Multiple system atrophy — clinical features, types, diagnosis, prognosis and treatment

Definition. Multiple system atrophy is a sporadic, progressive, adult-onset disorder characterised by autonomic dysfunction, parkinsonism and ataxia in any combination.

Types (textbook nomenclature). Subtypes include striatonigral degeneration (parkinsonian predominant), sporadic olivopontocerebellar atrophy (cerebellar predominant) and Shy–Drager syndrome (autonomic predominant).

Autonomic features and their timing — the key diagnostic clue. Orthostatic hypotension, impotence, urinary incontinence or retention is typically seen before the onset of motor symptoms, or within two years after the onset of motor symptoms. Table 53.2 emphasises severe dysautonomia early in the course of parkinsonism — orthostatic hypotension, urinary disorder, sexual dysfunction and gastrointestinal symptoms.

Motor features. Parkinsonism with a poor or unsustained motor response to levodopa therapy — this poor levodopa response is the single most useful clinical discriminator from idiopathic PD.

Additional neurological signs. There may be cerebellar or corticospinal (pyramidal) signs on physical examination. In Table 53.2 the syndrome is defined by severe dysautonomia plus a pyramidal or cerebellar syndrome.

Orthostatic hypotension — definition and measurement. A fall in systolic BP of 20 mmHg or diastolic BP of 10 mmHg within three minutes of standing. Delayed orthostatic hypotension occurs after six minutes, and some patients require standing for 10 minutes before the fall appears. Asymptomatic orthostatic hypotension is more common than the symptomatic form, and even when asymptomatic it predicts falls, cerebrovascular and cardiovascular disease and all-cause mortality.

Context among neurogenic causes of orthostatic hypotension. The commonest neurogenic causes are pure autonomic failure (PAF), Parkinson's disease with autonomic failure, and MSA. PAF is idiopathic and sporadic with widespread autonomic failure and reduced supine plasma noradrenaline; some PAF patients later manifest MSA. In all three there is decreased sympathetic and parasympathetic innervation of cardiac and extra-cardiac autonomic receptors. Orthostatic hypotension affects 30–40% of PD patients, against a pooled prevalence of 22% in community-dwelling older adults.

Epidemiology and place among the Parkinson-plus syndromes. MSA is listed among the causes very rarely observed as very late-onset parkinsonism — important, because in a very old patient with parkinsonism, drug-induced, vascular, PSP and Lewy body causes are far more likely.

Diagnosis. Diagnosis is clinical, resting on the triad of early severe dysautonomia + levodopa-unresponsive parkinsonism + cerebellar or pyramidal signs. Response to levodopa can be tested formally by the levodopa challenge (150–250 mg fasting, assessed every 30 minutes for two to three hours). Ioflupane SPECT is abnormal but does not separate MSA from PD. The differential includes PSP, corticobasal degeneration, dementia with Lewy bodies, vascular parkinsonism and normal pressure hydrocephalus.

Treatment — symptomatic only. Give an adequate trial of levodopa although the response is poor or unsustained. Treat orthostatic hypotension with droxidopa, midodrine, fludrocortisone and elastic venous compression, together with physical manoeuvres that reduce postural hypotension, adequate salt and fluid, head-up tilt at night, and withdrawal of drugs that worsen orthostasis — alpha blockers, nitrates, diuretics, calcium channel blockers, tricyclics and antiparkinsonian drugs. Manage bladder dysfunction (solifenacin has low brain penetration; catheterisation for retention), constipation, drooling with botulinum toxin, and dysphagia and dysarthria with speech and swallow therapy. Provide falls prevention, rehabilitation and caregiver support. Deep brain stimulation is not indicated.

MDS 2022 diagnostic criteria and imaging biomarkers. The Movement Disorder Society criteria for MSA (Wenning et al., Mov Disord 2022) replaced the 2008 consensus and define four levels of certainty — neuropathologically established, clinically established, clinically probable, and the research category of possible prodromal MSA. Nomenclature is now MSA-P (parkinsonian) and MSA-C (cerebellar). MRI markers are formally incorporated: the "hot cross bun" sign in the pons (seen in around 75% of MSA-C) and the hyperintense putaminal rim with putaminal atrophy in MSA-P. Brain-bank validation confirmed better early sensitivity, and a 2026 registry re-evaluation found the 2022 criteria gave 94% specificity for clinically established MSA versus 71% for clinically probable.

Prognosis and biomarkers. Prevalence is about 3.4–4.9 per 100,000, with mean onset near 55–60 years; median survival from symptom onset is 6–10 years (natural-history cohorts report 8.9–9.8 years), and severe symptomatic autonomic failure at diagnosis and early dysphagia predict shorter survival. α-Synuclein seed amplification assay in CSF and skin, and fibrillar phosphorylated α-synuclein in Schwann cells as an MSA-specific hallmark, are emerging diagnostic tools, and neurofilament light chain (NfL) is elevated in MSA and predicts mortality (Lancet Neurology 2024; npj Parkinson's Disease 2026). There is still no disease-modifying therapy; agents such as TEV-56286 are in Phase 2.