title: Natural history of multiple system atrophy in the USA: a prospective cohort study.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  US National Institutes of Health, Mayo Clinic, and Kathy Shih Memorial Foundation.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA. Electronic address: low@mayo.edu.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Low
authors.affiliation: Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Reich
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Jankovic
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Clifford W
authors.initials: CW
authors.lastname: Shults
authors.affiliation: Parkinson's Disease and Movement Disorders Center, Pennsylvania Hospital, Philadelphia, PA, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Stern
authors.affiliation: Department of Neurology, University of Massachusetts, Worcester, MA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Novak
authors.affiliation: Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Tanner
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Sid
authors.initials: S
authors.lastname: Gilman
authors.affiliation: Department of Neurology, University of Rochester, Rochester, NY, USA.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Marshall
authors.affiliation: Department of Neurology, University of Virginia Health System, Charlottesville, VA, USA.
authors.forename: Frederick
authors.initials: F
authors.lastname: Wooten
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, MO, USA; School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa.
authors.forename: Brad
authors.initials: B
authors.lastname: Racette
authors.affiliation: Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Chelimsky
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Singer
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Sletten
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Sandroni
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Mandrekar
mesh_terms: D000203:Activities of Daily Living / Q000523:psychology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002524:Cerebellar Ataxia / Q000175:diagnosis / Q000453:epidemiology / Q000523:psychology; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000175:diagnosis* / Q000453:epidemiology* / Q000523:psychology; D020734:Parkinsonian Disorders / Q000175:diagnosis / Q000453:epidemiology / Q000523:psychology; D011446:Prospective Studies; D012189:Retrospective Studies; D014481:United States / Q000453:epidemiology