Natural history of multiple system atrophy in the USA: a prospective cohort study

Phillip A Low, Stephen G Reich, Joseph Jankovic, Clifford W Shults, Matthew B Stern, Peter Novak, Caroline M Tanner, Sid Gilman, Frederick J Marshall, Frederick Wooten, Brad Racette, Thomas Chelimsky, Wolfgang Singer, David M Sletten, Paola Sandroni, Jay Mandrekar, Phillip A Low, Stephen G Reich, Joseph Jankovic, Clifford W Shults, Matthew B Stern, Peter Novak, Caroline M Tanner, Sid Gilman, Frederick J Marshall, Frederick Wooten, Brad Racette, Thomas Chelimsky, Wolfgang Singer, David M Sletten, Paola Sandroni, Jay Mandrekar

Abstract

Background: Multiple system atrophy is a rare, fatal neurodegenerative disorder with symptoms of autonomic failure plus parkinsonism, cerebellar ataxia, or both. We report results of the first prospective natural history study of multiple system atrophy in the USA, and the effects of phenotype and autonomic failure on prognosis.

Methods: We recruited participants with probable multiple system atrophy-of either the parkinsonism subtype (MSA-P) or the cerebellar ataxia subtype (MSA-C)-at 12 neurology centres in the USA specialising in movement or autonomic disorders. We followed up patients every 6 months for 5 years and assessed them with the Unified Multiple System Atrophy Rating Scale part I (UMSARS I; a functional score of symptoms and ability to undertake activities of daily living), UMSARS II (neurological motor evaluation), and the Composite Autonomic Symptoms Scale (COMPASS)-select (a measure of autonomic symptoms and autonomic functional status). We assessed potential predictors of outcome. We used Cox proportional hazards models to calculate univariate hazard ratios for shorter survival using age at disease onset as a continuous variable and sex, clinical phenotype, and early development of neurological and autonomic manifestations as categorical variables.

Findings: We recruited 175 participants. Mean age at study entry was 63·4 years (SD 8·6). Median survival from symptom onset was 9·8 years (95% CI 8·8-10·7) and median survival from enrolment was 1·8 years (0·9-2·7). Participants with severe symptomatic autonomic failure (symptomatic orthostatic hypotension, urinary incontinence, or both) at diagnosis (n=62) had a worse prognosis than those without severe disease (n=113; median survival 8·0 years, 95% CI 6·5-9·5 vs 10·3 years, 9·3-11·4; p=0·021). At baseline, patients with MSA-P (n=126) and MSA-C (n=49) had much the same symptoms and functional status: mean UMSARS I 25·2 (SD 8·08) versus 24·6 (8·34; p=0·835); mean UMSARS II 26·4 (8·8) versus 25·4 (10·5; p=0·764); COMPASS-select 43·5 (18·7) versus 42·8 (19·6; p=0·835). Progression over 5 years, assessed by change in UMSARS I, UMSARS II, and COMPASS-select, was modest.

Interpretation: Probable multiple system atrophy is a late-stage disease with short survival. The natural histories of MSA-P and MSA-C are similar and severe symptomatic autonomic failure at diagnosis is associated with worse prognosis.

Funding: US National Institutes of Health, Mayo Clinic, and Kathy Shih Memorial Foundation.

Conflict of interest statement

Conflicts of interest

Phillip A. Low, MD has no conflicts of interest to disclose.

Stephen G. Reich, MD has no conflicts of interest to disclose.

Joseph Jankovic, MD reports grants from Allergan, Inc; Ceregene, Inc; CHDI Foundation; GE

Healthcare; Huntington’s Disease Society of America; Huntington Study Group; Ipsen Limited; Lundbeck Inc; Michael J Fox Foundation for Parkinson Research; Medtronic; Merz Pharmaceuticals; National Institutes of Health; National Parkinson Foundation; St. Jude Medical; Teva Pharmaceutical Industries Ltd; UCB Inc; University of Rochester; Parkinson Study Group, during the conduct of the study; personal fees from Allergan, Inc; Auspex Pharmaceuticals, Inc; Ipsen Biopharmaceuticals, Inc.; Lundbeck Inc; Merz Pharmaceuticals; Teva Pharmaceutical Industries Ltd; UCB Inc; US World Meds., grants from Allergan, Inc; Ceregene, Inc; CHDI Foundation; GE Healthcare; Huntington’s Disease Society of America; Huntington Study Group; Ipsen Limited; Lundbeck Inc; Michael J Fox Foundation for Parkinson Research; Medtronic; Merz Pharmaceuticals; National Institutes of Health; National Parkinson Foundation; St. Jude Medical; Teva Pharmaceutical Industries Ltd; UCB Inc; University of Rochester; Parkinson Study Group, other from Cambridge; Elsevier; Future Science Group; Hodder Arnold; Lippincott Williams and Wilkins; Wiley-Blackwell, outside the submitted work;.

Matthew B. Stern, MD reports Consultant: Teva, Merz, Adamas, Civitas Equity: Civitas, Adamas Officer: International Parkinson and Movement Disorder Society.

Peter Novak, MD has no conflicts of interest to disclose.

Caroline M. Tanner, MD, PhD reports personal fees from Adamas Pharmaceuticals, personal fees from Pfizer Pharmaceuticals, outside the submitted work.

Sid Gilman, MD, FRCP has no conflicts of interest to disclose.

Frederick Wooten, MD has no conflicts of interest to disclose.

Brad Racette, MD has no conflicts of interest to disclose.

Thomas Chelimsky, MD reports grants from NIH-NIDDK, other from Ironwood Pharmaceuticals, outside the submitted work.

Wolfgang Singer, MD has no conflicts of interest to disclose.

David M. Sletten, MBA has no conflicts of interest to disclose.

Paola Sandroni, MD has no conflicts of interest to disclose.

Jay Mandrekar, PhD has no conflicts of interest to disclose.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Study flow diagram.
Figure 2
Figure 2
Kaplan-Meier survival curves for probability of dying (upper curve) in all subjects with MSA; and (middle curve) in subjects with MSA-P compared with those with MSA-C, MSAP, and (lower curve) subjects with severe symptomatic autonomic failure at diagnosis compared with those without severe symptomatic autonomic failure at diagnosis. Number at risk of subjects for selected time-points is provided.
Figure 2
Figure 2
Kaplan-Meier survival curves for probability of dying (upper curve) in all subjects with MSA; and (middle curve) in subjects with MSA-P compared with those with MSA-C, MSAP, and (lower curve) subjects with severe symptomatic autonomic failure at diagnosis compared with those without severe symptomatic autonomic failure at diagnosis. Number at risk of subjects for selected time-points is provided.
Figure 2
Figure 2
Kaplan-Meier survival curves for probability of dying (upper curve) in all subjects with MSA; and (middle curve) in subjects with MSA-P compared with those with MSA-C, MSAP, and (lower curve) subjects with severe symptomatic autonomic failure at diagnosis compared with those without severe symptomatic autonomic failure at diagnosis. Number at risk of subjects for selected time-points is provided.
Figure 2
Figure 2
Kaplan-Meier survival curves for probability of dying (upper curve) in all subjects with MSA; and (middle curve) in subjects with MSA-P compared with those with MSA-C, MSAP, and (lower curve) subjects with severe symptomatic autonomic failure at diagnosis compared with those without severe symptomatic autonomic failure at diagnosis. Number at risk of subjects for selected time-points is provided.

References

    1. Wenning GK, Colosimo C, Geser F, Poewe W. Multiple system atrophy. Lancet Neurol. 2004;3:93–103.
    1. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology. 1997;49:1284–8.
    1. Ubhi K, Low P, Masliah E. Multiple system atrophy: a clinical and neuropathological perspective. Trends Neurosci. 2011;34:581–90.
    1. Kuzdas-Wood D, Stefanova N, Jellinger KA, Seppi K, Schlossmacher MG, Poewe W, et al. Towards translational therapies for multiple system atrophy. Prog Neurobiol. 2014;118:19–35.
    1. Gilman S, Low PA, Quinn N, Albanese A, Ben-Schlomo Y, Fowler CJ, et al. Consensus statement on the diagnosis of multiple system atrophy. J Auton Nerv Syst. 1998;74:189–92.
    1. Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus conference on the diagnosis of multiple system atrophy. Neurology. 2008;71:670–6.
    1. Iodice V, Lipp A, Ahlskog JE, Sandroni P, Fealey RD, Parisi JE, et al. Autopsy confirmed multiple system atrophy cases: Mayo experience and role of autonomic function tests. J Neurol Neurosurg Psychiatry. 2012;83:453–9.
    1. Figueroa JJ, Singer W, Parsaik A, Benarroch EE, Ahlskog JE, Fealey RD, et al. Multiple system atrophy: prognostic indicators of survival. Mov Disord. 2014;29:1151–7.
    1. Sandroni P, Ahlskog JE, Fealey RD, Low PA. Autonomic involvement in extrapyramidal and cerebellar disorders. Clin Auton Res. 1991;1:147–55.
    1. Watanabe H, Saito Y, Terao S, Ando T, Kachi T, Mukai E, et al. Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients. Brain. 2002;125:1070–83.
    1. Geser F, Wenning GK, Seppi K, Stampfer-Kountchev M, Scherfler C, Sawires M, et al. Progression of multiple system atrophy (MSA): a prospective natural history study by the European MSA Study Group (EMSA SG) Mov Disord. 2006;21:179–86.
    1. Lipp A, Sandroni P, Ahlskog JE, Fealey RD, Kimpinski K, Iodice V, et al. Prospective differentiation of multiple system atrophy from Parkinson’s disease, with and without autonomic failure. Arch Neurol. 2009;66:742–50.
    1. Payan CA, Viallet F, Landwehrmeyer BG, Bonnet AM, Borg M, Durif F, et al. Disease severity and progression in progressive supranuclear palsy and multiple system atrophy: validation of the NNIPPS--Parkinson Plus Scale. PLoS ONE. 2011;6:e22293.
    1. Bensimon G, Ludolph A, Agid Y, Vidailhet M, Payan C, Leigh PN, et al. Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study. Brain. 2009;132:156–71.
    1. Wenning GK, Geser F, Krismer F, Seppi K, Duerr S, Boesch S, et al. The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol. 2013;12:264–74.
    1. May S, Gilman S, Sowell BB, Thomas RG, Stern MB, Colcher A, et al. Potential outcome measures and trial design issues for multiple system atrophy. Mov Disord. 2007;22:2371–7.
    1. Wenning GK, Tison F, Seppi K, Sampaio C, Diem A, Yekhlef F, et al. Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS) Mov Disord. 2004;19:1391–402.
    1. Suarez GA, Opfer-Gehrking TL, Offord KP, Atkinson EJ, O’Brien PC, Low PA. The Autonomic Symptom Profile. A new instrument to assess autonomic symptoms. Neurology. 1999;52:523–8.
    1. Ware JE, Snow KK, Kosinski M, Gendek B. SF-36 Health Survey: Manual and Interpretation Guide. Boston: The Health Institute, New England Medical Center; 1993.
    1. Geser F, Seppi K, Stampfer-Kountchev M, Kollensperger M, Diem A, Ndayisaba JP, et al. The European Multiple System Atrophy-Study Group (EMSA-SG) J Neural Transm. 2005;112:1677–86.
    1. Coon EA, Suarez MD, Ahlskog JE, Mandrekar J, Low PA, Singer W. Survival in Multiple System Atrophy – Insights from a Large Retrospective Cohort. Ann Neurol. 2014;76:S39.
    1. Low PA, Robertson D, Gilman S, Kaufmann H, Singer W, Biaggioni I, et al. Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2014;13:268–75.

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