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

doi:10.1016/s1474-4422(15)00058-7

Abstract

BackgroundMultiple system atrophy (MSA) is a rare, fatal neurodegenerative disorder exhibiting a combination of parkinsonism and/or cerebellar ataxia with autonomic failure. We report the first North American prospective natural history study of MSA, and the effects of phenotype and autonomic failure on prognosis.Methods175 subjects with probable MSA, both MSA-P and MSA-C, were recruited and prospectively followed for 5 years with evaluations every 6 months in 12 centers. Natural history was evaluated by Kaplan-Meier survival analysis. We compared MSA-P with MSA-C and evaluated predictors of outcome. These subjects were evaluated with 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.FindingsMean age of symptom onset was 63.4 (SD 8.57) years. Median survival from symptom onset by Kaplan-Meier analysis was 9.8 years (95% CI 8.8-10.7). Subjects with severe symptomatic autonomic failure (symptomatic orthostatic hypotension, urinary incontinence) at diagnosis had a worse prognosis, surviving 8.0 years (95% CI, 6.5-9.5, n=62) while remaining subjects survived a median of 10.3 years (95% CI, 9.3-11.4, n=113). At baseline MSA-P (n=126) and MSA-C (n=49) were not different in symptoms and function, UMSARS I, 25.2 (8.08) vs 24.6 (8.34), p=0.835; UMSARS II, 26.4 (8.77) vs 25.4 (10.51), p=0.7635; COMPASS_select), 43.5 (18.66) vs 42.8 (19.56), p=0.835. Progression, evaluated by change in UMSARS I, UMSARS II, COMPASS_select over the next 5 years, was not significantly different between MSA-P and MSA-C. Median time to death from enrollment baseline was 1.8 (95% CI, 0.9-2.7) years.InterpretationProbable MSA represents late-stage disease with short survival. Natural history of MSA-P and MSA-C are similar. Severe symptomatic autonomic failure at diagnosis is associated with worse prognosis.FundingNational Institutes of Health (P01 NS044233), Mayo CTSA (UL1 TR000135), the Kathy Shih Memorial Foundation, and Mayo funds.

Highlights

Multiple System Atrophy (MSA) is a neurodegenerative disorder expressing a combination of autonomic failure, parkinsonism and/or cerebellar ataxia,[1] with a disease annual incidence of 3/100,000 for subjects age 50-99 years.[2]
We report here a North American prospective study of 175 MSA subjects followed over 5 years
Symptoms (UMSARS I) and deficits (UMSARS II) were not different at baseline, and median time to death was only 1.8 years. This suggests that the Consensus Criteria for probable MSA5, 6 ensures high diagnostic accuracy but achieves this at a late stage of the disease

Summary

Introduction

Multiple System Atrophy (MSA) is a neurodegenerative disorder expressing a combination of autonomic failure, parkinsonism and/or cerebellar ataxia,[1] with a disease annual incidence of 3/100,000 for subjects age 50-99 years.[2] Disease progression is typically inexorable. A prospective natural history study of 141 MSA subjects followed over 2 years has provided novel information on MSA natural history in Europe.[15] We report here a North American prospective study of 175 MSA subjects followed over 5 years We included both MSA-Parkinsonism (MSA-P) and MSA-Cerebellar (MSA-C) in order to compare their natural history. We report the first North American prospective natural history study of MSA, and the effects of phenotype and autonomic failure on prognosis

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Conclusion