Clinical prognostic indicators in multiple system atrophy

Multiple system atrophy (MSA) is a neurodegenerative condition causing parkinsonism, cerebellar ataxia and/or dysautonomia. Typical survival is between 6-10 years, but some people die before five or after 15 years. This heterogeneity complicates advanced planning and clinical trial stratification. MSA prognostication studies have shown conflicting results, possibly due to diagnostic accuracy or study size. We report results from a study of survival prognostic factors in a cohort of 555 MSA patients (including the largest post-mortem confirmed cohort to date of 254 people) gathered through the Queen Square Brain Bank and the PROSPECT-M-UK multi-centre prospective cohort study. Through PROSPECT-M-UK, 318 clinically diagnosed MSA patients (17 overlapped with the QSBB cohort) were followed up annually over 5 years. The QSBB cohort clinical data was collected through retrospective review of primary and secondary care documentation. Survival analysis was performed using counting process Cox proportionate hazards modelling, Kaplan-Meier log-rank testing and landmark survival analysis to account for guarantee-time bias. Mean onset age in the combined cohort was 58.7±9.0y with median survival of 8.25y (95% CI:7.88-8.63). 28.8% were clinically diagnosed in-life with MSA-P, 23.8% MSA-C, 40.2% mixed and the rest as non-MSA diagnoses. Later disease onset was associated with shorter survival (HR=1.04, P<0.001). The commonest cause of death was respiratory infection (67%) followed by disease related decline (20%). Median survival from indoor wheelchair use, gastrostomy insertion or development of unintelligible speech was consistently <1.5 years (95% CI upper limits<2.4 years), making these reliable late-stage disease markers. Using landmark analysis, at 3 years from onset, negative prognostic factors included recurrent falls, unintelligible speech, use of catheters and of medication for orthostatic hypotension (HR = 1.57, 3.29, 1.76, 3.29;all P<0.05). At 5 years from onset, mobility milestones including walking aid use, outdoor and indoor wheelchair use (HR = 1.70, 1.93, 2.62;all P<0.01) became significant, whilst dysautonomia milestones (catheter and orthostatic support medication use) were no longer significant. Median individual Unified Multiple System Atrophy Rating Scale (UMSARS) progression rate (n=91) was 10.27 (IQR:5.31-14.30) points/year and did not correlate with symptom duration. Higher baseline UMSARS and faster UMSARS progression were negative prognostic factors of survival from baseline review (HR=1.03 and 1.07 respectively, both P<0.001). We show that in-clinic rating scales and clinical milestone assessment can aid MSA prognostication. Importantly, prognostic factors demonstrate time-dependent variability, which may contribute to previous heterogeneity observed in smaller studies. This knowledge is important for patient care and should inform future clinical trial stratification.