Country break-out session highlights

Symposium Paper

Country break-out session highlights

Franz Fazekas*,1, Klaus Gehring22, Paolo Gallo33, Christine LebrunFrénay44, Ester Moral55 & Kjell-Morten Myhr66

Individuals with multiple sclerosis (MS) spasticity present a wide range of symptoms and disability levels that are frequently challenging to manage. At the MS Experts Summit 2015, five country breakout sessions were conducted in parallel, and mainly in the native language, to examine various country-related aspects about the management of treatment-resistant MS spasticity. Topics covered included video documentation of MS spasticity management (Germany), use of cannabinoid medicines in daily practice (Italy), multidisciplinary approach to MS spasticity care (France), titration and adherence to treatments for MS spasticity (Spain) and management of MS symptoms (Norway/Rest of World). For the benefit of all attendees, session highlights were collated and presented in a Plenary Session which is summarized herein. Video documentation of MS spasticity management: Germany Gait disturbances, or fluctuations in movement during walking, are relatively common in patients with multiple sclerosis (MS) and may be associated with adverse outcomes such as falls. The therapeutic strategy for gait disturbances depends on their origin: ataxia (sensory or cerebellar), motor fatigue, paresis or spasticity. Spasticity has both positive and negative symptoms which influence the type of treatment required (Figure 1) . The complexity of spasticity demands that multiple specialties are involved and that different therapeutic approaches are used to provide best care for the individual patient. At the Neurozentrum am Klosterforst in Itzehoe, Germany, gait disturbances are evaluated by a multiprofessional team consisting of a neurologist(s), physical and rehabilitation medicine physician, physical therapist, MS nurse and prosthetist. Video footage of the patient is captured by affixing any type of camera (e.g., bridge camera, iPad, digital camcorder, web-cam or smartphone) to a tripod with at least 10 m walking distance in front. Typical timepoints for gait recordings are before and after starting a new symptomatic treatment and at the beginning and end of rehabilitation. The procedure should be performed at least once a year (within the context of the Multiple Sclerosis Functional Composite test) or on-demand in the event of disease progression. The examination includes the 25-foot walk test and 2-min walking distance test. Video documentation adds value to the management of MS-associated gait disorders. At the outset, video footage can assist the team in differentiating between the various gait disturbances. As an ongoing management tool, it enables detection of even minimal therapeutic effects and assists

Keywords: • gait disturbances • goals of therapy • multidisciplinary teams • multiple sclerosis • spasticity • symptom management • THC:CBD

oromucosal spray

Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, 8036 Graz, Austria Neurozentrum am Klosterforst, Itzehoe, Germany 3 Department of Neurosciences, DNS University Hospital of Padua, Padua, Italy 4 Centre Hospitalier Universitaire, Nice, France 5 Department of Neurology, Hospital Sant Joan Despí Moisès Broggi, Sant Joan Despí, Spain 6 Department of Neurology, Haukeland University Hospital, & University of Bergen, Bergen, Norway *Author for correspondence: Tel.: +43 316 38 12981; [email protected] 1 2

10.2217/nmt.15.58 © 2015 Future Medicine Ltd

Neurodegener. Dis. Manag. (2015) 5(6s), 00–00

part of

ISSN 1758-2024

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Symposium Paper Fazekas, Gehring, Gallo, Lebrun-Frénay, Moral & Myhr

Positive symptoms: • Exaggerated tendon jerks • Increased muscle tone • Mass synergy patterns • Clonus

Neuro-muscular problem

CNS-lesion

Exaggeration of ‘short-latency’ reflexes

BTX-A ITB Oral antispastics

Effect on muscular function

Effect on spinal-driven reflexes

Loss of ‘long-latency’ reflexes

Impaired mechanic muscular function

Spastic movement disorder

Negative symptoms: • Weakness • Loss of selective control • Fatigability • Slow movements

Rheological problem

Stretching splints/casts/orthesis training of antagonists

Figure 1. Algorithm of differentiated spasticity therapy. BTX: Botulinum toxin type A; ITB: Intrathecal baclofen therapy.

in demonstrating and evaluating patients’ individual therapeutic needs. Video documentation facilitates discussion of therapeutic approaches among colleagues and interdisciplinary teams and provides ‘hard’ evidence as needs be to negotiate with health insurance companies and health economic institutes. Herbal cannabis & cannabinoid medicines in MS daily practice: Italy The human endocannabinoid system is a homeostatic ‘supramodulatory’ system involved in numerous body processes including nociception, movement, neuromodulation, smooth muscle movement, inflammation, cytoprotection, feeding, perception, reward and cognition. Effects are mediated through the interaction of endogenous cannabinoids with their receptors localized in the central nervous system (CB1) or situated in the periphery (CB2 ; Figure 2) . Phytocannabinoids are molecules from the cannabis plant that act on human cannabinoid receptors. In developing modern cannabis-based medications, focus has mainly been on the two principal cannabinoids of the Cannabis sativa plant: δ-9 tetrahydrocannabinol (THC) and cannabidinol (CBD). A primary objective has been to achieve and maintain adequate therapeutic blood and tissue levels while avoiding unacceptable side effects. Manufacturing challenges have related mainly to intersubject pharmacokinetic variability, minimization of side effects (psychoactivity) associated with a rapid

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Neurodegener.Dis.Manag.(2015)5(6s)

increase in THC plasma levels (e.g., after smoking), limitations to the oral route of administration and poor aqueous solubility. Early formulations of cannabis-based medications for treatment of spasticity and other motor symptoms were primarily oral and outcomes were variable [1] . Sativex (THC:CBD) oromucosal spray has offered new opportunity for symptomatic relief of MS spasticity. Through its unique formulation (near 1:1 ratio of THC and CBD), oromucosal delivery method and predictable self-titration, THC:CBD oromucosal spray achieves a therapeutic window. A substantial body of clinical evidence supports its efficacy and safety as add-on therapy in patients with treatment-resistant MS spasticity [2–5] . In patients who perceive initial benefit, THC:CBD oromucosal spray maintains its effect during long-term use with no evidence of tolerance or need to increase the dose [6–8] . Conversely, there is apparent tolerance to side effects, with the incidence decreasing during continued use [9] . The most common adverse drug reactions in the first few weeks of exposure to THC:CBD oromucosal spray are dizziness and fatigue, especially if the dose is titrated quickly [10] . The effects are usually mild to moderate and tend to resolve within a few days even with continued treatment [10] . In long-term users of THC:CBD oromucosal spray (≥1 year), abrupt cessation was not associated with any specific or troublesome withdrawal syndrome and there was no evidence of diversion/abuse [7] .

future science group

Country break-out session highlights

CB1 receptors Mainly localized in the brain (hippocampus, cerebellum and cerebrum)

Symposium Paper

CB2 receptors Mainly situated in the perphery (spleen, tonsillar and immune cells)

CB1 receptors

CB2 receptors

Immune cells

Figure 2. Endogenous cannabinoids interact with cannabinoid receptors in the brain (CB1) and periphery (CB2). Reproduced with permission from Sobotta. Atlas der Anatomie des Menschen, with permission from Elsevier.

The ‘therapeutic window’ of THC:CBD oromucosal spray is best achieved when its use is combined with appropriate patient education. Treatment expectations must be discussed with the patient. THC:CBD oromucosal spray may take time to act and certain side effects may be experienced in the first few weeks of exposure. In terms of patient selection for treatment, it is important to remember that the level of response may differ per individual, especially in patients with severe MS spasticity. Multidisciplinary management of MS spasticity through MS networks: France MS is almost invariably a polysymptomatic disease [11] . As the type and severity of symptoms vary by patient, by MS type and often within the same patient over time, treatment requires an individualized approach. The imperceptibility of certain symptoms to friends, family and co-workers can be extremely isolating for persons with MS. Given that much energy may be consumed simply by coping with symptoms, a comprehensive management plan must incorporate elements of prevention, medication, rehabilitation and learning strategies. In France, multidisciplinary healthcare networks have developed well-defined treatment pathways and schedules to manage MS patients.


A core team for managing patients with MS spasticity might include a neurologist, radiologist, physician, physiotherapist and nurse, with additional support as needed from allied professionals. New technologies such as interactive websites and smartphone ‘apps,’ patients’ associations and auxiliary tools such as therapeutic education for patients and carers can all assist in MS management. Therapeutic education involves providing information about MS and related aspects such as self-rehabilitation, treatment, cognitive rehabilitation and fatigue. The aims are to improve or stabilize patients’ quality of life, maintain autonomy, increase compliance and prevent or decrease the risk of complications and relapse. Titration & adherence to new MS spasticity treatments: Spain Along with the introduction of newer treatment options for MS over the past 20 years, the goals of therapy have evolved. Treatment paradigms have shifted from ‘slow disease progression’ to ‘stop disease progression’ and are now approaching ‘repair’ (Figure 3) . Spasticity is among the most common symptoms of MS and its incidence and severity increase with disease duration [11] . When selecting therapy for symptomatic relief of MS

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Introduction of RRMS therapies in the EU

Out come measures


Address symptoms

Slow disease progression

Relapse rate1 1993 MRI lesion activity1 1 (T1, T2, G6+) MSFC EDSS1 2000 1996 1983

SC SC IFN-β-1a GA IFN-β-1b 1993 2001 1995 IM IFN-β1a Mitoxantrome 1997 2000

Stop disease progression

Repair

No evidence of disease activity (NEDA)1 2009 Sustained improvement12 011

Natalizumab 2005

Fingolimod 2010

DMF pegIFN-β-1a 2014

Alemtuzumab teriflunomide 2013

Figure 3. Evolution in the ‘goals of therapy’ for multiple sclerosis. DMF: Dimethyl fumarate; EDSS: Expanded Disability Status Scale; GA: Glatiramer acetate; IFNβ: Interferon-β; IM: Intramuscular; MRI: Magnetic resonance imaging; MSFC: Multiple Sclerosis Functional Composite; NEDA: No evidence of disease activity; RRMS: Relapsing remitting multiple sclerosis; SC: Subcutaneous.

spasticity, taking into consideration the pros and cons of each option is a critical aspect of treatment optimization. Oral baclofen is a standard first-line therapy for MS spasticity. Baclofen-induced muscle relaxation may improve range of motion and decrease symptoms of spasticity, flexor spasms, clonus and pain [12] . However, not all patients respond to baclofen, and associated adverse events (e.g., drowsiness, dizziness and weakness) can prevent the patient from reaching an effective dose. A starting dose of 5 mg/day may be uptitrated by 15 mg/day increments every 3 days (or more) to the commonly accepted maximum dose of 60 mg/day (in three or four divided doses). Abrupt cessation should be avoided due to risk of a withdrawal syndrome. Baclofen should not be used in patients who have seizure disorder, impaired renal function, severe psychiatric disturbances or confusion or in women who are lactating. Tizanidine is another relatively common oral first-line agent for MS spasticity. The few studies that have investigated tizanidine have provided some evidence of achieving a reduction in Ashworth scale scores, a decrease in subjective spasms and improvement in general spasms and clonus [12] . In some studies, however, incidences of adverse events (somnolence, dry mouth, asthenia and dizziness) and withdrawal rates were high compared with placebo [12] . The

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typical starting dose of 1–2 mg may be increased gradually in 1–2 mg increments over the course of one week to a maximum dose of 36 mg/day (in three divided doses). Possible safety issues include liver disorders, orthostasis and hallucinations. Tizanidine is not recommended in women taking oral contraceptives. Benzodiazepines (diazepam, clonazepam) are muscle relaxants and are often used in combination with baclofen and tizanidine. Caution is advised, however, as the sedative and depressant effects of baclofen and tizanidine may be enhanced. Benzodiazepines are associated with dependency and, if discontinued abruptly, can cause potentially serious side effects. Sativex ? (THC:CBD) oromucosal spray acts as a partial agonist–antagonist at the human cannabinoid CB1 receptor, enhancing cannabinoid-mediated clinical effects while limiting psychoactive and sedative effects. THC:CBD oromucosal spray is indicated for symptom improvement in adult patients with moderateto-severe MS spasticity who have not responded adequately to other antispasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy. The efficacy of THC:CBD oromucosal spray in the treatment of resistant MS-related spasticity has been demonstrated in randomized controlled trials [2– 4] . Approximately half of patients initiated on


Country break-out session highlights THC:CBD oromucosal spray will show an initial response (≥20% improvement from baseline on the spasticity 0–10 Numerical Rating Scale [NRS]) during a 4-week trial of therapy [4,5] . Three out of four initial responders will show a clinically relevant response (≥30% NRS improvement from baseline) after 2–3 months of treatment [4] . During long-term use, THC:CBD oromucosal spray has not been associated with cognitive decline or any significant changes in mood compared with placebo [13] . Early combination of THC:CBD oromucosal spray with baclofen and tizanidine can improve symptoms and minimize adverse effects by using different modes of action. To minimize the risk of adverse effects during initial exposure to THC:CBD oromucosal spray, gradual ‘up-titration’ is recommended; it may take up to 2 weeks (or longer) to obtain the best result. Doses should be spread throughout the day based on individual response and any tolerability issues that may arise. If adverse events (e.g., dizziness) occur, uptitration can be interrupted for a couple of days before restarting [10] . The specialized MS nurse has an important role in terms of treatment adherence and general management. Some of the many responsibilities of MS nurses are to provide advice and supportive information about the care plan (e.g., physiotherapy, medications and referral to other specialists), raise awareness of support sources (patients’ associations and social services) and facilitate appropriate scheduling with the physician or other clinical health professionals according to the patient’s individual needs.

Symposium Paper

MS spasticity symptoms management: Norway/rest of the world Minimal assessments to monitor MS spasticity clinically are motricity testing, disability scoring (Expanded Disability Status Scale), spasticity severity assessment (Ashworth Scale, 0–10 NRS) and the Penn Spasm Frequency Scale. Numerous other assessments are available to monitor function and general MS symptoms (Table 1) , although their application in daily practice is likely to occur only in selected cases. The goals of treatment of MS spasticity are to: ●● Improve functional mobility/walking; ●● Decrease pain; ●● Improve quality of life; ●● Ease rehabilitation; ●● Prevent and decrease complications (e.g., con-

tracture and pressure ulcer); ●● Ease care and facilitate hygiene.

The management strategy for MS spasticity includes several approaches that can be tailored to the needs of the individual patient (Figure 4) . An overarching strategy is to identify and eliminate trigger factors for spasticity such as pain, skin ulcers, bladder dysfunction and infections. Other options involve physical therapy, pharmacotherapy and orthopaedic/neurosurgical procedures as required. Financial & competing interests disclosure F Fazekas is serving/has served on scientific advisory boards for Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Pf izer, Novartis, Perceptive Informatics, Teva

Table 1. Examples of assessments for multiple sclerosis-related disorders and deficits. Domain

Assessment

Quality of life Pain Balance assessments Walking assessments

Multiple Sclerosis Impact Scale (MSIS)-29; EQ-5D VAS score Walking assessments; Romberg’s test Timed 25-foot walk; 12-item MS walking scale; 2-min walking test 9-hole peg test Visual acuity, scotoma, diplopia VAS score; Fatigue Severity Scale Obstipation, diarrhoea; incontinence Dysuria, urgency; retention, nocturia; incontinence N/A Paced Auditory Serial Addition Test; Symbol Digit Modalities Test

Hand function Visual function Fatigue Bowel disorders Urinary disorders Heat intolerance Cognition

MS: Multiple sclerosis; N/A: Not applicable; VAS: Visual analogue scale.



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Identify and remove or treat spasticity triggers

Spasticity team evaluation

Rehabilitation/ physiotherapy

Treatment options

Generalized spasticity

Medication

Regional spasticity Focal spasticity

Oral medications

Botulinum toxin injection

Intrathecal baclofen

Figure 4. Management strategy for multiple sclerosis spasticity. Pharmaceutical Industries Ltd; serves on the editorial boards of Cerebrovascular Diseases, Multiple Sclerosis Journal, Polish Journal of Neurology and Neurosurgery, and Swiss Archives of Neurology and Psychiatry; has received speaker honoraria and support from Biogen Idec, Bayer Schering, Bristol-Myers Squibb Merck Serono, Novartis, Sanofi Aventis, Shire, and Teva Pharmaceutical Industries Ltd. P 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, Merck Serono, Genzyme and Teva; has received research grants from the University of Padova, Veneto Region of Italy, the Italian Association for Multiple Sclerosis, the Italian Ministry of Public Health. C LebrunFrénay has participated in scientific congresses and received honoraria for attending conferences, membership of scientific committees and as serving as a consultant from Allergan, Almirall, Bayer Schering, Biogen Idec, Genzyme,

Merck Serono, Novartis, Sanofi, Teva; is a member of scientific committees for: CFSEP, ARSEP, ‘ la ligue’, PACASEP, OFSEP; is a member of the editorial board for Revue Neurologique, Neurologies, Neurones, SEP Neurosciences, Neurology and Therapy. E Moral has received compensation for conferences and/or advisory activities from Almirall, Bayer, Biogen, Genzyme, Merck-Serono, Novartis, Roche and Teva. K-M Myhr has participated in clinical treatment trials and/or advisory boards, received speaker honoraria, travel support and/or unrestricted research grants from Allergan, Almirall, Bayer Pharma, Biogen, Genzyme, Merck Serono, Novartis, Roche, Sanofi Aventis and Teva. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance was provided by Content Ed Net (Madrid, Spain), with funding from Almirall SA (Barcelona, Spain).

blind, randomized, placebo-controlled, parallelgroup study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol. Res. 32(5), 451–459 (2010).

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