The natural history of multiple system atrophy: a prospective European cohort study

Abstract

Background: Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA.

Methods: Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test.

Findings: 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56·2 (SD 8·4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9·8 years (95% CI 8·1-11·4). The parkinsonian variant of MSA (hazard ratio [HR] 2·08, 95% CI 1·09-3·97; p=0·026) and incomplete bladder emptying (HR 2·10, 1·02-4·30; p=0·044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9·4 [SD 5·9]), 74% (12·9 [8·5]), and 57% (21·9 [11·9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0·68, 0·5-0·9; p=0·006) and absent levodopa response (OR 3·4, 1·1-10·2; p=0·03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power.

Interpretation: Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials.

Figure 1

Study flow diagram Data refer to non-interpolated case numbers. Thus, patients who had incomplete data at one assessment could be included again later. EMSA=European MSA Study Group. ADL=activities of daily living. ME=motor examination. UMSARS=unified MSA rating scale.

Figure 2

Kaplan-Meier survival plot Overall survival analysis from symptom onset (A). Survival analysis stratified by phenotype (B).

Figure 3

Unified MSA rating scale progression Box plot of unified MSA rating scale (UMSARS) scores throughout the study period (A). Annualised progression rates stratified by categories of symptom duration (B). Annualised progression rates split by present or absent levodopa response (C). Red=UMSARS total. Green=UMSARS activities of daily living. Blue=UMSARS motor examination.

Figure 4

Sample size estimates Required sample size per group for various effect sizes and different scores. ADL=activities of daily living. ME=motor examination.