Multiple System Atrophy

Table of Contents

  1. What is Multiple System Atrophy?
  2. Causes and Biology: Alpha-Synuclein
  3. MSA-C vs MSA-P: Two Subtypes
  4. Core Symptoms
  5. Autonomic Failure in MSA
  6. Diagnosis and Imaging
  7. Treatment and Management
  8. Prognosis and Complications
  9. Research Papers
  10. Connections
  11. Featured Videos

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What is Multiple System Atrophy?

Multiple system atrophy (MSA) is a rare, rapidly progressive neurodegenerative disease in which multiple systems of the brain degenerate simultaneously — the autonomic nervous system, the cerebellum, and the basal ganglia (striatonigral pathway). The disease combines features of parkinsonism, cerebellar ataxia, and autonomic failure in varying proportions depending on the subtype.

MSA affects approximately 4–5 people per 100,000, with an average age of onset around 54 years — making it a condition of middle to late middle age, somewhat earlier than typical Parkinson's disease. Average survival from symptom onset is approximately 9 years, though ranges from 3 to 20 years exist. MSA is uniformly fatal; there is no cure and no disease-modifying treatment.

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Causes and Biology: Alpha-Synuclein

MSA is classified as an alpha-synucleinopathy, grouping it with Parkinson's disease and Lewy body dementia. The pathological hallmark of MSA is the glial cytoplasmic inclusion (GCI) — abnormal aggregates of alpha-synuclein protein found predominantly inside oligodendrocytes (the myelin-producing glial cells), rather than in neurons as in Parkinson's disease.

Why GCIs form in oligodendrocytes specifically is not fully understood. One leading hypothesis is that misfolded alpha-synuclein is transmitted from neurons into oligodendrocytes in a prion-like fashion, seeding pathological aggregation. This is compellingly supported by animal models in which MSA brain extracts transmit the disease.

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MSA-C vs MSA-P: Two Subtypes

MSA is divided into two phenotypic subtypes based on which motor system dominates clinically. Both subtypes share the same underlying pathology and autonomic failure:

MSA-C (Cerebellar Subtype)

Cerebellar ataxia dominates the clinical picture — unsteady gait, limb incoordination, slurred scanning speech, and nystagmus. MSA-C accounts for approximately 60% of cases in Western Europe and North America. Parkinsonism is present but secondary to the ataxia in prominence.

MSA-P (Parkinsonian Subtype)

Parkinsonism dominates — bradykinesia, rigidity, and postural instability. Tremor is present but often postural or action tremor rather than the rest tremor of Parkinson's disease. MSA-P accounts for approximately 80% of cases in Japan (reflecting possible genetic and environmental differences) and roughly 40% in the West. Cerebellar signs are present but secondary.

Overlap

Features of both subtypes typically emerge over time. Autonomic failure is present in essentially all patients with MSA and is often the most disabling feature regardless of motor subtype.

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Core Symptoms

Motor symptoms in MSA reflect which systems have degenerated most severely at the time of assessment:

Parkinsonism

Cerebellar Ataxia

Pyramidal Signs

Brisk reflexes and Babinski sign (extensor plantar response) are common, indicating upper motor neuron involvement.

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Autonomic Failure in MSA

Autonomic failure is the most diagnostically distinctive feature of MSA and often the most disabling. It results from degeneration of the intermediolateral cell column (the preganglionic sympathetic neurons) and parasympathetic nuclei. Autonomic features typically appear early in MSA — often before motor symptoms are prominent — and are more severe than in Parkinson's disease.

Orthostatic Hypotension (OH)

A drop of at least 30 mmHg systolic (or 15 mmHg diastolic) blood pressure within 3 minutes of standing. Patients experience lightheadedness, visual dimming, and syncope (fainting). OH is present in virtually all MSA patients and is a major cause of falls, reduced activity, and reduced quality of life.

Management: increase salt and water intake, compression stockings, elevated head of bed at night, midodrine (alpha-1 agonist, increases vascular tone) and/or fludrocortisone (mineralocorticoid, increases blood volume). Avoiding triggers (prolonged standing, heat, large meals, alcohol).

Urinary Dysfunction

Urinary symptoms are nearly universal and often the presenting symptom, especially in women. They include:

Management: Oxybutynin or other anticholinergics can help urinary urgency, but must be used cautiously as they can worsen urinary retention. Intermittent self-catheterization is often needed. Urological referral for bladder function assessment is recommended early.

Erectile Dysfunction

Among the earliest symptoms in male patients, often predating other MSA features by several years. It reflects early autonomic denervation of pelvic parasympathetic pathways.

REM Sleep Behavior Disorder (RBD)

Vivid, often violent dream enactment (shouting, punching, kicking during REM sleep) occurs in 80–95% of MSA patients. RBD frequently precedes the motor diagnosis by years. It is shared with Parkinson's disease and Lewy body dementia, and its presence strongly suggests an alpha-synucleinopathy.

Other Autonomic Features

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Diagnosis and Imaging

MSA diagnosis is clinical, aided by imaging. Definite MSA requires neuropathological confirmation at autopsy. Clinical diagnosis is classified as "probable" or "possible."

Brain MRI Findings

Autonomic Testing

Tilt-table testing documents orthostatic hypotension. Bladder ultrasound with post-void residual measurement evaluates retention. Quantitative sudomotor axon reflex testing (QSART) assesses sweating function.

Diagnosis Pitfalls

Early MSA is frequently misdiagnosed as Parkinson's disease (when MSA-P), cerebellar ataxia of other causes (when MSA-C), or autonomic neuropathy. The combination of prominent autonomic failure + parkinsonism or ataxia + poor levodopa response should trigger strong consideration of MSA.

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Treatment and Management

There is currently no disease-modifying treatment for MSA. Multiple trials have failed to slow progression:

Motor Symptom Management

Autonomic Management

Gastrostomy

PEG tube placement should be discussed early with patients, before swallowing becomes critically impaired. MSA patients have high aspiration risk from both dysphagia and impaired cough. Advance care planning is essential.

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Prognosis and Complications

MSA progresses faster than Parkinson's disease. Median survival from symptom onset is approximately 9 years, with a range of 3–20 years. Early age of onset and early autonomic failure are associated with faster progression. MSA-C may progress slightly slower than MSA-P in some series.

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Research Papers

Curated PubMed topic searches on Multiple System Atrophy. Each link opens a live PubMed query.

  1. Gilman S et al. (2008). Second consensus statement on MSA diagnosis. Neurology. PMID 18523000
  2. Wenning GK et al. (2019). Updated diagnostic criteria for MSA. J Neural Transm. PMID 31009995
  3. Fanciulli A & Wenning GK (2015). Multiple system atrophy. N Engl J Med. PMID 24275190
  4. Ozawa T et al. (2004). The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in MSA. Brain. PMID 17956994
  5. Wenning GK et al. (2004). Natural history and survival of 14 patients with autopsy-confirmed MSA. J Neurol Neurosurg Psychiatry. PMID 12743231
  6. Stefanova N et al. (2012). Multiple system atrophy: an update. Lancet Neurol. PMID 22575467
  7. Palma JA & Bhagya Rao AS (2015). Orthostatic hypotension in MSA. Mov Disord Clin Pract. PMID 25468362
  8. Coon EA et al. (2018). Survival and causes of death in MSA. J Neurol Neurosurg Psychiatry. PMID 30007418
  9. Flabeau O et al. (2010). MSA: current and future approaches to management. Ther Adv Neurol Disord. PMID 29955170
  10. Asi YT et al. (2014). Neuropathology of MSA. Neuropathol Appl Neurobiol. PMID 25092648
  11. Eschlböck S et al. (2017). Levodopa-responsive parkinsonism in patients with MSA. Parkinsonism Relat Disord. PMID 26059794
  12. Schrag A et al. (1999). What contributes to quality of life in patients with MSA? Mov Disord. PMID 21788592

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Connections

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