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Conclusions In this 20-year sample of U.S. hospital admissions of hip fractures, the rate of PD or parkinsonism was four times more than predicted. These osteoporotic hip fractures in PD patients led to higher rates of longterm care admissions. There was a lower rate of mortality in the PD population, which could potentially be explained by a lower prevalence of presenting comorbidities. Currently, we need to increase the awareness of fracture prevention in this population as well as increase the utilization of osteoporotic medications.
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Brauer CA, Coca-Perraillon M, Cutler DM, Rosen AB. Incidence and mortality of hip fractures in the United States. JAMA 2009; 302:1573–1579.
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Clubb VJ, Clubb SE, Buckley S. Parkinson’s disease patients who fracture their neck of femur: a review of outcome data. Injury 2006;37:929–934.
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Abou-Raya S, Helmii M, Abou-Raya A. Bone and mineral metabolism in older adults with Parkinson’s disease. Age Ageing 2009; 38:675–680.
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Gn€adinger M, Mellinghoff HU, Kaelin-Lang A. Parkinson’s disease and the bones. Swiss Med Wkly 2011;141:w13154.
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Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Mineral Res 2007;22: 465–475.
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Dubinsky RM, S.M. Lai SM. Mortality from combined carotid endarterectomy and coronary artery bypass surgery in the US. Neurology 2007;68:195–197.
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Melton LJ, 3rd, Leibson CL, Achenbach SJ, Bower JH, Maraganore DM, Oberg AL, Wocca WA. Fracture risk after the diagnosis of Parkinson’s disease: Influence of concomitant dementia. Mov Disord 2006;21:1361–1367.
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Guttman M, Slaughter PM, Theriault ME, DeBoer DP, Naylor CD. Parkinsonism in Ontario: comorbidity associated with hospitalization in a large cohort. Mov Disord 2004;19:49–53.
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Balash Y, Peretz T, Leibovich G, Herman T, Hausdorff JM, Giladi N. Falls in outpatients with Parkinson’s disease: frequency, impact, and identifying factors. J Neurol 2005;252:1310–1315.
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Impaired Self-Awareness of Motor Deficits in Parkinson’s Disease: Association With Motor Asymmetry and Motor Phenotypes Franziska Maier, MS,1 George P. Prigatano, PhD,2 Elke Kalbe, PhD,1,3,4 Michael T. Barbe, MD,1,3 Carsten Eggers, MD,1 Catharine J. Lewis, MS,1 Richard S. Burns, MD,5 Jeannine Morrone-Strupinsky, PhD,2 Guillermo Moguel-Cobos, MD,5 Gereon R. Fink, MD,1,3 and Lars Timmermann, MD1* 1
Department of Neurology, University Hospital Cologne, Cologne, Germany; 2Department of Clinical Neuropsychology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, USA; 3Institute of Neuroscience and Medicine, Cognitive Neurology Section, Research Center Ju¨lich, Germany; 4 Institute for Gerontology, University of Vechta, Vechta, Germany; 5 Movement Disorders Clinic, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, USA
ABSTRACT Background: This study investigated impaired selfawareness of motor deficits in nondemented, nondepressed Parkinson’s disease (PD) patients during a defined clinical on state. Methods: Twenty-eight PD patients were examined. Patients’ self-ratings and experts’ ratings of patients’ motor performance were compared. Patient–examiner discrepancies and level of impairment determined severity of impaired self-awareness. Motor exam assessed overall motor functioning, hemibody impairment, and 4 motor phenotypes. Neuropsychological tests were also conducted. Results: Signs of impaired self-awareness were present in 17 patients (60.7%). Higher severity of impaired self-awareness correlated significantly with higher postural-instability and gait-difficulty off scores (r 5 .575; P 5 .001), overall motor off scores (r 5 .569; P 5 .002), and higher left hemibody off scores (r 5 .490; P 5 .008). In multiple linear regression analyses, higher postural-instability and gait-difficulty off scores remained as the only significant predictor of impaired selfawareness severity.
-----------------------------------------------------------Additional Supporting Information may be found in the online version of this article. *Correspondence to: Prof. Dr. Lars Timmermann, Department of Neurology, University Hospital Cologne, Kerpener Str. 62, D-50937 Cologne, Germany;
[email protected] Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 25 May 2011; Revised: 19 April 2012; Accepted: 14 May 2012 Published online 18 June 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25079
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Conclusions: Postural instability and gait difficulties, disease severity, and right hemisphere dysfunction C 2012 seem to contribute to impaired self-awareness. V Movement Disorder Society Key Words: self-awareness; anosognosia; Parkinson’s disease; motor phenotype; hemibody score
Reports on impaired self-awareness of motor deficits (mISA) in Parkinson’s disease (PD) are scarce, mainly focusing on dopamine-induced dyskinesias.1–4 It has been suggested that dysregulation of frontal-subcortical loops because of dopaminergic overstimulation of mesocorticolimbic pathways might be responsible for mISA-PD.1,3,5 However, the results about a relationship between frontal executive dysfunction and mISA are controversial.2,3,5 We examined the relationship between mISA severity, neuropsychological functioning, and right hemisphere dysfunction in nondemented, nondepressed PD patients by calculating hemibody scores. According to anosognosia after left hemiparesis,6 we hypothesized that severe mISA-PD would relate to right hemisphere dysfunction and therefore to greater left-sided body impairment. Furthermore, we hypothesized that higher mISA levels would be associated with worse overall motor symptoms. Different motor phenotypes have been linked to the progression of PD.7,8 Postural instability and gait difficulties (PIGDs) have especially been associated with the development of cognitive decline.9 We examined the association between 4 motor phenotypes and mISA severity. We supposed that PIGDs are related to mISA severity in PD. Finally, we conducted a detailed analysis of mISA of motor symptoms other than dyskinesias, for example, tremor, during a clinically defined on state.
Patients and Methods There were 28 patients with idiopathic PD recruited from the Department of Neurology, University Hospital of Cologne. Depression and dementia were excluded using the Beck Depression Inventory–210 (score 20) and the Mini–Mental State Examination11 (score 25). Additional neurological/psychiatric diseases or deep brain stimulation were exclusion criteria. Patients gave written informed consent for participation. The ethics committee approved this study. Patients were assessed on the Unified Parkinson’s Disease Rating Scale–III (UPDRS-III).12 The levodopaequivalent daily dose (LEDD) was calculated,13 and patients were examined on and off medication. The following motor scores were calculated using UPDRS-III subitems: right/left hemibody scores (20– 26), tremor (20–21), rigidity (22), bradykinesia (23– 26 and 31), and PIGDs (27–30). All other instruments
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were conducted with patients in a ‘‘clinically defined on’’ state (at least 10 days of continuous intake of antiparkinsonian medication without medication changes). Finally, the following neuropsychological tests were applied: verbal fluency (letter S, animal naming),14 working memory—Wechsler Adult Intelligent Scale-III (WAIS-III) digit span subtest,15 problem solving— WAIS-III matrix reasoning subtest,15 and motor speed and motor control—Halstead Finger Tapping Test (HFTT).16 Neuropsychological raw scores were converted into T scores (50 6 10) to correct for age, education, sex, or handedness and for comparison with normative data.
Assessment of mISA The mISA test was applied to all patients. The mISA rating consisted of 2 parts: (1) examination of unawareness of motor symptoms and (2) assessment of severity of unperceived impairments. For part one, according to others,1 we developed an assessment including 6 different tasks. Before performance, the patient was asked whether she/he had general problems with this task. Then, the patient performed the task. Thereafter, the patient was asked whether she/he had performed like the examiner or whether she/he had noticeable difficulties performing the task. Per task, patients were questioned regarding PD-sensitive symptoms using a yes/no scale. Tasks and evaluated symptoms were: (1) sitting on a chair— tremor, dyskinesias; (2) finger tapping—tremor, dyskinesias, reduced speed, and amplitude of movement; (3) hand pronation–supination—tremor, dyskinesias, reduced speed, and amplitude of movement; (4) rising from a chair—tremor, dyskinesias, balance problems; (5) walking—tremor, dyskinesias, abnormal arm swing, shuffling, short steps, problems initiating walking, problems continuing walking, increased number of steps for turning; and (6) speaking—problems being heard in general, reduced voice clarity, being asked for repetition, problems being heard by examiner. Patients’ answers and examiner’s evaluations of motor performance were documented, videotaped, and rated by a second ‘‘blinded’’ video-rater. Discrepancies between self-ratings (patients) and expert evaluations (examiner/video-rater) were taken as indicators of mISA. A mISA severity score was calculated by multiplying the unperceived symptom with its rating on a 5-point scale (0–4) according to UPDRS-III ratings and then summing all severity ratings for each patient (for details, see Supplement).
Statistical Analysis The statistical analysis was conducted using IBM SPSS version 19.0 (SPSS Corp., Chicago, IL). The
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mISA severity score was used for multiple correlations. Level of significance for all analyses was set at 0.05. Multiple correlations were Bonferroni corrected by dividing the significance level by the number of correlated variables. Multiple linear regression models (stepwise method; significance level was 5% for entry and 10% for removal for each variable) were calculated for each correlation analysis and for a final analysis of significant predictors from the preceding analyses (for additional information, see Supplement).
Results Sociodemographic, clinical, and neuropsychological data for all patients are presented in Table 1. Patients’ mISA test results are shown in Table 2. Examiner and video-rater agreed on 50 of 56 discrepancies; 6 discrepancies were discussed in addition. Overall, 11 patients did not show mISA, whereas 17 patients (60.71%) had at least 1 discrepancy (range, 1–6; 2.00 6 2.14), resulting in 56 discrepancies. The calculated patient mISA severity score ranged between 0 and 16 (3.46 6 4.13).
Association of mISA Severity with UPDRS-III, LEDD, Age, Disease Duration Applying a significance level of 0.01, only UPDRSIII off scores (r ¼ .569, P ¼ .002) correlated significantly with mISA severity (Supplement Table 3), implying that higher mISA scores were related to higher overall motor impairment while off medication. In the regression analysis, UPDRS-III off score remained a significant predictor (R2 ¼ 0.324, corr. R2 ¼ 0.298, F ¼ 12.45, P ¼ .002).
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Table 1. Demographic, clinical, and neuropsychological
data for all patients Patients (n ¼ 28)
Age (y), mean 6 SD Gender (male/female) Handedness (right/left/ambidextrous) Education (y), mean 6 SD BDI-2, mean 6 SD MMSE, mean 6 SD Duration of disease (y), mean 6 SD UPDRS-III on, mean 6 SD UPDRS-III off, mean 6 SD Hemibody score right side off, mean 6 SD Hemibody score left side off, mean 6 SD LEDD (mg), mean 6 SD WAIS-III Matrix Reasoning T score, mean 6 SD WAIS-III Digit Span T score forward, mean 6 SD WAIS-III Digit Span T score backward, mean 6 SD Verbal fluency Letter S T score, mean 6 SD Verbal fluency Animal naming T score, mean 6 SD Finger-tapping score right hand T score, mean 6 SD Finger-tapping score left hand T score, mean 6 SD
60.32 6 9.68 20/8 25/1/2 11.82 6 4.10 11.04 6 5.12 28.71 6 1.41 7.68 6 6.07 19.04 6 9.52 37.75 6 13.49 12.68 6 5.60 12.04 6 5.68 757.86 6 447.50 50.00 6 9.20 52.16 6 10.21 47.60 6 11.14 52.72 6 9.74 53.86 6 9.08 34.70 6 15.12 40.67 6 15.08
SD, standard deviation; y, years; BDI-2, Beck Depression Inventory–2; MMSE, Mini Mental State Examination; UPDRS-III, Unified Parkinson’s Disease Rating Scale–III; off, off medication; on, on medication; LEDD, levodopa-equivalent daily dose; WAIS-III, Wechsler Adult Intelligence Scale–3.
Association of mISA Severity with Neuropsychological Parameters Level of significance was set at 0.00714. Using this level of correction, there was no significant correlation (Supplement Table 3). Left-hand HFTT score was the only significant predictor in the multiple regression analysis (R2 ¼ 0.205, corr. R2 ¼ 0.170, F ¼ 5.92, P ¼ .023).
Predictors of mISA Severity Association of mISA Severity with Hemibody On/Off Scores Level of significance set at 0.0125. mISA severity was significantly associated only with higher left hemibody off score (r ¼ .490, P ¼ .008) not with higher right hemibody off impairment (r ¼ .347, P ¼ .071; Supplement: Table 3). Linear regression analysis approved left hemibody off score as a significant predictor for mISA severity (R2 ¼ 0.240, corr. R2 ¼ 0.211, F ¼ 8.22, P ¼ .008).
Association of mISA Severity with Motor Phenotypes On/Off Scores Level of significance was set at 0.00625. Higher scores of mISA severity were significantly related to higher PIGD off scores (r ¼ .575, P ¼ .001; Supplement: Table 3). Multiple regression analysis also revealed off PIGD as a significant predictor for mISA (R2 ¼ 0.331, corr. R2 ¼ 0.305, F ¼ 12.84 P ¼ .001).
Multiple regression analysis was conducted to investigate the combined influence of all 4 significant predictors from the preceding analyses. The only significant predictor was the PIGD off score, explaining 30.4% (corrected R2) of the variance (R2 ¼ 0.331, F ¼ 12.367, P ¼ .002).
Discussion Unawareness not only exists for dopamine-induced dyskinesias but also for off symptoms partly improved by dopamine during the on state. Therefore, our findings might support the hypothesis that dopaminergic overstimulation of mesocorticolimbic loops (resulting in a cortical-subcortical dysregulation) might be responsible for mISA.1,3,5 In contrast to others,3 in our study mISA severity was unrelated to dopamine-dependent executive functioning. Nevertheless, our results are similar to others2 and are consistent with Starkstein et al,17 who suggested that in Alzheimer’s
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Table 2. Test of awareness of motor deficit Severity of unnoticed symptoma Motor symptom
Tremor Dyskinesias Reduced speed (FT and PS) Reduced amplitude (FT and PS) Reduced arm swing Shuffling and short steps Problems initiating and continuing walking Increased number of steps for turn Balance problems Speaking problems All symptoms
Patients presenting symptom (n ¼ 28)
15 6 27 26 19 19 9 14 3 24 28
(53.57) (21.43) (96.43) (92.86) (67.86) (67.86) (32.14) (50.00) (10.71) (85.71) (100.00)
Patients with at least 1 discrepancy
Number of all discrepancies
1
2
3
4
4 4 11 6 4 2 0 1 0 1 17
6 7 23 11 4 2 0 1 0 2 56
1 1 16 4 2 1 0 1 0 0 26
2 4 5 5 1 1 0 0 0 2 20
3 2 2 2 0 0 0 0 0 0 9
0 0 0 0 1 0 0 0 0 0 1
Values in parentheses are percentages. FT, finger tapping; PS, hand pronation–supination. a Severity of unnoticed symptom according to UPDRS-III scores: a higher score represents more impairment.
disease (AD), executive dysfunction may be independent of anosognosia. In addition, no relationship between any neuropsychological test and mISA severity was found. Perhaps subclinical cognitive deficits may be responsible for mISA, similar to AD, in which the amount of cognitive dysfunction shows association with anosognosia.18 In addition, nonmotor contributions such as anxiety and disability impairment have to be taken into consideration.19 Another dopaminerelated explanation might be linked to error-related negativity, probably modulated by the midbrain dopaminergic system.20 Moreover, with its impact on motivation,21 dopamine might influence the ability to detect motor deficits. Regarding motor phenotypes, mISA was significantly associated with PIGDs, which usually develop as PD progresses and frequently relate to cognitive decline.9,22–24 However, mISA severity was not related to disease duration or cognitive outcome. Interestingly, PIGD-related symptoms were adequately noticed by our patients. This might support the above-mentioned dopamine hypothesis. Concerning laterality of hemispheric degeneration, our findings are not as definite as findings from hemiparetic stroke patients.25 Nevertheless, we provide indirect evidence for a link between severity of right basal ganglia degeneration (and its cortical-subcortical loops), and mISA severity in PD. Robertson26 argued that the right prefrontal cortex may play an important role in attention and the capacity to be vigilant about one’s behavioral functioning. Vuilleumier27,28 suggested an association between anosognosia and the inability to detect motor errors. The small sample size of 28 PD patients limits the statistical power of our study. The questionable validity of the normality assumption for the mISA severity score is an additional limitation. Therefore, conclu-
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sions should be considered cautiously, and no cause– effect relationships can be determined. In conclusion, some PD patients may have difficulties perceiving their motor symptoms. Our data suggest that higher mISA severity might be related to clinical signs of right hemisphere dysfunction and worse overall motor impairment, especially PIGD.
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Sitek EJ, Soltan W, Wieczorek D, et al. Self-awareness of motor dysfunction in patients with Huntington’s disease in comparison to Parkinson’s disease and cervical dystonia. J Int Neuropsychol Soc. 2011;17:788–795.
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Leritz E, Loftis C, Crucian G, Friedman W, Bowers D. Selfawareness of deficits in Parkinson disease. Clin Neuropsychol. 2004;18:352–361.
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Bottini G, Paulesu E, Gandola M, Pia L, Invernizzi P, Berti A. Anosognosia for hemiplegia and models of motor control: insights from lesional data. In: Prigatano GP, ed. The Study of Anosognosia. New York, NY: Oxford University Press, 2010:17–38.
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Maetzler W, Liepelt I, Berg D. Progression of Parkinson’s disease in the clinical phase: potential markers. Lancet Neurol. 2009;8: 1158–1171.
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Selikhova M, Williams DR, Kempster PA, Holton JL, Revesz T, Lees AJ. A clinico-pathological study of subtypes in Parkinson’s disease. Brain. 2009;132:2947–2957.
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Taylor JP, Rowan EN, Lett D, O’Brien JT, McKeith IG, Burn DJ. Poor attentional function predicts cognitive decline in patients with non-demented Parkinson’s disease independent of motor phenotype. J Neurol Neurosurg Psychiatry. 2008;79: 1318–1323.
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Hautzinger M, Keller F, Ku¨hner C. [BDI-II; Beck DepressionsInventar Revision]. Franfurt am Main, Germany: Harcourt Test Services; 2006.
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Fahn S, Elton RL, Committee UD. Unified Parkinson’s Disease Rating Scale. In: Fahn S, Marsden CD, Calne D, Goldstein M, eds. Recent Developments in Parkinson’s Disease. Floral Park, NY: MacMillan Healthcare Information; 1987:153–163.
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Diener HC, Putzki N, eds. [Leitlinien fu¨r Diagnostik und Therapie in der Neurologie]. 4th ed. Stuttgart, Germany: Georg Thieme Verlag; 2008.
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Aschenbrenner S, Tucha O, Lange KW. [Regensburger Wortflu¨ssigkeits-Test (RWT)]. G€ ottingen: Hogrefe; 2000.
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von Aster M, Neubauer A, Horn R. [Wechsler Intelligenztest fu¨r Erwachsene (WIE). Deutschsprachige Bearbeitung und Adaptation des WAIS-III von David Wechsler.]. Frankfurt/Main, Germany: Harcourt Test Services; 2006.
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Starkstein SE, Sabe L, Chemerinski E, Jason L, Leiguarda R. Two domains of anosognosia in Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 1996;61:485–490.
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Starkstein SE, Sabe L, Petracca G, et al. Neuropsychological and psychiatric differences between Alzheimer’s disease and Parkinson’s disease with dementia. J Neurol Neurosurg Psychiatry. 1996;61:381–387.
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Demakis GJ, Hammond FM, Knotts A. Prediction of depression and anxiety 1 year after moderate-severe traumatic brain injury. Appl Neuropsychol. 2010;17:183–189.
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Stemmer B, Segalowitz SJ, Dywan J, Panisset M, Melmed C. The error negativity in nonmedicated and medicated patients with Parkinson’s disease. Clin Neurophysiol. 2007;118:1223–1229.
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Wise RA. Dopamine, learning and motivation. Nat Rev Neurosci. 2004;5:483–494.
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Burn DJ, Rowan EN, Allan LM, Molloy S, O’Brien JT, McKeith IG. Motor subtype and cognitive decline in Parkinson’s disease, Parkinson’s disease with dementia, and dementia with Lewy bodies. J Neurol Neurosurg Psychiatry. 2006;77:585–589.
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Age at Onset and Symptom Spread in Primary Adult-Onset Blepharospasm and Cervical Dystonia Davide Martino, PhD,1 Alfredo Berardelli, MD,2 Giovanni Abbruzzese, MD,3 Anna Rita Bentivoglio, MD,4 Marcello Esposito, MD,5 Giovanni Fabbrini, MD,2 Arianna Guidubaldi, MD,4 Paolo Girlanda, MD,6 Rocco Liguori, MD,7 Lucio Marinelli, MD,3 Francesca Morgante, PhD,6 Lucio Santoro, MD,5 and Giovanni Defazio, PhD1* 1
Department of Neurosciences and Sensory Organs and School of Motor Sciences, ‘‘Aldo Moro’’ University of Bari, Bari, Italy; 2 Department of Neurology and Psychiatry, Sapienza University of Rome and IRCCS Neuromed Institute, Pozzilli, Italy; 3Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Genoa, Italy; 4Department of Neurosciences, Catholic University, Rome, Italy; 5Department of Neurology, Second University of Naples, Naples, Italy; 6Department of Neurosciences, Psychiatry, and Anaesthesiological Science, University of Messina, Messina, Italy; 7 Department of Neurosciences, University of Bologna, Bologna, Italy
ABSTRACT Background: The site of dystonia onset is known to affect the risk of spread in primary adult-onset focal dystonia, but other factors possibly influencing spread are unknown. This study explored the relationship between age and spread of dystonia in primary adultonset focal dystonia. Methods: Two survival models analyzed spread of dystonia in a large cohort of patients with primary blepharospasm (BSP) and cervical dystonia. The first model was based on time interval between onset and spread of dystonia, and the second model was based on age at spread. Results: Patients presenting with BSP had a 2-fold higher rate of spread than those presenting with cervical dystonia, regardless of the survival model used. However, survival analysis, based on age at spread,
-----------------------------------------------------------Additional Supporting Information may be found in the online version of this article. *Correspondence to: Giovanni Defazio, Department of Neurological and Psychiatric Sciences, ‘‘Aldo Moro’’ University of Bari, Policlinico, Piazza Giulio Cesare 1, 70124 Bari, Italy;
[email protected] Funding agencies: This work was funded by the Comitato Promotore Telethon, Italy (grant no.: GGP05165). Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 25 October 2011; Revised: 15 May 2012; Accepted: 21 May 2012 Published online 13 August 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25088
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