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Updated: Sep 5, 2025
Comprehensive Autopsy Program for Individuals with Multiple Sclerosis
Published on: July 19, 2019
Diagnosing Premotor Multiple System Atrophy: Natural History and Autonomic Testing in an Autopsy-Confirmed Cohort
Ekawat Vichayanrat1, Fernanda Valerio1, Shiwen Koay1
1From the Autonomic Unit (E.V., F.V., S.K., J.N.-O., V.I.), National Hospital for Neurology and Neurosurgery, Queen Square; Department of Brain Repair and Rehabilitation (E.V., S.K., J.P., C.M., V.I.), Reta Lila Weston Institute for Neurological Studies (E.D.P.-F., N.Q., Y.M., J.H., T.W.), and Queen Square Brain Bank for Neurological Disorders (E.D.P.-F., N.Q., Y.M., J.H., T.W.), UCL Queen Square Institute of Neurology; Department of Uro Neurology (J.P.), National Hospital for Neurology and Neurosurgery; Department of Clinical and Movement Neuroscience (V.C., H.H.), and Department of Neuromuscular Diseases (Y.M.), UCL Institute of Neurology, Queen Square, London, United Kingdom; Service of Neurology (H.M., K.B.), Hospital Clinic, Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neuropathology (J.N.-O.), Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan; and The Lindo Wing (C.M.), Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom.
Background And Objectives:
Nonmotor 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 patients with MSA with nonmotor vs 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 patients with MSA with motor and nonmotor 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, sex, time from onset to diagnosis, disease duration, autonomic function tests, and plasma noradrenaline levels were evaluated.
Results:
Forty-seven patients with autopsy-confirmed MSA (age 60 ± 8 years; 28 men) were identified. Time from symptom onset to first autonomic evaluation was 4 ± 2 years, and the disease duration was 7.7 ± 2.2 years. Fifteen (32%) patients presented with nonmotor features including genitourinary dysfunction, orthostatic hypotension, or REM sleep behavior disorder before 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). Patients with MSA with early cardiovascular autonomic dysfunction (within 3 years of symptom onset) had shorter survival compared with 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 catheterization had shorter survival than those requiring catheterization later (6.2 years [4.6-7.8] vs 8.5 years [7.6-9.4]; p = 0.02). The survival of patients with MSA presenting with motor and nonmotor symptoms did not differ (p > 0.05).
Discussion:
Almost one-third of patients with MSA presented with nonmotor features, which could predate motor symptoms by up to 6 years. Cardiovascular autonomic failure and early urinary catheterization 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.
