Diagnosing Premotor Multiple System Atrophy: Natural History and Autonomic Testing in an Autopsy Confirmed Cohort

Background and Objectives: Non-motor features precede motor symptoms in many patients with multiple system atrophy (MSA). However, little is known about differences between the natural history, progression and prognostic factors for survival in MSA subjects with non-motor versus motor presentations. We aimed to compare initial symptoms, disease progression and clinical features at final evaluation and investigate differences in survival and natural history between MSA patients with motor and non-motor presentations.

Methods: Medical records of autopsy-confirmed MSA cases at Queen Square Brain Bank who underwent both clinical examination and cardiovascular autonomic testing were identified. Clinical features, age at onset, gender, time from onset to diagnosis, disease duration, autonomic function tests and plasma noradrenaline levels were evaluated.

Results: 47 autopsy-confirmed MSA patients (60+8 years; 28 males) were identified. Time from symptom onset to first autonomic evaluation was 4+2 years and disease duration was 7.7+2.2 years. Fifteen (32%) patients presented with non-motor features including genitourinary dysfunction, orthostatic hypotension or REM sleep behaviour disorder prior to developing motor involvement (median delay 1-6 years). A third (5/15) were initially diagnosed with pure autonomic failure (PAF) before evolving into MSA. All these patients had normal supine plasma noradrenaline levels (332.0+120.3 pg/ml) with no rise on head-up tilt (0.1+0.3 pg/ml).

MSA patients with early cardiovascular autonomic dysfunction (within 3 years of symptom onset) had shorter survival compared to those with later onset of cardiovascular autonomic impairment (6.8 years [5.6-7.9] vs 8.5 years [7.9-9.2]; p=0.026).

Patients with early urinary catheterisation had shorter survival than those requiring catheterisation later (6.2 years [4.6-7.8] vs 8.5 years [7.6-9.4]; p=0.02). The survival of MSA patients presenting with motor and non-motor symptoms did not differ (p>0.05).

Discussion: Almost one-third of MSA patients presented with non-motor features, which could predate motor symptoms by up to 6 years. Cardiovascular autonomic failure and early urinary catheterisation were predictors of poorer outcomes. A normal supine plasma noradrenaline level in patients presenting with PAF phenotype is a possible autonomic biomarker indicating later conversion to MSA.