 3 patients experience a generalized painful parestesiae required to interrupt the medication. The side effect started after 3 days of the initiation of FA e disappered after 24 hours the discontinuation of FA. 2 subjects suffer of TN with pain relief using medications (lamotrigine, pregabalin, gabapentin). In one subject the TN pain-related started suddenly after 3 and disapered in about 48 hours. No subjects experience new facial painful symptoms during FA therapy. Conclusion: In our sample the frequency of sensory painful side effects was around 10% and it represents the principal reason for discontinuation. Worsening of painful symptoms or new positive sensory symptoms may represent a limitation of using FA although we believe that prospective study specifically assessing the presence of pain are needed in order to understand possible predictors.

Drug Administration in January 2014. Given the reduced frequency of administration, a comparison with glatiramer acetate 20mg/mL daily (GA20) on adverse event (AE) incidence may provide important information to patients, clinicians, and health policy makers. The study aim was to conduct a mixed-treatment comparison of the incidence of total AEs (TAEs), all injection-related AEs (IRAEs), and injection-site reactions (ISRs) in RCTs of GA20 and GA40 in patients experiencing relapsing-remitting multiple sclerosis (RRMS). IRAEs include ISRs and other injection-related adverse events. TAEs include IRAEs and other AEs not directly related to injection. AE metrics are presented and analyzed on a per-patient, per-year basis. Materials and methods: Most pivotal trials report AEs as a percentage of patients experiencing ⩾1 AE. As this metric does not quantify multiple AEs experienced by the same patient, the incidence rate of all observed AEs/patient/year was used as a better safety comparator for treatments administered at different frequencies. Data from 2 published RCTs of GA40, GLACIER and GALA, were used in a Bayesian network meta-analysis to compare the incidence rate ratio (IRR) of TAEs, IRAEs, and ISRs between treatments and placebo, using GA40 as common comparator. The between-trial heterogeneity parameter tau was used to extrapolate estimates beyond the trials analysed and was informed from a recently published MS meta-analysis. Differences were considered statistically significant when confidence in IRR ⩾1 (PrIRR) was >95%. Results: 1613 patients from core arms in both trials were analysed. Patients receiving GA40 exhibited lower incidence of TAEs [GA20/GA40 IRR: 2.36(1.10-4.58), PrIRR: 98.1%], IRAEs [2.09(.99-3.91), 97.4%], and ISRs [2.09(.98-3.75), 97.4%] than did those treated with GA20. These results were highly significant at the 95% confidence level. Conclusions: RRMS patients treated with GA40 experienced significantly lower AE incidences than did patients treated with GA20. This safety improvement was likely driven by the reduced administration frequency of GA40 and may have a positive impact on patient adherence. Disclosure

Disclosure Dr. Solaro served as advisory board the following companies: Biogen Idec, Merck Serono. He received speaking honoraria from Bayer Schering, Biogen Idec, Merck Serono. He received research grants and support by the FISM (Fondazione Italiana Sclerosi Multipla) Dr. Trabucco, Dr Cella, Dr Tanganelli: nothing to disclose. P1150 Statistical comparison of adverse events for glatiramer acetate 20mg vs 40mg for the treatment of relapsing-remitting multiple sclerosis F.J. Zagmutt1, Y. Wu2, A. Grinspan3, S. Kolodny2, S. Gandhi2 1EpiX Analytics, Boulder, CO, 2Teva Pharmaceuticals, Frazer, PA, 3Teva Pharmaceuticals, Weston, FL, United States Background and goals: Glatiramer acetate 40mg/mL (GA40) administered 3 times weekly was approved by the US Food and

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This study was funded by a contract from Teva Neuroscience, Inc (USA) to EpiX Analytics LLC (USA). Dr. Francisco Zagmutt is a managing partner at EpiX Analytics. Ying Wu, Augusto Grinspan, Scott Kolodny, and Sanjay Gandhi are employees of Teva Pharmaceuticals. P1151 Comprehension of confidence intervals in audiovisual patient information materials for people with multiple sclerosis (COCO-MS): a web-based randomised controlled trial A.C. Rahn1,2, K. Riemann-Lorenz3, I. Backhus2, S. Köpke3, F. Fuest1, A. van de Roemer4, I. Mühlhauser1, C. Heesen5 1Unit of Health Sciences and Education, MIN Faculty, University of Hamburg, 2Institute for Neuroimmunology and Clinical MS Research, University Medical Center HamburgEppendorf, Hamburg, 3Nursing Research Unit, Institute of Social Medicine and Epidemiology, University of Lübeck, Lübeck, 4Institut für Didaktik in der Medizin, Michelstadt, 5Institute for


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Neuroimmunology and Clinical MS Research and Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Background: People with relapsing-remitting multiple sclerosis (pwMS) can choose between an increasing number of immunotherapy options. Evidence-based patient information materials about benefits and risks are needed to make informed treatment choices. Besides information about treatment effects, confidence intervals (CIs) can be helpful to assess the reliability of these estimates from clinical studies. Comprehensible communication of CIs remains a challenge in patient information. Aims: To evaluate the efficacy of three different versions of audio-visual patient information (PI) on CIs through a web-based randomised controlled trial (RCT) in pwMS. Methods: Three different audio-visual PI were developed on the basis of previously piloted written information. In the short version, CIs are explained without using an example, while in the other two versions illustrative examples of an apple farmer were used. The apple farmer wants to know the average weight of his apples (average weight version) and the effectiveness of a treatment to prevent apple trees from getting affected by worms (anti-worm treatment version). To assess comprehension on CIs in the RCT, a multiple choice questionnaire was developed as an outcome instrument. The resulting 6-item questionnaire was validated in a pilot study with 64 pwMS. Here, pwMS were randomised to the average weight text version (IG) or a standard information (CG) concerning CIs. Results: In the pilot study, significantly more questions were answered correctly in the IG than in the CG (4.8 vs 3.8 mean, p=0.02). Based on these data, 572 pwMS are needed for the web-based RCT. PwMS will be randomised to one of the three audio-visual versions or a standard information. Comprehension will be applied as primary endpoint and assessed with the multiple choice questionnaire (α⩽.05, β⩾.9). The RCT will start in June 2015 and data will be available in August 2015. Conclusions: Understanding CIs may help patients to compare treatment options and make informed decisions in line with their preferences and values. Pilot evaluation of an illustrative PI indicated that communication of CIs is possible. The RCT will show applicability of different ways of presentation, but also relevance from a patient perspective in a larger cohort. Data of the full RCT will be presented. Disclosure Anne Rahn: nothing to disclose. Karin Riemann-Lorenz: nothing to disclose. Imke Backhus: nothing to disclose. Sascha Köpke: nothing to disclose. Franz Fuest: nothing to disclose. Adrianus van de Roemer: nothing to disclose. Ingrid Mühlhauser: nothing to disclose. Christoph Heesen has received speakers honorary and research grants from Biogen, Merck Serono and Novartis Pharma. P1152 Sustained reduction in disability with alemtuzumab is associated with durable quality-of-life improvement on SF-36 over 4 years in CARE-MS II patients with

RRMS though most were treatment-free after year 1 R. Arroyo González1, T. Moreau2, H.-P. Hartung3, R.M. Hupperts4, M. Kita5, D.H. Margolin6, L. Kasten7, G. Giovannoni8, on behalf of the CARE-MS II Investigators 1Hospital Clinico San Carlos, Madrid, Spain, 2Burgundy University, Dijon University Hospital, Dijon, France, 3HeinrichHeine University, Düsseldorf, Germany, 4Orbis Medisch Centrum, Maastricht University Medical Center, Sittard, The Netherlands, 5Virginia Mason Hospital and Medical Centre, Seattle, WA, 6Genzyme, a Sanofi company, 7PROMETRIKA, LLC, Cambridge, MA, United States, 8Queen Mary University of London, Barts and The London School of Medicine, London, United Kingdom Background: In CARE-MS II, alemtuzumab-treated patients were significantly more likely to achieve 6-month sustained reduction in preexisting disability (SRD) and had greater qualityof-life (QoL) improvements than those treated with subcutaneous interferon beta-1a. Improvements in disability and QoL were evident through 4 years, despite most patients not receiving any treatment since Month 12. Goals: To examine the relationship between QoL, as measured by the Short-Form 36 Health Survey (SF-36), and SRD over 4 years in alemtuzumab-treated patients. Methods: CARE-MS II (NCT00548405) was a 2-year, phase 3, rater-blinded study in which patients with active relapsingremitting multiple sclerosis and inadequate response to prior therapy (⩾1 relapse) received alemtuzumab 12 mg at baseline and Month 12. As-needed retreatment after relapse or magnetic resonance imaging activity, or other disease-modifying therapy (DMT), was permitted in extension (NCT00930553). QoL was assessed using the 8 SF-36 scales. SRD was ⩾1-point reduction in Expanded Disability Status Scale score over 6 months (baseline score ⩾2.0). QoL change from baseline was determined by an unstructured covariance model (time by group interaction). Results: 393 (93%) alemtuzumab-treated patients entered the extension; 68% did not receive alemtuzumab since Month 12; 5% received another DMT. At Year 4, SF-36 physical component summary score was significantly improved from baseline for patients with 6-month SRD (5.1; P< 0.0001); improvement was greater in patients with SRD than without (group difference: 4.1; P=0.0003). There was no statistical between-group difference on the mental component summary. Patients with 6-month SRD had significant improvements from baseline on 7 of 8 scales: physical functioning, role-physical, general health, mental health, role-emotional, social functioning, and vitality (all P< 0.02). Scores were significantly more improved in patients with SRD than without on physical functioning, rolephysical, general health, role-emotional, and social functioning (all P< 0.03). Conclusion: Improvement in preexisting disability was associated with improved QoL measured by the SF-36, particularly on physical aspects of QoL. SRD-associated QoL gains in alemtuzumab-treated patients were maintained through Year 4, despite most being treatment-free for 3 years. These data provide evidence that SRD is a clinically meaningful outcome measure and show the impact of disability improvement on QoL.


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Poster Session 2, 21(S11) Disclosure Study supported by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. RAG: Compensation for serving as advisory board participant and speaker (Biogen, Novartis, Teva, Merck, Genzyme, Bayer, Almirall, and Roche). TM: Consulting and speaking fees (Biogen Idec, Sanofi Aventis, Genzyme, Teva Pharma, Bayer Schering, Merck Serono, Novartis, Roche, and Almirall). H-PH: Honoraria for consulting and speaking at symposia (Bayer Healthcare, BiogenIdec, CSL Behring, Genzyme, Merck Serono, Novartis, Octapharma, Roche, Teva, and Sanofi, with approval by the Rector of Heinrich Heine-University). RH: Research grants, speaker´s fees and honoraria for advisory boards (BIOGEN, Genzyme-Sanofi,TEVA,Novartis and Merck). MK: Personal compensation for serving as speaker or consultant (Genzyme, Biogen Idec, and Novartis). DHM: Employee of Genzyme. LK: Provides statistical support as a consultant for Genzyme. GG: Compensation for consulting, serving on a scientific advisory board, speaking, or other activities (Biogen Idec, Five Prime Therapeutics, Genzyme, GW Pharma, Merck-Serono, Novartis, Roche, Synthon, Teva, and Vertex Pharmaceuticals); compensation for serving as a journal editor (Multiple Sclerosis and Related Disorders); and research support (Serono). P1153 Factors associated with early disease-modifying drug (DMD) treatment initiation in newly diagnosed patients with multiple sclerosis (MS) A.L. Phillips1, N.C. Edwards2, M. Frean3, J.C. Locklear1 1EMD Serono, Inc., Rockland, 2Health Services Consulting Corporation, Boxborough, 3Boston Health Economics, Inc., Waltham, MA, United States Background: Successful management of multiple sclerosis (MS) may depend on initiating therapy early in the course of the disease. An understanding of the predictive value of the factors associated with disease-modifying drug (DMD) treatment initiation in newly diagnosed patients with MS may help optimize MS disease management programs and may improve patient outcomes. Goals: The objective of this evaluation was to evaluate if age, sex, geographic region, comorbidity, and year of diagnosis were associated with early DMD treatment initiation in newly diagnosed patients with MS. Methods: This was a retrospective analysis of newly diagnosed patients with MS receiving at least one DMD within 2 years of diagnosis, derived from a national, commercial US managed care database. A logistic regression model was used to predict early DMD treatment initiation, defined as having a DMD claim within 60 days of MS diagnosis. Explanatory variables included in the model were age group (18-34, 35-44, 45-54, 55-65), sex, baseline comorbidity index (Charlson Score 0, 1 or 2+), geographic region (Midwest, South, Northeast, and West), and year of diagnosis (2008-2012). Results: A total of 7,621 patients with MS met study inclusion criteria. The average age was 41.6 years (SD = 10.4), and 74.5% were female. Most patients were from the Midwest (34.0%) or

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South (31.9%) regions, reflective of the sampling for the national database used in this study. The average time from first MS diagnosis to first DMD was 128.3 days (SD=164.3), and the median time to treatment was 56 days. Examining the time to first treatment by 30-day increments demonstrated that 28.9% received their first DMD in less than 30 days, and approximately half of patients (52.4%) received treatment within 60 days (n=3,995). The model showed that older age groups (35-44, 45-54, and 55-65 vs. 18-34 age group; ORs 0.70-0.89; p< 0.05) and patients with MS living in the Northeast (vs. Midwest) (OR 0.87; p=0.023) were less likely to initiate a DMD within 60 days. Male patients, patients (OR 1.14; p=0.013) with a higher Charlson comorbidity score (2+ vs. 0) (OR 1.23; p=0.018), and patients who received their MS diagnosis in 2010 (OR 1.21; p=0.007) were more likely to initiate a DMD within 60 days. Conclusions: This study demonstrated that older age, male gender, greater comorbidity, Northeast region, and a 2010 diagnosis year were associated with DMD treatment initiation within 60 days of diagnosis. Disclosure ALP and JCL are employees of EMD Serono, Inc., Rockland, MA, USA (a subsidiary of Merck KGaA, Darmstadt, Germany). NCE received personal compensation as a Health Services Research consultant. MF is an employee of Boston Health Economics which receives funding from the study sponsor, EMD Serono. Study supported by EMD Serono, Inc., Rockland, MA, USA and Pfizer Inc, New York, NY, USA. P1154 Switching from initial first-line agents to other disease modifying therapies: an observational study E. Le Page, V. Deburghgraeve, A. Kerbrat, G. Edan Pôle des Neurosciences Cliniques, CIC-P 0203 INSERM, University Hospital, Rennes, France Background: While the therapeutic arsenal for MS continues to enlarge, algorithms for using disease modifying therapies (DMTs) are debated. Aim: To describe the reasons for stopping interferon beta (IFNB) or glatiramer acetate (GA) started as first line and the further therapeutic management in a cohort of 200 relapsing MS patients. Methods: Prospective observational study of the 200 most recent consecutive patients recorded in Rennes’s EDMUS database, satisfying the following criteria: relapsing MS at onset, first treated with IFNB or GA (collectively, DMT-1) for at least 3 months, stopping this DMT-1 and starting a DMT-2 during follow-up, and followed for at least 1 year after stopping DMT-1. We collected the reasons for stopping DMT-1, MS activity characteristics before starting DMT-1, during DMT-1 and during DMT-2 (relapses, mean EDSS change, new T2 or gadolinium enhancing lesions). Results: 149 females and 51 males of 28.7 (+/-8) years old at relapsing MS onset started treatment, 4.32 (+/-5) years after disease onset, with IFNB (n=145) or GA (n=55) (DMT-1), between January 2005 and January 2013, and were subsequently followed for 5.9 (+/-2) years. Mean number of relapses over the past two years was 1.66 (+/-0.9), and mean EDSS at baseline was 1.26


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(+/-1.1). 21 were secondary progressive at DMT-1 start. 72 (36%) patients stopped DMT-1 due to intolerance (general 55.5%, psychiatric 15.3%, cutaneous 19.4%, laboratory abnormalities 6.9%, other 2.9%). 7 women (3.5%) stopped to try to conceive. 121 (60.5%) patients stopped for lack of efficacy, among whom 113 switched to DMT-2 within 6 months of stopping DMT-1. These sub-optimal responders had a pre-switch annualized relapse rate of 0.86, mean annualized increase of EDSS by 0.52 and MRI activity (n= 82, 72.5%). After switching to IFNB (n=21), GA (n=23), natalizumab (n=26), mitoxantrone (n=24), fingolimod (n=14), alemtuzumab (n=3), azathioprine (n=1) and cyclophosphamide (n=1), annualized relapse rate decreased to 0.27, and mean annualized EDSS changed by 0.08. Conclusion: Patients in our cohort who switched from first line therapy due to sub-optimal response experienced a decreased annualized relapse rate and slower rate of disability accrual after switching therapies. Disclosure All authors: nothing to disclose related to the submitted work. P1155 Tailored case-based approach is successful in improving the use of disease-modifying therapies in multiple sclerosis T.F. Finnegan, R. Schaumburg Medscape, LLC, New York, NY, United States Objective: To measure whether neurologists’ knowledge and competence in using disease-modifying therapies (DMTs) in multiple sclerosis (MS) was improved after participation in online continuing medical education (CME) that consisted of two interactive case challenges. Background: Various new DMTs have been approved for MS in recent years. Translating data on efficacy, safety, and mechanism of action (MOA) of available DMTs and incorporating patient factors into effective treatment decisions is crucial for optimizing outcomes. Problem-based case studies may be a suitable method to educate clinicians on the best ways to optimize use of DMTs. Design and methods: A cohort of international neurologists (N = 188) who participated in a CME activity and completed all assessment questions was evaluated. The activity used patient scenarios with 4 interactive knowledge questions and 6 clinical decision questions with branching capability. Tailored feedback was provided based on potential consequences of clinical decisions and educational effect size was calculated using Cohen’s d to show the magnitude of consequence-based feedback. For knowledge questions, a paired 2-tailed t-test was used to assess differences in mean pre-assessment versus post-assessment scores. Results: Neurologists demonstrated a wide range (34%-80%) of understanding regarding concepts addressed by the clinical decision questions on the first attempt. After receiving tailored feedback, 15%-37% improved their understanding of the concepts by answering questions correctly on the second attempt (d=1.56; large effect size).They also showed significant improvement on knowledge questions (P < .05): correct responses on post-assessment questions (compared with the pre-assessment responses) were

7%-34% higher after CME completion (d=0.729; medium effect size) Specific results showed improvement in understanding initial DMT selection, how and when to switch DMTs, and the MOA of DMTs. Conclusions: Online problem-based education that incorporates clinical decisions was successful in improving knowledge and competence of neurologists regarding initial treatment decisions, switching to a new DMT, and the MOA of current DMTs. Disclosure Thomas F Finnegan: nothing to disclose. Ron Schaumburg: nothing to disclose This study was supported by Biogen P1156 Alemtuzumab infusion management: the British Columbia experience N. Bogle1, L. Harvey1, M. Ozog2, K. Sidhu1, A. Traboulsee1 1The University of British Columbia, Vancouver, BC, Canada, 2Genzyme, a Sanofi company, Cambridge, MA, United States Background: Alemtuzumab was approved in Canada in December 2013. In clinical trials, alemtuzumab 12 mg was administered as 2 annual courses on 5 consecutive days at baseline and on 3 consecutive days 12 months later. Infusion-associated reactions (IARs) occurred in a majority (>90%) of patients; 3% were serious. IAR prophylaxis in clinical trials included 1 g intravenous (IV) methylprednisolone on infusion Days 1-3 of a 5-day course, with optional symptomatic treatment. Goals: To describe clinical experience with alemtuzumab infusion strategies and IARs at this infusion site. Methods: Alemtuzumab 12 mg was administered on 5 days at baseline and on 3 days 12 months later. Patients received an antihistamine (cetirizine 10 mg) and an H2-antagonist (ranitidine 150 mg) in the morning of each infusion day. One hour before infusion, acetaminophen 1000 mg and 1 g IV methylprednisolone were administered on infusion Days 1-3, and on Days 4 or 5 as needed. Alemtuzumab was infused (rate of 25 mL/h) over 4 hours, with the option to decrease the rate to mitigate IAR occurrence or severity, or to increase the rate if the infusion was well tolerated. Cetirizine 10 mg and diphenhydramine 50 mg were given orally as needed during infusion. Post-infusion, patients were observed for 1-2 hours per study protocols, and in the evening given cetirizine and ranitidine as needed. Results: In our centre, 37 patients have been treated with alemtuzumab in a clinical trial or an investigator-sponsored study; 36 received 2 courses. All patients had at least 1 IAR. Most IARs were manageable and well-tolerated, and most occurred during the infusion. There were no anaphylaxis cases. Rash, urticaria, headache, and fatigue were reported after leaving the infusion centre and managed primarily with antihistamines, acetaminophen, and rest. Conclusion: In our clinical experience with alemtuzumab infusion, IARs have been manageable and tolerable with appropriate premedication, monitoring, slowing of infusion rate, and postinfusion medication. The incidence and severity of IARs were consistent with those in clinical trials.


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Poster Session 2, 21(S11) Disclosure Funding for writing/editorial support provided by Genzyme, a Sanofi company. NB: nothing to disclose. LH: nothing to disclose. MO: employee of Genzyme. KS: nothing to disclose. AT: consulting fees (Biogen, Chugai, Genzyme, MedImmune, Novartis, Roche, Serono, and Teva Innovation); principal investigator on clinical trials (Genzyme, Roche).

P1157 An evaluation of adherence between patients with multiple sclerosis newly initiating treatment with a self-injectable or an oral disease-modifying drug A.L. Phillips1, M. Frean2, J.C. Locklear1, J. Menzin2 1EMD Serono, Inc., Rockland, 2Boston Health Economics, Inc., Waltham, MA, United States Background: As the multiple sclerosis (MS) disease-modifying drug (DMD) class expands to include oral therapies, it is important to understand how route of administration may impact adherence. Goals: To evaluate medication adherence in MS patients newly initiating treatment with a self-injectable or an oral DMD. Methods: MS patients (age 18-63; ⩾1 medical claim with MS diagnosis: ICD-9-CM:340.xx) with ⩾1 DMD claim (first claim=index date), continuous eligibility 12 months pre- and post-index, and no DMD claim during the pre-index period were identified from the IMS LifeLink Plus database from 7/1/2010-6/30/2014. Patients were grouped by route of administration: self-injectable versus oral DMD. Fisher and Wilcoxon tests were used in unadjusted statistical comparisons. Logistic regression was used to evaluate the likelihood of adherence (12-month post-index medication possession ratio (MPR) (number of days medication supplied divided by number of days in refill interval) ⩾0.8 vs. < 0.8) to index DMD group. Covariates included age, sex, and baseline comorbidities. Results: The analysis included 7207 self-injectable and 1175 oral DMD patients (mean age: 43.0 vs 44.9, respectively; p< 0.0001). In unadjusted analyses, mean MPR was greater in the self-injectable vs oral DMD group (0.69 vs 0.68; p=0.0002, respectively). No difference in percentage of patients ⩾0.8 MPR: was observed (54.1% vs 53.0%, p=0.5075, respectively). Patients in the self-injectable group (9.9%) were more likely to switch compared with patients in the oral group (6.6%; p=0.0003); however, no differences were observed in proportion of patients discontinuing (26.6% vs. 28.2%; respectively, p=0.2710), time to discontinuation (mean number of days: 118.0 vs. 113.7; respectively, p=0.1341), or time to switch (mean number of days: 163.1 vs. 153.1; respectively, p=0.2519). After controlling for covariates, index DMD type was not a significant predictor of adherence (p=0.3473). Male sex and older age groups (vs 18-34) were associated with significantly higher likelihood of adherence (odds ratio [OR]: 1.20 and ORs: 1.22-1.33, respectively; p< 0.01). Depression was associated with a lower likelihood of adherence (OR: 0.62, p< 0.0001).

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Conclusions: In this analysis, there was no difference in adherence attributable to route of administration. Male sex and older age were associated with a higher likelihood of adherence, while depression was associated with a lower likelihood of adherence. Disclosure ALP and JCL are employees of EMD Serono, Inc., Rockland, MA, USA (a subsidiary of Merck KGaA, Darmstadt, Germany). MF and JM are employees of Boston Health Economics which receives funding from the study sponsor, EMD Serono. Study supported by EMD Serono, Inc., Rockland, MA, USA and Pfizer Inc, New York, NY, USA. P1158 Medication beliefs among relapsing-remitting multiple sclerosis patients who have discontinued disease modifying therapy against medical advice M.B. Glusman1, B. Roberg1, J. Thelen1, S. O’Bryan1, A. Ness1, S. Lynch2, D. Catley1, K. Goggin3, A. Bruce2, A. BradleyEwing3, K. Gould1, J. Bruce1 1Psychology, University of Missouri - Kansas City, Kansas City, MO, 2Neurology, University of Kansas Medical Center, Kansas City, KS, 3Psychology, Children’s Mercy Kansas City, Kansas City, MO, United States Objective: As many as 50% of patients with relapsing remitting multiple sclerosis (RRMS) prematurely discontinue disease modifying therapies (DMTs), which have been shown to delay disease progression, reduce new brain lesions, and decrease clinical exacerbations. Interventions designed to improve long-term adherence have had limited success. This study examined patient medication beliefs among adherent and nonadherent RRMS patients. Methods: Adherent (n=33) and nonadherent (n=72) RRMS patients completed the Adherence Determination Questionnaire (ADQ), Multiple Sclerosis Treatment Adherence Questionnaire (MS-TAQ), and Symptom Awareness and Perceived Ability to Manage Therapy Questionnaire (SAPAMT). Adherent patients reported having taken at least 80% of prescribed DMT doses over the previous 8 weeks. Nonadherent patients had discontinued DMTs against medical advice. Results: Nonadherent RRMS patients were less determined to adhere to DMTs (F(1, 103) = 81.77, p< .001, η2 =.44), and reported fewer medication management skills than adherent patients F(1, 103) = 43.82, p< .001, η2 =.30). Nonadherent patients also reported more barriers that interfere with medication use (F(1, 103) = 33.20, p< .001, η2 =.24). Conclusion: While several studies in the literature have examined self-reported adherence among MS patients who miss occasional doses or lack persistence, no studies have specifically examined medication beliefs among patients who have chosen to discontinue DMTs against medical advice. The current study demonstrates that MS patients who have discontinued DMTs against medical advice report fewer medication management skills, more medication barriers, and less adherence determination. Better understanding the belief characteristics of patients who choose not to take DMTs may help assist clinicians when discussing medication options with their patients.


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Disclosure Morgan Glusman has received funding from the University of Missouri-Kansas City (UMKC) Women’s Council and the UMKC School of Graduate Studies. Dr. Bruce has received funding and/or honoraria from the National Multiple Sclerosis Society, the National Hockey League, and the Archives of Clinical Neuropsychology. He is a member of the Novartis Unbranded Speakers Bureau and the Novartis Cognition in MS Medical Advisory Board. Dr. Lynch has received grant support for multi-center trials from Bayer, Roche, Genzyme, Biogen, Teva, Serono, Pfizer, Novartis, Actelion, Ono, Opexa, Accorda, NIH, and NMSS. This study was funded by Frontiers: The Heartland Institute for Clinical and Translational Research (grant proposal # 033718) and the National Multiple Sclerosis Society (grant proposal #033769). P1159 Shared decision making and disease modifying treatment history in NARCOMS A.R. Salter1, G. Wang1, T. Tyry2, R.J. Fox3, R.A. Marrie4, G.R. Cutter1, S.S. Cofield1 1Biostatistics, University of Alabama at Birmingham, Birmingham, AL, 2Dignity Health, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, 3Neurology, Cleveland Clinc, Cleveland, OH, United States, 4University of Manitoba, Winnipeg, MB, Canada Background: With increasing options for treatment choices, awareness of the benefits of the shared decision making model in multiple sclerosis (MS) is growing. MS patients’ use of disease modifying therapy [DMT] can vary by age and duration of disease and can include continuous use, switching and not using DMTs. Objective: To describe the socio-demographic and clinical characteristics associated with different patterns of treatment history for a large, heterogeneous cohort of persons with MS. To evaluate self-reported involvement in the decision associated with starting, switching, stopping and not taking DMTs. Methods: In Fall 2014, the North American Research Committee on Multiple Sclerosis (NARCOMS) registry participants summarized their overall history of treatment using a single item flow chart which included those who took no DMT (No-DMT), took an initial DMT and currently still take that DMT (Single), had a break on initial DMT and currently still take that DMT (Break), had a break on initial DMT but stopped taking DMT (Break-Stop), took an initial DMT but stopped taking that DMT (Single-Stop), switched DMTs and currently take a DMT (Switch) and switched DMTs but stopped taking a DMT (Switch-Stop). Additional selfreported clinical information and timing and involvement of the decision making for each treatment path were collected. Results: 7314(96.2%) responders completed the treatment history question: 988 (13.2%) No-DMT, 1496(20.0%) Single, 290(3.9%) Break, 156 (2.1%) Break-Stop, 703(9.4%) Single-Stop, 2849(38.1%) Switch, 1003(13.4%) Switch-Stop. The mean (SD) time from enrollment to 2014 was 10.7(4.8) years. The median change in Patient Determined Disease Step (PDDS) from enrollment to 2014 was 1 step in all groups except Single and Break who had a median change of 0. No-DMT participants were older and had longer disease duration than others combined (25.9 vs

18.3 years). Switch-Stop had the highest median (IQR) PDDS of 5/Late Cane (3/Gait Disability, 6/Bilateral Support). Shared involvement of participants and their physician in the decision making was higher for Single, Single-Stop, Switch and SwitchStop groups. Conclusion: NARCOMS participants self-reported distinct treatment histories, although these were well aligned to expected patterns associated with age and disease duration. Shared decision making was most prevalent in those taking DMTs, adding useful information about shared decision making often not available in provider databases. Disclosure Dr. Salter has received support for consulting services and grant support; no direct conflicts. Dr. Cofield has received support for consulting services from the American Shoulder and Elbow Society, DSMB service from MedImmune, and/or grant support for various entities; no direct conflicts. Dr. Fox has received support for consulting fees from Actelion, Biogen, MedDay, Novartis, Questcor, Teva, and XenoPort; no direct conflicts. Dr. Marrie has conducted clinical trials for sanofi-aventis; no direct conflict. Dr. Tyry has nothing to disclose. Ms. McNeal has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Cutter has consulting and/or DSMB commitments in Past 12 months. Participation of Data and Safety Monitoring Committees: All of the below organizations are focused on medical research: Apotek, Biogen-Idec, Cleveland Clinic(Vivus), Glaxo Smith Klein Pharmaceuticals, Gilead Pharmaceuticals, Horizon Pharmaceuticals, Modigenetech/Prolor, Merck/Ono Pharmaceuticals, Merck, Merck/ Pfizer, Neuren, Sanofi-Aventis, Teva, NHLBI (Protocol Review Committee), NINDS, NICHD (OPRU oversight committee). Consulting, Speaking fees & Advisory Boards: Consortium of MS Centers (grant), D3 (Drug Discovery and Development), Genzyme, Genentech, Jannsen Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, Novartis, Opexa Therapeutics, Receptos, Roche, EMD Serono, Spiniflex Pharmaceuticals, Somahlution, Teva pharmaceuticals, Transparency Life Sciences. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. Sources of funding: NARCOMS is supported by the CMSC and the Foundation of the CMSC. P1160 Patient-provider communication and perceived autonomy support among multiple sclerosis patients who discontinue disease modifying therapy against medical advice M.B. Glusman1, B. Roberg1, J. Thelen1, S. O’Bryan1, A. Ness1, S. Lynch2, D. Catley1, K. Goggin3, A. Bruce2, A. BradleyEwing3, K. Gould1, J. Bruce1 1Psychology, University of Missouri - Kansas City, Kansas City, MO, 2Neurology, University of Kansas Medical Center, Kansas City, KS, 3Psychology, Children’s Mercy Kansas City, Kansas City, MO, United States


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Poster Session 2, 21(S11) Objective: Poor medication adherence is pervasive in relapsingremitting multiple sclerosis (RRMS), with approximately 30-50% of patients prematurely discontinuing prescribed medication regimens. Patient-centered approaches, such as autonomy support, have been shown to promote shared decision-making between patients and providers. This study compared autonomy support and patient-physician communication among adherent and nonadherent RRMS patients. Methods: Adherent (n=32) and nonadherent (n=72) RRMS patients completed the Autonomy Support from Counselor-Health Care Climate Questionnaire (HCCQ). Higher scores on the HCCQ indicate that patients perceive more support from their providers when discussing disease management. In addition, a single item measure was administered that asked patients to rate how well their provider listens to their medication concerns. Adherent patients reported taking at least 80% of their disease modifying therapy (DMT); nonadherent patients had discontinued DMT against medical advice. Results: Nonadherent RRMS patients endorsed significantly poorer patient/physician communication (F(1, 103) = 20.90, p< .001, η2 =.176), and less perceived autonomy support (F(1, 103) = 21.60, p< .001, η2 =.180) than the adherent RRMS patients. Conclusion: To our knowledge, this is the first study to examine perceived provider autonomy support among nonadherent patients who have discontinued DMTs against medical advice. Patients who perceive less autonomy in their treatment options, and report poor communication with providers may be more likely to prematurely discontinue DMTs against medical advice. Future research should examine ways to improve physician communication to both convey the importance of medication adherence and maintain rapport so that patients feel comfortable discussing medication barriers. Disclosure Morgan Glusman has received funding from the University of Missouri-Kansas City (UMKC) Women’s Council and the UMKC School of Graduate Studies. Dr. Bruce has received funding and/or honoraria from the National Multiple Sclerosis Society, the National Hockey League, and the Archives of Clinical Neuropsychology. He is a member of the Novartis Unbranded Speakers Bureau and the Novartis Cognition in MS Medical Advisory Board. Dr. Lynch has received grant support for multi-center trials from Bayer, Roche, Genzyme, Biogen, Teva, Serono, Pfizer, Novartis, Actelion, Ono, Opexa, Accorda, NIH, and NMSS. This study was funded by Frontiers: The Heartland Institute for Clinical and Translational Research (grant proposal # 033718) and the National Multiple Sclerosis Society (grant proposal #033769).

P1161 Development of aquaporin4 antibody binding inhibitor: a preliminary data S.-M. Kim1, E.J. Ju2, S. Cheon1, B. Kim1, S.K. Yeon2, S.W. Kim3, O.H. Kwon4 1Department of Neurology, College of Medicine, Seoul National University, 2Center for Neuro-Medicine, Korea Institute of Science and Technology, seoul, 3Department of Anatomy, College of Medicine, Inha University, Incheon, 4Department

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of Neurology, College of Medicine, Eul-Ji University, seoul, Republic of Korea Neuromyelitis Optica (NMO) is a demyelinating autoimmune disease of optic nerve and spinal cord, triggered by binding of pathogenic IgG to aquaporin4 in the astrocyte and subsequent disruption of the blood brain barrier. We aimed to develop an inhibitor for the NMO-IgG. Diverse screening system and synthesis strategies were adapted as follows; First, virtual screening system was used for the 1.6 million compounds in the two commercial libraries (Asinex and ChemDiv); second, focused screening for major scaffold of 2,000 compounds among the CNS focused library of the Korea Institute of Science and Technology (KIST); third, structural aided new drug design for the both already known channel inhibitors and NMO-IgG binding inhibitors (arbidol). With those methods, two hundred four compounds were selected and screened for the inhibition of NMO-IgG binding in a high throughput screening system using human M23-aquaporin4 expressing U87MG cells and human NMO-IgG. Next, compounds that inhibited NMO-IgG were tested for the inhibition of the complement dependent cytotoxicity of NMO IgG. Finally, three hit molecules were identified that reduced both binding of NMO-IgG to aquaporin4 and complement dependent cytotoxicity mediated by NMO-IgG. Further study that evaluate the efficacy of these hit molecules are in progress using NMO in vivo model. Disclosure All authors: nothing to disclose P1162 Glycyrrhizic acid might reduce the NMO-IgG induced cell death by inhibition of the complement activation S.-M. Kim1, S.W. Kim2, E.J. Ju3, S.K. Yeon3, S. Cheon1, B. Kim1, M.S. Kim1, O.H. Kwon4, S.W. Ahn5, K.D. Park3 1Department of Neurology, College of Medicine, Seoul National University, Seoul, 2Department of Anatomy, College of Medicine, Inha University, Incheon, 3Center for Neuro-Medicine, Korea Institute of Science and Technology, 4Department of Neurology, College of Medicine, Eul-Ji University, 5Department of Neurology, College of Medicine, Jung Ang University, Seoul, Republic of Korea Neuromyelitis optica (NMO) is an inflammatory demyelinating disease in central nervous system. The pathogenesis of NMO involves binding of aquaporin4 autoantibody (AQP4-Ab) to the astrocyte, activation of the complement pathway, and subsequent breakdown of the blood brain barrier. The glycyrrhizic acid (GL) is a triterpene that is obtained from the roots and rhizomes of licorice. Here, we report that GL can decrease the complement dependent cytotoxicity in vitro model of NMO, by inhibiting the binding of C1q complex. Treatment of NMO patient sera (0.5, 1, 2.5, 5, and 10%) dose-dependently increased LDH release in both AQP4 overexpressed U87 cells and primary culture of mice astrocyte. Treatment of GL (0.1, 0.5, 1, 1.5, and 2 mM) reduced the complement mediated cytotoxicity of NMO IgG in a dose dependent manner. Though GL did not block the binding of NMO IgG to AQP4 overexpressed U87 cells, it reduced binding of C1q to NMO-IgG. Our result implies that GL might play a protective role


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in the pathogenesis of NMO, through the inhibition of the complement activation. Disclosure All authors: nothing to disclose

P1163 Rituximab treatment of MS: a single centre retrospective observational study F. Holm, C. Malmeström, L. Novakova, J. Lycke, M. Axelsson University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden

Background: Monoclonal antibodies targeting B-cells has become one of the most promising options in the treatment of autoimmune diseases. In multiple sclerosis (MS), rituximab (RTX) has been evaluated in two phase II studies. While RTX showed beneficial effects in relapsing-remitting (RR) MS, the study of primary progressive (PP) MS was negative. Yet, a subgroup analysis revealed lower rate of progression in younger patients with ⩾1 contrast enhancing lesion on MRI. RTX is not approved for MS, but the off-label use has over recent years increased in Sweden and comprises19,2% (May 2015) of all MS treatments. Objectives: To evaluate the reason, efficacy, safety and tolerability of RTX treatment in MS. Method: In this retrospective study we searched the Swedish MS register (SMSreg) and treatment registers for MS patients treated with RTX between 2008 to 2014. We identified 105 patients; 41 RRMS, 41 secondary progressive (SP) MS and 23 PPMS. Data were extracted from the SMSreg and medical chart review. RTX was initiated with 2 infusions of 1000 mg, 2 weeks apart, and then as single infusions at 6 months intervals. Results: Reasons for switching to RTX varied from one to several combined causes. In RRMS patients (n=41) the reason was treatment failure on other disease modulatory therapies (DMTs, 56%), JC virus antibody (JCV+) in natalizumab treated patients (34%), adverse events (AE) from previous DMT (20%), and neutralizing antibodies against interferon beta or natalizumab (NAB, 7%). The corresponding reasons for RTX in the PMS group (n=64) was disease activity and progression (90%), JCV+ (12%), AE (6%) and NAB (3%). Comparing the number patients having “relapses the last two years” and “relapses after RTX start” shows a reduction in both the RRMS patients (from 36,6% to 9,8%) and PMS patients (from 21,8% to 7,8%). RTX median treatment time was 13 (3-74) months. During RTX treatment of RRMS and PMS the median EDSS increased (+0.5, range 0-8,0 and +0.5, range 1,5-8,5), median MSSS decreased (-0.66, range 0,86-9,94 and -0.19, range 1,439,95). Infusion related reactions was 49,5% at first infusion, 13,3% at 2nd infusion, and 9,5% at 3rd RTX infusion. No severe AE was recorded. 16 patients stopped RTX treatment; 6 due to AE, 4 due to treatment failure and 6 of unknown reasons. Conclusions: RTX was well tolerated with no severe AE. RTX had no obvious effect on EDSS progression but decreased relapse rate and MSSS indicating a beneficial effect in both RRMS and PMS.

Disclosure Fredrik Holm: nothing to disclose Lenka Novakova: nothing to disclose Markus Axelsson: have had compensation for lectures and/or advisory boards from Biogen, Genzyme and Novartis. Clas Malmeström: has received honoraria for lecturing, advisory board councils, and travel expenses for attending meetings from Biogen Idec, Merck-Serono, Novartis and Genzyme, and has received unconditional research support from Biogen Idec. Jan Lycke: has received travel support and/or lecture honoraria from Biogen, Novartis, Teva and Genzyme/SanofiAventis; has served on scientific advisory boards for Almirall, Teva, Biogen, Novartis and Genzyme/SanofiAventis; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, Novartis and Teva. P1164 Mymsmagazin.com - effect of multimedial digital teaching for German speaking MS patients A. Raji1, G. Winkler1, L. Spies2, R. Opfer2 1Center of Neurology Hamburg, 2jung diagnostics GmbH, Hamburg, Germany Objective: To check for e-learning effect of patients and their care-givers by a new multimedial internet platform. Background: E-learning is a growing issue in patients education. In December 2014 mymsmagazin.com started with its first module: Online video-presentations for MS patients and caregivers. Furthur modules are in preparation. The editors, producers and presenters are neurologists. Design and methods: Up to now 6 topics were adressed: Brain atrophy, therapeutic options in scpMS, identification of relapses, treatment effect and safety of new oral MS drugs, sexual dysfunctions in MS patients, new therapeutical aspects in MS on AAN 2015. The e-learning effects were evaluated with topic specific questionairs. The prelearning knowledge was quantified and compared with the postlearning knowledge. By now there are about 300 responders. Results: The brain volume topic revealed a marked learning effect with raised knowledge in 90% of the responders. This result is caused by the relatively small prelearning knowledge. Subspecific questions e.g. concerning region brain atrophy show further educational needs. We found a good knowledge about different MS subtypes, nevertheless our presentation induced better understanding in 30% oft he resonders. There was a good prelearning level of self identification of relapses which could be improved in 20% of the responders. The viewers aknowledged a patient`s interview, describing symptoms and consecutive therapy including need of escalation. We found a lack of information concerning some new oral therapeutics. The video led to higher alertness for safety and changed prelearning rating of the viewers. Highest responses were received for the topic MS and sexual dysfunctions. The viewers were willing to present differentiated data of their own sexual disturbances. 90% complained symptoms and a majority described reduced sexual activity and interest. Conclusion: Online based e-learning is a successful tool for patient education. With additional individualized interactive modules further improvement can be expected.


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Poster Session 2, 21(S11) Disclosure

Disclosure

The authors have nothing to disclose.

This study is supported by Biogen (Cambridge, MA, USA). Darin T. Okuda reports personal fees for speaking activities from Acorda Therapeutics, Genzyme, and Teva Neuroscience, consulting and advisory board fees from Genzyme and Teva Neuroscience, and research support from Biogen, outside the submitted work; Christine Lebrun Frenay reports consulting and serving on advisory board from Biogen, Genzyme, Merck Serono, Almirall, Teva Neurosciences, Novartis. Aksel Siva reports personal fees for consulting and serving on a scientific advisory board from Bayer-Schering AG, Novartis, Biogen and Allergan within the last year, and travel and registration coverage for congresses or symposia from Bayer-Schering AG, MerckSerono, Gen Ilac, and Allergan. Professor Siva received research support from Bayer-Schering AG, outside the submitted work. Christophe Hotermans, Christian Von Hehn, and Brent Day: employees of and hold stock/stock options in Biogen; Maria Pia Sormani reports consulting for Biogen, Novartis, Teva, Merck Serono, Genzyme, Synthon, Actelion; Gina Remington has received honorarium (speaker’s bureau and advisory boards) from International Organization of MS Nurses, Biogen, Teva Neuroscience, Questcor/Mallinckrodt, and Genzyme; Braeden D. Newton reports no disclosures; Teresa Frohman: is a consultant and speaker for Biogen and Novartis; Elliot M. Frohman has received speaker fees from Biogen, Teva Neuroscience, and Acorda Pharmaceuticals, and consulting fees from Biogen, Teva Neurosciences, Abbott, Acorda Therapeutics, and Novartis. Orhun Kantarci reports no disclosures; Daniel Pelletier reports personal consulting fees from Genzyme, Novartis, Biogen, and Roche, grants from Biogen, outside the submitted work.

P1165 Multi-center, randomized, double-blinded assessment of Tecfidera® in extending the time to a first attack in radiologically isolated syndrome (RIS) (ARISE) D.T. Okuda1, C. Lebrun-Frenay2, A. Siva3, C. Hotermans4, C. Von Hehn4, M.P. Sormani5, D. Brent4, G. Remington1, B.D. Newton1, T. Frohman1, E. Frohman1, O. Kantarci6, D. Pelletier7 1UT Southwestern Medical Center, Dallas, TX, United States, 2Hôpital Pasteur, Nice, France, 3University of Istanbul, Istanbul, Turkey, 4Biogen, Cambridge, MA, United States, 5University of Genoa, Genoa, Italy, 6Mayo Clinic College of Medicine, Rochester, MN, 7University of Southern California, Los Angeles, CA, United States

Background and objective: Radiologically isolated syndrome (RIS) subjects possess MRI features highly typical for multiple sclerosis (MS) without clinical symptomatology suggestive of CNS demyelination. RIS subjects are frequently exposed to disease modifying therapies despite the lack of evidence-based medicine literature. Earlier treatment intervention may extend the time to the first acute or progressive clinical event resulting from central nervous system (CNS) demyelination and reduce new radiological activity . In addition, early treatment may result in more profound effects on reducing disability progression long-term. The objective of this upcoming investigation is to complete the first randomized, placebo-controlled trial (RCT) to study the efficacy of Tecfidera® in extending the time to a seminal acute or progressive demyelinating event in a cohort of U.S. RIS subjects. Methods: This multi-center, randomized (1:1; placebo:Tecfidera®), double-blinded 2-year trial will target RIS subjects from the United States who fulfill 2009 RIS Criteria. The primary end point (PEP) will be the time to the first acute or progressive neurological event resulting from CNS demyelination from study entry based on power calculations generated from a worldwide dataset (80% power, assumption of a 50% treatment effect: alpha=0.05 (two-sided) over 2 years, sample size n1=81, n2=82). Anticipating a drop out rate near 25%, 210 RIS subjects will be enrolled. We will evaluate the time from the initial MRI revealing incidental anomalies suggestive of multiple sclerosis to the first demyelinating event (acute or initial symptom resulting in a progressive clinical course) utilizing Kaplan-Meier survival analyses. Log-rank tests will be used to compare survival data between groups at univariate analysis. Secondary outcome measures will include the change in the number of new or enlarging T2 lesions, contrast enhancing lesions, T2-lesion volumes, and brain atrophy at 2-years. Environmental exposure, radiological images (brain and spinal cord MRI), cognitive function, and patient reported outcome data will be captured in addition to biological samples for future mechanistic studies. Results: Enrollment will begin in June 2015. Conclusion: This study aims to explore an important initiative of investigating the impact of early treatment intervention in subjects who possess the first visible manifestation of multiple sclerosis.

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Treatment of specific symptoms P1166 Depressive state and chronic fatigue in neuromyelitis optica I. Nakashima1, T. Akaishi1, T. Misu1, K. Fujihara1,2 1Department of Neurology, Tohoku University, 2Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan Background: Depression and chronic fatigue are frequently present in multiple sclerosis (MS); however, the prevalence rates have not been investigated in neuromyelitis optica (NMO). The effectiveness of levocarnitine for fatigue in NMO is also unknown. Material and methods: Thirty-nine consecutive NMO and 75 MS patients at Tohoku University Hospital were compared using self-rating questionnaires for depressive states (self-reported Quick Inventory of Depressive Symptomatology: QIDS-SR), daily activity (Performance Status: PS), and fatigue (Chalder Fatigue Scale: ChFS), as well as serum carnitine levels. A subgroup of patients with low carnitine levels were reevaluated regarding depression and fatigue after levocarnitine treatment. Results: Abnormal QIDS-SR and ChFS scores were identified in 70-80% of both diseases, and the severities of these symptoms were also comparable in MS and NMO. In both diseases, strong correlations were identified between the QIDS-SR and ChFS


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(p < 0.0001), as well as the EDSS and PS (p < 0.0001). Both the QIDS-SR and ChFS exhibited weak correlations with gait disturbance in MS and disease duration in NMO. The carnitine level was decreased in approximately 20% of both diseases; however, it was not correlated with the QIDS-SR or ChFS. Levocarnitine did not improve the QIDS-SR or ChFS. Conclusion: Depression and fatigue are equally prevalent in MS and NMO and are strongly correlated with one another. The measurement of serum carnitine levels and administration of levocarnitine are suggested to be unfounded. Disclosure Ichiro Nakashima: Recieved personal fees from Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Japan, and grants from LSI Medience Corporation. Tetsuya Akaishi: nothing to disclose. Tatsuro Misu: Received speaker honoraria from Bayer Schering Pharma, Biogen Idec Japan, Mitsubishi Tanabe Pharma Corporation, Asahi Kasei Medical Co., and Astellas Pharma Inc. and research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical Co., The Chemo-SeroTherapeutic Research Institute, Teva Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Teijin Pharma, and Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan. Kazuo Fujihara: Received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical and research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, and Genzyme Japan; he is funded as the secondary investigator (#22229008, 2010-2015) by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan and as the secondary investigator by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan. P1167 Effects of prolonged-release fampridine on leg muscle activity during treadmill walking in individuals with multiple sclerosis (FAMPKIN) L. Lörincz1, B. Zörner1, D. Weller1, K. Reuter1, S. Kapitza1, M. Farkas1, T. Sutter1, L. Filli1, M. Linnebank2 1Neurology, University Hospital Zürich and University of Zürich, Zurich, Switzerland, 2Helios-Klinik Hagen-Ambrock, Hagen, Germany Background: Ambulatory impairment is common in individuals with multiple sclerosis (MS). fampridine-PR (4-aminopyridine, prolonged-release formula) leads to increased walking speed in some patients with MS (Goodman et al., 2009, 2010). The mechanisms by which fampridine-PR improves walking speed, e.g. changes in muscle activity or movement patterns, are yet unknown.

Goal: The aim of this sub-study was to investigate the effects of fampridine-PR on walking speed, endurance and leg muscle activity in individuals with MS. Methods: 55 individuals with MS (34 women, 21 men; age: 48.4 +/- 9.7 years; median EDSS = 4.5) were included in this investigator-initiated, randomized, double-blind, controlled phase 2 trial with crossover design, which was supported by Biogen Idec. Walking speed (Timed-25-Foot Walk, T25FW), endurance (6-Minute Walk Test, 6mWT), and muscle activity patterns (activity duration, time point of “on”-set, “off”-set and peak activity) were assessed under treatment with fampridine-PR and placebo. For muscle activity measurements, surface electromyography (sEMG) of the musculus quadriceps femoris, tibialis anterior, gastrocnemius medialis and the hamstrings were recorded bilaterally during walking on a treadmill. Results: Walking speed and endurance were significantly improved during fampridine-PR treatment compared to placebo treatment (Wilcoxon signed-ranked test: P < 0.0001 for T25FW and 6MWT). For all parameters of muscle activity, there were no significant common treatment-induced changes over all patients. However, remarkable subject-specific changes of muscle activity and coordination were found in a subset of patients following treatment with fampridine-PR. Conclusion: Treatment with fampridine-PR improved ambulatory performance in a short- and a long-distance clinical walking test in subjects with MS. Although common effects of fampridinePR on leg muscle activity were absent, subject-specific adaptations of muscle activity were found in many patients and may contribute to an improved walking function during the treatment with fampridine-PR. Disclosure This study was funded by the Betty and David Koetser Foundation, the Clinical Research Priority Program “NeuroRehab” University of Zurich, the Swiss MS Society and Biogen Idec. Björn Zörner and Michale Linnebank received honoraria, grants and funding from Biogen Idec. P1168 Long-term effects of fampridine on walking ability in patients with multiple sclerosis: a double-blind, placebocontrolled, monocenteric phase II study (FAMPKIN-EXT) C. Meyer1, L. Filli1, S. Kapitza1, L. Lörincz1, D. Weller1, M. Farkas1, K. Reuter1, B. Zörner1, M. Linnebank2 1Neurology, University ‘Hospital Zürich and University of Zürich, Zurich, Switzerland, 2Helios-Klinik Hagen-Ambrock, Hagen, Germany Background: Dysfunctions of walking ability are among the major deficits in patients with multiple sclerosis (MS). Treatment with fampridine-PR (4-aminopyridine, prolonged-release formula), a blocker of voltage-gated potassium channels, leads to an increased walking velocity in many patients with MS (Goodman et al., 2009 und 2010). In the FAMPKIN-core-study we observed that fampridine-PR not only improved walking velocity, but also additional aspects of ambulation such as endurance, coordination and physical activity.


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Poster Session 2, 21(S11) Goal: The aim of the present investigator-initiated extensionstudy (supported by Biogen Idec) was to characterize the longterm effects of fampridine-PR on ambulatory function. Methods: Findings of the first year of FAMPKIN-EXT suggest a positive effect of fampridine-PR on walking velocity (Timed-25Foot-Walk, T25FW), endurance (6-Minute-Walk-Test; 6MWT) and the subjective perception of ambulatory function (12-item Multiple Sclerosis Walking Scale; 12MSWS) in 53 patients with MS. These results were based on an open-label, uncontrolled study design in which patients were examined after 11.5 months of continuous fampridine-treatment (twice 10mg per day) and after a two-week washout period. At the end of the second study year, the study design was altered by embedding two randomized, double-blind phases of 2 weeks placebo and fampridine-PR treatment. 34 patients (21 women, 13 men; age 51.5 +/- 9.3 years; EDSS 5.1 +/- 1.4) completed the second year of the extension-study to-date. Results: During the double-blind treatment period, the patients exhibited an increased walking velocity (+ 12.7%; plac: 9.5 +/8.5s; famp: 8.6 +/- 8.3s in T25FW; P = 0.0039), an improved endurance (+ 8.0%; plac: 334 +/- 160m; famp: 354 +/- 155m in 6MWT; P = 0.0254) and an improved self-assessment of ambulatory function (12MSWS; - 5.9 points; plac: 42.2 +/- 12.0 pts; famp: 36.4 +/- 11.8 pts; P = 0.0016). The clinical improvement of walking ability was associated with specific kinematic alterations of the gait pattern during treadmillbased gait analysis. These findings provide valuable insights into the underlying mechanisms of the long-term effects of fampridine-PR. Conclusion: The first two years of the extension-study confirm the long-term efficacy of fampridine-PR in MS patients. Moreover, the data emphasizes the potential of fampridine-PR as a well-tolerated symptomatic long-term treatment for patients with MS-related gait disorders. Disclosure This study was funded by the Betty and David Koetser Foundation, the Clinical Research Priority Program “NeuroRehab” University of Zurich, the Swiss MS Society and Biogen Idec. Björn Zörner and Michael Linnebank received honoraria, grants and fundig from Biogen Idec. P1169 The impact of peripheral nerve field stimulation on treatment of facial pain syndromes including trigeminal neuropathy attributed to multiple sclerosis J. Klein1, J.C. Eisele2, S. Sandi-Gahun1, G. Schackert1, T.A. Juratli1 1Neurosurgery, 2Neurology, University Hospital Carl Gustav Carus, Dresden, Germany Objective: Facial pain may pose a significant therapeutic challenge once the first line medical therapy has failed. Secondary pain syndromes, such as trigeminal neuropathy attributed to multiple sclerosis, may be particularly difficult to treat as established surgical options are limited to destructive procedures. Peripheral nerve field stimulation has been reported to be a promising modality for treatment of intractable facial pain. However, evidence is

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sparse. We therefore present our experiences with this minimally invasive and reversible technique in a small patient cohort. Methods: Records of ten patients who underwent implantation of one or several subcutaneous electrodes for trigeminal nerve field stimulation (Medtronic Pisces Quad Plus, IPG: PrimeAdvanced) were analysed. Patients’ data, including pain location, etiology, duration, previous treatments, long-term effects and complications, were evaluated. Results: Two patients suffered from trigeminal neuropathy attributed to multiple sclerosis. Other syndromes were classical trigeminal neuralgia not treatable by microvascular decompression, persistent idiopathic facial pain, post-herpetic neuropathy and trigeminal neuropathy following radiation therapy. Average patient age was 74.2 years (range 57-87), and average symptom duration was 10.6 years (range 2-17). Eight patients proceeded to implantation after successful trial. Average follow-up after implantation was 11.3 months (range 5-28). Using the visual analogue scale, average pain intensity was 9.3 (range 7-10) preoperatively and < 1 (range 0-3) postoperatively. Six patients reported absence of pain with stimulation; two had only a slight constant pain without attacks. Complications were minor and comprised an electrode defect which entailed replacement, a wound breakdown requiring a local revision, and an IPG-dislocation without surgical consequence. Conclusion: Peripheral nerve field stimulation may be effective treatment option for refractory trigeminal neuropathic pain when established therapies have failed. Likewise, a patient with atypical facial pain showed significant reduction in pain intensity. Two more patients with trigeminal neuropathy attributed to multiple sclerosis are currently scheduled for trial stimulation and final implantation, respectively, and will be reported on once follow-up data is available. Disclosure Johann Klein: nothing to disclose. Judith Eisele: nothing to disclose. Sahr Sandi-Gahun: nothing to disclose. Gabriele Schackert: nothing to disclose. Tareq A. Juratli: nothing to disclose.

P1170 Compound functional improvement after treatment with nabiximol in multiple sclerosis G. Coghe1, M. Pau2, F. Corona2, G. Illomei3, J. Frau1, L. Lorefice1, G. Fenu1, E. Mamusa4, G. Spinicci4, M.G. Marrosu5, E. Cocco1 1Department of Public Health, Clinical and Molecular Medicine, 2Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, 3Studio Radiologico del Corso, 4ASL8, 5University of Cagliari, Cagliari, Italy Background: Recently, Nabiximol was approved as a treatment in MS spasticity. However, most data leading to its approval and clinical use, although widely recognised, are based on subjective scales. Objective: To quantitatively assess the functional modifications in spasticity induced by Nabiximol in MS.


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Methods: A group of patients were enrolled. Inclusion criteria were a diagnosis of MS according to the 2010 McDonald criteria, being able to walk for at least 6 m regardless of the use of aids and the ability to assume Nabiximol according to medical judgment and the Italian drugs agency (AIFA) criteria. All patients were non-responders to previous spasticity treatments. For each patient were evaluated,Numeric rating scale (NRS), three-dimensional gait analysis (spatial-temporal and kinematic) and ultrasound elastography of the rectus femoris at baseline (T0-T1) and after one month of Nabiximol. Kinematic data were expressed means of Gait Profile Score (GPS) and real time elastography was scored with scale from 0 (no stifness) to 5 (maximum stiffness). Variation of each parameter (from T0 to T1) was evaluated at by means of one-way ANOVA. Results: Twenty patients were enrolled - 9 male and 11 female with mean EDSS of 5.3 (SD ± 0.81) and mean reduction of NRS during Nabiximol of 1.88 (NRS response rate was 65%). The spatial-temporal parameters of gait revealed an increase in speed (+15%, p < 0.001), cadence (+6%, p < 0.001) and stride length (+10%, p < 0.001) after treatment. Regarding the kinematics data, the GPS after treatment was reduced by 10% (p < 0.001): Significant changes involved the pelvic district, hip rotation and knee flexion-extension. All patients showed an improvement at real time elastography examination with a mean reduction of 1.0 point (p< 0.001). Conclusion: We found that treatment with Nabiximol is able to improve speed, cadence and stride length. The kinematic of gait patterns results closer to the physiologic values. Furthermore the real time elastography showed significant morphological changes in muscular stiffness. What is more interesting is that the results concern an heterogeneous group of patients composed by NRS responder and nonresponders suggesting that the effects of the drug are more complex that a “pure” antispastic action. Disclosure The authors have nothing to declare about this work. P1171 A final report of an observational post-marketing safety registry of patients primarily from the United Kingdom who have been prescribed an oromucosal spray containing Δ9-tetrahydrocannabinol and cannabidiol (THC:CBD) T. Etges, A. Taylor, K. Karolia, H. Lauder, B. Daka, S. Wright GW Pharmaceuticals, Cambridge, United Kingdom Introduction: THC:CBD oromucosal spray (Sativex) was first granted market approval in Canada April 2005, and the United Kingdom (UK) in June 2010, for the treatment of resistant Multiple Sclerosis (MS) spasticity; safety exposure is now estimated to be above 45,000 patient years. As a postmarketing Risk Management Plan commitment, an observational registry to collect patient safety data on patients receiving the THC:CBD oromucosal spray was set up following its approval in the UK, followed later by Germany and Switzerland, with the aim of determining the long term safety in clinical practice. Methodology: Twice a year the registry was opened to prescribing physicians. Where possible all prescribers of the THC:CBD

oromucosal spray in the UK and selected MS centres in Germany and Switzerland were invited to voluntarily report data on patients’ use of the spray and events of special interest. Targeted questions were asked relating to significant psychiatric adverse events (AEs), falls requiring medical attention, suicidality, drug abuse liability, dependence and driving ability. This is a final report following the main Registry closure in the UK after advice from the Regulatory Agency concluded sufficient data had been obtained from UK patients to characterise the long term safety profile. The Registry remains open in Germany and Switzerland. Results: Overall the data comprises the follow-up of 941 patients covering 2200 patient-years of exposure, 761 were from the UK (of 3493 eligible), 178 from Germany and 2 from Switzerland. The mean and median daily doses were 5.4 (SD 4.89) and 4.4 sprays respectively. Females comprised 57% and males 43% of patients, the mean age was 51 years (SD 10.83). Within this cohort 83% reported benefit from the treatment. A total of 32% of the patients stopped treatment; approximately ⅓ due to lack of effectiveness and ¼ citing AEs. Psychiatric AEs of significance were reported in 6% of the patients, suicidality was 2% and 6% reported falls that required medical attention. Driving ability worsened in 2% of patients, but improved in 7%. Other commonly reported AEs included dizziness (3%), depression (3%), and fatigue (2%). There were no signals to indicate abuse, diversion or dependence. Conclusions: The long term risk profile is in-keeping with the known (labelled) safety profile of Sativex and this data supports Sativex being a well-tolerated and effective medication for the treatment of resistant MS spasticity. Disclosure T. Etges Shareholder: Has Shares with GW Pharmaceuticals (study sponsor) / Directorship(s): Director of Pharmacovigilance at GW Pharmaceuticals (study sponsor) / other: Employed by GW Pharmaceuticals (study sponsor). A. Taylor other: Employed by GW Pharmaceuticals (study sponsor). K. Karolia Shareholder: Has Shares with GW Pharmaceuticals (study sponsor) / other: Employed by GW Pharmaceuticals (study sponsor). H. Lauder Shareholder: Has Shares with GW Pharmaceuticals (study sponsor) / other: Employed by GW Pharmaceuticals (study sponsor). B. Daka Shareholder: Has Shares with GW Pharmaceuticals (study sponsor) / other: Employed by GW Pharmaceuticals (study sponsor). S. Wright Shareholder: Has Shares with GW Pharmaceuticals (study sponsor) / Directorship(s): Research and Development Director at GW Pharmaceuticals (study sponsor) / other: Employed by GW Pharmaceuticals (study sponsor)

P1172 Using a wrist worn motion sensor to identify and quantify upper limb tremor in people with multiple sclerosis S. Teufl1, B. Stansfield1, F. van Wijck1, J. Preston1,2 1School of Health and Life Science, Glasgow Caledonian University, Glasgow, 2MS Service Ayrshire & Arran, Irvine, United Kingdom


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Poster Session 2, 21(S11) Introduction: More than 25% of people with Multiple Sclerosis (MS) experience tremor, which considerably affects quality of life. There is currently no objective measurement for tremor characteristics. This proof-of-concept project used a wrist-worn motion sensor to establish an objective measurement of tremor in people with MS. Methods: Five participants with tremor due to MS and 10 controls performed standardised tasks (ARAT/FAHN) wearing a wrist-worn motion sensor (AX3). Motion capture was used to validate the sensor-output. Frequency content of the signal was examined in Matlab, using Fast-Fourier-analysis in all three axes. Frequency content above 3Hz was identified, as it was hypothesised that this would only be apparent during periods of observed tremor and not in control participants. An Occupational Therapist rated tremor according to clinical scales as gold standard for tremor detection. Results: Where tremor was observed to occur it was possible to detect it using a simple frequency cut-off. A 100% detection rate with no false positives was achieved in this initial sample. Examination of all three axes for evidence of tremor ensured all occurrences of tremor were detected. In contrast using the resultant acceleration signal did not allow the detection of all instances of tremor. None of the control data produced false positive results. Only in an activity designed to simulate tremor did the detection algorithm show the presence of tremor. There were no differences in the outcomes of the sensor and motion capture. Conclusion: The results provide encouragement that a simple tremor detection algorithm may be possible in those with MS. This algorithm should be implemented on data of each individual axis of acceleration data. This on-going project will test the algorithm in a wider group of people with MS associated tremor to ensure wide applicability. This solution will allow multi-day, freeliving tremor monitoring to assess the effectiveness of interventions. Disclosure This study is funded by the Multiple Sclerosis Society. Stefan Teufl: nothing to disclose; Dr Ben Stansfield: nothing to disclose; Dr Jenny Preston: nothing to disclose; Prof Frederike van Wijck: nothing to disclose P1173 Evaluating the effect of enhanced physical activity and energy management on fatigue in patients suffering from multiple sclerosis: the MS TeleCoach study M. D’hooghe1, G. Van Gassen2, D. Kos3, B. Van Wijmeersch4, B. Willekens5, D. Decoo6, M. Cambron7, I.-K. Penner8, P. Vanderdonckt9, J. Debruyne10, R. Crols11, A. Lysandropoulos12, S. Elsankari13, P. Seeldrayers14, A. Mélin15, P. Laloux16, O. Bouquiaux17, R. Reznik18, G. Nagels1,7 1NMSC, Melsbroek, 2Teva Pharma Belgium, Wilrijk, 3Health Care/Occupational Therapy, Artesis University College Antwerp, Antwerpen, 4MSreva, Overpelt, Overpelt, 5UZA, University of Antwerp, Antwerpen, 6AZ Alma, Sijsele, 7Center for Neurosciences, UZBrussel, VUB, Brussel, Belgium, 8Department of Cognitive Psychology and Methodology, University of Basel, Basel, Switzerland, 9AZ Groeninge, Kortrijk, 10UZ Gent, Gent, 11ZNA Middelheim, Antwerpen, 12Hôpital Erasme, ULB,

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Universitaires Saint-Luc, UCLouvain, Bruxelles, Charleroi, Charleroi, 15CHC Clinique Saint-Joseph, Liège, 16CHU Mont-Godinne, UCLouvain, Godinne, 17Centre Hospitalier de l’Ardenne, Vivalia, Libramont, 18Centre Neurologique de de Réadaptation Fonctionelle, Fraiture, Belgium 14CHU

Background: There is a great potential for telehealth, in which telemonitoring of a clinical parameter is combined with remote follow-up of a therapeutic intervention, in multiple sclerosis (MS) care. Fatigue in the context of MS is a complex symptom that affects 75-95% of all patients, of which 50-60 % classify fatigue as interfering most seriously with the activities of daily life. Aim: This pilot telehealth study evaluated whether telecoaching with a focus on energy management and enhancement of physical activity was able to improve fatigue in MS patients with moderate to severe fatigue during a 12 week-period. Methodology: 70 MS patients with moderate to severe fatigue were evaluated over 12 weeks in their home setting, with 4 assessments. Inclusion criteria were: having relapsing remitting MS, an EDSS of 4 or lower, treatment with glatiramer acetate for at least 6 weeks and a score of 53 or higher on the Fatigue Scale for Motor and Cognitive functions (FSMC). Patients with age 60 or above, with MDD, with severe cognitive impairment, injuries and pregnant patients were excluded. In a 2 week run-in period, daily activity was measured using the mobile MS TeleCoach handhold device. During the 12 week follow-up phase, fatigue was measured 3 times a day using the VAS impact on fatigue question and physical activity was continuously monitored via an integrated accelerometer in the MS TeleCoach. Patients receive coaching advice thrice weekly to enhance their physical activity (gradually increasing by 5 % versus baseline, every 3 weeks) compared to their baseline physical activity. Clinical status of the patient and 5 outcome measures (FSMC, Modified Fatigue Impact Scale, Short Form-36, Hospital Anxiety Depression Scale and Illness Perception Scale) were assessed at all visits. Results: The mean difference in total FSMC score between end and start of the study was -6.37 (p=0.000056). The mean difference in the cognitive subscale of the FSMC score between end and start of the study was -2.9 (p=0.0011) and the mean difference in the motor subscale of the FSMC score between end and start of the study was -3.46 (p=0.00074). For the cognitive subscore, the mean FSMC score changed from severe to moderate fatigue classification. Further analysis differentiates between responders and non-responders to this telemedicine approach. Conclusion: A telehealth intervention using the MS TeleCoach device significantly decreased fatigue in Ms patients assessed with the FSMC. Disclosure This study is sponsored by Teva Pharma Belgium. GVG is a full-time employee of Teva Pharma Belgium. GN has received travel grants and scientific grants from Teva Pharma, Biogen, Merck, Sanofi, Novartis and Bayer. MB D’hooghe received honoraria as part of a consultancy agreement from Allergan, Bayer-Schering, Biogen Idec, Merck-Serono, Novartis and Sanofi-Aventis-Genzyme. She received travel or


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speaker honoraria from Biogen Idec, Bayer, Merck-Serono, Novartis and Teva. MC has nothing to disclose. IKP has received research grants from Bayer Switzerland AG and the Swiss Multiple Sclerosis Society and has received honoraria for serving as speaker at scientific meetings, consultant, and as member of scientific advisory boards for Actelion, Bayer Pharma AG, Biogen Idec, Genzyme, Merck Serono, Novartis and Teva. DK has nothing to disclose. BW has served as a member of advisory boards of Biogen-Idec, Genzyme, Bayer, Merck-Serono, Novartis, has been lecturer in meetings sponsored by BiogenIdec, Novartis, Bayer, for which she received financial compensation and she has been supported for travel to conferences by Biogen-Idec, Merck-Serono, Bayer, Novartis, TEVA. DC has been invited and received speaker and consultancy fees of Bayer-Scherign, Biogen-Idec, Merck- Serono, Novartis, Roche, Sanofi-Genzyme, Teva and UCB. BVW has nothing to disclose. RC has been invited to congresses by Teva, Merck Serono, Biogen, Novartis, Merck, Genzyme. JDBr received travel grants and scientific grants and as member of scientific advisory boards from Teva Pharma, Biogen, Bayer, Genzyme, Merck Serono, Novartis. D. Decoo has received compensations for industry-driven trials by Bayer, Biogen, Merck, Medtronic, Newron, Novartis, Sanofi, Teva and consultation honorary by Biogen, Merck, Novartis, Sanofi & Teva. AM has received travel grants and research support from SanofiGenzyme, Bayer-Schering, Merck Serono, Teva Pharmaceuticals, Novartis and Biogen Idec. P1174 A systematic appraoch for the evaluation of neurogenic bladder in MS patients A. Miravalle, S. Sillau, B. Valdez, K. Jerkins, B. Flynn University of Colorado, Aurora, CO, United States Background: Urinary system symptoms are present in 50-90% of MS patients, causing a negative effect on the quality of the individual’s social, occupational and sexual life. Currently, there are no published guidelines for the evaluation of MS patients with neurogenic bladder. The present study provides evidence-based guidelines for the evaluation and risk stratification for these patients. Methods: We developed a systematic approach for the assessment of neurogenic bladder in MS patients. All patients that met inclusion criteria received a bladder ultrasound, UA, and QOL questionnaires. These questions are part of Multiple Sclerosis Quality of Life Index (MSQLI), and NeuroQOL. Based on the results of the questionnaire, clinical risk factors (presence of spinal cord disease, male gender, disease duration over 15 years) and bladder ultrasound, patients were randomized to standard of care evaluation in clinic (group 1) or referral to urology for urodynamic studies (groups 2). Results: Seventy patients were enrolled. All patients met inclusion criteria and complete the entire list of questionnaires. Twelve patients had a UTI at baseline, and had to be re-enrolled after UTI was treated. Seventy five percent of patients (n=40) met criteria for randomization in group 2 and had a subsequent follow up with Urology. Of those patients, 26% had greater than 150 cc on

post-void residual (PVR). MSQLI results for all patients enrolled in the study was 4, suggesting a significant impact on QOL from neurogenic bladder symptoms (range 0-12). There was a strong correlation between female gender and risk of UTI (p=0.04). There was some evidence of association between disease duration and UTI (p=0.0759 (99% CI ( 0.0738, 0.0781). Conclusion: This study provides a practical approach for the evaluation of patients with neurogenic bladder. Preliminary data from the first round of evaluation suggest a high incidence of symptoms or impact on QOL from MS patients (75%). Interestingly, this study was able to identify significant impact on QOL before patient’s PVR reached abnormal levels. Further evaluation of outcomes will continue as patients complete standard of care urological follow up visits. Disclosure No significant potential conflict of interest disclosures for this study

P1175 Efficacy of fampridine modified-release on ambulation in neuromyelitis optica: a pilot study K.P. Mutch1, M. Wilson1, R. Manohar2, S. Zhao1, H. Leggett3, S. Hamid1, L. Elsone1, A. Jacob1 1Neuromyelitis Optica, 2Neurophysiology, 3NeuroResearch Centre, Walton Centre NHS Trust, Liverpool, United Kingdom Background: Transverse myelitis (TM) associated with Neuromyelitis Optica (NMO) can be severe and is well known to reduce mobility early in the disease. Fampridine Modified-Release (MR) 10mg tablets twice daily, is a potassium channel blocker that improves walking speed in MS in 25-35% of patients. Its use has not been reported in NMO. Goals: To perform a pilot unblinded study assessing the safety and efficacy of Fampridine-MR in patients with ambulatory deficits due transverse myelitis associated with NMO. Study design: 25 participants with definite NMO were identified through purposive sampling from the UK NMO service. Following screening and assessment for eligibility, 16 participants (13 AQP4-IgG positive) took Fampridine-MR 10mg tablet twice daily for 8 weeks. Primary endpoint was consistency of improvement in timed 25feet walk (T25FW). Response was defined as faster speeds for two on-treatment measurements compared to three off treatment measurements (two pre- taking fampridineMR and one post-fampridine-MR). Repeated t-test was used to compare on-treatment measurements against off-treatment. Secondary outcome was the Twelve Item Multiple Sclerosis Walking Scale (MSWS-12), a self-assessment tool for patientreported walking ability. Results: Of the 16 patients, 13 (81%) were female and the median age was 55yrs (range 23-69). One patient was excluded from analysis as she had a relapse while on treatment. The remaining 15 patients were analysed with intention to treat (2 did not complete follow-up due to adverse reactions but were included in analysis). Three patients (20%) responded. The mean percentage increase in T25FW compared to off-treatment was 53% in responders. MSWS-12 improved by 8 points compared to pre-treatment in the responder group.


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Poster Session 2, 21(S11) Conclusion: Fampridine-MR 10mg appears safe in NMO. Improvement in walking speed and MSWS occurred in 20 % of patients, similar to MS. Disclosure Kerry Mutch: nothing to disclose Martin Wilson: nothing to disclose radhika Manohar: nothing to disclose Sizheng Zhao: nothing to disclose Helen Leggett: nothing to disclose Shahd Hamid: nothing to disclose Liene Elsone: nothing to disclose Anu Jacob: received honoraria related to clinical trial advisory boards from Chugai and Shire pharmaceuticals and speakers honoraria from Chugai, Biogen and Terumo BCT. This study was supported by a research grant from Biogen.

P1176 Genome-wide pharmacogenomic study of response to cannabinoids in MS spasticity patients J.L. Ruiz Peña1, A. González-Pérez2, S. Eichau1, M.I. GarciaSanchez1, M.E. Saez2, M. Rus1, M. Lucas Lucas3, A. Alcina4, F. Matesanz4, G. Izquierdo Ayuso1 1MS Clinic, Department of Neurology, Hospital Virgen Macarena, 2Centro Andaluz de Estudios Bioinformáticos (CAEBi), 3Universidad de Sevilla, Sevilla, 4Instituto de Parasitología y Biomedicina ‘López Neyra’, CSIC, Granada, Spain Background: THC:CBD oromucosal spray is increasingly being used to treat resistant spasticity in patients with multiple sclerosis (MS) but a proportion of individuals do not respond. We aimed to identify genetic determinants of lack of response to THC:CBD spray in patients with MS spasticity (MSS). Methods: After prospective observational clinical follow-up in MSS patients on a ‘trial of therapy’ with THC:CBD spray, we performed a Genome Wide Association Study (GWAS). Affymetrix 6.0 chips and Plink software were used to identify single nucleotide polymorphisms (SNPs) that could predict response. Results: 36 MSS patients were evaluable: 25 responders (-20% on spasticity 0-10 Numerical Rating Scale [NRS] score after 4 weeks, 69%), 9 non-responders, and 2 patients who did not tolerate treatment. Mean age was 50 y; 70% were female. Initial mean Expanded Disability Status Score was 6.8 and mean NRS was 7.8. MS types were: Secondary Progressive 70%, Primary Progressive 21%, and Relapsing Remitting 9%. At 4 weeks, responders had a mean NRS score of 5.5. After strict quality control, 703,436 SNPs were analyzed. Five SNPs had p-values below 10^-5, corresponding to 3 distinct signals in chromosomes 4, 5 and 6. Signal 1 (rs10018930 and rs10033229, p=6.55 10^-6) in chromosome 4 was located within the large first intron of the ELOVL fatty acid elongase 6 gene (ELOVL6), encoding an enzyme that catalyzes synthesis of saturated and monounsaturated fatty acids. Allele frequency (identical in both markers) was 12% and 67% among responders and nonresponders, respectively. Signal 2 in chromosome 5 was located at two DNase clusters 20kb downstream the gene SEMA6A, which encodes a member of the semaphoring family previously implicated in MS. This signal encompasses two different SNPs

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(rs11241390, p=3.23 10^-6; rs17139724, p=5.21 10^-7) both monomorphic in responders and with allele frequencies in nonresponders of 39% and 44% respectively. Signal 3 was observed in chromosome 6 (rs7763280, p=5.48 10^-6) within the genomic sequence of the LYRM4 gene transcripts variants 1 and 3, a gene associated with inflammatory bowel disease, an autoimmune disorder that shares pathogenic pathways with MS. Allele frequency was 32% and 94% among responders and non-responders. Conclusion: This is the first GWAS on response of MSS patients to cannabinoids. Some results may be extrapolated to pharmacological response to cannabinoids in treatment of other diseases. Disclosure JLRP has received speaking honoraria from Novartis GIA has received honoraria or consultation fees from Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis, Teva, Novartis, Genzyme, and Almirall. The rest of authors have nothing to declare P1177 Multicenter, prospective, observational study aimed at evaluating SAtivex efFEcts (effectiveness and tolerability) in a large population of Italian multiple sclerosis patients: SA.FE. study F. Patti1, S. Messina1, M.P. Amato2, M.D. Benedetti3, R. Bergamaschi4, A. Bertolotto5, S. Bonavita6, R. Bruno Bossio7, V. Brescia Morra8, P. Cavalla9, D. Centonze10, G. Comi11, S. Cottone12, M. Danni13, A. Francia14, A. Fuiani15, C. Gasperini16, A. Ghezzi17, A. Iudice18, G. Lus19, G.T. Maniscalco20, M.G. Marrosu21, M. Mirabella22, E. Montanari23, C. Pozzilli24, M. Rovaris25, E. Sessa26, D. Spitaleri27, M. Trojano28, P. Valentino29, M. Zappia1, C. Solaro30 1University of Catania, Catania, 2Department NEUROFARBA, University of Florence, Florence, 3University of Verona, Verona, 4Fondazione Istituto Neurologico C. Mondino, Pavia, 5CRESM, Ospedale san Luigi Gonzaga, Orbassano, 6I Clinc of Neurology, II University of Naples, Naples, 7Provincial Health Authority of Cosenza, Operating unit Neurology and Center Multiple Sclerosis, Cosenza, 8University Federico II, Naples, 9University of Torino, Torino, 10MS Clinical and Research Center, Tor Vergata University, Rome, 11San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, 12Multiple Sclerosis Center Department of Neurology, A.O.O.R. Villa Sofia-Cervello, Palermo, 13Azienda Ospedali Riuniti, Ancona, 14’Sapienza’ University of Rome, Multiple Sclerosis Center Department Neurol. Psich., Rome, 15University of Foggia, Foggia, 16Ospedale San Camillo Forlanini, Rome, 17Ospedale S. Antonio Abate, Gallarate, 18Azienda Ospedaliero Universitaria Pisana, Pisa, 19Department of Clinical and Experimental Medicine and Surgery ‘F Magrassi e A Lanzara’, Second University of Naples, 20Multiple Sclerosis Centre of AORN ‘A. Cardarelli’, Naples, 21Department of Medical Sciences, University of Cagliari, Cagliari, 22Università Cattolica del Sacro Cuore, Rome, 23Ospedale civile di Fidenza, Fidenza, 24Ospedale S. Andrea, Rome, 25Multiple Sclerosis Center - Neurorehabilitation Unit Scientific Institute Santa Maria Nascente, Fondazione Don Carlo Gnocchi, Milan, 26IRCCS - Centro Neurolesi Bonino Pulejo, Messina, 27UOC Neurologia AORN San G. Moscati, Avellino, 28University of Bari, Bari, 29University ‘Magna Graecia’,


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Catanzaro, 30Als3 Genovese, Neurology Unit Department Head and Neck, Genova, Italy Background: Spasticity is a common disabling symptom of multiple sclerosis (MS). The approval of THC:CBD oromucosal spray provides a new option for resistant to other medications moderate to severe MS spasticity. Since introduction in Italy in Q3 2013 a web-based official registry collects data from all prescribed patients. Aim: To describe effectiveness and tolerability of THC:CBD oromucosal spray use in daily practice in a large Italian population. Methods: We collected data from the e-registry between Jan ‘14 and Feb ‘15. Spasticity evolution in the 0-10 NRS scale is available at baseline 1 (trial period) and 6 months. Other parameters such as treatment discontinuation, tolerability and daily dose have been collected. Results: 30 large MS centers provided data from 1534 patients. Mean age: 51.0 y (SD 9.6), gender: 52.8% female, mean MS duration 17.6 y (SD 8.6), EDSS mean score 6.4 (SD 1.2), MS type: 63.7% SP, 19.9% RR, 16.1% PP. A total of 1350 patient reached 1st month visit. Out of the 1534 patients, 61.9% of patients continued treatment after proving enough effect (>20% spasticity improvement from baseline) and acceptable tolerability. About 25%of patients showed NRS improvement over 30%. From the discontinuing, 51% reported lack of effectiveness, 31.5% tolerability and 8% reported both. Main adverse events leading to discontinuation after 1 month were cognitive/psychiatric (43/242), fatigue (42/242), drowsiness (41/242), dizziness (31/242), gastrointestinal related symptoms (22/242) and oral discomfort (10/242). A total of 559 patients reached the 6 months visit at analyses date (41.4% from possible). Two hundred twenty-five patients (40.2%) reached NRS improvements over 30% at 6 months. The mean number of puffs were 6.8±2.6 (1st month) and 6.2±2.8 (6th month, p< 0.0001). Five serious adverse events were reported (1 renal failure, 1 death for acute myocardial infarction, 1 hypertensive crisis, 1 laryngeal carcinoma and 1 breast cancer). Multivariate analysis showed patients in progressive MS (80% of sample) have higher chances to improve vs. RR MS patients (OR 1.5, p=0.002, 95% CI 1.2-2.0). Conclusion: THC:CBD oromucosal spray is effective and well tolerated in the management of resistant MS spasticity. Strict use of the trial period helps the responders’ selection. Patients’ improvement is slightly better in practice than in clinical trials, with lower mean doses. No herbal cannabis-related risks (abuse, diversion) found. Disclosure Dr Patti has received honoraria for scientific lectures and travel payment from Biogen Idec, Novartis, Teva, Genzyme, Bayer Schering, Merck Serono, Almirall. Dr Messina has received honoraria for scientific lectures form Biogen Idec, Almirall and travel payment from Novartis, Biogen Idec, Genzyme, Almirall Bayer Schering, Merck Serono. Prof. Maria Pia Amato serves on scientific advisory boards for Biogen Idec, Merck Serono and receives speaker honoraria and research support from Biogen Idec, Merck Serono, Novartis, Almirall and Genzyme. Dr Benedetti has nothing to disclose

Dr Bergamaschi has received honoraria for scientific lectures and travel payment from Biogen Idec, Novartis, Teva, Genzyme, Bayer Schering, Merck Serono, Almirall. Dr Bertolotto has received honoraria for scientific lectures and travel payment from Biogen Idec, Novartis, Teva, Genzyme, Bayer Schering, Merck Serono, Almirall. Dr Bonavita received speaker and advisory board honoraria from Biogen, Novartis and Merck-Serono Dr Bruno Bossio received gran for advisory board activities from Almirall Dr Brescia Morra has received honoraria for scientific lectures and travel payment from Biogen Idec, Novartis, Teva, Genzyme, Bayer Schering, Merck Serono, Almirall. Dr Cavalla has nothing to disclose Dr. Diego Centonze is an Advisory Board member of Almirall, Bayer Schering, Biogen, Genzyme, GW Pharmaceuticals, Merck-Serono, Novartis, Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen Idec, Genzyme, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi-Aventis, Teva. He is also an external expert consultant of the European Medicine Agency (EMA), and the principal investigator in clinical trials for Bayer Schering, Biogen Idec, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-aventis, Teva. His preclinical and clinical research was supported by grants from Bayer, Biogen, Merck Serono, Novartis e Teva. Dr Comi has received honoraria for scientific lectures from Biogen Idec, Novartis, Teva, Genzyme, Bayer Schering, Merck Serono, Almirall. Dr Cottone has nothing to disclose Dr Danni has nothing to disclose Dr Francia received grant for advisory board activities from Almirall Dr Fuiani has nothing to disclose Dr Gasperini received honoraria from Biogen, Genzyme, Novartis, Merck Serono, Almirall, Teva Dr Ghezzi received honoraria from Biogen, Genzyme, Novartis, Merck Serono, Almirall, Teva Dr Iudice has nothing to disclose Dr Lus received honoraria from Biogen, Genzyme, Novartis, Merck Serono, Almirall, Teva Dr Maniscalco received speaking and advisory honoraria from Biogen, Novartis and Teva Dr Marrosu has received speaker honoraria and honoraria for serving on advisory board activities from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis and Teva, and research grants from Merck Serono and Novartis. Dr Mirabella received honoraria from Biogen, Genzyme, Novartis, Merck Serono, Almirall, Teva Dr Montanari received honoraria from Biogen, Genzyme, Novartis, Merck Serono, Almirall, Teva Dr Pozzilli received honoraria for scientific lectures from Biogen Idec, Novartis, Teva, Genzyme, Bayer Schering, Merck Serono, Almirall. Dr Rovaris received honoraria from Biogen, Genzyme, Novartis, Merck Serono, Almirall, Teva Dr Sessa received honoraria from Biogen, Genzyme, Novartis, Merck Serono, Almirall, Teva Dr Spitaleri has nothing to disclose


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Poster Session 2, 21(S11) Dr Trojano received honoraria for scientific lectures from Biogen Idec, Novartis, Teva, Genzyme, Bayer Schering, Merck Serono, Almirall. Dr Valentino has nothing to disclose Dr Zappia has received compensation for consulting services from Boehringer-Ingelheim, Lundbeck, Union Chimique Belge and scientific grants from AIFA- Agenzia Italiana del Farmaco, Novartis, Lundbeck Dr Solaro received honoraria from Biogen, Genzyme, Novartis, Merck Serono, Almirall, Teva P1178 Effects of fampridine in MS patients with walking disability on gait parameters F.A. Rodriguez-Leal, K. Thomas, J. Eisele, R. Kern, T. Schultheiss, T. Ziemssen Multiple Sclerosis Center, Center of Neurological Science. University Hospital Carl Gustav Carus, Dresden, Germany Introduction: Multiple Sclerosis (MS) is a chronic inflammatory and degenerative disease, often presenting with gait impairment. Fampridine is a symptomatic treatment used in MS patients with an EDSS score between 4-7, but less than 50% are responders in clinical studies. Longterm outcome is not known in these patients. Objective: To monitor multimodally the longterm outcome of gait in MS patients treated with Fampridine up to three years. Methods: Multimodal gait assessment was performed by an electronic walkway system (GAITRite), the Timed-25 Foot Walk Test, the 2-minute walk test and the Multiple Sclerosis Walking Scale-12 at the beginning of the treatment, 2 weeks after beginning of treatment and every year. Functional Ambulation Profile (FAP) was used as main parameter for gait analysis with GAITRite. FAP is calculated using velocity, step and leg length ratio, step time, asymmetry of step length and dynamic base of support. Results: 158 patients were included, of which 98 (68%) were female and 60 (32%) were male. Mean age of patients was 53.65 (± 10.99 SD), mean EDSS was 5.16 (± 1.34 SD) and 5.3 (+ 1.14 SD) for responders and non-responders, respectively. 67 patients (42,41%) were patients with diagnosis of RRMS, 52 (32,91%) had diagnosis of SPMS and 39 (24,68%) had diagnosis of PPMS. Population was divided in responders and non-responders to Fampridine. In GAITRite analysis, all responders showed an increase in FAP score by 5% (p=0.07, two-tailed t-Test), and a significant increase in Velocity from a mean of 68.46 (+34.25 SD) to 82.43 (+38.7 SD, p< 0.05 two-tailed t-Test) and Cadence from 85.66 (+26.95 SD) to 93.01 (+97.88 SD, p< 0.05 two-tailed t-Test), at baseline and after the first two weeks, respectively. After one year, a significant decrease was detected as part of the progressive disease process. PPMS Responders demonstrated greater decrease from the second year on. SPMS and RRMS responders also showed this decrease over time after two years, but less pronounced. From the start on, non-responders showed clear decrease in FAP score over time, most remarkable during the first year. Conclusion: in a large cohort in real world, Fampridine has shown significant improvement in gait parameters in responding MS patients. Long-term effects showed a relative improvement in gait parameters in patients responding to Fampridine, while

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disease progression recorded as worsening of EDSS or FAP score affected all patients negatively. Disclosure Francisco Rodriguez-Leal: nothing to disclose. Katja Thomas: has received honorarium from Novartis, Bayer and Biogen idec. Judith Eisele: nothing to disclose Raimar Kern: nothing to disclose Thorsten Schultheiss: nothing to disclose Tjalf Ziemssen: is on the scientific advisory board for Bayer Healthcare, Biogen Idec, Novartis, Merck-Serono, Teva, Genzyme, and Synthon; has received speaker honorarium from Bayer Healthcare, Biogen Idec, Genzyme, MSD, GSK, Novartis, Teva, Sanofi, and Almirall; and has received research support from Bayer Halthcare, Biogen Idec, Genzyme, Novartis, Teva, and Sanofi.

P1179 Is fatigue associated with impaired walking in patients with multiple sclerosis? U. Dalgas1, M. Langeskov-Christensen1, A. Skjerbæk2, E. Jensen2, I. Baert3, P. Feys3 1Aarhus University, Aarhus, 2The Danish MS Hospitals in Ry and Haslev, Ry, Denmark, 3BIOMED, REVAL Rehabilitation Research Institute, Hasselt University, Hasselt, Belgium Background: It is unclear whether a relationship between fatigue and walking performance exists in patients with multiple sclerosis (MS). Objective: To investigate whether an association exists between fatigue and walking impairment in a large group of MS patients covering a wide range of age and disability levels. Methods: A cross-sectional multicenter study design was applied. Ambulatory MS patients (Expanded Disability Status Scale (EDSS) 0-6.5; n = 189) were tested at 11 sites. Objective tests of walking performance included short walking tests (Timed 25-Foot Walk (T25FW), 10-Metre Walk Test (10mWT) at usual and fastest speed and the timed up and go (TUG)), while the long walking tests included (the 2- and 6-Minute Walk Tests (MWT)). Subjective walking performance was tested applying the Multiple Sclerosis Walking Scale (MSWS). Fatigue was measured by the modified fatigue impact scale (MFIS) consisting of a total (MFIStotal) and three subscales (MFISphysical, MFIScognitive and MFISpsychosocial). Uni- and multivariate regression analysis were performed to evaluate whether a relationship existed. Results: MFIStotal was negatively associated with long (6MWT) and composite (TUG) walking measures. MFISphysical showed a significant albeit weak relationship to walking speed in all walking capacity tests, which persisted in the multivariate linear regression analysis. Subjective walking performance (MSWS) was related to MFIStotal as well as to all other subscales of MFIS, showing stronger relationships than objective measures of walking. Conclusions: Physical fatigue is weakly associated with objective walking performance, while general fatigue, physical fatigue, cognitive fatigue and psychosocial fatigue is weakly to moderately related to subjective walking performance, when analysed in a large heterogeneous sample of MS patients.


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Disclosure Ulrik Dalgas: nothing to disclose Martin Langeskov-Christensen: nothing to disclose Anders Skjerbaek: nothing to disclose Ellen Jensen: nothing to disclose Ilse Baert: nothing to disclose Peter Feys: nothing to disclose P1180 Effects of internet-based exercise (e-training) on fatigue and other patient reported behavioural outcomes (PRO) in patients with relapsing-remitting multiple sclerosis (RRMS) N. Jäckel1, A. Tallner2, Ö. Virsevci3, N. Denkinger3, K. Sebald3, M. Mäurer4, M. Lang3,5, H. Schreiber3,5 1Pediatrics, Ortenau Klinikum Offenburg, Offenburg, 2Institute of Sports Science and Sport, Friedrich Alexander University, Erlangen, 3Neurological Practice and Neuropoint Academy, Ulm, 4Department of Neurology, Caritas Krankenhaus, Bad Mergentheim, 5NeuroTransData (NTD) Study Group on Multiple Sclerosis, Neuburg, Germany Objective: To evaluate the impact of structured, internet-guided exercise (e-training) on profile/expression of fatigue and other behavioural PROs, i.e. depression, cognition, self-perception, disease coping and quality of life (QoL), in MS patients. Methods: Prospective, multicenter study of 12 months with assessments at baseline/BL and after 3, 6, 9 and 12 months (T3/ T6/T9/T12). 83 RRMS patients (aged 18-60 yr, mean: 36.6) cared at ambulant MS centers (Mc Donald, EDSS 0-3.5, FSMC total scale > 43, stable on INFbeta-1b at study onset) were randomized to an instant training group (TG1) that trained for 3 months (BLT3), and a delayed training group (TG2) that, after a 3 month waiting period, trained for 6 months (T3-T9). Outcomes: Primary: fatigue (FSMC total, motor and cognitive subscores). Secondary: MS-specific QoL/FAMS, clinical outcomes (neurostatus, relapses, EDSS), depression/ADS, daytime sleepiness/ESS, self-assessment of attent. Deficits/FEDA, disease coping/FKV, BICAMS cognition battery (SDMT/ AVLT/BVMT), and mobility (two-minute walk test/TMWT, timed up and go test/TUG). E-training included Internetguided strength and endurance training at home, 2-3 times/ week, for 10-60 min. Results: After 3 months of exercise (BL-T3) TG1 had highly significant less fatigue (FSMCtot decreasing by -5.98 pts.; p=0,001, effect size/ES -0,56). This effect was observed in motor fatigue (FSMCmot: -3.46 pts.; p< 0.01, ES -0.61), and, albeit to a lesser extent, in cognitive fatigue (FSMCcog p< 0.01, ES-0.42). In TG2, the exercise effect was only significant for motor fatigue after 3 months; global fatigue insignificantly decreased both after 3 and 6 months exercise. Irrespective of duration of exercise, improved fatigue was not stable in TG1 and TG2, but reversed to higher scores after termination of exercise. Comparing TG1 to TG2, the magnitude of the exercise effect on fatigue was insignificantly different. However, the benefit of exercise on fatigue was smaller in the clinically more affected TG2 group. In TG1, significantly more exercise-related improvements were seen in FAMS (p< 0,05) and FEDA (p< 0,04) compared to TG2, and depression tended to improve more in TG1 (ADS, p< 0.1).

Conclusion: The findings indicate that e-Training significantly (1) improves MS patients` fatigue. (2) The exercise effect (EE) is essentially realized after 3 months and only persists with training. (3) The size of the EE on fatigue and other behavioral PROs might depend on disease severity. Disclosure N. Jäckel has been compensated for travel expenses from Bayer Healthcare. A. Tallner has received honoraria for consultancy and lectures including travel costs from Novartis, Teva, Bayer Healthcare and Biogen. Ö. Virsevci, N. Denkinger, K. Sebald: no disclosures to indicate. M. Mäurer has received honoraria for lectures and Research and travel grants from Bayer Healthcare, Biogen, Genzyme, Merck. Novartis, Teva M. Lang has received honoraria for lectures and research and travel grants from Bayer Healthcare, Biogen, Teva, Merck, Novartis, Allmirall and Genzyme. H. Schreiber has received honoraria for lectures and research and travel grants from Bayer Healthcare, Biogen, Teva, Novartis, Merck, Allmiral and Genzyme. P1181 Treatment of balance problems with Nintendo Wii-Fit games in multiple sclerosis patients: a pilot study Y. Zenginler1, E. Tarakci2, D. Tarakci3, A. Ozdincler2 1Division of Physiotherapy and Rehabilitation, Faculty of Health Science, Biruni University, 2Division of Physiotherapy and Rehabilitation, Faculty of Health Science, Istanbul University, 3Division of Physiotherapy and Rehabilitation, Faculty of Health Science, Medipol University, Istanbul, Turkey Background: Balance disorder is a common symptom in patients with multiple sclerosis (MS). It is an important problem that needs to be treated especially to increase mobility and independence and to prevent falls. The Nintendo Wii-Fit offers a simple and affordable type of virtual reality therapy that is being used increasingly in different cases, but there are not enough studies published about its efficiency in patients with MS. Objectives: The aim of this study is to investigate the effects and usability of Nintendo Wii Fit games on balance problems of MS patients. Methods: 6 MS patients (median age 47 years (range 32-59), median score of Expanded Disability Status Scale 4 (range 3.5-6), median BMI 22.15 kg/m2 (range 18.96-33.77)) enrolled and participated to a balance exercise program which involved Nintendo Wii Fit games Penguin Slide, Table Tilt, Ski Slalom, Heading and Balance Bubble for 16 supervised sessions that each one takes 45 minutes. Before and after the treatment, participants evaluated by Nintendo Wii Fit + Balance Board, Berg Balance Scale (BBS) and one leg stance test. Results: After intervention statistically significant improvements founded in; one leg stance test for right (p=0.022) and left leg (p=0.029), BBS (p=0.026), Wii age (p=0.044) and Nintendo Wii Fit balance games, (Penguin Slide (p=0.003), Table Tilt (p=0.005), Ski Slalom (p=0.005), Balance Bubble (p=0.016)). No significant differences were identified between before and after treatment results


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Poster Session 2, 21(S11) considering center of gravity (COG) (COG for right leg (p=0.125), COG for left leg (p=0.125)) and Heading game (p=0.256). Conclusions: The study demonstrated that Nintendo Wii Fit games is effective for improving balance in MS patients and the results shows that the NintendoWii Fit provides a safe, enjoyable, suitable and effective method that can be added to conventional treatments to improve the static balance of patients with MS; however, further work is required. Disclosure Yonca Zenginler: nothing to disclose Ela Tarakci: nothing to disclose Devrim Tarakci: nothing to disclose Arzu Ozdincler: nothing to disclose P1182 THC:CBD oromucosal spray as an add-on therapy in a large population of Italian multiple sclerosis patients (SA.FE. study) F. Patti1, S. Messina1, M.P. Amato2, M.D. Benedetti3, R. Bergamaschi4, V. Brescia Morra5, F. Buttari6, P. Cavalla7, M. Danni8, A. Fuiani9, C. Gasperini10, D. Ippolito11, G.T. Maniscalco12, M. Matta13, M. Mirabella14, E. Montanari15, A. Nuara16, V. Palmieri17, D. Paolicelli18, L. Petrucci19, S. Pontecorvo20, C. Pozzilli21, M. Russo22, G. Salamone23, E. Signoriello24, G. Spinicci25, D. Spitaleri26, E. Tavazzi27, E. Trabucco28, M. Trotta29, M. Zaffaroni30, C. Solaro28, M. Zappia1 1University of Catania, Catania, 2Department NEUROFARBA, University of Florence, Florence, 3University of Verona, Verona, 4Fondazione Istituto Neurologico C. Mondino, Pavia, 5University Federico II, Naples, 6MS Clinical and Research Center, Tor Vergata University, Rome, 7University of Torino, Torino, 8Azienda Ospedali Riuniti, Ancona, 9University of Foggia, Foggia, 10Ospedale San Camillo Forlanini, Rome, 11I Clinc of Neurology, II University of Naples, 12Multiple Sclerosis Centre of AORN ‘A. Cardarelli’, Naples, 13CRESM, Ospedale san Luigi Gonzaga, Orbassano, 14Università Cattolica del Sacro Cuore, Rome, 15Ospedale civile di Fidenza, Fidenza, 16San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, 17Provincial Health Authority of Cosenza., Operating Unit Neurology and Center Multiple Sclerosis, Cosenza, 18University of Bari, Bari, 19Azienda Ospedaliero Universitaria Pisana, Pisa, 20’Sapienza’ University of Rome, Multiple Sclerosis Center Department Neurol. Psich., 21Ospedale S. Andrea, Rome, 22IRCCS - Centro Neurolesi Bonino Pulejo, Messina, 23Multiple Sclerosis Center Department of Neurology, A.O.O.R. Villa Sofia-Cervello, Palermo, 24Department of Clinical and Experimental Medicine and Surgery ‘F Magrassi e A Lanzara’, Second University of Naples, Naples, 25Department of Medical Sciences, University of Cagliari, Cagliari, 26UOC Neurologia AORN San G. Moscati, Avellino, 27Multiple Sclerosis Center - Neurorehabilitation Unit Scientific Institute Santa Maria Nascente, Fondazione Don Carlo Gnocchi, Milan, 28Als3 Genovese, Neurology Unit Department Head and Neck, Genova, 29University ‘Magna Graecia’, Catanzaro, 30Ospedale S. Antonio Abate, Gallarate, Italy Background: Spasticity is a common disabling symptom of multiple sclerosis (MS). The approval of THC:CBD oromucosal

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spray provides a new option for resistant to other medications moderate to severe MS spasticity. Aim: To describe possible differences in term of effectiveness and tolerability of adding on THC:CBD oromucosal spray to patients already treated with baclofen alone or with other antispastic drugs (BA) vs. patients treated with other anti spastic drugs (AS). Methods: We collected data from the THC:CBD oromucosal spray Italian e-registry in a period between Jan ‘14 and Feb ‘15. Spasticity was evaluated by the 0-10 NRS scale. Other parameters such as treatment discontinuation, tolerability, daily dose and use with other antispastic drugs have been collected. Results: We gathered information from 30 large MS centers. We obtained data from a total of 1534 patients. A total of 1350 patient reached 1st month visit (4 weeks’ trial period). Out of 1350 patients, 1055 (78.1%) have been treated with THC:CBD oromucosal spray as add-on with baclofen, 219 (16.2%) with baclofen plus other antispastic drugs, 35 (2.6%) with tizanidine, 11 (0.8%) with tizanidine plus other antispastic drugs, and 147 (10.8%) with other antispastic drugs (dantrolene, botulinum toxin, benzodiazepines, gabapentin, pregabalin, eperisone). For 67 patients data were not available. We compared BA patients (1274) vs AS patients (193). At 1st month visit the mean number of puffs/day was 6.8±2.6 in BA patients and 6.6±2.7 in AS patients (p=0.07) wheras at 6 months was 6.3±2.8 in BA and 6.2±2.7 (p=0.12). At 1st month visit 62.2% of BA patients and 62.2% of AS patients reached a 20% NRS improvement. NRS at 6th months was 4.8±1.7 in BA patients and 5.3±1.4 in AS patients (p=0.18). No differences in adverse events were found between groups. Conclusion: THC:CBD oromucosal spray is effective for the management of resistant MS spasticity independently of the concomitant medication used, either baclofen alone or in association with other antispastic drugs. Disclosure Dr Patti has received honoraria for scientific lectures and travel payment from Biogen Idec, Novartis, Teva, Genzyme, Bayer Schering, Merck Serono, Almirall. Dr Messina has received honoraria for scientific lectures form Biogen Idec, Almirall and travel payment from Novartis, Biogen Idec, Genzyme, Almirall Bayer Schering, Merck Serono. Prof. Maria Pia Amato serves on scientific advisory boards for Biogen Idec, Merck Serono and receives speaker honoraria and research support from Biogen Idec, Merck Serono, Novartis, Almirall and Genzyme. Dr Benedetti has nothing to disclose Dr Bergamaschi has received honoraria for scientific lectures and travel payment from Biogen Idec, Novartis, Teva, Genzyme, Bayer Schering, Merck Serono, Almirall. Dr Brescia Morra has received honoraria for scientific lectures and travel payment from Biogen Idec, Novartis, Teva, Genzyme, Bayer Schering, Merck Serono, Almirall. Dr Buttari has nothing to disclose Dr Cavalla has nothing to disclose Dr Danni has nothing to disclose Dr Fuiani has nothing to disclose Dr Gasperini received honoraria from Biogen, Genzyme, Novartis, Merck Serono, Almirall, Teva Dr Ippolito has nothing to disclose


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Dr Maniscalco received speaking and advisory honoraria from Biogen, Novartis and Teva Dr Matta has nothing to disclose Dr Mirabella received honoraria from Biogen, Genzyme, Novartis, Merck Serono, Almirall, Teva Dr Montanari received honoraria from Biogen, Genzyme, Novartis, Merck Serono, Almirall, Teva Dr Nuara has nothing to diclose Dr Palmieri has nothing to disclose Dr. Paolicelli received honoraria for consultancy and/or speaking from Biogen Idec, Merck-Serono, Almirall, Sanofi-Aventis, TEVA, Novartis and Genzyme. Dr Petrucci has nothing to disclose Dr Pontecorvo received honoraria for speaking activities from Biogen Idec Dr Pozzilli received honoraria for scientific lectures from Biogen Idec, Novartis, Teva, Genzyme, Bayer Schering, Merck Serono, Almirall. Dr Russo has nothing to disclose Dr Salamone has nothing to disclose Dr Signoriello has nothing to disclose Dr Spinicci has nothing to disclose Dr Spitaleri has nothing to disclose Dr Tavazzi has nothing to disclose Dr Trabucco has nothing to disclose Dr Trotta has nothing to disclose Dr Zaffaroni has nothing to disclose Dr Zappia has received compensation for consulting services from Boehringer-Ingelheim, Lundbeck, Union Chimique Belge and scientific grants from AIFA- Agenzia Italiana del Farmaco, Novartis, Lundbeck Dr Solaro received honoraria from Biogen, Genzyme, Novartis, Merck Serono, Almirall, Teva P1183 THC:CBD discontinuation in a large population of Italian multiple sclerosis patients (SA.FE. study) F. Patti1, S. Messina1, M.P. Amato2, M.D. Benedetti3, R. Bergamaschi4, V. Brescia Morra5, F. Buttari6, P. Cavalla7, M. Danni8, A. Fuiani9, C. Gasperini10, D. Ippolito11, G.T. Maniscalco12, M. Matta13, M. Mirabella14, E. Montanari15, A. Nuara16, V. Palmieri17, D. Paolicelli18, L. Petrucci19, S. Pontecorvo20, C. Pozzilli21, M. Russo22, G. Salamone23, E. Signoriello24, G. Spinicci25, D. Spitaleri26, E. Tavazzi27, E. Trabucco28, M. Trotta29, M. Zaffaroni30, C. Solaro28, M. Zappia1 1University of Catania, Catania, 2Department NEUROFARBA, University of Florence, Florence, 3University of Verona, Verona, 4Fondazione Istituto Neurologico C. Mondino, Pavia, 5University Federico II, Naples, 6MS Clinical and Research Center, Tor Vergata University, Rome, 7University of Torino, Torino, 8Azienda Ospedali Riuniti, Ancona, 9University of Foggia, Foggia, 10Ospedale San Camillo Forlanini, Rome, 11I Clinc of Neurology, II University of Naples, 12Multiple Sclerosis Centre of AORN ‘A. Cardarelli’, Naples, 13CRESM, Ospedale san Luigi Gonzaga, Orbassano, 14Università Cattolica del Sacro Cuore, Rome, 15Ospedale civile di Fidenza, Fidenza, 16San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, 17Provincial Health Authority of Cosenza, Operating unit Neurology and Center Multiple Sclerosis, Cosenza, 18University of Bari, Bari, 19Azienda Ospedaliero Universitaria Pisana, Pisa, 20Department of Neurol. Psich., ‘Sapienza’ University of Rome,

Multiple Sclerosis Center, 21Ospedale S. Andrea, Rome, 22IRCCS - Centro Neurolesi Bonino Pulejo, Messina, 23Multiple Sclerosis Center Department of Neurology, A.O.O.R. Villa Sofia-Cervello, Palermo, 24Department of Clinical and Experimental Medicine and Surgery ‘F Magrassi e A Lanzara’, Second University of Naples, Naples, 25Department of Medical Sciences, University of Cagliari, Cagliari, 26UOC Neurologia AORN San G. Moscati, Avellino, 27Multiple Sclerosis Center - Neurorehabilitation Unit Scientific Institute Santa Maria Nascente, Fondazione Don Carlo Gnocchi, Milan, 28Als3 Genovese, Neurology Unit Department Head and Neck, Genova, 29University ‘Magna Graecia’, Catanzaro, 30Ospedale S. Antonio Abate, Gallarate, Italy Background: Spasticity is a common disabling symptom of multiple sclerosis (MS). The approval of THC:CBD oromucosal spray provides a new option for resistant to other medications moderate to severe MS spasticity. Aim: To describe time to discontinuation in a large population of Italian MS patients treated with Sativex. Methods: We collected data from THC:CBD Italian e-registry in a period between Jan ‘14 and Feb ‘15. Spasticity was evaluated by the 0-10 NRS scale. Other parameters such as treatment discontinuation, tolerability, daily dose and use with other antispasticdrugs have been collected. Results: We gathered information from 30 large MS centers. Out of 1534 collected patients 503 (38.1%) discontinued treatment at a median time of 35 days. In particular 395 patients (25.7%) discontinued within 3 months. From the discontinuing, 51% reported lack of effectiveness, 31.5% tolerability and 8% reported both. A multivariate analysis showed no clinical or demographic factors significantly associated with THC:CBD discontinuation. Conclusion: Real-life data showed patients discontinued treatment within one months, showing the 4 weeks trials is effective in identifying those patients where THC:CBD could be effective and limiting the economic burden of THC:CBD on health system.

Disclosure Dr Patti has received honoraria for scientific lectures and travel payment from Biogen Idec, Novartis, Teva, Genzyme, Bayer Schering, Merck Serono, Almirall. Dr Messina has received honoraria for scientific lectures form Biogen Idec, Almirall and travel payment from Novartis, Biogen Idec, Genzyme, Almirall Bayer Schering, Merck Serono. Prof. Maria Pia Amato serves on scientific advisory boards for Biogen Idec, Merck Serono and receives speaker honoraria and research support from Biogen Idec, Merck Serono, Novartis, Almirall and Genzyme. Dr Benedetti has nothing to disclose Dr Bergamaschi has received honoraria for scientific lectures and travel payment from Biogen Idec, Novartis, Teva, Genzyme, Bayer Schering, Merck Serono, Almirall. Dr Brescia Morra has received honoraria for scientific lectures and travel payment from Biogen Idec, Novartis, Teva, Genzyme, Bayer Schering, Merck Serono, Almirall. Dr Buttari has nothing to disclose Dr Cavalla has nothing to disclose Dr Danni has nothing to disclose Dr Fuiani has nothing to disclose


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Poster Session 2, 21(S11) Dr Gasperini received honoraria from Biogen, Genzyme, Novartis, Merck Serono, Almirall, Teva Dr Ippolito has nothing to disclose Dr Maniscalco received speaking and advisory honoraria from Biogen, Novartis and Teva Dr Matta has nothing to disclose Dr Mirabella received honoraria from Biogen, Genzyme, Novartis, Merck Serono, Almirall, Teva Dr Montanari received honoraria from Biogen, Genzyme, Novartis, Merck Serono, Almirall, Teva Dr Nuara has nothing to diclose Dr Palmieri has nothing to disclose Dr. Paolicelli received honoraria for consultancy and/or speaking from Biogen Idec, Merck-Serono, Almirall, Sanofi-Aventis, TEVA, Novartis and Genzyme. Dr Petrucci has nothing to disclose Dr Pontecorvo received honoraria for speaking activities from Biogen Idec Dr Pozzilli received honoraria for scientific lectures from Biogen Idec, Novartis, Teva, Genzyme, Bayer Schering, Merck Serono, Almirall. Dr Russo has nothing to disclose Dr Salamone has nothing to disclose Dr Signoriello has nothing to disclose Dr Spinicci has nothing to disclose Dr Spitaleri has nothing to disclose Dr Tavazzi has nothing to disclose Dr Trabucco has nothing to disclose Dr Trotta has nothing to disclose Dr Zaffaroni has nothing to disclose Dr Zappia has received compensation for consulting services from Boehringer-Ingelheim, Lundbeck, Union Chimique Belge and scientific grants from AIFA- Agenzia Italiana del Farmaco, Novartis, Lundbeck Dr Solaro received honoraria from Biogen, Genzyme, Novartis, Merck Serono, Almirall, Teva

Quality of life P1184 It’s all about personality: its impact on health, coping, psychological well-being and quality of life L. Strober, A. Costanzo, J. DeLuca, N. Chiaravalloti Kessler Foundation, West Orange, NJ, United States Background: It is well appreciated that personality plays a role on one’s health, well-being, and perceptions and management of their illness. Previously, the concept of a “Type D or Distressed” Personality has been described as a combination of higher levels of neuroticism and lower levels of extraversion/social discomfort. Medical patients with a Type D Personality have been found to have poorer health outcomes, greater psychological difficulties, greater reports of fatigue, and overall reduced quality of life. Objective: The purpose of the present study was to determine the incidence of Type D Personality and examine its impact on health, coping, psychological functioning, and overall quality of life in a multiple sclerosis (MS) sample. Method: Two hundred and thirty individuals with MS were administered measures of personality. Thirty seven (16%) were found to be “Type D+.” Participants completed measures of

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disease symptoms, disease management, psychological functioning, self-efficacy, locus of control (LOC), and quality of life. Results: “Type D” individuals reported greater levels of fatigue (p < .001) and pain (p = .001). They reported lower levels of provider relationship and communication (p = .026), perceived self-efficacy in managing their MS (p < .001), and poorer adherence (p =.030). They also employed maladaptive coping styles such as mental disengagement (p = .007), behavioral disengagement (p < .001), denial (p = .002), venting emotions (p < .001), and substance use (p < .001). In contrast, they were less likely to use adaptive coping such as planning (p = .015), active coping (p = .018), and positive interpretation and growth (p = .002). “Type D +” individuals reported a lower sense of general self-efficacy (p < .001) and LOC (p < .001) and greater depression (p < .001) and anxiety (p < .001). They also reported a lower satisfaction with life (p < .001) and greater perceived stress (p < .001). Finally, with regard to functional outcomes, a greater percentage of those considering leaving the workforce were found to be “Type D.” (χ2 = 4.22, p = .040). Conclusions: Consistent with the literature in other medical populations, the existence of Type D Personality is associated with several negative outcomes in MS. Given this, consideration and assessment of personality traits appears warranted in hopes of assuring optimal outcomes and tailoring one’s interventions. Disclosure Study was funding by the National Institutes of Health K23HD069494 P1185 An assessment of felt-stigma in multiple sclerosis R.J. Mills1, Z. Eva2, A. Tennant3, C.A. Young2,4, TONiC 1Neurology, Lancashire Teaching Hospitals Trust, Preston, 2Neurology, The Walton NHS Foundation Trust, Liverpool, United Kingdom, 3Swiss Paraplegic Research, Notwill, Switzerland, 4Neuroscience, Liverpool Hospital University, Liverpool, United Kingdom Background: Patients with multiple sclerosis (MS) commonly report their experience of negative attitudes directed towards them from members of the public or employers or even other healthcare professionals. This negative perception by others may be called enacted stigma. When patients with MS come to believe that these negative perceptions apply to them, they may be described as having internalised stigma. Such stigma may impact negatively on psychological wellbeing and social engagement. Despite its importance, felt-stigma in MS has hitherto received little attention. Objective: To assess the relationship between stigma and other clinical features of MS. Method: The Stigma Scale for Chronic Illnesses (SSCI-8) was administered to patients with clinically definite MS as part of the TONiC study, a multicentre, UK study of factors affecting quality of life in MS. The SSCI-8 incorporates both enacted and internalised stigma and has been adapted as a short-form version of the Stigma Scale-24, for use in neurological conditions. The Hospital Anxiety and Depression Scale and the Neurological Fatigue Index were coadministered; demographics and disease characteristics were also captured. The results were analysed using Spearman correlation and Mann-Whitney U/Kruskall-Wallis ANOVA (alpha 0.01). Results: 722 records were available for analysis. Mean age was 49 years, mean disease duration 11.5 years, 72% were female,


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67% had relapsing remitting disease, 86% had EDSS ⩽6.5. There was no correlation between stigma and age or disease duration but there was moderate correlation with fatigue (rho 0.52), depression (rho 0.58) and anxiety (rho 0.4) and significantly greater stigma in both depressed or anxious subjects (HAD scales⩽11). There was no difference in stigma between the sexes or across marital status but it was significantly lower in subjects who were still working. Patients with secondary progressive MS had significantly more stigma than other disease types, those with rapidly evolving MS the least. There was significant difference by disability, with increasing levels of stigma with increasing levels of EDSS, the highest in EDSS 7.0-7.5. Conclusion: The relationships between felt-stigma and basic demographic and clinical features of MS were demonstrated in a large population-based sample, for the first time. Possible reasons behind the associations are discussed and further work would be directed at determining causation behind any of the associations.

square probability, substantial item misfit and multidimensionality. An item based solution could only be achieved across the development and validation samples by deletion of 7 out of 12 items and accepting weak reliability indices. A testlet solution was found, which retained all the items, by grouping items according to the 3, originally intended factors; no variance was shed with a trivial degree of inter-testlet dependency, the scale was unidimensional. Conclusion: Data from the HHI-12 could be fitted to the Rasch model which confirmed valid measurement in an MS population. The scale was shown to be unidimensional suggesting that a factor of higher order than the notional factors inherent in the scale’s development was being measured; indeed, for MS, these 3 factors could not be reproduced. The scale might require further qualitative validation in an MS sample or would be a useful comparator for other scale development. Disclosure

Disclosure Mills RJ, Zitnik E, Tennant A and Young CA declare no conflicts of interest for this work. The TONiC study was supported by unrestricted grant support from NIHR, MNDA, Walton Neuroscience Charity, Biogen, Novartis, Roche, Teva. P1186 Rasch analysis of the Herth Hope Index in multiple sclerosis R.J. Mills1, A. Tennant2, C.A. Young3,4, TONiC 1Neurology, Lancashire Teaching Hospitals Trust, Preston, United Kingdom, 2Swiss Paraplegic Research, Notwill, Switzerland, 3Neurology, The Walton NHS Foundation Trust, 4Neuroscience, Liverpool Hospital University, Liverpool, United Kingdom Background: Hope contributes to positive psychosocial outcomes in people with chronic illness and disability. It also results in greater life satisfaction, self-esteem, and proactive coping. A commonly used generic scale is the 12-item Herth Hope Index (HHI-12), which was adapted in 1992 from the longer Herth Hope Scale, in order to provide an abbreviated instrument to assess hope in adults in clinical settings. It includes three notional factors of ‘inner sense of temporality and future’, ‘inner sense of positive readiness and expectancy’ and ‘interconnectedness with self and others’ and was validated in patients with cancer and other chronic illness. A total summed score was deemed to be valid. Objective: To assess the factor structure and, by Rasch analysis, the construct validity of the HHI-12 in multiple sclerosis (MS). Method: The HHI-12 was given to patients with clinically definite MS as part of the TONiC study, a multicentre, UK study of factors affecting quality of life in MS. Factor analysis was performed based on a polychoric correlation matrix on the whole data sample. For the Rasch analysis, the data were randomly split into a development sample and a sample set aside for validation. Results: 700 records were available for analysis. The sample had characteristics typical of a wider MS population. Exploratory factor analysis revealed two factors which did not correspond to the original proposed, 3-factor, structure. The scale did not fit the Rasch model expectations with highly significant overall chi

Mills RJ, Tennant A and Young CA declare no conflicts of interest for this work. The TONiC study was supported by unrestricted grant support from NIHR, MNDA, Walton Neuroscience Charity, Biogen, Novartis, Roche, Teva. P1187 Neurological Coping Index-MS: a short positive coping scale for multiple sclerosis R.J. Mills1, A. Tennant2, C.A. Young3,4, TONiC Group 1Royal Preston NHS Trust, Preston, United Kingdom, 2Swiss Paraplegic Research, Nottwil, Switzerland, 3Walton Centre NHS Trust, 4University of Liverpool, Liverpool, United Kingdom Background: Coping in multiple sclerosis (MS) refers to cognitive and behavioural efforts to manage stresses imposed by the illness. It has been reported that therapeutic interventions to enhance more appropriate coping strategies can improve the patients´ quality of life. The current study assesses a short scale for positive coping, which meets the Rasch measurement model. Methods: Following qualitative interviews with people with MS, and item extraction, a draft Coping Index and the COPE were given to MS patients attending hospital clinics in the UK. Data from the Index were fit to the Rasch model. Fit was judged by a non-significant chi-square, item and person fit residual SD < 1.4; and both the assumptions of local independence of items and unidimensionality upheld. Differential Item Functioning (DIF) was tested for age, gender, marital status, disease duration and type, and EDSS level. Concurrent validity was ascertained against the COPE. Results: 722 people with MS participated; their mean age was 48.9 years (SD11.6) and mean duration of 11.5 years (SD9.1). 71.9% were female. 60.60% had relapsing-remitting MS; 23.3% secondary progressive MS; 5.8% rapidly evolving relapsing-remitting MS and 10.3% primary progressive MS. 37.6% had an EDSS< 4. Data from 43 draft items were fit to the Rasch model. Initial fit was poor with strong indications of multidimensionality. Consequently two sets of items were considered and, after adjustments for locally dependency and misfit, a 12 item set of positive coping strategies was retained (Chi-Square 23.1 [df 16]; p=0.11;


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Poster Session 2, 21(S11) mean item fit residual 0.084; SD 0.25; α reliability 0.85). There was no Differential Item Functioning (item bias) for age, gender, type of disease, or EDSS level. The scale showed positive correlations (>0.4) with its respective comparator domains on the COPE. There was no significant difference in positive coping levels between males and females, but those with the secondary progressive form of the condition had marginally lower positive coping levels than other forms of the condition (p=0.032). Conclusion: The Neurological Coping Index-MS is a self-completed, short scale of positive coping for those with MS, built from the patient experience and satisfying the Rasch measurement model. It provides a disease-specific scale for this important moderating construct. The scale is free for use in not-for-profit settings. Disclosure Mills RM: nothing to disclose. Tennant A: nothing to disclose. Young CA has received financial support for research and educational purposes, hospitality, fees for speaking and advisory boards, from Biogen Idec, Genzyme, Novartis, Roche, and Teva. The TONiC study was supported by unrestricted grant support from NIHR, MNDA, Walton Neuroscience Charity, Biogen, Novartis, Roche, Teva.

P1188 Quality of life improvements in patients with active relapsing-remitting multiple sclerosis are not impacted by acute infections after receiving alemtuzumab in CARE-MS II P. Vermersch1, G. Giovannoni2, J.A. Cohen3, T. Moreau4, S. Wray5, D.H. Margolin6, L. Kasten7, on behalf of the CARE-MS II Investigators 1University of Lille, Lille, France, 2Queen Mary University of London, Barts and The London School of Medicine, London, United Kingdom, 3Cleveland Clinic, Cleveland, OH, United States, 4Burgundy University, Dijon University Hospital, Dijon, France, 5Hope Neurology, Knoxville, TN, 6Genzyme, a Sanofi company, 7PROMETRIKA, LLC, Cambridge, MA, United States Background: Alemtuzumab, approved in >40 countries for treatment of relapsing multiple sclerosis (MS), showed superior efficacy over subcutaneous interferon beta-1a (SC IFNB-1a) and a manageable and consistent safety profile across clinical trials. In the phase 3 CARE-MS II study (NCT00548405), infections were more common with alemtuzumab than with SC IFNB-1a (77% vs 66%), but were predominantly mild to moderate in severity; serious infection incidence was low (4%). Alemtuzumab treatment was also associated with significantly greater improvements in quality of life (QoL) than SC IFNB-1a over 2 years. Goals: To examine whether infections impacted QoL outcomes in relapsing-remitting MS patients with an inadequate response to a prior therapy treated with alemtuzumab. Methods: Patients with active relapsing-remitting MS who had an inadequate response to a prior therapy (⩾1 relapse after 6 months’ treatment) received alemtuzumab 12 mg/day on 5 consecutive days at baseline and 3 consecutive days 12 months later, or SC IFNB-1a 44 µg 3 times weekly over 2 years. QoL was assessed using Functional Assessment of Multiple Sclerosis (FAMS [scale 0-176]), Short-Form 36-Item survey (SF-36)

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physical component summary (PCS) and mental component summary (MCS [scales 1-100]), and EuroQol-5 Dimension Visual Analog Scale (EQ-5D VAS [scale 0-100]). As no significant treatment differences on MCS were seen, it was not included in this analysis. Results: By the end of Year 2, alemtuzumab-treated patients had significantly improved QoL mean change from baseline compared with SC IFNB-1a-treated patients on FAMS (alemtuzumab-treated patients vs SC IFNB-1a-treated patients: 6.4 [n=417] vs 1.8 [n=173]; P=0.0168), SF-36 PCS (2.4 [n=417] vs 0.6 [n=172]; P=0.0083), and EQ-5D VAS (3.8 [n=419] vs -0.9 [n=172]; P=0.0079). Patients with infection had similar mean change from baseline as those without infection in all QoL measures. Alemtuzumab-treated patients with infection maintained significantly improved QoL mean change from baseline compared with all SC IFNB-1a-treated patients on FAMS (6.8 [n=321]; P=0.0062), SF-36 PCS (2.7 [n=322]; P=0.0098), and EQ-5D VAS (3.8 [n=324]; P=0.0123). Conclusion: Infections did not impact QoL outcomes and, importantly, alemtuzumab-treated patients with infections had improved QoL compared with SC IFNB-1a-treated patients. These findings support the favourable benefit-risk profile of alemtuzumab in patients who had an inadequate response to prior therapy. Disclosure Study supported by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. PV: Honoraria and consulting fees (Biogen Idec, GenzymeSanofi, Bayer, Novartis, Teva, Merck-Serono, GSK, and Almirall), and research support (Biogen Idec, Bayer, Novartis, and Merck-Serono). GG: Compensation for consulting, serving on a scientific advisory board, speaking, or other activities (Biogen Idec, Five Prime Therapeutics, Genzyme, GW Pharma, Merck-Serono, Novartis, Roche, Synthon, Teva, and Vertex Pharmaceuticals); compensation for serving as a journal editor (Multiple Sclerosis and Related Disorders); and research support (Serono). JAC: Personal compensation for serving as a consultant or speaker (EMD Serono, Genentech, Innate Immunotherapeutics, and Vaccinex). TM: Consulting and speaking fees (Biogen Idec, Sanofi Aventis, Genzyme, Teva Pharma, Bayer Schering, Merck Serono, Novartis, Roche, and Almirall). SW: Consulting fees (Accorda, Biogen Idec, EMD Serono, Genzyme, Novartis, Questcor, and Teva); served on speakers bureaus (Accorda, Bayer HealthCare Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme, Novartis, Questcor, Sanofi Aventis, and Teva). DHM: Employee of Genzyme. LK: Provides statistical support as a consultant for Genzyme. P1189 Health-related quality of life in individuals with multiple sclerosis and validation of a method to map MSIS-29 on EQ-5D O. Ernstsson1, P. Tinghög1, K. Alexanderson1, J. Hillert2, K. Burström3,4,5 1Insurance Medicine, Clinical Neuroscience, 2Neuro, Clinical Neuroscience, 3LIME, 4Public Health Sciences, Karolinska Institutet, 5Health Care Services, Stockholm County Council, Stockholm, Sweden


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Background: Mapping is a method to predict utility values from other health outcomes measures. This is a useful strategy that can facilitate economic evaluation when appropriate data for such purpose are not available. A mapping was previously conducted to predict EQ-5D utility scores from the condition-specific Multiple Sclerosis Impact Scale (MSIS-29), but has not yet been externally validated. Aim: 1) To validate and find potential improvements in previous efforts of mapping the health-related quality of life measure MSIS-29 on the generic EQ-5D and 2) to describe the health-related quality of life by sociodemography, disease severity, and work incapacity in a Swedish multiple sclerosis (MS) sample. Methods: This was a cross-sectional register-based study including 767 individuals with known severity level of MS who individually rated both MSIS-29 and EQ-5D at the same point in time. The previously developed mapping algorithm was applied to predict EQ-5D utility scores from MSIS-29, whereas the predictive accuracy was assessed by mean absolute error (MAE) and root mean square error (RMSE). Potential improvements of the mapping algorithm were explored through ordinary least squares regression. Results: Lower mean utility scores were found among women, those with higher age, low educational level, more severe MS, or on full-time sickness absence or disability pension. By applying the mapping algorithm, the predicted mean EQ-5D utility score of the total sample was 0.77 compared to the observed mean utility score of 0.75 (MAE: 0.12, RMSE: 0.18). The predictive ability was more accurate for individuals reporting EQ-5D score ⩾0.5 (n=693, MAE: 0.10, RMSE: 0.12) compared to individuals reporting EQ-5D score < 0.5 (n=74, MAE: 0.39, RMSE: 0.42). A minor reduction in prediction error was found when adding information on disease severity and work incapacity. Conclusion: The mapping algorithm including solely MSIS-29 responses had the highest predictive performance in groups with better health. The identification of these individuals is challenging as the variations in predictive accuracy mainly concerned the valuation on EQ-5D and not necessarily the MS severity. Project supported by Biogen and Swedish Research Council for Health, Working Life and Welfare Disclosure OE, PT, KA and KB: nothing to disclose. JH received honoraria for serving on advisory boards for Biogen and Novartis and speaker’s fees from Biogen, Merck-Serono, Bayer-Schering, Teva and Sanofi-Genzyme. He has served as P.I. for projects sponsored by, or received unrestricted research support from, Biogen, Sanofi-Genzyme, Merck-Serono, TEVA, Novartis and Bayer-Schering. His MS research is funded by the Swedish Research Council and the Swedish Brain Foundation. This project is funded by Biogen and the Swedish Research Council for Health, Working Life and Welfare (2007-1762). P1190 Measuring the impact of multiple sclerosis: enhancing the MSIS-29’s performance S. Cano1, S. Cleanthous1, E. Kinter2, J. Hobart3, P. Marquis1, J. Petrillo4, G. Sabatella4, X. You4

1Modus

Outcomes, Boston, MA, United States, 2Biogen, Zug, Switzerland, 3Peninsula College of Medicine and Dentistry, Plymouth, United Kingdom, 4Biogen, Cambridge, MA, United States Background: ADVANCE is a Phase 3, randomised, doubleblind, parallel-group (with a 1-year placebo-controlled period) study assessing the efficacy and safety of subcutaneous peginterferon beta-1a in relapsing-remitting multiple sclerosis (RRMS) patients. Objectives: The aim of this analysis was to use Rasch Measurement Theory (RMT) methods to evaluate the Multiple Sclerosis Impact Scale (MSIS-29), and to explore an optimised scoring structure based on empirical post-hoc analyses. Methods: Longitudinal blinded data from the 1512 randomised patients in ADVANCE were analysed. In Stage-1, RMT methods examined: scale-to-sample targeting, threshold ordering, item fit and dependency, and reliability. In Stage-2, a post-hoc revision of the MSIS-29 scoring structure by conceptual regrouping of items was conducted and re-evaluated using the same RMT methods. Results: Stage-1 analyses showed strengths and limitations of the MSIS-29. Strengths for the Physical & Psychological Impact subscales included: ordered thresholds for all items, minimal dependency (1 & no pair of items), and good reliability (Person Separation Index >0.87). However, limitations included item misfit (percentage failing adjusted Chi-square criteria: 15% Physical; 11% Psychological) and mis-targeting (item-threshold coverage (percentage): 58% both sub-scales), implying a ceiling effect (i.e. limited coverage for MS patients with mild disability levels (EDSS 0-3). In Stage-2, items were re-categorised into three sub-scales: “Symptoms”, “Psychological” & “Limitations”, which improved item misfit (percentage failing adjusted Chi-square criteria: 0% for all revised sub-scales) and targeting (item-threshold coverage (percentage): 80%; “Symptoms”; 71% “Psychological”; 66% “Limitations”). Conclusion: This study highlights two key issues. First, item fit analyses support the clinical suggestion that the items of the MSIS-29 might be better grouped in more than two sets. Second, targeting analyses suggest that the MSIS-29’s measurement of less disabled people might be improved by adding items in the lower range of the measurement continuum. The revised MSIS-29 scoring structure demonstrates improved psychometric properties and interpretability, but remains mis-targeted and is sub-optimal for patients with mild disability (EDSS < 3.0). Disclosure This study is sponsored by Biogen (Cambridge, MA, USA). SC, SC, PM: consultants who received fees to perform the analysis. JH: consulting fees, honoraria, or support to attend conferences and meetings from Acorda, Biogen, Genzyme, Merck Serono, Novartis. EK, JP, GS and XY are all employees and stockholders of Biogen.

P1191 Coping strategies used by people with multiple sclerosis D. Holland1, R.M. Mills2, A. Tennant3, C.A. Young1,4, TONiC Group


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Centre NHS Trust, Liverpool, 2Royal Preston NHS Trust, Preston, United Kingdom, 3Swiss Paraplegic Research, Nottwil, Switzerland, 4University of Liverpool, Liverpool, United Kingdom Introduction: While coping strategies have been shown to influence adjustment and perceived quality of life in multiple sclerosis (MS), little is known about how personal and clinical characteristics influence coping strategies employed. The aim of our study was to identify coping strategies used by people with MS, examining differences across demographics and disease type. Methods: As part of the multi-centre, UK TONiC study, MS patients completed the COPE60 questionnaire and provided data on demographic and clinical characteristics. We generated median frequencies for use of each coping item, using SPSS22 to compare use between gender, age and disease type using the Mann-Whitney U test. Results: We recruited 722 patients: average age 49 (17-82); 27.5% male, 72.5% female. Average disease duration was 11.5 months (0-49), with 60.6% Relapsing-Remitting (RR) and 33.6% Progressive (10.3% Primary). Commonest coping strategies were Acceptance, Active Coping, Positive Reinterpretation and Planning (Md 6-7); least used Substance Use, Religiosity and Denial (Md 0-1). Women use more Religiosity (Z=-2.01, p=0.04), Emotional (Z=-4.732, p=< 0.001) and Instrumental Support (Z=3.09, p=0.008), men preferring Humour (Z=-3.031, p=0.002). Those under age 60 use more Substance Use and Humour (Z=2.27, p=0.02; Z=-2.38, p=0.02), those over 60 preferring Religiosity, Suppression of Competing Activities, Restraint, Planning and Acceptance (Z=-5.06, p=< 0.01; Z=-3.644, p=< 0.01; Z=-3.45, p=< 0.01; Z=-2.247, p=0.025; Z=-2.73, p=0.006). Progressive patients utilised more Religiosity, Restraint, Mental and Behavioural Disengagement (Z=-2.3, p=0.02; Z=-2.6, p=< 0.01; Z =-2.4, p=0.02; Z=-3.372, p=< 0.01), whilst RR patients preferred Substance Use and Emotional Support (Z=-3.38, p=< 0.01; Z=-2.075, p=0.04). Conclusions: Our results show MS patients favour an active, adaptive coping approach. There were differences in strategy preference across gender, although both sexes utilised problemand emotion-focused strategies. Older patients showed a more problem-focused approach, not evident in previous literature. Progressive MS patients show several avoidant coping strategies, which may reflect a protective nature of mental avoidance or a maladaptive pattern for the progressive disease pathway. Disclosure Holland D, Mills R, Tennant A: nothing to disclose. Young CA has received financial support for research and educational purposes, hospitality, fees for speaking and advisory boards, from Biogen Idec, Genzyme, Novartis, Roche, and Teva. The TONiC study was supported by unrestricted grant support from NIHR, MNDA, Walton Neuroscience Charity, Biogen, Novartis, Roche, Teva. P1192 Treatment satisfaction and side effect experience with fingolimod and dimethyl fumarate for multiple sclerosis: findings from an online patient cohort

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R. Sasane1, L. Rasouliyan2, B. Katic3, P. Wicks3, E. Flood4, J.J. Ko1, K. Johnson1, V. Herrera1 1Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States, 2Icon plc, Barcelona, Spain, 3PatientsLikeMe, Cambridge, MA, 4Icon plc, Bethesda, MD, United States Objective: To describe treatment satisfaction and the side effect (SE) experience of patients taking fingolimod (FTY) or dimethyl fumarate (DMF). Background: Elucidation of tolerability and patient-reported SE experience among patients taking FTY or DMF in the real-world are warranted to help inform treatment decision-making. Methods: Relapsingremitting multiple sclerosis (RRMS) patients in the United States were identified from an online patient community, PatientsLikeMe. Current or past users of FTY or DMF were invited to complete a crosssectional survey on treatment satisfaction and occurrence of treatmentspecific SEs. Current users were defined as those currently on FTY or DMF for a minimum of 7 days. Descriptive statistics characterized the sample, and logistic regression models using a penalized likelihood approach assessed the impact of drug type on treatment satisfaction and the occurrence of 9 SEs (abdominal pain, back pain, cough, diarrhea, flushing, headache, flu-like symptoms, nausea and vomiting), which included the 5 most frequent SEs reported in each drug’s label, while controlling for demographics and disability. Results: A total of 281 patients completed the survey; 190 were currently taking either FTY (n=61) or DMF (n=129) and 91 had discontinued either FTY (n=32) or DMF (n=59). The overall sample of current users was predominantly White (87% vs. 88%), female (77% vs. 80%), and on average 46 vs. 50 years old (FTY vs. DMF). While satisfaction with efficacy was comparable between the treatment groups, satisfaction with convenience and SEs favored FTY over DMF (p< 0.01). In adjusted models, patients currently taking DMF were 7.5 times more likely to report experiencing any of the 9 SEs versus patients currently taking FTY (odds ratio: 7.5; 95% confidence interval: 3.5, 15.9). Patients who discontinued DMF were more likely to indicate SEs as a reason for discontinuation versus FTY (78% vs. 44%, respectively). Conclusions: This study utilized an online patient community to capture real-world, patient-reported experiences of SEs and treatment satisfaction. Overall, as reported by patients, SEs appear to be more common and more often a reason for discontinuation for those taking DMF versus FTY. Future research involving a larger sample and a longitudinal design could provide additional insights on real-world patient experiences of medication for RRMS and the relationship between tolerability and adherence. Disclosure Drs. Sasane, Ko, Johnson, and Herrera are employees of Novartis Pharmaceutical Corporations, and own stock in the company. Mr. Rasouliyan and Dr. Flood are employees of Icon plc. Drs. Katic and Wicks are employees of PatientsLikeMe P1193 Worry and self-esteem in multiple sclerosis E. Zitnik1, R.M. Mills2, A. Tennant3, C.A. Young1,4, TONiC Group


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Centre NHS Trust, Liverpool, 2Royal Preston NHS Trust, Preston, United Kingdom, 3Swiss Paraplegic Research, Nottwil, Switzerland, 4University of Liverpool, Liverpool, United Kingdom

S. Baldini, L. Pippolo, P. Annovazzi, M. Zaffaroni, M. Roscio, D. Baroncini, F. Grassivaro, A. Ghezzi Multiple Sclerosis Study Center. AO S. Antonio Abate, Gallarate (VA), Italy

Introduction: Low self-esteem (SE) and worry have both been shown to contribute to poorer quality of life outcomes in people with multiple sclerosis (MS). However, there is little published data examining these factors and how they relate to demographic and disease characteristics. Method: The Penn State Worry Questionnaire (PSWQ-16) and the Rosenberg Self-Esteem Scale (RSES-10) were administered to patients with MS as part of the TONiC study, a multicentre, UK study of factors affecting quality of life in MS. The Hospital Anxiety and Depression Scale and the Neurological Fatigue Index were coadministered; demographics and disease characteristics were also captured. The results were analysed using Spearman correlation and Mann-Whitney U/Kruskall-Wallis ANOVA (alpha 0.01). Results: 722 records were available for analysis. Mean age was 49 years, mean disease duration 11.5 years, 72% were female, 67% had relapsing-remitting disease (RRMS), 86% had EDSS ⩽6.5. Worry was moderately correlated with negative SE (rho 0.5); there was no correlation between worry or SE and age or disease duration. Worry was not correlated with fatigue whereas SE was (rho 0.43). Both worry and negative self-esteem were significantly greater in depressed and anxious subjects (HAD scales⩽11). Worry was significantly higher in females, and in those not working; there was no difference in SE between the sexes but it was significantly greater in working subjects. There were no differences across marital status. Patients with secondary progressive MS (SPMS) had significantly less SE than other disease types, those with rapidly evolving MS the most. By contrast, relapsing-remitting subjects were the most worried. SE decreased with increasing levels of disability with the least SE at EDSS 7.07.5. Worry remained high from minimal disability through to EDSS⩽7.5 but was lower in those with EDSS⩾8. Conclusion: Worry is high across all EDSS levels until EDSS 8.0 and at all durations of MS; it is greatest in patients with RRMS, perhaps reflecting the unpredictability of the condition. SE was found to correlate to fatigue, level of disability and employment status and is lowest in patients with SPMS. Worry relates to negative SE, and both are linked to anxiety and depression. Further studies are needed to determine causations behind these associations.

Background and objective: Narrating the experience of the disease and sharing it with the physician has both relational and therapeutic implications that represent the most innovative feature of Narrative Medicine (NM). An effective therapeutic management should therefore include not only quantitative clinical evaluations, but also patients own experiences, his/hers life events, relationships and their meanings.Here we report the experience of a pilot project whose aim was to create a tool that could complement the traditional medical report with NM data. Materials and methods: In the setting of a single Italian Multiple Sclerosis (MS) centre, an plain spreadsheet (NM file) was created to spontaneously collect NM information reported by patients and relatives during routine outpatient visits. NM file consists of three domains: A) personal history (family and life events, work and social relationships), B) personal characteristics (personality traits, emotions and beliefs towards MS and MS-related therapies) and C) relationship with MS centre personnel and organization (respect of visit schedule and prescriptions, emotional experiences). Each NM file is accessible, password-protected, by any physician, psychologist and nurse working in the MS centre for consultation and further compiling. Results: Since October 2014, 150 relapsing-remitting MS patients (79,8% F, 20,2% M) mean age 42,18 +/- 12, Median EDSS 2 (range 0 - 7) have been included in the project and a corresponding NM spreadsheet was created for each patient. 90% of patients had multiple data entries in the file, for a average of 3 records per patient. Most filled domain was A (48% entries), while B and C had respectively 36% and 16% entries. Conclusions: NM files could help understand disease course, pairing clinical events with patients’ life events, emotions and experiences. An integrated clinical and NM approach could simplify medical choices and promote therapeutic alliance as it improves communication among MS centre workers and the cure of the patient as a whole. Quantitative analysis with patient and workers self administered questionnaires are warranted to determine whether our NM file effectively fulfils the aim.

Disclosure Zitnik E, Mills RJ, Tennant A:nothing to disclose. Young CA has received financial support for research and educational purposes, hospitality, fees for speaking and advisory boards, from Biogen Idec, Genzyme, Novartis, Roche, and Teva. The TONiC study was supported by unrestricted grant support from NIHR, MNDA, Walton Neuroscience Charity, Biogen, Novartis, Roche, Teva. P1194 Narrative-medicine approach to multiple sclerosis patients, description of a tool to integrate clinical data and patients experiences and emotions

Disclosure SB declares no disclosures related to this project/manuscript. LP declares no disclosures related to this project/manuscript. PA declares no disclosures related to this project/manuscript. MZ declares no disclosures related to this project/manuscript. MR declares no disclosures related to this project/manuscript. DB declares no disclosures related to this project/manuscript. FG declares no disclosures related to this project/manuscript. AG declares no disclosures related to this project/manuscript. P1195 Quality of life for patients with multiple sclerosis treated with autologous haematopoietic stem cell transplantation (AHSCT) M. Smilowski1, L. Szczechowski1, G. Helbig2, M. KrawczykKulis2, S. Kyrcz-Krzemien2


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Poster Session 2, 21(S11) 1Department

of Hematology and Bone Marrow Transplantation, A.Mielecki Hospital of Medical University of Silesia, 2Department of Hematology and Bone Marrow Transplantation, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland Background: Multiple sclerosis (MS) has a significant impact on patient`s quality of life (QoL) which depends on disability status, fatigue and mental health. Autologous haematopoietic stem cell transplantation (AHSCT) should be considered as a therapeutic approach for patients with aggressive relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) who failed the conventional therapy. Objectives: To evaluate the QoL, fatigue and their relationship with neurological disability status in patients who underwent AHSCT for RRMS/SPMS. Methods: Twenty six patients with refractory RRMS (22 patients) and SPMS (4 patients) who met the eligibility criteria for AHSCT and completed a 1 year observation. The eligibility criteria were consistent with the guidelines of the European Group for Blood and Marrow Transplantation (EBMT) from 2012. The patient`s QoL was evaluated using MSIS-29 scale (Multiple Sclerosis Impact Scale-29), MusiQol (Multiple Sclerosis International Quality of Life questionnaire). The fatigue was additionally evaluated using MFIS (Modified Fatigue Impact Scale). All scales are validated for polish population. The disability status was assessed using Expanded Disability Status Scale (EDSS). The examination was performed before AHSCT, and 6 and 12 months thereafter. All computations were performed using StatSoft Poland analysis software (version 9.0). Results: The mean MSIS-29 score was 84 before transplant, and 77 and 62 at 6 and 12 months post-transplant, respectively (p< 0.05). The mean MFIS score before AHSCT was 34.7 and decreased to 28.9 and 25.2 at 6 and 12 months, respectively (p< 0,05). For the MusiQoL, the mean score was 42, 37 and 31 before AHSCT and 6 and 12 months thereafter, respectively. (p< 0.05). The median EDSS score was 6.0 before treatment and decreased to 5.5 and 5.25 at studied time points after transplant, respectively (p< 0,05). A positive correlation between EDSS and MSIS-29 (r=0,43; p< 0,05), MusiQoL (r=0,51; p< 0,05) and MFIS (r=0,38; p< 0,05) was observed. Conclusions: AHSCT as a treatment option for aggressive RRMS and SPMS has a significant impact on QoL resulting in lower scores in MSIS-29, MusiQol and MFIS scales. Disclosure Marek Smilowski: nothing to disclose Lech Szczechowski: nothing to disclose Grzegorz Helbig: nothing to disclose Malgorzata Krawczyk-Kulis: nothing to disclose Slawomira Kyrcz-Krzemien: nothing to disclose P1196 Impact of psychological variables on the quality of life of multiple sclerosis patients L. Fàbregas1,2,3, M. Planes2, M.E. Gras2, L. Ramió-Torrentà3,4 1Neurodegenerative Diseases and Acquired Neurological Damage Center, Institut d’Assistència Sanitària, Santa

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Caterina Hospital, Salt, 2Health Psychology Research Group, Research Institute for Quality of Life, University of Girona, 3Neuroimmunology and Multiple Sclerosis Unit, Dr. Josep Trueta University Hospital, Girona Biomedical Research Institute, 4Faculty of Medicine, University of Girona, Girona, Spain Background: The assessment of quality of life (QoL) is an essential measure to determine the impact of disease and the effects of interventions from the viewpoint of patients. Research indicates that people with MS refer to poorer QoL than other groups of chronic patients. Objective: To study the impact of psychosocial variables on QoL of patients with relapsing-remitting multiple sclerosis (RRMS). Material and methods: An 18-month prospective cohort study with a sample of 49 RRMS patients. Perceived stress was measured monthly. Clinical forms of stress (anxiety and depression), coping strategies and the degree of disability, the number of relapses and pseudo-relapses were measured at baseline and every 6 months. Personality and QoL were measured at baseline and the end of the study. Results: Patients were found to have a generally good QoL and this remained stable during the study (t=1.15 and p=0.25). The best QoL predictors were low anxiety and depression levels, male sex and a low number of pseudo-relapses (R2= 0.8 and p=0.005). The best psychological-QoL subscale predictors were high levels of physical-QoL subscale, low scores on the personality dimension for ´harm avoidance´ and ´reward dependence´ (R2 =0.72 and p=0.005). Furthermore, the best physical-QoL subscale predictors were high levels of psychological-QoL subscale, low scores of the degree of disability, low perceived stress level and low scores in the personality dimension for ´self-transcendence´ and male sex. Patients with lower levels of physical-QoL tended to be on antidepressant treatment (R2=0.86 and p=0.005). Conclusions: The study shows that perceived stress, anxiety, depression and pseudo-relapses have a significant negative impact on QoL. These variables are treatable. It also suggests that the QoL of patients with RRMS may improve as a result of psychological interventions (as part of the biopsychosocial care in neurorehabilitation) aimed at managing stress and its clinical forms. Disclosure Laura Fàbregas: nothing to disclose Montserrat Planes: nothing to disclose Maria Eugenia Gras: nothing to disclose Eva Vidal: nothing to disclose Lluís Ramió-Torrentà: serves on scientific advisory boards for Biogen Idec and Merck-Serono and has received speaker honoraria from Biogen Idec, Novartis, Bayer, Merck-Serono, Genzyme, Teva Pharmaceutical Industries Ltd. P1197 Insomnia in low to mild disability multiple sclerosis patients is not an independent factor for low quality of life M. Mendonça1,2, P. Viana3, E. Rodrigues4, C. Fernandes5, A. Matas6, R. Barreto7, R. Peralta3,8, R. Geraldes3,9 1Department of Neurology, Centro Hospitalar de Lisboa Ocidental, 2CEDOC, Nova Medical School, Universidade Nova


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de Lisboa, 3Department of Neurology, Centro Hospitalar de Lisboa Norte - Hospital de Santa Maria, Lisbon, 4Department of Neurology, Centro Hospitalar do Funchal, Funchal, 5Department of Neurology, Hospital Garcia de Orta, Almada, 6Department of Neurology, Centro Hospitalar de Trás-osMontes e Alto Douro, Vila Real, 7Department of Neurology, Centro Hospitalar de Entre-o-Douro e Vouga, Santa Maria da Feira, 8Sleep / EEG Laboratory, Centro Hospitalar de Lisboa Norte - Hospital de Santa Maria, 9Faculdade de Medicina, University of Lisbon, Lisbon, Portugal

Neuro-ophthalmology

Introduction: Sleep disorders are common in patients with multiple sclerosis (MS) and are associated with lower quality of life (QoL). Insomnia is frequent in MS patients, and is associated with lower self-rated QoL. However as insomniac patients also have higher rates of other medical and psychiatric comorbidities, we questioned if Insomnia per se is independently associated with lower QoL, in low to mild disability MS patients. Methods: The inMS (Insomnia in Multiple Sclerosis) study was a hospital-based multicenter, observational, cross-sectional study of patients with MS designed to study chronic insomnia disorder. It included 206 patients. From this cohort, all subjects with Expanded Disability Status Scale (EDSS) < 4 were included in the current analysis. Insomnia was diagnosed according to the International Classification of Sleep Disorders (ICSD)-III. QoL was evaluated with a Visual Analog Scale (VAS) from 0 to 100. Depression and Anxiety were evaluated using the Hospital Anxiety and Depression Scale and for Fatigue, Fatigue Severity Scale was used. Univariate analysis was performed using the Mann-Whitney and Chi-Square test. A multivariate linear regression was performed with QoL VAS as the outcome. The variables with a lower significance were sequentially removed in order to obtain the final model. Level of significance was defined as 0.05. Results: 163 patients were included, 34 with insomnia. Mean QoL VAS score was significantly different between insomniac subjects (68.0, 95% CI: 62.6 - 73.5) and non-insomniacs (77.2, 95% CI: 74.3 - 80.0; p = 0.002). The first iteration of the model included age, time since diagnosis, presence of medical comorbidities, anxiety, depression, fatigue and insomnia as variables. Insomnia had a p-value of 0.648. In the last iteration of the model, only Fatigue (p=0.021) and Depression (p< 0.001) were significantly associated with QoL. No severe multicollinearity issues were present in the analysis. Conclusion: Insomnia is associated with lower self-reported QoL in patients with MS with low to mild disability. Nevertheless, insomnia is not independently related with QoL. The lower QoL in insomniac MS patients is probably related to their higher frequency of depressive symptoms and fatigue - factors that we identify to relate with QoL. When trying to have an impact in insomniac MS patients QoL, physicians should be aware, and treat, associated fatigue and depression.

Background: Visual Fields (VF) abnormalities measured by Standard Automated Perimetry have been described in eyes from Multiple Sclerosis (MS) patients without history of Acute Optic Neuritis (AON). Local VF defects may correspond to local lesions in afferent visual pathway and general VF depression might indicate more diffuse damage. VF outcomes have shown positive correlations with visual acuity, retinal damage by Optical Coherence Tomography (OCT) and visual functioning by Multifocal Visual Evoked Potentials. Aim: To investigate VF defects in NON-eyes from a cohort of MS patients addressing the relationship between these defects and clinical and imaging parameters of diffuse damage to evaluate its role as marker of neurodegeneration in MS. Methods: We performed neurological and ophthalmic examinations including OCT and Magnetic Resonance Imaging (MRI) analyses on 107 MS patients. We used a modified version of the classification described in the Optic Neuritis Treatment Trial and Ocular Hypertension Treatment Study to separate participants into two groups: impaired or normal VF groups. We used Spectralis Heidelberg segmentation tool for OCT quantification and SIENAX to evaluate Normalized Brain Parenchymal volume (NBPV), Grey (NGMV) and White Matter Volume (NWMV) and Lesion Volume (LV). We used general linear models adjusted for sex, age at the time of study, disease duration and the use of MS disease-modifying therapies to compare the adjusted means of neurological disability, brain and retina surrogate markers of neurodegeneration between the two groups. Results: VF defects in non-ON eyes were detected in 78 out of 107 patients (72%) at baseline. MS patients with impaired VF suffered greater cognitive disability than those with normal VF as reflected by the significantly lower score in the BRB-N-Executive subscore (p=0.027). These patients also showed significantly lower NBPV (p=0.023), NGMV (p=0.05), higher lesion load in optic radiations LV (p=0.012), and a trend to thinner Ganglion Cell layer thickness (p=0.079) compared to those with normal VF. Conclusions: These results suggest that VF impairment captures diffuse chronic damage in MS, overcoming the widely described role of the VF as measurement of visual outcomes due to AON.

Disclosure The authors have no conflicts of interest to declare. The inMS study was performed as part of the programme “Esclerose Múltipla para Internos de Neurologia” (EMIN), a portuguese educational programme for young neurologists, sponsored by Biogen Idec.

P1198 Visual field impairment as a marker of diffuse damage in multiple sclerosis S. Ortiz-Perez, B. Sanchez-Dalmau, R. Torres-Torres, M. Andorra, N. Sola, S. Llufriu, M. Sepúlveda, A. Saiz, P. Villoslada, E.H. Martinez-Lapiscina Hospital Clinic and Institut d’Investigació August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain

Disclosure Santiago Ortiz-Perez: nothing to disclose. Bernardo Sanchez-Dalmau: nothing to disclose. Ruben Torres-Torres: nothing to disclose. Magi Andorra: nothing to disclose. Maria Sepúlveda: nothing to disclose. Sara Llufriu: nothing to disclose. Nuria Sola: nothing to disclose. Albert Saiz: nothing to disclose.


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Poster Session 2, 21(S11) Pablo Villoslada has received consultancy fees from Heidelberg Engineering regarding the clinical applications of OCT. Elena H Martínez-Lapiscina: nothing to disclose. P1199 Molecular imaging of In vivo human retina by Raman spectroscopy: basis and MS and healthy voluntaries profile E.H. Martinez-Lapiscina1, O. Batet2, I. Torre2, A. Gonzalez2, A. Campos2, I. Bilbao2, D. Perez2, E. Fraga-Pumar1, R. TorresTorres1, Y. Rossello2, B. Sanchez-Dalmau1, I. Amat-Roldan2, P. Villoslada1 1Hospital Clinic and Institut d’Investigació August Pi i Sunyer (IDIBAPS), University of Barcelona, 2Expert Ymaging SL, Barcelona, Spain Background: Retina reflects changes common to Central Nervous System (CNS) damage. Optical Coherence Tomography (OCT) has revealed Ganglion Cell Layer (GCL) thinning in Multiple Sclerosis (MS), Parkinson Disease and Alzheimer Disease. In MS, Inner Nuclear Layer thickening has been associated with inflammation and neurodegeneration (e.g. oedema due to Müller Cell dysfunction). OCT changes are a reflection of the neurodegeneration, but it cannot discriminate the different underlying mechanisms in these neurodegenerative disorders. Molecular imaging of the retina may discriminate these mechanisms because it is sensitive to changes in different molecular pathways. Aim: To develop and validate a system for molecular imaging of human retina by coupling Raman Spectroscopy (RS) to a confocal Scanning Laser Ophthalmoscope (RS-cSLO). Methods: We developed a prototype of RS-cSLO for measuring key molecules related with inflammation and neurodegeneration in human retina. After acquisition, the signal is processed using bioinformatics tools (e.g. principal component analysis (PCA)) to identify retinal RS signature associated with biological processes and to discriminate subgroups of patients. We obtained the RS from reference molecules (e.g. polyethylene) and evaluated reproducibility of RS-cSLO. We acquired a set of spectra from eyes from MS patients with (n:7 eyes) and without previous acute optic neuritis (n:11 eyes) and healthy voluntaries (n:25 eyes). We performed PCA followed by discriminant analyses to construct two scores for discriminate MS and Optic Neuritis. Results: The RS-cSLO was able to obtain the expected spectra from a reference molecule (e.g. polyethylene). Retina spectra from healthy controls showed high inter-subject [>95%] and intra-subject [88.1%-96.5%] reproducibility. No serious adverse events were observed, only transitory dry eye as side-effect. The PCA classifiers were able to group cases accordingly the disease category without significant overlap. Conclusions: RS provides a new approach to address molecular changes from human retina in vivo with high reproducibility and good safety. RS discriminates molecular phenotypes of MS eyes with and without prior AON from healthy eyes. Disclosure Elena H Martínez-Lapiscina: nothing to disclose. Oscar Batet has received consultancy fees as employee of Expert Ymaging SL, a private company. He holds stocks of Expert Ymaging SL for value greater than 10,000$

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Iratxe Torre has received consultancy fees as employee of Expert Ymaging SL, a private company Antoni Gonzalez has received consultancy fees as employee of Expert Ymaging SL, a private company Albert Campos has received consultancy fees as employee of Expert Ymaging SL, a private company Iker Bilbao has received consultancy fees as subcontracted of Expert Ymaging SL, a private company. He holds stocks of Expert Ymaging SL for value greater than 10,000$ Dídac Pérez has received consultancy fees as employee of Expert Ymaging SL, a private company Elena Fraga: nothing to disclose. Rubén Torres-Torres: nothing to disclose. Yago Rosselló has received consultancy fees as subcontracted of Expert Ymaging SL, a private company. He holds stocks of Expert Ymaging SL for value greater than 10,000$ Bernardo Sanchez-Dalmau: nothing to disclose. Ivan Amat-Roldan has received consultancy fees as subcontracted of Expert Ymaging SL, a private company. He holds stocks of Expert Ymaging SL for value greater than 10,000$ Pablo Villoslada has received consultancy fees from Novartis, Roche, and Heidelberg Engineering. He is founder and hold stocks of Bionure Farma SL.

P1200 Hyperacute steroid therapy in patients with recurrent optic neuritis E.Y. Osinga, B.W. van Oosten, W.A.E.J. de Vries-Knoppert, A. Petzold Neurology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands Introduction: The purpose of this study was to find out if patients with recurrent episodes of optic neuritis who are started on hyperacute treatment with corticosteroids have a better visual outcome. Furthermore the optimal time span for hyperacute treatment was determined. Methods: This is a retrospective explorative case review of consecutive patients presenting to a tertiary specialist centre with a diagnosis of optic neuritis and prospectively collected OCT data from January 2010 till January 2014. Episodes of optic neuritis were established and type of treatment was identified. One inclusion criterion was that patients had to have recurrent episodes of optic neuritis. The primary clinical outcome was best corrected high contrast visual acuity, recorded before and at least 3 months after the episode of optic neuritis. The secondary outcome was retinal nerve fibre layer thickness, ganglion cell complex and the inner nuclear layer thickness established before and after a minimum of 3 months after the episode of optic neuritis using the Spectralis Spectral domain optical coherence tomography (OCT). Results: In total 19 patients with recurrent episodes of optic neuritis were identified, with 40 episodes of recurrent optic neuritis. Treatment started within two days after onset of symptoms was compared to delayed treatment. A significant better outcome of visual acuity was found in these episodes (p=0.036). When treatment was started after 5 days, no significant better visual outcome was established. The thickness of retinal layers showed a trend of less atrophy in eyes treated within two days.


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Conclusion: Hyperacute steroid therapy, defined as within 2 days after onset of symptoms, may lead to a better recovery of visual function compared to delayed steroid therapy or no treatment in patients with recurrent episodes of optic neuritis.

Mahmut Kaya: nothing to disclose. Egemen İdiman: nothing to disclose. Derya Kaya: nothing to disclose. Onur Bulut: nothing to disclose. Hatice Limoncu: nothing to disclose.

Disclosure E.Y. Osinga: nothing to disclose. B.W. van Oosten: nothing to disclose W.A.E.J. De Vries-Knoppert: nothing to disclose A. Petzold: Is member of the OCTIMS committee. P1201 What are the differences determined by optic coherence tomography and neuroopthalmological parameters in optic neuritis due to neuromyelitis optica and multiple sclerosis? F. Idiman1, M. Kaya2, E. Idiman3, D. Kaya4, O. Bulut3, H. Limoncu3 1Neurology, Dokuz Eylul University, 2Ophthalmology, 3Neurology, 4Geriatry Division, DEÜ, Izmir, Turkey Background and aim: Neuromyelitis optica (NMO) and Multiple Sclerosis (MS) cases reveal certain differences in optic neuritis. We aimed to determine the contribution of these differences to clinical diagnosis,prognosis and pathogenesis. Material and medhods: We compared statistically matched age, gender,onset age,disease duration groups of 18 NMO (median age 42; 14F/4M; onset age 36.5; duration 7 years; 3 attacks; and 36 eyes) and 21 MS (median age 35; 16F/5M; onset age 26; duration 6 years; 2 attacks; and 42 eyes) according to optic neuritis history (ONH) (+) or (-) . The neuro-opthalmological parameters (visual acuity/VA, color vision/CV, visual fields/VF, pupil sizes/PS and functions/PF, ocular fundoscopy/OF) and spectral domain optical coherence tomography (OCT) peripapillary retinal nerve fiber layer (RNFL) thickness and macular thickness. In addition thickness of each retinal layers(ganglion cell,nuclear,pigment epithelium etc.) was measured. Results: In NMO, VA was lower in ONH(+) eyes (p< 0.008). There was no VA difference among MS-ONH(+) cases. When compared with MS, VA was significantly lower in NMO (p< 0.001). In both NMO (p< 0.001) and MS (p< 0.004) CV was lower in ONH(+) eyes. Again, CV was significantly lower in NMO than MS (p< 0.001). In ONH(+) eyes, PS was greater than others both in NMO (p< 0.001) and MS (p< 0.05). NMO-ONH(+) eyes had greater PS than MS-ONH(+) (0.002). In comparison, VF abnormalities were greater in NMO (p< 0.001). NMO-ONH(+) eyes’ RNFL thickness was significantly lower than NMO-ONH(-) and MS-ONH(+) (p< 0.001). OCT values were compared among MS-ONH(+) and (-), ONH(+) eyes being thinner only at central and temporal quadrant RNFL (p< 0.001). When each group’s retinal layers’ thickness was compared, median thickness appeared lower in NMO; yet, statistically only inner retinal layers were thinner (p< 0.005). NMO-ONH (+) eyes had lower macular thickness than MS-ONH(+) eyes. Conclusion: The results show optic neuritis in NMO and MS has different features, probably due to different pathogenesis. These differences contribute to differential diagnosis and prognosis. Disclosure Fethi İdiman: nothing to disclose.

P1202 The association between multiple sclerosis and uveitis T.G. Olsen, J. Frederiksen Department of Neurology, University of Copenhagen, Glostrup, Denmark Objective: Uveitis and multiple sclerosis (MS) are considered to be somewhat associated. What is the prevalence of MS-associated uveitis? We set out to study this question through a systematic search of contemporary literature. Method: A systematic search of the database Pubmed.com using the following MeSH-terms ”[Multiple Sclerosis]” AND ”[Uveitis]” was undertaken. All studies with a prevalence of MS-associated uveitis were included. Of the 215 original hits 26 studies were included. Additional 6 studies from the related citations were included. Results: The prevalence of MS in patients with uveitis differs from 0,7% to 30,4%, while the prevalence of uveitis in patients with MS differs from 0,65% to 36,7%. All types of uveitis are seen among the patients with multiple sclerosis. Conclusion: The 32 studies are difficult to compare due to differences in the size of the cohort, differences in study design as well as different diagnostic cri-teria for MS and especially uveitis. Based on the biggest retrospective studies the prevalence of MS-associated uveitis seems to be approximately 1% - both for patients with uveitis as well as for patients with MS. To further investigate the association between MS and uveitis bigger prospective studies are needed. Disclosure Tine Gadegaard Olsen: nothing to disclosure. Jette Frederiksen: nothing to disclosure. P1203 Neuromyelitis optica spectrum disorder can be distinguished at onset of optic neuritis by combining brain and optic nerve MRI D.S. Buch Neurology, Fondation Ophtalmologique A. de Rothschild, Paris, France Background: Half of Neuromyelitis Optica Spectrum Disorders (NMO-SD) present with acute optic neuritis (ON) as a first manifestation but no radiological spectrum clearly distinguish it from more common types of ON. Objective: To evaluate the diagnostic accuracy of combining anterior visual pathway and brain MRI to detect NMO-SD among patients with an acute optic neuritis. Method: Retrospective study of acute episodes from NMO-SD and clinically isolated syndrome (CIS) manifesting as an ON and admitted between January 2009 and December 2010. For all


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Poster Session 2, 21(S11) patients complete radiological and clinical data’s were available. Imaging were analysed by a neuroradiologist who was blinded to the clinical diagnosis. Multiple sclerosis was defined according to 2010 revised Mc Donald’s criteria. MRI of anterior visual pathway were performed on 3 mm coronal slices using T2 weighted and fat suppressed T1 weighted sequence with gadolinium and described according to anatomical segments. Results: We compared 19 ON episodes from 15 NMO-SD to 33 CIS-ON. Absence of dissemination in space was the rule in NMO-SD (0% vs 45%; p 0.001). T2 weighted and T1 with Gadolinium were most of the time in accordance at description of size and location of optic nerve hypersignal. Optic nerve hypersignal were located as follow, respectively for CIS vs NMO-SD: orbital 94% vs 74% (p=0.08); canalar: 27% vs 53% (p=0.08); cisternal: 15% vs 58% (p=0.01); chiasmatic: 3% vs 37% (p=0.01); retro-chiasmatic: 0% vs 16% (p=0.04). MRI seemed to detect potentially more often than ophthalmologic examination bilateral involvement in NMO-SD (47% vs 31%; p 0.5). Between CIS and NMO-SD, size of enhancement (median (Q1-Q3)): 13mm (10-16) vs 28mm (19-35) (p 0.01) or the number of affected segments: 1 (1-2) vs 3 (2-6) (p 0.01) were discriminant. Bilateral optic nerve involvement and/or lesion length of 3 segments or more (or 30 mm or more) in absence of dissemination in space were suggestive of NMO-SD: sensitivity 68 % (43-87); specificity 97 % (8499); p 0.01. Conclusion: Combining brain and optic nerve MRI seems performant to detect patients at high risk of NMO-SD-ON. Disclosure Dr Buch received a travel grant from Biogen Dr Savatovsky received fees for speaking or consulting fees from Bayer, PhilipsHealthcare and from GE Healthcare for transport and housing for ASNR meeting. Dr Deschamps reports no disclosure. Dr Gout received consulting and lecture fees from Allergan, Almirall, Bayer Schering Pharma, Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi and Teva Pharma P1204 Role of Aquaporin 4 antibodies in the first optic neuritis: a retrospective study in Argentina E. Carnero Contentti1, M. De Virgiliis2, F. Leguizamon3, J.P. Hryb1, J. Celso3, J.L. Di Pace1, M. Perassolo1 1Neurology, Buenos Aires University, Hospital Carlos G. Durand, 2Universidad de Buenos Aires, Hospital P. Lagleyze, 3Neurology, Hospital Alvarez, Buenos Aires, Argentina Background: Optic neuritis (ON) may appear in isolation or may herald multiple sclerosis (MS) or neuromyelitis optica (NMO). An overlap between NMO and MS, in the early stage of the disease may occur. Aquaporin-4 (AQP4) antibodies can have diagnostic and prognostic value in patients who present first ON. Objective: To study how useful it was to systematically determine AQP4 in a cohort with first ON patients and to investigate the prognostic implications of AQP4 seropositive. Methods: A retrospective revision of clinical records was performed in Buenos Aires from June 2008 to May 2015. AQP4 was tested in 42 patients with first ON in the following contexts:

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typical ON (TON) and atypical ON (AON) for MS. Differential diagnosis were classified according to clinical criteria in NMO spectrum disorders, multiple sclerosis (MSON), chronic relapsing inflammatory ON (CRION), and single isolated ON (SION). Radiological, biochemical, diagnostic and prognostic data was collected, TON vs AON patients were compared. Indirect immunofluorescence assay on a substrate of monkey cerebellum was executed to evaluate. Results: The proportion seropositive was 40% for TON vs 40.9% for AON. Visual acuity (VA) baseline was poor in AON (p< 0.02) and these patients were associated with worse VA outcome as VA of counting fingers only (p < 0.000001) at 6 months comparing AON vs TON during a mean follow-up of 3.27 (±1.79) years. Bilateral ON occurred in 15 patients (6 seropositive). Disease severity not differs significantly between seropositive and seronegative. AQP4 positivity not correlated with the number of ON relapses. AQP4 was detected in 80% of NMOSD (limited and/or defined) patients and in none of the MSON patients. In all of the remaining differential diagnostic (CRION and SION), the seropositive rate was 0%. Conclusion: AQP4 should be routinely determined in first TON and AON patients. Prospective studies and larger number of patients are needed to allow us to confirm these outcomes. Disclosure E. Carnero Contentti: nothing to disclose M. De Virgiliis: nothing to disclose F. Leguizamon: nothing to disclose JP Hryb, J Celso: nothing to disclose JL Di Pace: nothing to disclose M. Perassolo: nothing to disclose

P1205 Chronic relapsing inflammatory optic neuropathy (CRION) clinical characteristics and treatment response Y. Rito1, J. De la Rosa1, T. Gómez2, J. Flores1, T. Corona1 1Laboratory of Clinical Neurodegenerative Diseases, 2Neuro-Ophthalmology, National Institute of Neurology and Neurosurgery, Mexico, Mexico Introduction: CRION is a rare recurrent optic neuritis uni or bilateral without auto-antibody NMO-IgG (Neuromyelitis Optic). The prevalence and incidence is unknown. The degree of loss of visual acuity can be very serious, even with intravenous methylprednisolone (MTPD). CRION could be caused by secondary diseases like Multiple Sclerosis (MS), NMO, Lupus and Sjogren as the most frequent. The objective of this study is to establish the clinical characteristics and treatment response of CRION. Method: Cohort study with patients diagnosed with CRION from 2006 to December 2014. Through medical record, we obtained clinical and treatment information. We recorded each ON event by LogMar score and it was compared by Wilcoxon and Friedman for more than 3 groups. Results: We identified 22 cases, but 2 of them have not CRION criteria and 2 have not enough information. We included 18 patients (15 women and 3 men), mean age 33.2 years (±8.7). The unilateral ON occurred on 15 patients (8 OI, 7OD) and 3 bilateral. Seven patients suffered more than 2 ON events. Mean of days until MTPD


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treatment was 7.6, 2.7 and 4.5 days (p=0.05) for each relapse. Period between relapses was 21.2 months mean. Just 4 patients have defined disease (1 MS, 1Lupus, 2NMO) at 38.5 months mean. MRI showed enhancement optic nerve on 7 patients, while just 4 had other demyelinating lesions. Eight patients did not response to preventive treatment. There was significant difference between visual acuity (VA) pre vs post treatment at first and second ON treated with MTPD (p=0.012, p=0.013), but not fot 3 relapse (p=0.109). Conclusion: The prevalence of CRION was high compared whit another countries. Adult females were the most affected, even younger than those reported in the literature. Recovery was important in the first attacks, but not in the third. Preventive treatment can be challenging due to lack of response. Disclosure Y. Rito: Nothing to disclose. J. De la Rosa: Nothing to disclose. T. Gómez: Nothing to disclose. J. Flores: Nothing to disclose. T. Corona: Nothing to disclose.

Results: In MS we found significantly increased CSF KFLC and LFLC levels compared to controls, as well as an increased ratio KFLC/LFLC in CSF (all p< 0.001). No group differences emerged regarding serum FLC. CSF LFLC (p=0.001, r=-0.4) and the CSF ratio KFLC/LFLC (p< 0.005, r=0.4) correlated with the percentage of periventricular lesion load. CSF FLC and the CSF ratio KFLC/LFLC did not correlate with cortical thinning. No correlations emerged between FLC and demographical or clinical data, including physical disability. Conclusion: Our study demonstrates increased intrathecal synthesis of KFLC and LFLC in MS, which supports the notion of an altered B-cell response. The relations of FLC data with MRI based measures of periventricular lesion load further suggest these markers to be involved in the pathophysiology of MS, although they appear to be less relevant for cortical pathology. Disclosure

Biomarkers P1206 Increased cerebrospinal fluid immunoglobulin free light chain levels in relation to lesion load and cortical thinning of multiple sclerosis patients M.M. Voortman1, T. Stojakovic2, M. Jehna3, H. Scharnagl2, S. Ropele1, T. Seifert-Held1, J.-J. Archelos1, S. Fuchs1, C. Enzinger1,3, F. Fazekas1, M. Khalil1 1Neurology, 2Clinical Institute of Medical and Chemical Laboratory Diagnostics, 3Division of Neuroradiology, Medical University of Graz, Graz, Austria Introduction: Cerebrospinal fluid (CSF) immunoglobulin free light chains (FLC) have been proven a rapid and quantitative alternative measure to oligoclonal bands, with comparable diagnostic sensitivity and specificity in multiple sclerosis (MS). Thus far, only scarce information exists on the relation of FLC to magnetic resonance imaging (MRI) metrics, in particular with measures of brain regions with close proximity to the CSF, i.e. cortical and periventricular regions. Objective: We aimed to compare FLC kappa (KFLC) and lambda (LFLC) levels in CSF and serum between MS patients and controls, and investigate their relation to conventional and non-conventional MRI based measures of cortical thinning and periventricular lesion load. Methods: KFLC and LFLC in CSF and serum were assessed by nephelometry (FreeliteTM, The Binding Site Group Ltd. Birmingham, UK) in 61 MS patients (clinically isolated syndrome n=48, relapsingremitting MS n=13) and 60 non-inflammatory neurologic controls. The ratio KFLC/LFLC was calculated for both CSF and serum. Routine CSF work up included analysis of serum and CSF immunoglobulin levels IgG, IgM and IgA, albumin concentration and CSF cell count. MS patients underwent MRI at 3T to determine the extent of cortical thinning (Freesurfer image analysis suite (v5.3.0)) and periventricular lesion load (segmented semi-automatically on FLAIR images).

This study was supported by ministerial funding of the Austrian Federal Ministry of Economics and Research. Ms. Voortman, MsC: nothing to disclose. Dr. Stojakovic: nothing to disclose. Dr. Jehna: nothing to disclose. Dr. Scharnagl: nothing to disclose. Dr. Ropele: nothing to disclose. Dr. Seifert-Held: nothing to disclose. Dr. Archelos: nothing to disclose. Dr. Fuchs: nothing to disclose. Dr. Enzinger has received funding for travel and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis Genzyme and Teva Pharmaceutical Industries Ltd./ sanofi-aventis; research support from Merck Serono, Biogen Idec., and Teva Pharmaceutical Industries Ltd./sanofi-aventis; serving on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Genzyme, Merck Serono, Novartis, and Teva Pharmaceutical Industries Ltd./sanofiaventis; academic editor for PLOSOne. Dr. Fazekas: nothing to disclose. Dr. Khalil has received funding for travel and speaker honoraria from Bayer Schering Pharma, Novartis Genzyme, Merck Serono, Biogen Idec, and Teva Pharmaceutical Industries. P1207 Circulating MicroRNAs as biomarkers in chronic progressive multiple sclerosis J. Vistbakka, S. Hagman, I. Elovaara Neuroimmunology Unit, School of Medicine, University of Tampere, Tampere, Finland Background: Micro-RNAs (miRNAs) are small non-coding molecules that regulate gene expression at the post-transcriptional level. Because of their key role in the immune system regulation, miRNAs are associated with several autoimmune diseases including multiple sclerosis (MS). In MS, dysregulation of miRNAs is mostly studied in cell populations, but little attention is paid to circulating miRNAs that however own strong biomarker potential due to their exceptional stability in body fluids.


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Poster Session 2, 21(S11) Objective: To identify profiles of circulatory miRNAs in chronic progressive MS and their association to disease progression. Methods: The expression of miRNAs were analyzed from 80 chronic progressive MS patients and 31 healthy controls (HC) using miScript miRNA array/assay. First, the expression of 84 different miRNAs from the samples of 18 primary progressive MS (PPMS) patients and 10 controls was analyzed. Thereafter, 10 most promising miRNAs were validated on a larger patient material (31 PPMS, 31 secondary progressive MS (SPMS) patients and 21HC). Results: 10 out of 84 miRNAs (miR-124-3p, miR-375, miR211-5p, miR-141-3p, miR-130b-3p, miR-376c-3p, miR-128-3p, miR-191-5p, miR-26a-5p, miR-24-3p) were expressed differentially in PPMS when compared to controls that were further studied in the validation cohort. Among the validated miRNAs, four (miR-128-3p, miR-376c-3p, miR-26a-5p, miR-191-5p) were upregulated in chronic progressive group in comparison to controls. According to subtype analysis, upregulation of these four miRNAs were strongest in PPMS in comparison to controls and SPMS. In turn miR-128-3p correlated positively with progression index (r=0,400, p=0,026) in SPMS patients. No correlations were found between the miRNAs and EDSS nor disease duration. Conclusion: Our results indicate an abnormal expression of microRNAs in chronic progressive MS and their possible association to disease progression. Observed differences of miRNA profiles in SPMS and PPMS need to be evaluated in the future studies. Disclosure Julia Vistbakka: nothing to disclose Sanna Hagman: nothing to disclose Irina Elovaara: nothing to disclose P1208 Higher concentrations of mtDNA in CSF of SPMS and PPMS patients C.E. Leurs1, L.J. Balk1, A. Malekzadeh2, P. Podlesniy3, R. Trullas3, B.M.J. Uitdehaag1, J. Killestein1, C.E. Teunissen2 1Department of Neurology, MS Center Amsterdam, VU University Medical Center, 2Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands, 3Institute of Biomedical Research of Barcelona, CSIC-IDIBAPS, CIBERNED, Barcelona, Spain Background: Multiple sclerosis has a variable prognosis and lacks a reliable laboratory prognostic marker. Due to the fact that neurons are highly dependent on aerobic energy provided by mitochondria, we hypothesized that mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF) could be a possible marker for disease severity in MS. However, the levels of mtDNA in cerebrospinal fluid of MS patients have not been investigated. Objective: To evaluate if CSF concentrations of mtDNA in MS patients have potential to differentiate between MS disease phenotypes and correlate to measures of disability. Methods: 54 RRMS patients, 29 SPMS, 15 PPMS, 26 noninflammatory control subjects and 8 inflammatory control subjects were included. Using a digital polymerase chain reaction technique, circulating cell-free mtDNA was measured in CSF

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from study participants. Natural log of mtDNA copies was used as outcome in the linear regression analyses. Preliminary results: Patients with SPMS showed a significant higher concentration of circulating cell-free mtDNA in the CSF compared to non-inflammation control subjects (p=0.012). Patients with PPMS exhibited a higher concentration of circulating cell-free mtDNA in CSF compared to the non-inflammatory control group (p=0.052). There were no significant differences between the subgroups RRMS, SPMS and PPMS. There was a trend of increasing median mtDNA copies uL/CSF with increasing EDSS categories (0-3; 3,5-5,5; 6-10). Interpretation: The need of a trustworthy biomarker predicting and monitoring disease progression is obvious. If confirmed in separate, independent cohorts, concentrations of mtDNA in CSF may be a promising biomarker for the early detection of SPMS and PPMS patients. Disclosure C. Leurs: nothing to disclose. L. Balk: nothing to disclose. A. Malekzadeh: nothing to disclose. P. Podlesniy: nothing to disclose. R. Trullas: nothing to disclose. B.M.J. Uitdehaag: has received personal compensation for consulting from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche and TEVA. J. Killestein: has accepted speaker and consulting fees from Merck-Serono, Biogen Idec, Teva, Genzyme and Novartis. C. Teunissen: serves on the advisory board of Fujirebio and Roche, received research consumables from Euroimmun, IBL, Fujirebio, Invitrogen and Mesoscale Discovery, and performed contract research for IBL, Shire, Boehringer, Roche and Probiodrug; and received grants from the European Commission, the Dutch Research Council (ZonMW), Association of Frontotemporal Dementia/Alzheimer’s Drug Discovery Foundation, ISAO and the Alzheimer’s Drug Discovery Foundation. P1209 Extracellular vesicles cargo as a novel biomarker in multiple sclerosis M. Sáenz-Cuesta1,2, A. Alberro1, M. Muñoz-Culla1,2, I. OsorioQuerejeta1,2, H. Irizar1,2, Á. Prada1,2,3, E. Santamaría4, J. Fernández-Irigoyen4, T. Castillo-Triviño1,2,5, J. Olascoaga1,2,5, D. Otaegui1,2 1Multiple Sclerosis Unit, Biodonostia Health Research Institute, 2Spanish Network on Multiple Sclerosis, 3Laboratoy of Immunology, Donostia University Hospital, San Sebastián, 4Proteomics Unit, Navarrabiomed and Foundation Miguel Servet, Pamplona, 5Department of Neurology, Donostia University Hospital, San Sebastián, Spain Background: Extracellular vesicles (EVs) are small membranebound particles released from almost all cells. They play a key role in cell-to-cell communication carrying lipids, proteins and small RNAs (EV cargo). EVs have been proposed as biomarkers in several diseases due to the ease to obtain them and the large biological information they provide. We previously demonstrated the relationship between their concentration in blood and multiple


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sclerosis (MS) clinical status and also, the effect of IFNβ and natalizumab on them. However, their role in the pathogenesis of MS is not well elucidated. Objectives:Our aim was to analyze the EV cargo comparing the profiles of i) RNA in serum and cerebrospinal fluid (CSF) from MS patients with IgM+ and IgM- oligoclonal band (OCB); ii) protein from healthy controls and untreated patients and iii) miRNA from fingolimod-treated patients before the first dose and 5 hs later. Material and methods: EVs were obtained from serum/plasma (blood) and CSF through differential centrifugation and exoquick kit. The cargo isolation was performed as follow: total and micro RNA with miRNeasy serum/plasma kit and proteins with a ureabased lysis buffer. We performed RNAseq and GeneChip miRNA array to analyze total and microRNA respectively. For proteins iTRAQ labelling and LC-MS/MS mass spectrometer was performed. Results: RNA cargo showed enrichment in sncRNA (especially snoRNA) in EVs from serum and CSF. We found 83 (in serum EV) and 111 (in CSF EV) differential expressed sncRNA when comparing patient with IgM+ and IgM- OCB. In the protein cargo analysis from healthy controls and untreated patients, 9 highly differentiated proteins were found, the most being involved in coagulation. Finally, we found an important effect in sncRNA expression before and 5 h after the first dose of fingolimod. Conclusion: EV cargo is a potential source of novel biomarkers, based on proteins and sncRNA differences between MS and healthy controls. Besides, it could be applied as a treatment monitoring tool. Disclosure Matías Sáenz-Cuesta: This work was partially founded by a Novartis grant. Ainhoa Alberro: nothing to disclose Maider Muñoz-Culla: nothing to disclose Iñaki Osorio-Querejeta: nothing to disclose Haritz Irizar: nothing to disclose Álvaro Prada: nothing to disclose Enrique Santamaría: nothing to disclose Joaquín Fernández-Irigoyen: nothing to disclose Tamara Castillo-Triviño: nothing to disclose Javier Olascoaga: nothing to disclose David Otaegui: nothing to disclose

P1210 Impact of cerebrospinal fluid lipocalin-2 on brain iron accumulation and clinical progression in multiple sclerosis M. Khalil, A. Renner, C. Langkammer, C. Enzinger, S. Ropele, T. Stojakovic, H. Scharnagl, G. Bachmaier, J.J. Archelos, S. Fuchs, T. Seifert-Held, F. Fazekas Medical University of Graz, Graz, Austria Objective: Magnetic resonance imaging (MRI) studies have demonstrated increased iron accumulation in the basal ganglia of multiple sclerosis (MS) patients. Recently we demonstrated reduced cerebrospinal fluid (CSF) transferrin levels in MS which could be associated with this phenomenon. Experimental studies suggest that lipocalin-2 (LCN2), an acute phase protein involved in innate

immunity may also play an important role in the immunopathogenesis of MS. LCN2 has further been reported to exert iron delivery properties in an transferrin independent mechanism. However, it has not yet been investigated if these proteins are related to clinical signs of progression and iron sensitive imaging in MS. We therefore aimed to investigate LCN2 and transferrin levels in cerebrospinal fluid and serum of patients with clinically isolated syndromes (CIS) and MS compared to controls. We further assessed their relation to the evolution of the disease as indicated by clinical follow-up data and the longitudinal changes of iron accumulation in deep gray matter brain structures as evidenced by MRI R2* relaxometry. Methods: We analyzed CSF and serum LCN2 by ELISA (BioPorto Diagnostics, Gentofte, Denmark) and transferrin and ferritin by nephelometry in 55 MS (clinically isolated syndrome (CIS) N=45, MS N=10; median clinical follow-up 4.7 years) and 63 controls. In CIS/MS, we assessed brain iron in subcortical grey matter (caudate nucleus, globus pallidus, putamen, thalamus) by 3T MRI R2* relaxometry at baseline and follow-up (median follow-up 2.2 years). Results: Compared to controls we found reduced serum (p< 0.01) and CSF (p< 0.001) LCN2 and CSF transferrin (p< 0.001) levels in MS. CSF LCN2 correlated with CSF transferrin (r=0.5, p< 0.001).In clinically stable CIS/MS patients CSF LCN2 levels correlated with iron accumulation within the basal ganglia (r=0.502, p< 0.05). Considering CIS patients, binary logistic regression analysis identified higher CSF LCN2 levels as independent factor predicting conversion to clinical definite MS (CDMS) (p< 0.05) during the follow-up period. Conclusion: Our study indicates altered LCN2 regulation in the early phase of MS which appears to be linked to both MS activity and iron accumulation in the basal ganglia. The association of these phenomena over the course of the disease and for their relation with clinical progression deserves further study. Disclosure Dr. Khalil has received funding for travel and speaker honoraria from Bayer Schering Pharma, Novartis Genzyme, Merck Serono, Biogen Idec, and Teva Pharmaceutical Industries. Dr. Renner reports no disclosures. Dr. Langkammer reports no disclosures. Dr. Enzinger has received funding for travel and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis Genzyme and Teva Pharmaceutical Industries Ltd./ sanofi-aventis; research support from Merck Serono, Biogen Idec., and Teva Pharmaceutical Industries Ltd./sanofi-aventis; serving on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Genzyme, Merck Serono, Novartis, and Teva Pharmaceutical Industries Ltd./sanofiaventis; academic editor for PLOSOne. Dr. Ropele reports no disclosures. Dr. Stojakovic reports no disclosures. Dr. Scharnagl reports no disclosures. Dr. Bachmaier reports no disclosures. Dr. Archelos reports no disclosures. Dr. Fuchs reports no disclosures. Dr. Seifert-Held reports no disclosures. Dr. Fazekas serves on scientific advisory boards for BayerSchering, Biogen Idec, Genzyme, Merck Serono, Pfizer, Novartis


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Poster Session 2, 21(S11) and Teva Pharmaceutical Industries Ltd.; serves on the editorial boards of Cerebrovascular Diseases, Multiple Sclerosis, the Polish Journal of Neurology and Neurosurgery, Stroke, and the Swiss Archives of Neurology and Psychiatry; and has received speaker honoraria and support from Biogen Idec, Bayer Schering, Merck Serono, Novartis, Pfizer, Sanofi-Aventis, Shire and Teva Pharmaceutical Industries Ltd. P1211 Circulating miR-150 in cerebrospinal fluid is a novel biomarker for multiple sclerosis P. Bergman, E. Piket, M. Khademi, T. James, M. Lindén, I. Kockum, L. Brundin, F. Piehl, T. Olsson, M. Jagodic Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden Multiple Sclerosis (MS) is a complex immune-mediated and demyelinating disease of the central nervous system and one of the most common causes of neurological disability in young adults. To date the cause of MS is unknown and there is a lack of validated biomarkers for early diagnosis, prognosis and response to therapy. The objective of this study was to explore the possibility to use circulating microRNAs (miRNAs) in cell-free cerebrospinal fluid (CSF) as novel biomarkers for MS. Using TaqMan miRNA low-density array cards we could reliably detect 88 miRNAs in samples from patients with clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS) and controls (other neurological disorders with (iOND) and without (OND) an inflammatory component) (pooled n=13-15 per group). Validation in independent individual samples (n=142) using real-time PCR demonstrated significant differences in levels of miR-145 and miR-150 between MS and OND. Using an even larger cohort (n=430), we could replicate the finding of increased levels of miR-150, but not miR-145, in MS compared to both control groups. We also observed higher miR-150 levels in CIS patients that converted to MS compared to those that did not convert during follow up, as well as in RRMS patients with more active disease that subsequently started treatment with Natalizumab, both suggesting correlation of miR-150 with clinical disease activity. Natalizumab significantly reduced miR-150 levels in CSF whereas levels in plasma were increased, strongly suggesting the immune cells as the main source of circulating miR-150 in CSF. Levels of miR-150 also correlated with immunological parameters such as CSF cell count, IgG index and presence of oligoclonal bands, as well as with the three established immune-associated CSF biomarkers; C-X-C motif chemokine 13 (CXCL13), matrix metallopeptidase-9 (MMP-9), and osteopontin (OPN). Taken together, our findings demonstrate miR-150 as a putative novel biomarker of inflammation and clinical disease activity in MS, with the potential to be used for early diagnosis of MS and to predict inflammatory active disease. Disclosure Petra Bergman: nothing to disclose Eliane Piket: nothing to disclose Mohsen Khademi: nothing to disclose Tojo James: nothing to disclose Magdalena Lindén: nothing to disclose Ingrid Kockum: nothing to disclose

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Lou Brundin has received honoraria for lectures, consultancy and educational activities from BiogenIdec, Merck Serono, SanofiAventis and Teva, and personal compensation for activities with SAS, Biogen Idec, Novartis and Teva as participant on advisory boards, consulting and/or speaking and commercial engagements. Fredrik Piehl has received unrestricted academic research grants from BiogenIdec and Novartis, and compensation for lectures and/or participation in advisory boards from Biogen, Merck Serono, Novartis, Sanofi, Roche and Teva, which have been exclusively used for the support of research activities. Tomas Olsson has received unrestricted MS research grants from Biogen, Novartis, Genzyme and Astra Zeneca, advisory board compensations from Biogen, Genzyme and Novartis, and research grants from the Swedish Research Council, the AFA Foundation, the Swedish Brain Foundation, Maragareta af Ugglas Foundation, Knut and Alice Wallenberg Foundation, and AstraZeneca-Science for Life Laboratory collaboration. Maja Jagodic has received research grants from the Swedish Research Council, the Swedish Association for Persons with Neurological Disabilities, the Swedish Brain Foundation, the Swedish Medical Society, Petrus and Augusta Hedlunds Foundation, the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, and AstraZeneca-Science for Life Laboratory collaboration.

P1212 Exosomal RNA signature in multiple sclerosis patients I. Selmaj, M. Mariasiewicz, K.W. Selmaj, M.P. Mycko Department of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, Lodz, Poland Exosomes are a membrane vesicles released from the endocytic compartment of live cells that play an important role in cell-tocell communication. The major contents of the exosomes are short RNAs that can interfere with the function of the acceptor cells. In order to analyze the role of exosomes in the relapsing remitting multiple sclerosis (MS) we have isolated exosomes from serum, urine and cerebrospinal fluid (CSF) of the MS patients and control subjects. Subsequently we have extracted and exosomal RNA and processed them for the next generation sequencing analysis with the HiSeq platform. We have found that both serum and urine exosomes are a reach source of the shortRNA (< 300 nt) in MS patients. All the sequences have been grouped into 14 different RNA categories: CDBox, HAcaBox, RefSeq_antisense, lincRNA, lincRNA_antisense, miRNA, other_ ncRNA, other_ncRNA_antisense, rRNA, piRNA, rfam, scaRNA, tRNA and tRNA_like. RefSeq_antisense, linc RNA and lincRNA_ antisense represented the largest fraction of frequences derived from MS patients serum or urine exosomes (27%, 22% and 21%, respectively). Interestingly, miRNA constituted only about of 2.5% of all exosomal RNA sequences. We have identified several sequences of short RNA including miRNA as differentially expressed in MS patients. Thus our data demonstrated diverse RNA content in serum, urine and CSF exosomes of MS patients and highlight a potential role of short RNA sequences as a new biomarkers of MS.


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Supported by NCN PRELUDIUM grant to IS, NCN MAESTRO 2012/04/A/NZ6/004234 grant to KS and PSPB-0072010 grant to MPM. Disclosure Igor Selmaj: nothing to disclose Magdalena Mariasiewicz: nothing to disclose Krzysztof W. Selmaj: nothing to disclose Marcin P Mycko: nothing to disclose P1213 Protein-based biomarker predicts conversion from clinically isolated syndrome to multiple sclerosis M. Comabella1, E. Borràs2, E. Cantó1, M. Choi3, L.M. Villar4, J.C. Álvarez-Cermeño4, C. Chiva5, O. Vitek3, E. Sabidó2, X. Montalban1 1Multiple Sclerosis Centre of Catalonia/Neuroimmunology Department, Vall d’Hebron University Hospital & VHIR, 2Proteomics Unit (CRG), University Pompeu Fabra (UPF), Barcelona, Spain, 3Department of Statistics, Purdue University, West Lafayette, IN, United States, 4Hospital Ramón y Cajal, Madrid, 5Universitat Pompeu Fabra (UPF), Barcelona, Spain Background: Cerebrospinal fluid (CSF) protein biomarkers are important tools for prognosis in patients with clinically isolated syndromes (CIS). We took advantage of the capabilities of targeted mass spectrometry to accurately identify biomarkers in CSF samples from CIS patients and evaluate their classification power in terms of conversion to clinically definite multiple sclerosis (CDMS). Methods: CSF samples from CIS patients who converted to CDMS (n=25) and patients who remained as CIS during followup (n=25) were included in the study. Samples were analyzed by nanoLC-selected reaction monitoring (SRM). SRM assays were designed for 24 proteins known to be prognostic in CIS patients based on in-house spectral libraries built from tandem mass spectra. The SRM assays developed were used to identify and quantify the targeted proteins in a QTRAP 5500. Five isotopically labeled peptides were spiked in each sample as internal standards and used for normalization in a sparse quantitation strategy. Results: A total of 28 peptides representing 19 of the pre-selected proteins (23 proteoforms when including isoforms and variants) were consistently detected and quantified across all measured patients. All quantified proteins were challenged to correctly classify CIS patients into those who converted to CDMS and those who continued as CIS. We performed a predictor selection combined with cross-validation to select a combination of proteins with predictive ability, and evaluated their performance using receiver operating characteristic (ROC) curves on a separate set of subjects. To assess the robustness of the selected candidate protein combinations, the whole cross-validation process was repeated 500 times. Protein combinations that were more frequently selected in these analyses were chosen as the final protein combinations. In particular, the combination of two proteins was selected repeatedly above the rest. Our results show that the measurement of these two protein combination can discriminate between CIS patients who develop CDMS and those who remained as CIS with the highest specificity and sensitivity

(AUC = 0.86). We also generated probability maps to provide neurologists with a precise probability of conversion to CDMS for each patient. Conclusions: We have established a biomarker assay based on the combination of two CSF proteins which is able to classify, with high predictive performance, CIS patients according to their risk of conversion to MS. Disclosure E Cantó, E Borràs, M Choi, C Chiva, O Vitek, and E Sabidó report no disclosures. LM Villar has received compensation for consulting services, travel expenses for scientific meetings, and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Genzyme, and Novartis. JC Álvarez-Cermeño has received compensation for consulting services and speaking from Bayer-Schering, Merk-Serono, Biogen-Idec, Teva, Sanofi-Aventis, and Novartis. M Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, and Novartis. X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall and Roche. P1214 Evaluation of postulant predictive and prognostic biomarkers in multiple sclerosis: Fetuin-A, S100B and GFAP A. Altintas1, S. Akkas-Yazici1, V. Lehmensiek2, H. Tumani2 1Department of Neurology, Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey, 2Department of Neurology, Ulm University, Ulm, Germany Aim: To predict conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and to differentiate between relapsing and progressive subytpes of MS, we analized the utility of the biomarkers Fetuin-A, S100B and GFAP in cerebrospinal fluid (CSF) and serum. Background: Despite the possibility to establish early diagnosis of MS on the basis of the revised McDonald 2010 criteria, there is still a need for more reliable biomarkers as predictors for disease progression after first clinical manifestation. Methods: The study comprised treatment-naive, newly diagnosed CIS (n=23), relapsing-remitting (RR) (n=22) and primary-progressive (PP) MS (n=7) patients.Samples were collected following a relapse (CIS and RRMS) within one month. Age and gendermatched pseudotumour cerebri patients (n=10) were choosen as controls. Demographic, clinical and radiologic data of each patient were recorded. Besides routine CSF-serum analysis; the candidate biomarkers Fetuin-A (inflammatory activity), S100B (astrocytic activity) and glial-fibrillary-acidic-protein[GFAP] (astrogliosis) were assessed via quantitative immunoassays (ELISA). CIS-group was followed-up for a median time of two years. Median disease duration of PPMS was 4.5 (3.75-6) years.


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Poster Session 2, 21(S11) Results: The Qalb (CSFalb/serumalb) and IgG-index were found significantly higher in PPMS (p=0.001; p=0.020). Fetuinantibody-index[AI] (Qfetuin/Qalb) differentiated between controls and MS (p=0.0001), and within MS subgroups there was a non-significant gradual decrease from CIS, RRMS to PPMS. CSF-GFAP and S100B were significantly increased in patients with severe disability (EDSS>6) compared to those with moderate (EDSS3-6) and mild (EDSS< 3) scores independently of disease subtype (p=0.012; p=0.019). All biomarkers did not differentiate between CIS patients either converting (n=9) or non-converting (n=9) to MS over follow-up time (p>0.05). Conclusions: While all investigated biomarkers are not helpful to predict conversion from CIS to MS, Fetuin-AI shows a weak correlation between the MS subtypes with highest levels in PPMS patients. CSF-GFAP and S100B are associated with severe disability independently of the disease subtype. Disclosure A. Altintas: Dr. Altintas received research grants to her department from The Scientific and Technological Research Council Of Turkey-Health Sciences Research Grants numbers:109S070, 112S052. Dr.Altintas also, reports receiving honoraria from Merck-Serono, Gen Ilac and Teva; S. Akkas-Yazici: Nothing to disclosure. H. Tumani: Dr.Tumani received financial support for research activities and also personal compensation for consulting, serving on a scientific advisory board and speaking from Bayer, Biogen, MerckSerono, Teva, Roche, Genzyme Virotech. V. Lehmensiek: Nothing to disclosure. P1215 Chitinase 3-like 1 is associated with the response to interferon-beta in multiple sclerosis patients C. Matute1, J. Río1, L.M. Villar2, S. Malhotra1, J.C. ÁlvarezCermeño2, X. Montalban1, M. Comabella1 1Multiple Sclerosis Centre of Catalonia/Neuroimmunology Department, Vall d’Hebron University Hospital & VHIR, Barcelona, 2Hospital Ramón y Cajal, Madrid, Spain Background: Recent studies point to a prognostic role for chitinase 3-like 1 (CHI3L1) in patients with multiple sclerosis (MS), particularly at the time of the first neurological event or clinically isolated syndrome. Here, we investigated a potential association between CHI3L1 and the response to first-line disease modifying therapies (DMT) such as interferon-beta (IFNb) and glatiramer acetate (GA). Methods: Relapsing-remitting MS (RRMS) patients treated with IFNb or GA were classified into responders and non-responders after 1 year of treatment. Non-responders to DMT were patients fulfilling 2 or 3 of the following criteria: (i) presence of ⩾1 relapses; (ii) increase of ⩾1 points in the EDSS score; (iii) presence of ⩾3 active lesions on the 1-year brain MRI. Patients satisfying only 1 or none of the 3 criteria were considered responders to DMT. A total of 107 RRMS patients were included in the study, 76 treated with IFNb and 31 with GA. Of these, 62 patients were responders to IFNb and 19 to GA. The remaining patients were considered as non-responders to IFNb (n=14) or GA

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(n=12). CHI3L1 levels were determined in serum samples at baseline and after 12 months of treatment with DMT by enzymelinked immunosorbent assay. Differences between groups were analyzed by means of an ANOVA for repeated measures. Results: Overall, IFNb therapy did not modify serum CHI3L1 levels after 12 months of treatment when compared with the basal time point (time effect: p=0.803). However, a trend for higher CHI3L1 levels was observed in patients treated with GA for 12 months (time effect: p=0.061), being similar in GA responders and non-responders. A statistically significant responder effect was observed for IFNb, and serum CHI3L1 levels were higher in responders compared with non-responders (group effect: p=0.020). No similar group effect was observed for GA-treated patients (p=0.580). Finally, no significant group by time interactions were found between responders and nonresponders to IFNb or GA. Conclusions: These results further expand the prognostic implication of CHI3L1 in MS, and point to a role for CHI3L1 as biomarker of response to IFNb in RRMS patients. Disclosure C. Matute and S. Malhotra report no disclosures. J Rio has received speaking honoraria and travel grants from Bayer-Schering, Merck-Serono, Biogen, Teva, Sanofi, and Novartis. LM Villar has received compensation for consulting services, travel expenses for scientific meetings, and speaking honoraria from Bayer, Merk Serono, Biogen, Teva, Genzyme, and Novartis. JC Álvarez-Cermeño has received compensation for consulting services and speaking from Bayer, Merk-Serono, Biogen, Teva, Sanofi, and Novartis. X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer, Biogen, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi, Teva, Almirall and Roche. M Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen, Teva, Sanofi, Genzyme, and Novartis.

P1216 Elevation of serum Sema4A in neuromyelitis optica spectrum disorder (NMOsd) T. Okuno1, T. Koda1, K. Miyamoto2, K. Takata3, M. Kinoshita3, S. Kusunoki2, A. Kumanogoh4, Y. Nakatsuji1, H. Mochizuki1 1Neurology, Osaka University Graduate School of Medicine, Suita, 2Neurology, Kinki University, Sayama, 3Neurology, Osaka General Medical Center, Osaka, 4Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Suita, Japan Background: Sema4A is a class IV semaphorin which plays an important role in the activation of Th-cells. We previously established ELISA system to measure Sema4A and reported that serum Sema4A levels are significantly higher in multiple sclerosis (MS) than those in other neurological diseases. MS patients with high Sema4A titer have higher serum IL-2 level, suggesting that


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Sema4A participates in the pathogenesis of MS by activating Th cells. Although Th cells as well as anti-aquaporin 4 antibody (AQP4ab) play important roles in neuromyelitis optica (NMO), the involvement of Sema4A in NMO remains to be elucidated. Method: Serum Sema4A levels were analyzed by ELISA in 38 patients with NMOsd and 129 patients with MS. All NMOsd patients were positive for serum anti-aquaporin 4 antibody (AQP4ab). MS was diagnosed according to the Macdonald criteria. We compared clinical characteristics of patients with high Sema4A levels (＞3000 U/ml) to those with low Sema4A levels（⩽3000 U/ml). Results: The serum Sema4A titers were significantly higher in NMOsd patients than those in patients with MS (6740± 10048 versus 3508±6867 U/ml, p = 0.039). The average age of onset in patients with high Sema4A levels was significantly younger than that with low Sema4A levels (38.5±12.4 versus 53±13.2, p = 0.031). Patients with higher Sema4A levels had a significantly less severe EDSS score in acute exacerbations (3.52±1.0 versus 5.67±1.78, p=0.0009) and after remissions (4.78±2.4 versus 2.0±0.98, p=0.0009). Their relapse rate tended to decrease, although this difference was not significant. Conclusion: The levels of serum Sema4A in NMOsd is as high as those in MS. Sema4A plays important roles in the pathogenesis of NMO as well as MS. Disclosure Tatsusada Okuno, Toru Koda, Katsuichi Miyamoto, KazushiroTakata, Makoto Kinoshita, Susumu Kusunoki, Atsushi Kumanogoh, Yuji Nakatsuji and Hideki Mochizuki: nothing to disclose P1217 Quantitative sterol signatures of cerebrospinal fluid in multiple sclerosis and neuromyelitis optica spectrum disorder I.H. Jeong1, J.-Y. Moon2, J.J. Lee2, S.-H. Kim1, J.-W. Hyun1, W. Kim3, A. Joung1, M.H. Choi2, H.J. Kim1 1Department of Neurology, National Cancer Center, Goyang-si, 2Materials and Life Science Research Division, Korea Institute of Science and Technology, 3Department of Neurology, The Catholic University of Korea, Seoul, Republic of Korea Background: The disturbances of the cholesterol homeostasis in the pathogenesis of central nervous system autoimmunity have been suggested. However, little is known about the cholesterol metabolic signatures, especially in cerebrospinal fluid (CSF). Objectives: In the present study, we investigated whether the level of CSF sterol differs quantitatively among multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and healthy controls (HC). Methods: The sterol signatures were performed to measure 17 endogenous and 3 dietary plant sterols using a highly reproducible gas chromatography-mass spectrometry method. Until now, CSF samples from 36 patients with MS, 46 patients with NMOSD and 12 healthy controls were examined. Results: Among the sterols examined, 12 were quantitatively detected from CSF. The levels of 2 cholesterol precursors (desmosterol and lathosterol), 3 plant sterols, and the metabolic ratios

of 7α-hydroxycholesterol and 7β-hydroxycholesterol (7α-OHC / 7β-OHC) obtained from patients with MS and NMOSD were significantly higher than those of HC (p < 0.001). The concentration of free cholesterol and metabolic ratios of 24- and 7-reductases, which are corresponding to cholesterol/desmosterol and cholesterol/7-dehydrocholesterol, respectively, were significantly higher in NMOSD than in MS and HC (p = 0.003). In contrast, the metabolic ratios of 7α-OHC to cholesterol were significantly higher in MS than in NMOSD (p = 0.007) and HC (p = 0.001), respectively. A similar pattern was found in the 7β-OHC/cholesterol ratio (p < 0.05). Conclusion: Our preliminary results show that perturbation of sterol pathways is linked to the pathological process of CNS autoimmunity. Significant differences in the level of free cholesterol and 7α(β)-OHC/cholesterol ratios suggest that alterations in cholesterol metabolism associated with disease process differ between MS and NMOSD. Disclosure This study was supported by the Bio & Medical Technology Development Program (M3A9B6069339) through the Ministry of Science, ICT & Fuure Planning. P1218 pharmacokinetics and pharmacodimamics of rituximab in NMOSD and RRSM treated patients A. Sala, F. Marnetto, P. Valentino, M. Capobianco, S. Malucchi, A. Bertolotto Multiple Sclerosis Centre, ASO S. Luigi, Orbassano, Italy Rituximab (RTX) is a monoclonal antibody (Ab) that binds CD20 on B cells. RTX has been shown to limit relapses in relapsing remitting multiple sclerosis (RRMS) and neuromyelitis optica spectrum disorders (NMOSDs). Aim: For the first time we studied the pharmacokinetics of RTX in NMOSD and RRSM patients (pts) evaluating free RTX and Ab to RTX, comparing these results to the quantification of CD19 mRNA Bcells by RT-PCR method (Marnetto, 2014) in order to find an optimal dosing and monitoring regimen of treatment. Patients and method: 72 sera from CReSM bio-bank were selected as followed: 42 of 5 NMOSD pts and 30 of 9 RRMS pts on going with RTX. We tested also 3 healthy controls (HC) and 4 sera before the 1st infusion of RTX (T0). Time points selected: 1) 1 month (mth) before cycle n=12; 2) during the cycle n=5; 3) 1-2 mth n=16; 4) 3-4 n=10; 5) 5-6 n=21;6) 8-9 n=7; 7) 10-23 n=9 after the end of cycle. We used commercial quantitative ELISA kit (PROMONITOR). The free RTX cut-off is 0.75ug/ml; Ab to RTX cut-off is 140 AU/ml. Results: 3 HC and 4 T0 samples were negative. Ab to RTX: none of analyzed samples were positive. RTX free: group 1: 2/12, 16%, were positive at low level (5.7 and 1.9 ug/ml); group 2: 100% positive with high concentration (mean ug/ml±SD 144.7±60.64); group 3: 100% positive (132.7±51.59); group 4:100% positive (29.56±34.04);


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Poster Session 2, 21(S11) group 5:14/21 positive, 66.6% (3.53±3.52); group 6: 1/7 positive, 14% (1.8 ug/ml); group 7:100% negative. There is no statistically significant difference between group 2 and 3 (p=0.709). Between group 3 and all other groups there is always a statistically significant difference, as well as between group 5 and groups 6 and 7. RT-PCR CD19: Before the RTX infusion, all samples showed detectable values, while during treatment and in all months after infusion the CD19 mRNA was not detectable. Conclusion: Starting from 3-4 mth after the end of RTX infusion, the free RTX decreases in statistically significant manner and after 6 mth the level is under cut-off. This may support the repeating RTX infusion at 6-9 mth intervals, but is convenience to personalized the regimen of infusion. So open questions are: how long does the effect of RTX even when it is no longer detectable? What is the lower concentration preventing the increase of CD19 Bcells? Nowadays we consider the best approach a treatment based on monitoring the percentage of CD19 Bcells, but this preliminary data could improve and refine the timing of re-infusion. Disclosure Sala Arianna: received refunds from Biogen Idec Marnetto Fabiana: received refunds from Biogen and Euroimmun Valentino Paola: received refunds from Biogen Idec Capobianco Marco: received refunds from Farmades, Aventis, Serono, and Dompé Biotec for attending several conferences. Malucchi Simona: received refunds from Farmades, Aventis, Serono, and Dompé Biotec for attending several conferences. Bertolotto Antonio: received refunds from Farmades, Aventis, Serono, and Dompé Biotec for attending several conferences and fees for lectures by Serono, Aventis, Dompé Biotec and Biogen Idec; funds for research and for staff members from Serono, Aventis and Dompé Biotec. P1219 Using TMA methodology to Investigate differential expression of the complement pathway in MS grey matter lesions S. Loveless1,2, O.W. Howell3, K.E. Harding1,2, L.M. Watkins3, B.P. Morgan4, J.W. Neal1,4, N.P. Robertson1,2 1Institute of Psychological Medicine and Clinical Neurology, Cardiff University, 2Helen Durham Centre for Neuroinflammatory Disease, University Hospital of Wales, Cardiff, 3Institute of Life Sciences, Swansea University, Swansea, 4Institute of Infection and Immunity, Cardiff University, Cardiff, United Kingdom Introduction: Tissue microarray (TMA) methodology, in conjunction with immunohistochemistry (IHC), allows rapid analysis of tissue with a large number of novel antibodies. This approach has potential to prioritise protein targets for detailed morphometric (gene expression) and biochemical analysis (biomarkers). Methods: TMAs were prepared using formalin fixed paraffin embedded human brain tissue obtained from the Multiple Sclerosis (MS) Tissue Bank (Imperial College) from 13 cases of neuropathologically validated MS. Pre-characterised tissue cores were taken from donor blocks and inserted into recipient paraffin wax blocks according to a pre-prepared grid. Two TMA grids (120

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cores each) were constructed. 5um slides were cut and processed for IHC using an automated DAKO staining system with antibodies against Complement (C) activation proteins (C3b, C1q) and C regulatory proteins (C1 Inhibitor [C1inh], clusterin [clust], CR1 and Factor H [fH]) as well as cell and tissue markers (HLA, GFAP, MOG, Iba-1). The individual TMA cores were digitally imaged, and quantification of immunolabelled cells was performed. C1q, C3b, C1inh, and clust were used as markers of the classical C pathway, whilst C3b, fH, CR1 and clust were used as markers of the alternative C pathway. Pearson correlation was used to examine the relationships between the numbers of positively stained cells of each antibody. Logistic regression was used to analyse the association between antibody staining patterns in grey matter (GM) lesions versus normal appearing GM tissue. Results: Correlation was observed between C1q and C3b (R2=0.7), C1inh (R2=0.48) and clust (R2=0.58) respectively; C3b and C1inh (R2=0.39); C3b and clust (R2=0.50); C1inh and clust (R2=0.47) of the classical pathway (p< 0.0001). For the alternative pathway: no correlation was observed between C3b and CR1 or fH. Correlation was seen for C3b and clust (R2=0.51); CR1 and fH (R2=0.57); CR1 and clust (R2=0.34); fH and clust (R2=0.59). C1q was associated with GM lesions (p=0.04) after correction for other members of the classical pathway, whereas for the alternative pathway both fH (p=0.038) and clust (p=0.015) were associated. Conclusion: We have identified differential expression of C proteins in GM lesions, thus targeting C for monitoring and therapy in MS. This methodology enables us to prioritise protein targets for future detailed morphometric analysis in a larger cohort of tissue samples. Disclosure This work was funded by a BNS project grant. P1220 Combined CSF and MRI longitudinal study of grey matter damage in multiple sclerosis may allow prediction and monitoring of disease progression R. Magliozzi1,2,3, F. Facchiano4, S. Rossi4, M. Castellaro5, A. Gajofatto2, S. Montemezzi6, F. Pizzini6, A. Bertoldo5, M. Pitteri2, M.D. Benedetti2, O. Howell7, S. Monaco2, R. Reynolds3, M. Calabrese2 1Istituto Superiore di Sanità, Cell Biology and Neuroscience, Rome, 2Neurological and Movement Sciences, University of Verona, Verona, Italy, 3Imperial College London, Division of Brain Sciences, London, United Kingdom, 4Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, 5Information Engineering, University of Padova, Padova, 6Diagnostics and Pathology, University of Verona, Verona, Italy, 7College of Medicine, Swansea University, Swansea, United Kingdom Background: Multiple sclerosis (MS) is characterized by variable accumulation of motor, sensory and cognitive deficits during the progressive phase. It is becoming increasingly accepted that cerebral grey matter (GM) damage provides the best correlate of the rate of clinical progression, and that meningeal infiltrates represent the main source of inflammatory molecules that released in the cerebrospinal fluid (CSF) may mediate a gradient of tissue injury in the adjacent GM.


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Objectives: A new approach combining advanced 3T MRI imaging of GM changes with extensive protein analysis of patient CSF has been performed to identifying specific biomarkers and imaging tools to predict/monitor GM pathology and its association with disease progression. Methods: A specific workflow for the optimization of CSF collection/storage from MS patients, enrolled according to well-defined clinical/MRI findings, has been optimized in the MS Centre of Verona, to minimizing protein/RNA degradation and ensuring the highest analysis reproducibility. Immune-assay technique (Luminex technology, Bio-Plex X200 equipped with magnetic washer workstation) has been used for protein analysis of the baseline presence and levels of more than 70 inflammatory mediators in the CSF collected at the disease onset from MS patients with high (n=17) and low (n=17) GM damage, as revealed by 3-Tesla optimized MRI sequences (Double inversion recovery, FLAIR, T1, Susceptibility Mapping and Neurite Orientation Dispersion and Density Imaging) and control cases (n=6), all age-matched. Results: Protein analysis revealed the expression of different panels of molecules in the CSF of the two groups of MS patients stratified for the level of GM pathology. In particular, higher levels of cytokines (IFN-γ, IFN- λ1, TNF, LIGHT, IL4, IL6, GM-CSF, MIF), chemokines (CXCL1, CXCL25, CCL6, CCL1) and other molecules, such as TNFR1, MMP1, MMP2, pentraxin-3 and chitinase 3-like, were found in the CSF of MS patients with higher GM lesion load and more rapid disease progression. Conclusions: A potential pattern of molecular biomarkers of GM pathology in MS has been identified and, after further validation, may be proposed together with combined imaging correlates as useful tools for patient stratification and for identification of new therapeutic targets to prevent or block disease progression. (Study supported by the Progressive MS Alliance grant no PA 0124 and the Italian Minister of Health grant no GR-2010-2313255) Disclosure Magliozzi Roberta: nothing to disclose Francesco Facchaino: nothing to disclose Stefania Rossi: nothing to disclose Francesca Pizzini: nothing to disclose Castellaro Marco: nothing to disclose Marco Pitteri: nothing to disclose Alessandra Bertoldo: nothing to disclose Alberto Gajofatto: nothing to disclose Stefania Montemezzi: nothing to disclose Maria Donata Benedetti: nothing to disclose Howell Owain W.: nothing to disclose Richard Reynolds: nothing to disclose Salvatore Monaco: nothing to disclose Massimiliano Calabrese: has received consulting and/or lecture fees and/or travel grants from Bayer Schering, Biogen Idec, Genzyme, Novartis and Teva P1221 Retrospective and prospective studies of the CD62L as a predictive marker of PML risk in NTZ-treated MS patients B. Pignolet1, N. Breuil1, F. Bucciarelli1, F. Umuhoza1, L. Scandella1, P. Vermersch2, J. de Sèze3, B. Brochet4, J.-C.

Ouallet4, J.-F. Moreau4, S. Pittion-Vouyouvitch5, P. Labauge6, T. Vincent7, M. Comabella8, C. Lebrun-Frenay9, D. Brassat1, on the behalf of BIONAT, CFSEP and BESTMS 1CHU Toulouse, Toulouse, 2CHRU Lille, Lille, 3CHRU Strasbourg, Strasbourg, 4CHU Bordeaux, Bordeaux, 5CHU Nancy, Nancy, 6CHRU Montpellier, 7CHU Montpellier, Montpellier, France, 8VHIR, Barcelona, Spain, 9CHU Nice, Nice, France Background: Current MS treatment strategy is called “escalation” with first and second line therapy. NTZ is used mostly as second line therapy essentially because of a higher risk of severe adverse effects. Indeed, concerns about safety appeared with cases of progressive multifocal encephalopathy (PML), a severe adverse effect due to JC virus infection that could lead to death. So, there is an urgent need to find biomarkers of PML risk to rationalize the use of NTZ. Objectives: To confirm CD62L as a robust PML prediction marker, in 2 NTZ-treated patients cohort. Methods: 2 NTZ-treated cohorts have been used. The bionat cohort with 1200 patients starting NTZ. A prospective biological samples collection analyzed in a retrospective manner was performed (2007-2015), and a prospective second cohort of 500 patients at high PML risk. Using flowcytometry, we determined the level of CD62L expression on CD4 T cells derived from both frozen PBMC (BIONAT and the prospective cohort) and fresh PBMC (in the prospective cohort only). A stratification algorithm will be presented for refining the smallest subgroup of high risk patients. The Number of avoided PML using the algorithm will be modelized. Results: Using the retrospective study in the BIONAT cohort, we confirmed that the low level of CD62L on CD4 T cells assessed at 2 years after NTZ initiation could be used as a biomarker of PML risk development (p=0.0013). Conclusion: CD62L is a robust marker for stratifying PML risk in our cohort and may allow to reduce NTZ-related PML cases, when integrated in a stratification algorithm. Disclosure David Brassat has received speaking honoraria and travel expenses for scientific meetings in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals. The other authors: nothing to disclose. P1222 Plasmapheresis sessions do not alter sensitivity of standardized cell based immunofluorescence assay for anti-AQP4 antibody detection in neuromyelitis optica patients P.M.S. Assis1, B.P.A. Prado-Junior2, A.S. Souza1, R.C.S. Bruder1, R.B. Souza1, F. von Glehn3,4, F.C.G. Rocha1, F.L. Leite5, A.S. Moraes5, A.A. Barreira2, E.A. Donadi2, D.G. Brum1 1Faculdade de Medicina de Botucatu - Universidade Estadual Paulista, UNESP, Botucatu, 2Universidade de Sao Paulo Campus Ribeirao Preto, Ribeirão Preto, 3Universidade Estadual de Campinas, UNICAMP, Campinas, Brazil, 4Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, United States, 5Universidade Federal de São Carlos, UFSCAR, São Carlos, Brazil


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Poster Session 2, 21(S11) Introduction: Neuromyelitis optica (NMO) is a severe inflammatory central nervous system autoimmune disease with a characteristic predilection for the optic nerves and spinal cord. NMO is more frequent in regions with non-Caucasian populations such as in Brazil and is an important differential diagnosis among others CNS demyelinating disorders. It is specific biomarker, serum antiAQP4 antibodies, could be detected by several commercial methods, including cell based immunofluorescence assay. The known clinical sensitivity and specificity varies among 58-76% and 94-100% respectively. It was demonstrated that the serum antiAQP4ab titles varies according to the disease’s phase (relapsing vs. remitting) and patients’ treatment; therefore, the sensibility of assays could vary. Objective: To analyze the sensitivity of cell based immunofluorescence assay after each session of plasmapheresis. Methods: We tested peripheral blood samples from fifteen NMO patients under methylprednisolone therapy followed by plasmapheresis, before each session (total 5 sessions per patient) for detection of anti-AQP4 antibody in a standardized cell based immunofluorescence assay employing recombinant human AQP4 (Euroimmun AG, Germany). The known specificity of the test is 100% and sensitivity is 78%. Results: Before starting first plasmapheresis session, five (33.3%) patients presented seronegative results and ten (66.7%) were seropositive. The seronegative patients remained negative after all sessions. Interesting, even after the fourth session of plasmapheresis, all seropositive patients had anti-AQP4 antibodies detected by the assay. Conclusion: Plasmapheresis sessions do not alter sensitivity of standardized cell based immunofluorescence assay employing recombinant human AQP4. Keywords: neuromyelitis optica, plasmapheresis, anti-AQP4 antibody, standardized cell based immunofluorescence assay. Disclosure The authors declare no conflict of interest. 1. Paula Mikaela Sales Assis: Nothing to disclose 2. Benedito de Pina Almeida Prado-Junior : Nothing to disclose 3. Andreia da Silva Souza: Nothing to disclose 4. Rita de Cassia Siqueira Bruder: Nothing to disclose 5. Renata Brant de Souza: Nothing to disclose 6. Felipe Von Glehn: Nothing to disclose 7. Fernando Coronetti Gomes da Rocha: Nothing to disclose 8. Fábio Lima Leite: Nothing to disclose 9. Ariana de S. Moraes: Nothing to disclose 10. Amilton Antunes Barreira: Nothing to disclose 11. Eduardo Antonio Donadi: Nothing to disclose 12. Doralina Guimarães Brum: Nothing to disclose Financial support: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and grant #12/ 50839-4, São Paulo Research Foundation (FAPESP). P1223 Markers of long-term disability in RRMS patients treated with interferon beta J. Río1, Á. Rovira2, M. Tintoré1, S. Otero-Romero3, M. Comabella1, À. Vidal-Jordana1, I. Galán1, J. Castilló1, G. Arrambide1, C. Nos1, C. Auger2, J. Sastre-Garriga1, X. Montalban1

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1Multiple

Sclerosis Centre of Catalonia/Neuroimmunology Dept, 2MRI Unit, Radiology Dept, 3Multiple Sclerosis Centre of Catalonia/Neuroimmunology Dept & Epidemiology Dept, Vall d’Hebron University Hospital & VHIR, Barcelona, Spain Objectives: The aim of this study is to investigate the early clinical and radiological (MRI) predictors of long-trem disability in patients with RRMS treated with IFNb. Methods: Consecutive patients with RRMS treated with IFNb underwent brain MRI before the onset of therapy with IFNb and 12 months after and a neurological assessment every 3 or 6 months. Patients were classified based on the presence of active lesions (new T2 or gadolinium enhancement), presence of relapses, disability increase or combinations of all these variables after one year of therapy. Cox-Regresion analysis was performed in order to identify clinical and MRI predictive variables of longterm disability. The primary endpoint was defined as the increase of at least 2 EDSS points during the follow-up period. Results: We included 233 RRMS patients with a clinical and MRI examination and with a follow-up of 8 years. In the first year of treatment 23% of patients had relapses, 15% had an increase of at least 1 EDSS-point and 60% had active lesions. Thirty-four percent of patients were free of clinical and MRI activity after one year of therapy. Prediction model analysis showed that both the combination of >2 active lesions plus clinical activity (relapses and/or progression) (Rio score ⩾ 2) (HR 3.3 95% CI 1.7-6.4) and the isolated presence of radiological activity (HR 2.9 95% CI 1.5-5.6) were significant for identifying patients with poor prognosis after the long follow-up period. No evidence of disease activity (NEDA) and modified Rio score fail to predict long therm disability. Overall, all measures of clinical or radiological activity during the first year of therapy had a satisfactory negative predictive value although a poor positive predictive value. Only combined clinical and radiological measure (Rio score) had a moderate positive predictive value. The presence of active lesions was the more sensitive measure (74%) for predicting disability while the combined measures (Rio and modified Rio scores) were the more specific. Conclusions: In patients with RRMS treated with IFN beta the combined clinical-radiological activity measures and active lesions on MRI during the first year of treatment have an acceptable prognostic value for identifying patients with long-term disability. Disclosure J Río has received speaking honoraria and personal compensation for participating on Advisory Boards from: Almirall; BayerSchering Healthcare; Biogen-Idec; Genzyme; Merck-Serono; Novartis; Teva and Sanofi-Aventis. A Rovira serves on scientific advisory boards for NeuroTEC and on the editorial board of the American Journal of Neuroradiology and Neuroradiology, has received speaker honoraria from Bayer Schering Pharma, Sanofi-Aventis, Bracco, Merck Serono, Teva Pharmaceutical Industries Ltd. and Biogen Idec, receives research support from Bayer Schering Pharma, and serves as a consultant for Novartis. M Tintoré has received compensation for consulting services and speaking honoraria from Bayer-Schering, Merck-Serono, BiogenIdec, Teva, Sanofi-Aventis, and Novartis.


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M Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, and Novartis. G Arrambide has received compensation for consulting services from Biogen-Idec. J Sastre-Garriga has received compensation for consulting services or speaking honoraria from Merck-Serono, Biogen-Idec, Teva, Almirall and Novartis. X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall. J Castilló, A Vidal-Jordana, I Galán, C Nos, S OteroRomero and C Auger report no conflict of interest related to this work. P1224 Serum NfL levels in early relapsing remitting MS are increased and correlate with CSF and MRI measures J. Kuhle1, A. Mathias2, C. Soneson3, G. Disanto4, G. Bonnier2, C. Barro5, M. Canales2, M. Schluep2, R. Du Pasquier2, G. Krueger6, C. Granziera2 1Neurology, University Hospital Basel, Basel, 2CHUV Lausanne, 3SIB Swiss Institute of Bioinformatics, Lausanne, 4Ospedale Civico, Lugano, 5University Hospital Basel, Basel, 6Siemens Healthcare, Lausanne, Switzerland Background: Axonal loss is thought to be the pathological substrate underlying accrual of permanent disability in MS. Neurofilaments are the structural scaffolding proteins of neurons, axons and dendrites. We have developed an assay for neurofilament light chain (NfL) measurements in serum samples. To date little is known about correlations of NfL concentrations in serum and corresponding cerebrospinal fluid (CSF) samples and their respective relation to conventional and more advanced MRI measures of disease impact in patients with early relapsing remitting MS (RRMS). Methods: 31 RRMS patients underwent CSF and serum sampling at baseline. After 3.6 years (median, interquartile range 1.5-4.4) 19 of these and 10 newly recruited RRMS patients and 18 healthy controls had an advanced MRI scan at 3T and a serum sampling on the day of MRI assessment. CSF and serum NfL concentrations were measured using an electrochemiluminescence immunoassay. NfL levels of MS patients and controls were compared using a linear model, adjusting for age and gender. Longitudinal changes in serum NfL were evaluated using a linear model with the time between the first and the second sample as predictor. Pearson correlations were calculated between serum NfL levels and MRI measures. Results: NfL levels in CSF and corresponding serum samples were highly correlated (R=0.62, p=0.0002). Levels in serum were higher in MS patients compared to controls at both time points (pCSF=0.005, median 9.0 pg/ml; pMRI=0.008, 10.4 pg/ml; healthy controls: 1.3 pg/ml) and did not change significantly over time (p=0.56). In patients, serum NfL levels correlated positively with white matter (WM) lesion volume (R=0.67, p< 0.0001), but not

grey matter lesion volume (R=0.15, p=0.44) and negatively with WM magnetization transfer ratio (MTR, R=-0.41, p=0.029). Conclusions: CSF and serum NfL levels were highly correlated and elevated in RRMS versus healthy controls. Serum NfL levels correlated with white matter lesion volume and WM MTR. Our findings further support a potential role for quantifying NfL in MS patient’s serum to assess ongoing axonal damage and warrant confirmation in larger patient cohorts. Disclosure JK: has received research support by an ECTRIMS Research Fellowship Programme, University of Basel, Swiss MS Society, Swiss National Science Foundation, Protagen AG, Roche, Genzyme and Novartis. AM: reports no disclosures. CS: reports no disclosures. GD: reports no disclosures. GB: reports no disclosures. CB: reports no disclosures. MC: reports no disclosures. MS: has served as a consultant for Merck-Serono, has received honoraria, payment for development of educational presentations and travel support from Biogen-Idec, Genzyme, Merck-Serono, Novartis, and Sanofi-Aventis. RDP: has served on scientific advisory boards for Biogen Idec, Genzyme, Merck Serono, Novartis, and Teva, and has received funding for travel or speaker honoraria from Biogen Idec, Teva, Merck Serono, and Genzyme. GK: works for Siemens Healthcare USA. CG: has served on scientific advisory boards and received speaker honoraria from Novartis.

P1225 Circulating microRNAs (miRNAs) serve as a biomarker for diagnosis, disease stage, prognosis, treatment response and disability in multiple sclerosis R. Gandhi, B. Healy, A. Paul, K. Regev, F.V. Glehn, C. DiazCruz, T. Gholipour, S. Egorova, P. Nejad, B. Patel, B. Glanz, P. Kivisakk, T. Chitnis, H. Weiner Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, United States Objective: To determine the role of circulating miRNAs as a biomarker for Multiple Sclerosis (MS). Background: MicroRNA (miRNAs) are single stranded, small noncoding RNA molecules that regulate gene expression and protein synthesis and are involved in fundamental biological processes. Stable expression of miRNA in plasma and serum, makes them ideal potential candidate to identify immune biomarker related to MS. Design and methods: We categorized MS patients into different group categories based upon clinical and magnetic resonance imaging (MRI) parameters and analyzed serum samples to measure expression of miRNA using SyBr green PCR. This study was divided into two phases; discovery and validation, to determine miRNA based biomarker for following biomarker categories: disease diagnosis, disease stage, prognosis, response to treatment and disability related to MS. During the discovery phase we tested 8-10 subjects in different groups and measured expression of 627


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Poster Session 2, 21(S11) miRNAs in serum. During validation phase, we selected miRNA from discovery group analysis and tested selected miRNAs on 20-40 subjects. We tested about 500 subjects during this biomarker study including MS patients, healthy controls and other neurologic and autoimmune disease patients. Results: We identified 18 miRNAs that differentiated MS patients from healthy controls both in discovery and validation group. Among these, we found significantly differential expression of miR-320, miR-484 and let-7 in MS compared to the controls. miR320 has been recently shown to be involved in regulating cell proliferation and metastasis. Let-7 miRNAs regulate stem cell differentiation, T cell activation, activate TLR-7 and are linked to neurodegeneration. We found 11 miRNAs that were differentially expressed in secondary progressive MS patients compared to relapsing remitting MS patients; among these were the miRNAs such as miR-30e, that were also found in our published MS plasma study and are known to regulate IL-10 expression. We found 21 miRNAs that were validated and correlated to EDSS among these; 11 were negatively correlated suggesting decreased miRNA expression was associated with higher EDSS. We also found 16 miRNAs that could predict response to FTY720 treatment and discriminate FTY720 responders from non-responders MS patients. Conclusions: Our findings establish specific miRNAs as readily accessible blood biomarkers to monitor disease status in MS. Disclosure Roopali Gandhi received research support from Biogen, Novartis, and Merck-Serono. Brian Healy received research support from Merck-Serono, Novartis and Genzyme. Howard L. Weiner has research support from Serono, Biogen, Therapix, Novartis, Genzyme, Teva. Anu Paul, Keren Regev, Felipe Von Glenn, Camilo Diaz-Cruz, Taha Gholipour, MD, Parham Nejad, Bonny Patel have nothing to disclose. Bonnie Glanz and Pia Kivisakk have research support from Serono. Svetlana Egorova and Tanuja Chitnis have research support from Novartis and Serono.

P1226 Cerebral antioxidant glutathione (GSH) in major subtypes of multiple sclerosis: relations with MRI measures and clinical status I.-Y. Choi1,2,3, P. Lee1,3, P. Adany1, A.J. Hughes4, D.R. Denney4, S.G. Lynch2 1Hoglund Brain Imaging Center, 2Neurology, 3Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, 4Psychology, University of Kansas, Lawrence, KS, United States Background: Glutathione (GSH) plays a crucial role in cerebral antioxidant defense and is quantitatively the most important in this defense system. Because GSH is consumed during the protective process against oxidative stress, maintaining high GSH is shown to be a cellular priority. The impaired GSH system further leads to mitochondrical damage and lesion formation. Our previous findings showed lower cerebral GSH levels in patients with secondary progressive MS (SPMS) compared to healthy controls [Choi, MSJ 2011]. In this study, we confirmed and extended our

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early study on new, larger subject samples with neuropsychological and extensive MRI measures using a new 3T MRI system. Objectives: To determine GSH deficits across major phenotypes of MS; and examine correlations between GSH measures and patients’ MRI indices, cognitive performance and functional status. Method: GSH and MRI measures were obtained on 48 MS patients (14 RRMS, 14 PPMS, 20 SPMS) and 20 healthy controls at 3T. All subjects completed a battery of cognitive tests yielding scores on processing speed, memory and executive function, and functional status measures including EDSS and questionnaires pertaining to fatigue, depression and perceived stress. Cerebral GSH levels were measured in all subjects using a multiple quantum chemical shift imaging technique [Choi & Lee, NBM 2012]. Results: GSH levels were significantly lower in SPMS (p< .02) and PPMS (p< .03), compared with RRMS and controls (age 48.7±12.6 yrs). Because RRMS (39.1±10.1 yrs) patients were younger than SPMS (52±7.8 yrs) and PPMS (54.1±7.9 yrs), all analyses were controlled for age by using covariance and partial correlation. GSH levels were correlated with patients’ disability ratings on the EDSS, fatigue, depression and stress, while conventional MRI measures (lesion volumes, whole brain atrophy, gray and white matter volumes) were not correlated with any of them (p⩾0.07). However, MRI measures, but not GSH, were correlated with cognitive performance, especially processing speed. The exception was a test of verbal learning and memory, for which both sets of measures were related to GSH levels. Conclusion: Current study replicated our previous results of lower GSH in SPMS and further in PPMS, indicating an important role of oxidative stress particularly in the progressive stage of MS. Furthermore, the predictive value of GSH with respect to patients’ clinical status appears to be distinct from that of MRI measures. Disclosure Sharon G. Lynch has participated in Multi-center MS trials and grants funded by biogen, Teva, Novatis, Acorda, Opexa, Roche, Genentech, Genzyme, Sun Pharma, Vaccinex, Actelion, NMSS, and NIH. This work was partially funded by Grant RG 4495-A-4 from NMSS. In-Young Choi: nothing to disclose. Phil Lee: nothing to disclose. Peter Adany: nothing to disclose. Abbey J. Hughes: nothing to disclose. Douglas R. Denney: nothing to disclose. P1227 Search of biomarkers for multiple sclerosis by RNA, microRNA, and exome sequencing approaches M. Comabella1, J.C. Triviño2, L. Negrotto1, N. Reinwick3, M. Vallverdú1, J. Castilló1, N. Fissolo1, S. Malhotra1, X. Montalban1 1Multiple Sclerosis Centre of Catalonia/Neuroimmunology Department, Vall d’Hebron University Hospital & VHIR, Barcelona, 2Bioinformatics Department, Sistemas Genómicos, Valencia, Spain, 3Howard Hughes Medical Institute, The Rockefeller University, New York, NY, United States Background: Biomarkers are needed in multiple sclerosis (MS) to understand the complex and multifactorial heterogeneity of


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the disease, particularly disease activity biomarkers that may help to distinguish between different MS clinical courses or activity phases of the disease. Here, we aimed to identify disease activity biomarkers in MS by applying RNA, microRNA, and DNA sequencing approaches. Methods: DNA and peripheral blood mononuclear cells were collected from 12 healthy controls and 44 untreated MS patients. The MS group included 10 patients with early relapsing-remitting MS (in the first 5 years after disease onset; RRMS), 11 RRMS patients with benign disease course (defined by the presence of EDSS scores ⩽3.0 after ⩾15 years from disease onset), 12 patients with secondary progressive MS (SPMS), and 11 patients with primary progressive MS (PPMS). RNA sequencing was performed using the Illumina technology and the Tophat method and Cufflinks for differential expression. MicroRNA sequencing was performed on an Illumina HiSeq2500 sequencing platform, and FASTQ files were annotated using an in house RNA sequence annotation pipeline; analysis was conducted with the miRDeep2 method and DESeq2 for differential expression. Exome sequencing from DNA samples was based on an Illumina HiSeq2000 sequencing platform and Agilent’s SureSelect Target Enrichment System for 51Mb; for variant calling, GATK and VarScan algorithms were used. A complete integrative bioinformatics analysis was applied using RNA sequencing, microRNAs and exomes methods based on systems biology methodology. Results: Compared to other clinical forms and healthy controls, patients with benign disease course were characterized by a significant over-expression of HSPA1B, a gene coding for a member of the heat shock protein 70 family (adjusted p-values < 0.05). Patients with PPMS had an up-regulation of genes induced by the pro-inflammatory transcription factor nuclear factor kappa B, in particular interleukin (IL)-1beta and IL-6 (adjusted p-values < 0.01). In patients with early RRMS, an over-expression of microRNA 132 (hsa-miR-132) was associated with a significant downregulation of the hsa-miR-132-regulated gene heparin-binding EGF-like growth factor (HBEGF; adjusted p-values < 0.05). Conclusions: These results point to different molecular mechanisms operating in MS clinical forms, and proposed candidates may have the potential to become disease activity biomarkers in MS patients. Disclosure JC Triviño, L Negrotto, N Reinwick, M Vallverdú, J Castilló, S Malhotra report no disclosures. M Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, and Novartis. X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall and Roche. P1228 Differential associations of intrathecally produced immunoglubulin (Ig)G and IgM with radiological findings in early multiple sclerosis

J. Oechtering1, C. Pfuhl1, R. Wenzel2, J.R. Behrens1, L. Rasche1, R.M. Giess1, J. Wuerfel3, A.U. Brandt1, K. Wakonig1, F.C. Pache1, E. Freitag1, J. Bellmann-Strobl1, F. Paul1,4, K. Ruprecht1 1Neurology, Charité - Universitätsmedizin Berlin, Berlin, 2Department of Neurology, Suedhaerz Klinikum, Nordhausen, 3Radiology, Universitätsmedizin Göttingen, Göttingen, 4Neurocure Clinical Research Center, Berlin, Germany Background: While intrathecal immunoglobulin (Ig)G production is a characteristic feature of multiple sclerosis (MS), some patients with MS additionally have an intrathecal production of IgM. Calculation of the percentage of the intrathecally produced IgG/IgM among the total intrathecal IgG/IgM allows to quantitatively determine the extent of intrathecal IgG/IgM synthesis. Objective: To correlate the percentage intrathecal IgG and IgM synthesis with radiological findings in patients with early MS. Methods: Data from comprehensive cerebrospinal fluid (CSF) examinations, including determination of oligoclonal bands (OCB) and calculation of the percentage intrathecally produced IgG and IgM, were collected from 104 patients (70 female, median [range] age 32 [18-56] years) with clinically isolated syndromes or early relapsing-remitting MS. Patients also underwent 3 Tesla magnetic resonance imaging (MRI). CSF and MRI data were correlated by Spearman correlation and frequencies compared by Fisher`s exact test. Results: The percentage of intrathecally produced IgG correlated with the number of T2-weighted lesions (r=0.23, p=0.024), but not with the number of contrast-enhancing lesions (CEL) or with the patients’ age. In contrast, the percentage intrathecally produced IgM did not correlate with the number of T2-weighted lesions, but showed a trend for association with the number of CEL (r=0.2, p=0.08), and was inversely correlated with age (r=0.26, p=0.013). When grouping patients according to increasing intrathecal IgG synthesis into those without OCB, those with OCB but no calculated IgG synthesis >0%, and those with OCB and a calculated IgG synthesis >0%, there was an increase in T2-weighted lesions with increasing IgG synthesis. Likewise, the percentage of patients that met the Barkhof-Tintore criteria ⩾1 juxtacortical lesion, ⩾3 periventricular lesions, and ⩾1 CEL/⩾ 9 lesions increased with increasing IgG synthesis. Whereas intrathecal IgG synthesis was not associated with infratentorial lesions, patients with an intrathecal IgM synthesis more frequently had infratentorial lesions (13/23) than patients without an intrathecal IgM synthesis (18/60),(p=0.04). Conclusions: Our data suggest differential associations of intrathecal IgG and IgM synthesis with radiological findings in patients with early MS. Analyses of the extent of intrathecal IgG and IgM production may help to closer define disease phenotypes and could also be of prognostic relevance. Disclosure JO received travel grants and travel attendance from Bayer Healthcare and Biogen Idec. RMG received financial support for travel and congress attendance from Novartis CP received financial support for travel and congress attendance from sanofi-aventis/Genzyme JW serves on advisory boards for Novartis and Biogen Idec. He received research grants from Novartis and Teva Pharmaceuticals,


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Poster Session 2, 21(S11) and speaker honoraria from Bayer, Novartis, Teva Pharmaceuticals and Biogen Idec. JW is supported by the German ministry of education and research (BMBF/KKNMS). AUB is cofounder and director of Motognosis. He received research grants from Novartis; travel support from Novartis and Biogen Idec; speaker honoraria from Heidelberg Engineering, Novartis, Bayer and Biogen Idec. He serves on the VISION study advisory board from Biogen Idec. JBS has received speaking fees and travel grants from Bayer Healthcare, sanofi-aventis/Genzyme, and Teva Pharmaceuticals. FP is supported by the Deutsche Forschungsgemeinschaft, the EU FP7 Framework Program (combims.eu), the Guthy Jackson Charitable Foundation, the Bundesministerium für Bildung und Forschung (Competence Network Multiple Sclerosis and N2 Advisims). FP has received research support, travel reimbursement and personal compensation for activities with Alexion, Bayer, BiogenIdec, Chugai, Teva, MerckSerono, Novartis, SanofiGenzyme, MedImmune. LR has received a travel grant from Bayer Healthcare KR has received research support from Novartis as well as speaking fees and travel grants from Guthy Jackson Charitable Foundation, Bayer Healthcare, Biogen Idec, Merck Serono, sanofi-aventis/Genzyme, Teva Pharmaceuticals, and Novartis; and is supported by the German Ministry of Education and Research (BMBF/KKNMS, Competence Network Multiple Sclerosis). P1229 Global metabolomics identifies perturbation of multiple metabolic pathways in multiple sclerosis patients P. Bhargava, E.M. Mowry, P.A. Calabresi Johns Hopkins University, Baltimore, MD, United States Objective: To compare the metabolic profile of subjects with relapsing remitting multiple sclerosis (MS) and healthy controls. Background: Given that metabolic changes have been reported by recent studies in animal models of MS, we hypothesized that metabolic pathway markers in MS would be measurably different from healthy controls. Design and methods: Plasma was obtained from 27 subjects with RRMS and 27 healthy controls (HC) who were matched for age, sex and ethnicity, divided into a discovery cohort (15 MS/15 HC) and a validation cohort (12 MS/12 HC). Samples underwent methanol extraction followed by liquid/ gas chromatography coupled with mass-spectrometry at Metabolon Inc. (Durham, NC). Metabolites were identified by automated comparison of the ion features in the experimental samples to a reference library of chemical standard entries. Data analysis was performed using SIMCA-14.0 to build a partial least squares-discriminant analysis (PLS-DA) model and MetaboAnalyst 3.0 for individual compound and pathway enrichment analysis. Results: The mean age of subjects was 37.6 ± 8.7 years, and 80% were female. In MS patients, the median EDSS was 1.0 (IQR:1.5), median disease duration was 1 year (IQR:1-6 years) and 19 (70%) subjects were untreated. A total of 676 metabolites were measured, out of which 61 (42 up-regulated, 19 down-regulated) were significantly altered between the groups in the discovery cohort and 92 (38 up-regulated, 54 down-regulated) were significantly altered between groups in the validation cohort. Utilizing PLS-DA, it was possible to accurately classify the two groups based on their

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metabolomic profile in the discovery cohort (Q2=0.51, CV ANOVA-0.3), validation cohort (Q2=0.37, CV ANOVA-0.05) and as a combined cohort (Q2=0.54, CV ANOVA-0.0004). The pathways involved in MS patients included neuropeptide metabolism (elevated N-acetylaspartate & N-acetylaspartatyl-glutamate), redox homeostasis (decreased beta & gamma-tocopherol, elevated oxidized-cysteinyl glycine & cysteine), lipid metabolism (elevated long-chain fatty acids, PUFA), bile acid metabolism (reduced secondary bile acids), heme metabolism (elevated heme & reduced bilirubin), arginine & ornithine metabolism (elevated ornithine) and phenylalanine metabolism. Conclusions: Comparative global metabolic profiling revealed that MS patients have a distinct metabolic profile. This could serve as an important tool for biomarker discovery and provide insights into the pathogenesis of the disease. Disclosure Pavan Bhargava: is the recipient of a Sylvia Lawry Physician Fellowship Award from the National Multiple Sclerosis Society Ellen M. Mowry: is funded by the National MS Society and the National Institutes of Health (NINDS K23 NS067055). She receives free medication from Teva Neuroscience Inc. for a clinical trial and has research funding from Biogen Idec. Peter A. Calabresi: Received consulting honorarium from Abbott, Vaccinex, and Vertex. Grant support from Novartis, MedImmune and Biogen

P1230 Role of the C-terminal fragment of osteopontin in multiple sclerosis C. Comi1, G. Cappellano1, E. Orilieri1, M.F. Soluri1, N. Clemente1, C.L. Gigliotti1, E. Boggio1, D. Vecchio1, M. Sorosina2, F. Martinelli-Boneschi2, G. Comi2, M. Caldano3, A. Bertolotto3, M. Leone4, L. Ambrogio5, D. Sblattero1, R. Cantello1, U. Dianzani1, A. Chiocchetti1 1Università del Piemonte Orientale, Novara, 2San Raffaele Scientific Institute - Institute of Experimental Neurology, Milan, 3San Luigi Hospital, Torino, 4Casa Sollievo della Sofferenza, San Giovanni Rotondo, 5Santa Croce Hospital, Cuneo, Italy Background: Osteopontin (OPN) is a proinflammatory cytokine highly expressed in demyelinating plaques of MS and experimental autoimmune encephalomyelitis (EAE), and OPN-/- mice develop a mild form of EAE. In inflammatory sites, OPN is cleaved by thrombin into N- (OPN-N) and C-terminal (OPN-C) fragments with different ligands and functions. Anti-OPN autoantibodies (Abs) have been detected in patients with rheumatoid arthritis. Objectives: Aim of the work was to search for anti-OPN autoAbs in the serum of MS patients and to evaluate their effect in EAE. Methods: Anti-OPN autoAbs were assessed by ELISA using full length OPN (OPN-FL), OPN-N, or OPN-C. EAE was induced using MOG 35-55 in C57BL/6 mice pre-vaccinated with ovalbumin (OVA)-linked OPN-FL, OPN-N, OPN-C, or OVA alone. Secretion of interleukin (IL)-17 and interferon (IFN)-γ induced in vitro by MOG35-55 was evaluated by ELISA in spleen lymphocytes. Results: Anti-OPN autoAbs were detected in both patients and controls, but their amount was significantly higher in patients than


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in controls (p=0.0001). RR patients displayed higher levels compared to both primary or secondary progressive patients. Moreover, anti-OPN levels were increased in relapsing-remitting (RR) patients during the remission phase, whereas decreased during the relapse phase. The levels of anti-OPN-C autoAbs were higher than those against OPN-N in all patients. Vaccinations with the OPN constructs significantly decreased EAE severity, and the protective effect correlated with decreased secretion of IL-17 and IFN-γ. However, the best effect was obtained with OPN-C, which induced significantly faster and more complete remission than the other OPN vaccines. Conclusions: OPN-C plays a key role in MS and EAE and novel drugs targeting OPN-C may be proposed for MS therapy. Disclosure This work wassupported by the Fondazione Italiana Sclerosi Multipla (FISM, Genova 2010/R/12-2011/R/11), the Associazione Italiana Ricerca sul Cancro (IG 10237, AIRC, Milano), Fondazione Amici di Jean (Torino), and the Fondazione Cassa di Risparmio di Cuneo (Cuneo), and PRIN Project 2009 (MIUR, Rome). None of authors has any financial interest in the matter of the manuscript. Disclosure of conflict of interest: All authors disclose no financial interest.

MRI and cognition P1231 Different patterns of gray and white matter microstructural abnormalities are associated to PASAT and SDMT performances in relapsing remitting multiple sclerosis M.A. Rocca1,2, G.C. Riccitelli1, E. Pagani1, L. Vacchi1, B. Colombo2, P. Preziosa1,2, A. Falini3, G. Comi2, M. Filippi1,2 1Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, 2Department of Neurology, 3Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy Background: The symbol digit modalities test (SDMT) has been proposed as a promising alternative to the paced auditory serial addition test (PASAT) to evaluate information processing speed in MS. Objective: To investigate the relationship between the patterns of gray matter (GM) atrophy and white matter (WM) microstructural abnormalities with performances at PASAT and SDMT in relapsing remitting (RR) MS patients. Methods: Using a 3.0 Tesla scanner, high-resolution 3D T1-weighted, diffusion tensor (DT) and dual-echo images were acquired from 171 RRMS patients and 80 healthy subjects (HC). All patients performed PASAT and SDMT tests. Regional GM atrophy was estimated using a voxel-based morphometry analysis, while WM microstructural abnormalities were investigated with tract based spatial statistical analysis. Correlations between performances at PASAT/SDMT and regional GM/WM abnormalities were assessed at a p< 0.05, familywise corrected for multiple comparison. Results: Compared to HC, RRMS patients showed the expected patterns of GM atrophy, involving the deep GM nuclei and cortical regions located in the fronto-parietal-temporo-occipital lobes, as well as a distributed microstructural involvement of the WM

skeleton. In RRMS patients, significant correlations were found between worse PASAT scores and atrophy of the deep GM nuclei, and GM regions of fronto-temporal-occipital lobes. Worse SDMT performance correlated with atrophy of deep GM nuclei, and several GM regions of the fronto-temporal lobes. Diffusivity abnormalities (decreased fractional anisotropy [FA], increased mean [MD], axial [AD] and radial [RD] diffusivity) of supratentorial WM tracts correlated to both PASAT and SDMT performance. PASAT performance was also correlated with decreased FA and increased RD of the bilateral cerebral peduncles; whereas SDMT performance was associated with decreased FA and increased RD of several infratentorial regions located in the cerebellum and brainstem. Conclusions: In RRMS, distinct patterns of GM atrophy and WM microstructural abnormalities are associated with performance at PASAT and SDMT tests; while poor PASAT performances was correlated with GM and WM damage of supratentorial brain regions, poor SDMT performances extended the correlation also at WM abnormalities of infratentorial regions. These findings suggest that different neural system may be involved in abnormalities at these two tests. Disclosure Partially supported by a grant from Italian Ministry of Health (GR-2008-1138784/GR-2009-1529671) and Fondazione Italiana Sclerosi Multipla (FISM2012/R/8). GC Riccitelli, E. Pagani, L. Vacchi, B. Colombo, P. Preziosa, A. Falini have nothing to disclose. M.A. Rocca received speakers honoraria from Biogen Idec, Novartis and ExceMed. G. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Excemed. M. Filippi has received compensation for consulting services and/ or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis. P1232 Selective cognitive impairment is correlated with regional corpus callosum index in a cohort of relapsing remitting multiple sclerosis patients in Chile E. Ciampi1,2, R. Uribe1,2, M. Vasquez3, A. Marquez1, A. Burgos4, D. Reyes3, A. Reyes3, E. Vergara3, C. Pinto3, P. Feliu3, D. Weaver3, C. Carcamo3 1Neurology, Pontificia Universidad Católica de Chile, 2Neurology, Hospital Dr. Sótero del Río, 3Pontificia Universidad Católica de Chile, Santiago, Chile, 4MIT Massachusetts Institute of Technology, Cambridge, MA, United States Background: Corpus Callosum Index (CCI) is a simple and easy to perform measure of brain atrophy. Brief evaluations have been able to show relevant cognitive impairment, with a real utility in clinical practice. Goals: To describe the correlation between brief cognitive tests, total, and regional CCI in relapsing remitting multiple sclerosis (RRMS). Methods: Patients were selected from a prospective database of the Universidad Católica MS Programme. We included a


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Poster Session 2, 21(S11) cross-sectional cohort of RRMS patients with brief cognitive tests for processing speed (SDMT), episodic memories (verbal, CVLT; visual, BVMT), working memory (PASAT), inhibitory control (Stroop), cognitive shifts (FAS), as well as fatigue (Krupp), depression (Beck), and quality of life scales (MSIS29). Total and regional (anterior, middle, posterior) CCI was obtained by a trained neurologist from sagittal T1 weighted images and correlated with cognitive scores within 3 months of clinical evaluation. Results: A total of 67 patients were included, 63% female, mean age 34.5 years, mean disease duration 5 years, median EDSS 1 (range 0-6.5), 96% were receiving disease modifying treatment (DMT), and 91% had >12 years of education. Episodic memories were mostly affected, verbal (CVLT) in 34.3% and visual (BVMT) in 31.3%, followed by working memory (PASAT) in 25.4% of patients. Total and regional CCI were correlated with EDSS (Rho -0.57 and -0.43 respectively, p< 0.001). Total CCI was also correlated with processing speed (SDMT, partial Rho 0.37, p=0.024); anterior CCI was correlated with working memory (PASAT partial Rho 0.48, p=0.003); and posterior CCI with SDMT (partial Rho 0.4, p=0.015). These results were corrected by age, gender, education, depression, fatigue and quality of life scores. Conclusions: CCI is a simple brain atrophy measure and it is correlated with selective cognitive impairment. It may be an affordable tool to identify MS patients at risk, and in a near future may be a useful follow-up instrument. Disclosure EC received educational grants from the ECTRIMS Clinical Training Fellowship Programme 2013-2014. She has served as an advisory board member for Genzyme and Biogen, as well as professional travel and accommodation stipends from Novartis and Merck. RU has served as an advisory board member for Genzyme, as well as professional travel and accommodation stipends from Biogen, Novartis, Merck, Teva. MV reports no conflicts of interest. AM reports no conflicts of interest. AB reports no conflicts of interest. DR reports no conflicts of interest. AR has received reimbursement for developing educational presentations for Genzyme and travel and accomodation stipends from Genzyme and Merck. EV has received reimbursement for developing educational presentations for Genzyme and Novartis, and travel and accomodation stipends from Genzyme, Novartis and Merck. CP professional travel and accommodation stipends from Merck. PF reports no conflicts of interest. DW reports no conflicts of interest. CC has served as an advisory board member for Genzyme, Merck Serono LATAM, and Novartis Chile. She has received reimbursement for developing educational presentations for, Merck Serono LATAM, Bayer and Novartis Chile, as well as professional travel and accommodation stipends. P1233 Structural connectivity and cognitive performance in multiple sclerosis

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S. Llufriu1, E. Martinez-Heras1, N. Sola-Valls1, M. Sepulveda1, F. Varriano2, Y. Blanco1, E.H. Martinez-Lapiscina1, P. Villoslada1, A. Prats2, A. Saiz1 1Center for Neuroimmunology, Neurology Service, Hospital Clinic and Institut d’Investigació August Pi I Sunyer (IDIBAPS), University of Barcelona, 2Laboratory of Surgical Neuroanatomy, Universitat de Barcelona, Barcelona, Spain Background: Cognitive impairment in multiple sclerosis (MS) could be associated with abnormal whole brain connectivity or damage of specific connections between grey matter regions. Objectives: We aimed to evaluate the association between structural connectivity impairment and cognitive performance in patients with MS. Methods: Fifty-nine patients with MS and 29 healthy volunteers (HV) were included. To create individual structural networks and fractional anisotropy (FA)-weighted connectivity matrices, we performed probabilistic tractography by high order fiber orientation distributions estimated with constrained spherical deconvolution. Each network was represented by an 85x85 connectivity matrix, including 68 cortical, 16 subcortical parcellations and brainstem segmentation. Global and edge network metrics were calculated and correlated with cognition. The Brief Repeatable Battery was used to evaluate cognitive performance. Results: Compared to HV, MS patients showed significantly (p< 0.05) decreased global efficiency and increased average path length of the whole network while we did not find differences in strength, transitivity, assortativity and communicability. Patients showed decreased FA (p< 0.001) in 312 out of 3570 edges. Significant correlations were found between assortativity and episodic memory tests (Rho between -0.33 to -0.35, p=0.019 to 0.007) and between strength, global efficiency and average path length and visuospatial memory (p< 0.05). Episodic memory performance correlated (p< 0.001) with FA of connections of left medial temporal lobe and basal ganglia, visuospatial memory with connections of left insula, cingulates and parietal cortices. Attention tests (Symbol Digit Modalities Tests and Paced Auditory Serial Addition Test) were correlated with FA of several edges, in cerebellum, thalamus, limbic areas, frontal and parietal cortices. Fluency was correlated with left cingulate and temporal connections. Patients with cognitive impairment (2 or more tests below 2 standard deviations) showed decreased FA between left entorhinal cortex and lingual, pericalcarine and medialorbitofrontal cortex, and between right insula, hippocampus and parahippocampus. Conclusion: While patients with MS partially maintain integrity of whole brain network, the performance of different cognitive functions is associated with integrity of specific connections. Cognitive impairment was associated with impaired connectivity of medial temporal lobes.

Disclosure Sara Llufriu: nothing to disclose. Eloy Martínez-Heras: nothing to disclose. Nuria Sola-Valls: nothing to disclose. Maria Sepulveda: Nothing to disclose. Federico Varriano: nothing to disclose. Yolanda Blanco: nothing to disclose.


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Elena H. Martínez Lapiscina: nothing to disclose. Pablo Villoslada: received compensation for advisory from Roche, Novartis and Bionure Incorporation. Alberto Prats: nothing to disclose. Albert Saiz: received compensation for advisory and speaking from Bayer-Schering, Merck- Serono, Biogen-Idec, SanofiAventis, Teva Pharmaceutical Industries Ltd and Novartis. P1234 Deep gray matter volume and cognitive functions in clinically isolated syndrome J. Laczó1,2, E. Hynčicová1, L. Martinkovič1, A. Kalina1, M. Vyhnálek1,2, T. Nikolai1,3, J. Hort1,2, E. Meluzínová1 1Department of Neurology, Charles University in Prague, 2nd Faculty of Medicine and Motol University Hospital, Prague, 2St. Anne’s University Hospital Brno, International Clinical Research Center, Brno, 3Department of Neurology, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic Background: Slowing of information-processing speed (IPS) together with attentional deficit and executive dysfunction are among primary cognitive deficits in multiple sclerosis, where pathology in the basal ganglia and thalamus may play a key role. However, whether these cognitive deficits are typical for clinically isolated syndrome (CIS) and what role plays here deep gray matter (DGM) pathology is poorly understood. Objectives: To investigate performance in IPS, attention and executive function, and association of these cognitive functions with DGM volumes in patients with CIS. Methods: Patients with CIS on interferon-β (n=47) underwent brain MRI and neuropsychological testing. Using FSL software, volumes of the DGM structures (thalamus, caudate nucleus, putamen, globus pallidus and nucleus accumbens) were calculated. Neuropsychological testing assessed: IPS using the Paced Auditory Serial Addition Test (PASAT) and the Symbol Digit Modalities Test (SDMT), attention using the Digit Span Forward (DSF) and executive function using the Trail Making Test B (TMT B). Results were compared to age, gender and education matched healthy controls (n=45). Results: Patients and controls did not differ in basic demographic characteristics. Patients had poorer performance in PASAT (p=.008), SDMT (p=.003), DSF (p=.014) and TMT B (p⩽.001) tests. No differences were found between patients and controls in the volumes of the DGM structures. Among patients, DSF and TMT B correlated with volume of the right globus pallidus (r=0.36, p=.027 and r=0.34, p=.039). Conclusions: Slowing of IPS, attentional deficit and executive dysfunction are present in patients with CIS and may be associated with volume reduction of the globus pallidus. Disclosure Jan Laczó: nothing to disclose Eva Hynčicová: nothing to disclose Lukáš Martinkovič: nothing to disclose Adam Kalina: nothing to disclose Martin Vyhnálek: nothing to disclose Tomáš Nikolai: nothing to disclose

Hort Jakub: nothing to disclose Eva Meluzínová: nothing to disclose P1235 Cerebral atrophy and cognitive reserve in multiple sclerosis: a MRI study G. Fenu1, F. Cabras2, L. Lorefice1, J. Frau1, G. Coghe1, M.A. Barracciu3, L. Loi3, V. Sechi3, F. Contu3, S. Murru3, V. Lai3, S. Mallus3, M. Boi3, G. Sbrescia3, E. Cocco1, M.G. Marrosu1 1Multiple Sclerosis Center, 2Multiple Sclerosis Center, Radiology Unit, Binaghi Hospital, University of Cagliari, 3Radiology Unit, Binaghi Hospital, ASL8, Cagliari, Italy

Background: Cognitive impairment is a common symptom in MS associated with MRI measures, especially with cerebral atrophy (CA). A possible role of Cognitive Reserve Theory (CR) in MS has frequently been suggested. Aim of this study is to evaluate the role of CR in MS and the relationship between CR and CA. Methods: A group of 54 MS patients (MS) and 16 healthy controls (HC) were recruited. Exclusion criteria: corticosteroids and/or relapse in the previous month for MS and consuming psychoactive drugs. Neuropsychological assessment (NPA) was performed using BICAMS Italian normative values (Goretti et al., 2014). CR was evaluated by CR Index Questionnaire (CRIq, Nucci et al., 2012), a semi-structured interview validated for Italian populations, composed by 4 score: Total, Education, Working and Leisure Time. MS and HC underwent brain MRI using 1.5 T MR imaging system. Post-processing to obtain Normalized Volume of Brain (NBV), Grey Matter (NGV) and White Matter (NWV) volume was performed using SIENAX. Results: No significant difference was detected between MS and HC regarding age (mean: 44.0+-10.6 vs 48.0 +-9.9 p=ns), gender (F/M: 38/16 vs 9/7 p=ns) and education (mean: 11.6 +-4.1 vs12.8 +-4.8 p=ns). Clinical features of MS were: EDSS (mean: 2.5+-1.6 ), years of disease duration (mean: 11.7+-7.8). Raw score of NPA in MS: SDMT: mean 46.5+-15.7; CVLT-II: 45.5+-11.8; BVMT-R: 22.2+- 8.3. T Test showed a significant difference between MS and HC regarding NBV ml (mean 1477.54+-81.6 vs 1518.8+-41.4 p=0.009), NWV ml (mean 682.0,+-39.2 vs 716.8+-21.9 p=0.000), while no significant difference regarding NGV ml (mean 795.5, SD 63.0 vs 801.9+-32.1 p=ns) was found. Pearson Test showed a correlation between NGV and all NPA score (SDMT: r=0.53, p=0.000; CVLT: r=0.35, p=0.004; BVMT: r=0.414, p=0.001), while no correlation between NGV, NGV and NBV and NPA in HC was detected. CRIq Score showed a correlation with all NPA, especially CRILeisure time score (SDMT: r= 0.44, p=0.000; CVLT: r=0.396, p=0.002; BVMT: r=0.399, p=0.001). ANOVA shoved a relationship between SDMT and both NGV (p=0.000 CI 95% 0.06-0.17) and CRIq (p=0.001 CI 95% 0.17-0.65). Conclusion: Our data suggested that CR could play a role in cognition in MS, particularly the activity in leisure time (i.e. reading, social and artistic activities), supporting a better cognitive functioning and balancing brain pathology. Larger studies are needed to establish how and when enhancing CR could improve cognition in MS.


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Poster Session 2, 21(S11) Disclosure No conflict of interest exists regarding the present paper. Dr. Lorefice received speaker fee from Teva and serves on scientific advisory boards for Biogen. Dr. Fenu received honoraria for consultancy from Novartis and for speaking from Merck Serono and Teva. Dr. Frau serves on scientific advisory boards for Biogen, received honoraria for speaking from Merck Serono and Teva. Dr. Coghe received speaker fee from Teva. Professor Marrosu and Professor Cocco have received honoraria for consultancy or speaking from Bayer, Biogen-Idec, Novartis, Sanofi-Genzyme, Serono and Teva. Cabras Federico, Loi Luciano, Sechi Vincenzo, Contu Franco, Murru Sergio, Lai Virgilio, Mallus Stefano, Boi Maurizio, Sbrescia Gennaro, Barracciu Maria Antonietta: nothing to disclose P1236 Localized atrophy of the thalamus is related to changes in cognitive processing speed in MS patients N. Bergsland1,2,3, R. Zivadinov1,4, M.G. Dwyer1, R.H. Benedict5 1Buffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States, 2MRI Research Laboratory, IRCCS Don Gnocchi Foundation ONLUS, 3Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy, 4MR Imaging Clinical Translational Research Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 5University at Buffalo, State University of New York, Buffalo, NY, United States Background: While thalamus atrophy is common in MS, no studies have investigated thalamus surface-based shape changes over time with respect to healthy controls (HCs). Moreover, although impaired processing speed affects a significant portion of MS patients, the temporal-spatial dynamics with respect to atrophy remain poorly understood. Objectives: To explore the thalamus and other deep gray matter structure differences between MS and HCs over time in relationship to cognitive processing speed. Methods: 44 relapsing remitting and 20 secondary progressive MS patients were scanned using 3T MRI at baseline and at 3 year follow-up. In addition, 22 HC subjects, group matched for age and sex, were studied. FMRIB’s Integrated Registration and Segmentation Tool (FIRST) software was used to segment the the thalamus, caudate and putamen from 3D-T1 scans. Surface-based shape analysis of the structures was performed. General linear models, adjusted for age and sex, were fit to the data to assess group differences in both volumetric- and surface-based metrics. In the MS group only, relationships with the Symbol Digit Modalities Test (SDMT), a measure of cognitive processsing speed, was also assessed. Results: Compared to HCs, MS patients presented with significantly smaller volumes of the examined structures at baseline. For the thalamus and caudate, differences in shape were mostly localized along the lateral ventricles whereas no consistent surface alterations were found in the putamen. Over 3 years, longitudinal

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shape analysis did not reveal any preferential surface changes. SDMT scores were related to volumes at baseline of all three structures investigated but changes over time were not. SDMT changes at followup were related to local surface changes in the anterior and superior areas of the thalamus (p = .01 and p = .07 for the left and right, respectively). Conclusions: Longitudinal shape analysis in the MS group revealed associations between local atrophy and change in SDMT. These findings highlight the role that more fine-grained image analysis methods may play in helping to unravel the complex relationships between thalamus atrophy and cognitive impairment in MS. Disclosure Mr. Bergsland has nothing to disclose. Dr. Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health. Dr. Dwyer has received personal compensation from Claret Medical and EMD Serono, and research grant support from Novartis. Dr. Benedict has received research support from Accorda, Biogen Idec, Genzyme, Novartis, and Questor. He has consulted for Biogen Idec, Genzyme, Genentech and Novartis. He has performed CME-related activities for EMD Serono. He has received royalties from Psychological Assessment Resources, Inc. P1237 Association between memory impairment and hippocampus in patients with clinically isolated syndrome E. Hyncicova1, E. Meluzinova1, M. Vyhnalek1,2, T. Nikolai1,3, L. Martinkovic1, A. Kalina1, J. Hort1,2, J. Laczo1,2 1Department of Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, 2International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, 3Department of Neurology, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic Background: Multiple sclerosis (MS) is a chronic disease of young adults, where beside motor and visual deficits also cognitive impairment, including memory, is present. Recent studies indicated that cognitive impairment may be present also in patients with clinically isolated syndrome (CIS), who are at a high risk of MS. Studies focusing on structural brain correlates of memory impairment in CIS patients are lacking. Objective: To assess whether verbal and non-verbal memory recall and recognition are impaired in patients with CIS and to determine their relationship to hippocampal volume. Patients and methods: Overall, 38 patients with CIS on interferon beta and 30 age-, gender- and education-matched healthy controls underwent a standard protocol (including clinical and laboratory evaluation, brain magnetic resonance imaging (MRI), and cerebrospinal fluid assessment) and a detailed neuropsychological testing including Rey Auditory Verbal Learning Test


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(AVLT) and Brief Visual Motor Test Revised (BVMT-R) to evaluate verbal and non-verbal memory. Hippocampal volumes were analysed by FSL First. Results: Patients with CIS and controls did not differ in basic demographic characteristics. Patients with CIS were impaired on verbal immediate memory recall (AVLT trials 1-5, p=.016), delayed recall after 30 minutes in AVLT (p=.007) and recognition in AVLT (p=.004) compared to controls. Patients with CIS were further impaired on nonverbal memory immediate recall (BVMT-R trials 1-3, p< .001) and delayed recall in BVMT-R (p=.002) but not on recognition in BVMT-R (p=.787). There were no differences in right and left hippocampal volumes between patients with CIS and controls. There was no correlation between verbal and nonverbal memory tasks and hippocampal volumes. Conclusion: Our results suggest that verbal and nonverbal memory impairment is present already in patients with CIS. We did not find any association between memory performance and hippocampal volumes. Disclosure Eva Hyncicova: nothing to disclose Eva Meluzinova: nothing to disclose Martin Vyhnalek: nothing to disclose Tomas Nikolai: nothing to disclose Lukas Martinkovic: nothing to disclose Adam Chadima: nothing to disclose Jakub Hort: nothing to disclose Jan Laczo: nothing to disclose P1238 eMotionS: emotional memory impairment and amygdala activation in multiple sclerosis H.E. Hulst1, Q. van Geest1, B.M.J. Uitdehaag2, F. Barkhof3, J.J.G. Geurts1 1Anatomy and Neurosciences, 2Neurology, 3Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands Background: In multiple sclerosis (MS), emotional memory is relatively understudied. However, the amygdala of MS patients can show various abnormalities, including demyelination, atrophy, iron deposition and functional alterations during processing of emotional faces. The aim of this study was to explore the relationship between emotional memory and amygdala activation in patients with MS. Methods: Neuropsychological testing, psychiatric interview, and (f)MRI (1.5T) were performed in 39 MS patients (24 female; mean age 48.04±8.33 years) and 25 healthy controls (HCs; 16 female; mean age 46.76±8.74 years). The fMRI paradigm consisted of neutral to highly negative emotional pictures which subjects had to rank in an emotional category (neutral (1) to highly emotional (4)). Two weeks after scanning, a recognition task was performed. Based on recognition of highly emotional pictures, patients were categorized as emotional memory impaired (EMI; n=12) when they performed 1.5 SD below the mean score of HCs. Otherwise, patients were categorized as emotional memory preserved (EMP; n=27). Results: None of the subjects met the criteria for a mental disorder. Compared to HCs, EMP and EMI patients scored significantly lower on verbal learning and memory and information

processing speed. Left amygdala volume was significantly lower in EMP patients compared to HCs, whereas the right amygdala was significantly smaller in both EMP and EMI patients compared to HCs. During processing of emotional pictures, decreased activation of the right amygdala, right parahippocampal areas and hypothalamus was observed in EMI patients versus HCs (unclustered, z⩾3.1, p⩽.001). Decreased hypothalamic activation was also observed in EMI patients compared to EMP patients (unclustered, z⩾3.1, p⩽.001). A regions of interest analysis confirmed decreased activation in de amygdala in EMI patients versus HCs. Conclusions: The present results indicate that reduced activation in the amygdala (important for emotion regulation), parahippocampal areas (essential for memory) and the hypothalamus can be related to impaired emotional memory in patients with MS. Disclosure This study was funded by the Dutch MS research Foundation, grant number 08-648. Dr. H.E. Hulst has served as a consultant for Novartis, Teva Pharmaceuticals, Genzyme, MerckSerono and Biogen Idec. Q. van Geest MSc, has served as a consultant for Novartis. Prof. B.M.J. Uitdehaag has received consultation fees from Biogen Idec, Novartis, MerckSerono, and Danone Research. Prof. F. Barkhof serves on the editorial boards of Brain, European Radiology, the Journal of Neurology, Neurosurgery & Psychiatry, Neurology, Multiple Sclerosis and Neuroradiology and serves as a consultant for Bayer-Shering Pharma, Sanofi-Aventis, BiogenIdec, TEVA pharmaceuticals, Genzyme, Merck-Serono, Novartis, Roche, Synthon, Jansen Research and Lundbeck. Prof. J.J.G. Geurts is an editor for Multiple Sclerosis Journal, associate editor for BMC Neurology, and serves on the editorial boards of Neurology and MS International; he is a member of the scientific advisory board of the Dutch MS Research Foundation, of the MS Society of Canada and a scientific steering committee member of the International Progressive MS Alliance; he has served as a consultant for MerckSerono, Novartis, Biogen Idec, Genzyme and Teva Pharmaceuticals. P1239 Region-based structural MRI measures offer better specificity in correlation with cognitive performance in patients with secondary progressive multiple sclerosis P. Adany1, I.-Y. Choi1,2,3, D.R. Denney4, A.J. Hughes4, S. Belliston2, S.G. Lynch2, P. Lee1,3 1Hoglund Brain Imaging Center, 2Neurology, 3Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, 4Psychology, University of Kansas, Lawrence, KS, United States Background: Studies of patients’ performance on neuropsychological tests have generally yielded only modest correlations with conventional MRI measures of MS such as lesion volume (LV) and whole brain atrophy. One reason may be that whole brain measures may not adequately reflect cognitive performance that engages specific brains regions, depending on the task at hand. Even differentiating between gray and white matter in brain atrophy measures affords some improvement, with gray matter volume (GMV) typically resulting in higher correlations with cognitive performance than white matter volume (WMV). The


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Poster Session 2, 21(S11) current study investigated brain atrophy in gray and white matter as well as sub-brain regions that are implicated in cognitive deficits in MS, in relation to performance on a cognitive battery in patients with secondary progressive MS (SPMS). Objectives: To examine the relationship between region-based MRI analysis of brain atrophy in the corpus callosum, periventricular area, and cerebellum/brainstem, and cognitive deficits in patients with SPMS. Method: 24 SPMS patients and 19 healthy controls matched with respect to gender, age, and education completed a cognitive battery yielding scores of processing speed, memory, and executive function. Magnetic resonance imaging yielded both conventional whole brain values (LV, GMV, WMV), and volumetric measures of the corpus callosum, periventricular area (thalamus, corpus striatum, third ventricle, lateral ventricles) and cerebellum/brainstem. Results: Patients differed significantly from controls on whole brain LV and GMV; the difference in WMV was not significant (p=.06). They also had larger ventricular volumes and smaller tissue volumes in all specific regions surveyed. Patients performed more poorly than controls on all measures of memory and processing speed, but not on measures of executive planning or executive attention. Patients’ performance on measures of memory and processing speed were highly correlated with the volume of the corpus callosum and all periventricular volumes except the thalamus. Patients’ performance on executive planning and attention was related to cerebellum and brainstem volumes. Correlations with regional volumes of interest consistently exceeded those for conventional whole brain measures. Conclusion: More refined understanding of the association between cognitive performance and imaging measures in patients with MS may result from a focus on regional volumes of interest.

Objectives: To evaluate the effect of a home-based computerized program for retraining attention dysfunction in MS on behavioral performance and fMRI activity during cognitive processing. Methods: Relapsing-remitting (RR) MS patients aged 18-55 years, who failed ⩾ 2 tests of attention on an extensive neuropsychological evaluation (NP), and EDSS ⩽6.0, were randomly allocated to specific (ST) or nonspecific (nST) computerized training, in one-hour sessions, twice a week for three months. All the patients enrolled underwent the NP and a functional MR imaging (fMRI) while performing the Variable Attentional Control (VAC) and the N-Back (NB) tasks, before and after the completion of the cognitive training. The Cognitive Impairment Index (CII) as a measure of global cognitive function was calculated for each patient. A repeated measures ANOVA was used to evaluate changes in the CII and in brain activity during fMRI (SPM8) as a function of the computerized training. Results: Twenty-one RRMS patients have been included in the analysis, 9 patients were assigned to the ST, whereas 12 were assigned to the nST. No differences were found between the 2 groups regarding sex, age, disease duration, relapse rate in the year before the training, EDSS score and the baseline CII. Patients exposed to the ST experienced a more pronounced reduction of the CII in comparison to patients trained with the nST (ST: 16.11±3.55 vs 7.78±1.1; nST: 16.58±3.20 vs 10.83±2.55; p=0.014). Furthermore, patients exposed to the ST showed an increase in left prefrontal cortex (p< 0.05FWE corrected) during the first compared to the second fMRI scan during both the NB and the VAC task. This effect was not present in nST subjects. Conclusions: Our preliminary data showed that an attention ST could ameliorate the global cognitive functions as measured by the CII, and that this training could also modify patterns of prefrontal activity during the execution of cognitive tasks.

Disclosure Sharon G. Lynch is funded by the National Multiple Sclerosis Society, and has participated in Multi-center MS trials and grants funded by Biogen, Teva, Novatis, Acorda, Opexa, Roche, Genentech, Genzyme, Sun Pharma, Vaccinex, Actelion, NMSS, and NIH. This work was partially funded by Grant RG 4495-A-4 from NMSS. In-Young Choi: nothing to disclose. Phil Lee: nothing to disclose. Peter Adany: nothing to disclose. Abbey J. Hughes: nothing to disclose. Douglas R. Denney: nothing to disclose. P1240 Computer-assisted rehabilitation of attention in patients with multiple sclerosis increases functional activity in the left prefrontal cortex P. Iaffaldano1, R.G. Viterbo1, L. Fazio1, P. Taurisano1, C. Tortorella1, R. Romano1, E. Portaccio2, M. Mancini1, G. Blasi1, A. Bertolino1, M.P. Amato2, M. Trojano1 1Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, 2Department of NEUROFARBA, University of Florence, Florence, Italy Background: The effect of cognitive rehabilitation in multiple sclerosis (MS) is still controversial to date.

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Disclosure Iaffaldano P. has served on scientific advisory boards for Biogen Idec, and has received funding for travel and/or speaker honoraria from Sanofi-Aventis, Biogen Idec, Teva and Novartis. Amato M.P. received personal compensation from Merck Serono, Biogen, Bayer Schering, Genzyme, Teva and Novartis for serving on scientific advisory board and for speaking, received financial support for research activites from Merck Serono, Biogen Idec, Bayer Schering, Genzyme, Novartis, Genzyme and Teva. Tortorella C. has served on scientific advisory boards for Biogen, Merck Serono, Bayer-Schering and Novartis. She received also funding for travel, consulting and speaker honoraria from Biogen, Merck Serono, Bayer-Schering, Teva, Genzyme, Novartis and Almirall. Trojano M. has received honoraria for consultancy or speaking from Biogen, Sanofi-Aventis, Merck Serono and Bayer-Schering and research grants from Merck Serono, Biogen and Novartis. Viterbo RG, Fazio L, Taurisano P, Romano R, Portaccio E, Mancini M, Bertolino A, Blasi G: nothing to disclose. P1241 Evolution of cognitive impairment during the first 10 years of RRMS D. Wybrecht1,2, F. Reuter1,3, F. Pariollaud1,3, W. Zaaraoui1, A. Le Troter1, A. Rico1,3, S. Confort-Gouny1, E. Soulier1, J.P. Ranjeva1, M. Guye1,3, J. Pelletier1,3, B. Audoin1,3


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1CNRS

7339, CRMBM Aix Marseille Université, Marseille Cedex, of Neurology, Sainte Anne Military Hospital, Toulon Cedex, 3Pôle de Neurosciences Cliniques, Timone Teaching Hospital, Marseille, France 2Department

We aimed to assess the evolution of cognitive impairment during the first ten years of RRMS and the potential impact of brain lesions accumulation on cognitive decline. Twenty-six patients were enrolled in a ten years longitudinal study after their first clinical attack. Neuropsychological assessment including 28 measures was performed at three time points (baseline, year one, year ten) and explored four cognitive domains: general intellectual functioning, memory, attention/speed of information processing and executive functions. To limit the bias of test-retest effect only measures obtained at years one and ten were included in the analysis. The raw scores of patients for each measure were transformed into z-scores using published normative data when available or raw scores of matched controls (n=35 for year one and n=31 for year ten). For each cognitive domain, the mean z-score of each patient was determined (mean z-score under 1.5 was considered as abnormal). Lesion probability mapping was used to study the potential relationships between lesion accumulation and cognitive or physical decline during the follow-up (p< 0.05, corrected). For executive functions, 11.5% of patients were classified as impaired at year one and 42% at year ten (p=0.01, Fischer’s exact test). For general intellectual functioning, 27% were impaired at year one and 11.5% at year ten (p=0.3). For memory, 11.5% were impaired at year one and 4% at year ten (p=0.6). For attention/ speed of information processing, 27% were impaired at year one and 38% at year ten (p=0.5). At year one, 50% of patients showed at least one cognitive domain impaired, 19.2% showed at least two domains impaired and 7.7% at least three domains impaired. At year ten, 53.8% of patients showed at least one domain impaired, 38.5% showed at least two domains impaired and 3.8% at least three domains impaired. The median EDSS was 0.5 [range: 0-3] at year one and 1.5 [range: 0-6.5] at year ten. During the follow-up, significant decline of executive functions was associated with lesions accumulation in the bilateral frontal, parietal and temporal lobes. EDSS worsening was associated with lesions accumulation in the cerebellum and semi oval centers. The present study demonstrates that progression of cognitive impairment during the first ten years of RRMS is associated with lesions accumulation in almost all supratentorial brain regions and is characterized by decline of executive functions. Disclosure Dr Wybrecht, Dr Reuter, Dr Pariollaud, Dr Zaaraoui, Dr Le Troter, Dr Rico, Dr Confort-Gouny, Dr Soulier, Dr Ranjeva, Dr Audoin, Dr Guye report no disclosures. Dr. Pelletier serves on scientific advisory boards for Biogen Idec and Novartis and has received research support from ARSEP

P1242 Reduced cerebral blood flow in cognitively impaired relapsing-remitting multiple sclerosis patients

S.-P. Hojjat1, C.G. Cantrell2, A. Feinstein1, Z. Shirzadi1, B. Macintosh1, K. Lanctot1, W. Swardfager1, L. Zhang1, L. Lee1, P. O’connor1, T. Carroll2, R. Aviv1 1University of Toronto, Toronto, ON, Canada, 2Northwestern University, Chicago, IL, United States Purpose: We sought to utilize Pseudocontinuous Arterial Spin Labeling (pCASL) to assess white matter (WM)/ gray matter (GM) perfusion abnormality in patients diagnosed with relapsingremitting multiple sclerosis (RRMS) with (RRMS-I) and without (RRMS NI) cognitive impairment (CI) as compared with healthy control participants (HC). Methods: 19 HC and 39 age-matched RRMS patients were prospectively recruited. The Minimal Assessment of Cognitive Function In Multiple Sclerosis was utilized to assess cognitive performance. Cerebral blood flow (CBF) measure calculated from pCASL data were compared across different groups using voxel based morphometry (VBM). Demographic and normalized morphologic measures were compared across each of the test groups using a two sample t-test (p< 0.05) and those found as significantly different between the groups were chosen as covariates for the respective VBM analysis. Results: 20 RRMS were classified as being cognitively impaired. Comparing RRMS-I to HC reduced CBF was present in the corpus callosum (CC), pons and cingulate gyrus and focal frontal and temporal regions. Compared to HC, RRMS-NI displayed reduced CBF in CC, caudate head/body, pons, insula and cingulate gyrus and focal frontal, parietal, temporal and occipital regions. Comparing RRMS-I -and, RRMS-NI we found reduced CBF in the left precentral gyrus, right and left supplementary motor areas and focally within the frontal lobes. There was a significant reduction in GM perfusion in the RRMS-NI and RRMS-I as compared to the HC. Conclusion: Significant WM and GM perfusion reduction was present in RRMS-I compared to HC and RRMS-NI in anatomically significant regions associated with CI.

Disclosure Seyed-Parsa Hojjat: Nothing to disclose P1243 Abnormal structural network in correlation with cognitive impairment in neuromyelitis optica spectrum disorder E.B. Cho1,2, J.-K. Seong3, C.E. Han3, J. Chin1,2, G.Y. Lee3, J.-H. Shin3, H.-J. Cho1,2, J.M. Seok1,2, H. Jang1,2, H. Park1,2, S.W. Seo1,2, S.T. Kim4, D.L. Na1,2, K.-H. Lee1,2, B.J. Kim1,2, J.-H. Min1,2 1Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 2Neuroscience Center, Samsung Medical Center, 3Department of Biomedical Engineering, Korea University, 4Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Neuromyelitis optica (NMO) is a demyelinating disease of the central nervous system (CNS) predominantly affecting optic nerve, and spinal cord. However, recent studies have shown that brain involvement in NMO is not uncommon and some of patients have cognitive dysfunction.


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Poster Session 2, 21(S11) The aim of this study was to investigate (1) whether there is cognitive dysfunctions in patients with NMO spectrum disorders (NMOSDs), (2) whether patients with NMOSD shows a disruption of white matter network and (3) whether the change of network is correlated with cognitive dysfunction in these patients. We prospectively enrolled patients with NMOSD (N=15) with anti-aquaporin4-antibody and multiple sclerosis (MS, N=13) and age- and sex-matched healthy controls (N=22). Subjects underwent 3.0-Tesla brain magnetic resonance imaging and neuropsychological tests. We established the existence of structural connections between any pair of the 90 cortical and sub-cortical regions using deterministic tractography. Network-based statistic analysis (NBS) was used to assess differences in the interregional connectivity matrix between patients with NMOSD, patients with MS and healthy controls. The correlations between the characteristics of hub node, from which more than two disrupted connections originate, and cognitive test performance were evaluated. The NMOSD patients showed cognitive impairment in trail making test (TMT) A/B, 2-second and 3-second paced auditory serial addition test (PASAT), spatial span forward/backward, Controlled Oral Word Association Test and Digit Symbol Coding Test (DST) and MS patients showed impaired performance only in DST compared to healthy controls, respectively. In NMOSD patients, the disrupted subnetwork consisted of bilateral prefrontal, right anterior cingulate and right temporal pole areas and the hub nodes were the right superior frontal and right orbital part of superior frontal cortex. The performances on TMT-B and PASAT 2s were significantly associated with characteristics of hub nodes. In MS patients, the inter-hemispheric connections were mainly disrupted and there were no significant correlations between a hub node, the right supplementary motor area, and DST. This is the first report to use NBS to show disrupted structural connections present in NMOSD. Our findings highlighted that altered structural connectivity between nodes of the prefrontal, anterior cingulate and temporal pole areas are associated with frontal lobe dysfunction in NMOSD.

digit modalities test, however, are not informed by an explicitly specified neuro-cognitive theory. Therefore, their outcome depends on a number of cognitive processes, e.g., perceptual speed, divided attention, memory, visual scanning and tracking. It is unclear what the exact neuro-cognitive processes are that constrain IP. In the present study, we applied a test that is based on a mathematically formalised theory, the “theory of visual attention” (TVA). This test disentangles the constituent components of IP by modelling a growth function on basis of subjects’ response accuracy in a visual whole report task. It has been successfully used in studies of other neurological disorders, but it is unclear how it compares to conventional neuropsychological tests. Goals: To identify the key components underlying IP deficits in early and late stages of MS and their correlation to conventional neuropsychological tests. Methods: 69 MS-patients were recruited and assigned to two groups: EarlyMS (N=23) with disease durations < 2 years, and lateMS (N=46) with disease durations >12 years. Control data was obtained from 69 matched healthy subjects. Conventional neuropsychological assessment was performed using a 2-hour battery including tests of attention, memory, and executive function. TVA-based assessment of IP was performed using the whole report paradigm, providing estimates of four components of IP: perceptual threshold (t0), iconic memory (µ), processing speed (C), and visual short-term memory storage capacity (K). Results: In EarlyMS conventional test performance was in the normal range, but TVA-based assessment found deficits in K (d=1.3, p< .001), µ (d=.9, p< .01) and C (d=.6, p< .05). In LateMS, 18 patients had CI according to conventional testing. TVA-based assessment reveald an additional deficit in t0 (d=.6, p< .01) and a more elevated reduction in µ (d=1.4). T0 correlated with conventional test performance in lateMS (r=-.52, p< .01) and earlyMS (r=-47, p< .05). Conclusions: The core components of IP are affected already at an early stage. The late stage is characterized by an additional deficit in t0. Much of CI seems to be reflected by t0, the ability to recognize visual items even at very short exposures. TVA as an innovative tool may indicate CI at a preclinical stage.

Disclosure

This study is supported by: Merck Serono GmbH, Germany, a division of Merck KGaA, Darmstadt, Germany Köhler, Faiss, Hoffmann, Sailer, Schwab, Zettl: Received institutional research grants and personal honoraria as speaker from Biogen Idec, Bayer, Genzyme, Merck Serono, Novartis and TEVA Sanofi. Kunkel: Received a travel support from biogen. Bublak, Fischer, Stadler: nothing to disclose.

Nothing to disclose

Cognitive assessment and development

Disclosure

P1244 Disentangling the information processing deficit in multiple sclerosis: insights from a parameter-based approach M. Fischer1, P. Bublak2, J. Faiss3, F. Hoffmann4, A. Kunkel3, M. Sailer5, M. Schwab2, E. Stadler5, U.K. Zettl4, W. Köhler1, for HIPPOCOMS Study Group 1Klinik für Neurologie und Neurologische Intensivmedizin, Fachkrankenhaus Hubertusburg, Wermsdorf, 2FriedrichSchiller-Universität, Jena, 3Asklepios Fachkliniken Brandenburg GmbH, Teupitz, 4Universitätsklinikum Rostock, Rostock, 5Universitätsklinik für Neurologie, Magdeburg, Germany

P1245 Cognitive impairment according to detection of cerebellar involvement by oculomotor testing in early multiple sclerosis A. Moroso1,2, A. Ruet1,2, M. Deloire1, S. Cubizolle1, F. Munsch2, J. Charré-Morin1, A. Saubusse1, J.-C. Ouallet1, S. RivaudPechoux3,4, B. Brochet1,2 1Bordeaux Hospital University Center, 2Inserm U 862 Neurocentre Magendie, Bordeaux, 3Institut du Cerveau et de la Moëlle Epinière, 4Hôpital de la Salpêtrière, Paris, France

Background: 40% of patients with multiple sclerosis (MS) suffer from cognitive impairment (CI). A core area of CI is information processing speed (IP). Conventional tests of IP, such as the symbol

Background: Up to 31% of patients encounter infratentorial lesion in early multiple sclerosis (MS) and 40% to 70% suffer from cognitive impairment. However, the clinical impact of

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cerebellar alteration is underestimated and few studies attempted to link saccadic impairment evocative of cerebellar damage and cognitive disability. Objectives: To compare cognitive pattern in patients with cerebellar (C) symptoms versus non-cerebellar patients (NC) within the first year after a clinically isolated syndrome (CIS), and healthy controls (HC). Methods: Twenty-one patients and 13 matched HC underwent an eyetracking protocol. Cerebellar impairment was defined by registration of saccadic intrusions and/or at least 10% of dysmetria at oculomotor (OM) recording. This criteria was compared to Nine Hole Peg Test (NHPT) performance. Visually-guided, memoryguided and antisaccade paradigms were used to assess respectively attention, working memory (WM) and inhibition. Latencies, gain and error rates were considered, as final eye position ratio (FEPR) for memory-guided saccade. Rao´s battery was completed by attention, WM, executive functions (EF) and information processing speed (IPS) tasks. Computerised Speed Cognitive Test (CSCT), Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Task (PASAT) scores and cognitive domain z-scores were analysed for correlation with specific oculomotor tasks in C, NC patients and HC. Results: Nine patients fulfilled saccadic criteria for cerebellar impairment. NHPT was significantly increased in early MS patients versus HC but did not discriminate between C and NC groups. C patients had impaired WM z-score compared to NC and performed worse than NC and HC at SDMT and CSCT. No difference in oculomotor cognitive parameters was found between the three groups. A correlation between SDMT and visually-guided saccade latencies (attention) was found considering all patients (p=0,02, r=-0,51). IPS z-score tended to be correlated with antisaccade error rate (EF). Trends also appeared in C patients subgroup: IPS z-score and PASAT increased along with memory-guided saccade latency and FEPR respectively (WM). Conclusion: All patients displayed IPS impairment and only C patients presented WM impairment in comparison to NC. OM testing did not seem more sensitive than classic neuropsychological assessment in early MS. NHPT did not allow to discriminate C versus NC patients according to oculomotor criteria in this population. Disclosure Pr B. Brochet or his institution received research grants and/or consulting fees from Biogen, Bayer, Novartis, Genzyme, Roche, Medday, Merck-Serono, and Teva. Dr A. Ruet or her institution received fees for research and symposium from Novartis, Biogen-Idec, Merck-Serono, Bayer Healthcare, Roche, and Teva. Dr J-C. Ouallet JCO has received consultancy fees, speaker fees,research grants (non-personal), and honoraria from Novartis, Biogen-Idec, Merck-Serono, Bayer Schering, Roche, Almirall, Teva and GenzymeSanofi-Aventis. Amandine Moroso received a research grant from the Fondation pour la recherche médicale (DEA20140630564) Deloire M., Cubizolle S., Munsch F., Charré-Morin J., Saubusse A., Rivaud-Pechoux S.: nothing to disclose P1246 Cognitive dysfunction in patients with multiple sclerosis treated with first line disease modifying therapy

S. Ozakbas1, B. Piri Cinar2, G. Kosehasanogullari3, P. Yigit1 Eylul University, Izmir, 2Giresun State Hospital, Giresun, 3Usak State Hospital, Usak, Turkey 1Dokuz

Multiple sclerosis (MS) is a chronic autoimmune disease that can deteriorate cognitive function even in the early stages. Cognitive impairment occurs in 40-65% of patients with MS. Several clinical trials have shown beneficial effects of first line disease modifying therapies (DMTs) on cognitive measures in MS. The aim of the present study was to compare the various preparations of interferon beta (IFNB) and glatiramer acetate (GA) based on their effects on cognitive status in MS. This was a multi-center, examiner-blinded, controlled, prospective study. Adult relapsing remitting MS (RRMS) patients who initiated IFNB or GA treatment enrolled in the study. Age, sex and education-matched healthy control people were also evaluated cognitively at the same scheduled visits. For cognitive evaluation The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery, which included the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-2 (CVLT2) and the Brief Visuospatial Memory Test-Revised (BVMT-R) used. 146 (107 female, mean age 29.2) newly diagnosed subjects and 102 healthy control (68 female, mean age 29.9) were enrolled into this study. They were categorized into three DMT groups; IFNB 1a SC (49 subjects, mean age 29.4), IFNB 1b (44 subjects, mean age 28.9) and GA (53 subjects, mean age 30.4). SDMT scores improved in all groups at month 12 vs. baseline (IFNB 1a SC: 39.50 vs. 43.85, p= 0.09; IFNB 1b: 37.9 vs. 43.1, p= 0.031; GA: 36.78 vs. 44.01, p= 0.002). BVMTR score also improved at month 12 (IFNB 1a SC: 25.2 vs. 27.91, p=0.027; IFNB 1b: 24.9 vs. 27.42, p=0.03; GA: 23.96 vs. 27.18, p=0.002). CVLT2 improved at month 12 (IFNB 1a SC: 49.2 vs. 51.8, p=0.042; IFNB 1b: 47.5 vs. 51.2, p=0.01; GA: 46.3 vs. 51.3, p=0.003). 44 patients (30.1%) were found to be cognitively impaired at study entry on the basis of SDMT. At follow-up number of cognitively impaired patients decreased to 31 (p=0.009). Number of cognitively impaired patients decreased from 49 (33.6%) to 34 on the basis of CVLT (p=0.03), and 39 (26.7%) to 29 on the basis of BVMTR at month 12. Patients were stable at month 18 and month 24. There was no significant difference in the treatment arms. The results of our study revealed a significant improvement in the cognitive function since twelfth month of initiation of IFNB or GA in patients with RRMS. We found no difference between IFNBs and GA on the basis of effect on cognitive status of patients. Disclosure Serkan Ozakbas has nothing to disclose Bilge Piri Cinar has nothing to disclose Gorkem Kosehasanogullari has nothing to disclose Pinar Yigit has nothing to disclose

P1247 Correlation between cognitive impairment and behavioral symptoms in relapsing remitting multiple sclerosis patients M. López-Góngora, L. Querol, S. Figueroa-Bonaparte, A. Escartín


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Poster Session 2, 21(S11) Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain Background and objective: Cognitive and behavioral symptoms are common in multiple sclerosis. The association among these variables has not been widely investigated. Previous results demonstrate a relation between self-awareness and neurobehavioral symptoms. The objective is to assess the relationship between cognitive functions and behavioral symptoms in relapsing remitting multiple sclerosis (RRMS) patients. Method: A total of 143 (93 women) RRMS patients were included. Mean age: 37,7±=9,4 years; mean time of evolution: 8,1±6,3 years. Patients were assessed with the Brief Repeatable Battery of Neuropsychological Tests. They answered depression and fatigue scales and the Frontal Systems Behavior Scale (FrSBe) that measures symptoms of apathy, disinhibition and executive dysfunction. The Expanded Disability Status Scale Score (EDSS) was obtained. Results: Group was divided in two. Group 1: 83 patients with no cognitive impairment (CI) and group 2: 60 patients with CI. Group 1 showed significant negative correlations between: Spatial delayed memory with apathy (p=0,007) and executive dysfunction (p=0,018). Symbol digit modalities test (SDMT) with apathy (p=0,008) and executive dysfunction (p=0,001). EDSS positively correlated with apathy (p=0,003) and executive dysfunction (p=0,028). Group 2 showed correlations between: Selective reminding test with apathy (p=0,007 and 0,023) and disinhibition (p=0,044). SDMT with apathy (p=0,001) and executive dysfunction (p=0,031); verbal fluency with apathy (p=0,025). The EDSS score correlated with all FrSBe subscales (apathy p< 0,001, disinhibition p=0,026 and executive dysfunction p=0,016). For both groups, positive correlations were observed between depression and fatigue scores with all FrSBe subscales (p< 0,001). Conclusions: Results suggest a weak correlation between cognitive function and behavioral symptoms. Fatigue and depression have a strong correlation with behavior scores independently from the patient’s cognitive status. Physical disability has a good correlation with all FrSBe subscales in patients with CI. In conclusion, behavioral symptoms are better correlated to variables as fatigue and depression than to cognitive variables in both non CI and CI groups.

1Department

of Psychology, Loyola University Andalucía, Psychology Department, University of Seville, 3Multiple Sclerosis Unit, Virgen Macarena University Hospital, Sevilla, Spain 2Experimental

Introduction: Some studies have showed alerting and orienting attentional impairment in relapsing-remitting multiple sclerosis (RRMS) patients evidenced by the Attentional Network Test (ANT) and Event-Related Potentials analysis. However, nothing is known about alpha band brain oscillations related with attentional networks in this clinical sample. The present study analyzes alpha band Event-Related Desynchronisation (ERD) during alerting and orienting conditions in a sample of RRMS patients. Methods: 26 patients with RRMS (mean EDSS = 2.4 ± 1.5; mean duration of the disease = 7.15 ± 4.35 years) and 25 healthy controls were assessed (not differ in socio-demographic variables. Exclusion criteria: No motor impairment or the presence of a relapse in the last month and/or the presence of clear signs of depression or other psychopathological conditions). All the participants performed an attentional task (ANT) to assess attentional neural networks. 64 Electroencephalographic (EEG) channels were recorded while participants performed ANT test. Reaction times (RT), Accuracy and low (7-9 Hertz) and high (10-12 Hertz) alpha band ERD were analyzed in the No Cue (NC), Central Cue (CC) and Spatial Cue (SC) conditions of the paradigm. The ERD analyses were done in the interval between the cue and the imperative stimulus (500ms pre imperative). Results: Behavioral responses were slower in the patient group under all conditions (F1, 50 = 26.64; p< 0.001). Regarding EEG data, controls and patients showed the maximum alpha ERD values in the Cz and FcZ electrodes for all cue conditions. ERD analysis related to the Cue Conditions showed statistical differences between groups in the NC (Low alpha band: F1, 49 = 14.51; p < 0.001; High alpha band: F1, 49 = 8.81; p < 0.01), and the CC conditions (Low alpha band: F1, 49 = 5.22; p = 0.02; High alpha band: F1, 49 = 6.34; p =0.01). Analysis performed in the SC condition showed no statistical differences between groups (p>0.05). Conclusions: A general slowing in reaction time for the RRMS group is seen here, as in previous studies. Moreover, alpha band ERD results suggest changes in the process of expectation in RRMS patients that may explain the higher RT found in this group. The spectral modulations found in these patients compared to the changes in ERPs described in previous studies suggest multiple processes involved in the cognitive impairment for this pathology.

Disclosure Authors have nothing to disclose.

Disclosure

P1248 Altered alpha brain oscillations related with alerting and orienting impairment in relapsing remitting multiple sclerosis patients A. Galvao-Carmona1,2, M. Bejarano-Guisado2, M. Borges3, M.D. Páramo3, J.L. Ruíz-Peña3, G. Izquierdo3, M. Vázquez-Marrufo2

A Galvao-Carmona: nothing to disclose. M Bejarano-Guisado: nothing to disclose. M Borges: nothing to disclose. D Páramo: nothing to disclose. JL Ruíz-Peña: nothing to disclose. G Izquierdo: nothing to disclose. M Vázquez-Marrufo: nothing to disclose.

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