What is Multiple System Atrophy (MSA)?
Multiple system atrophy is a rare, fatal, adult-onset neurodegenerative disorder characterized by progressive autonomic failure combined with either parkinsonism or cerebellar ataxia, caused by α-synuclein accumulation in oligodendrocytes forming glial cytoplasmic inclusions. 1, 2
Core Disease Characteristics
MSA is a sporadic α-synucleinopathy that typically begins between ages 55-65 years with relentless progression and a median survival of approximately 6 years from diagnosis 1, 3. The disease fundamentally differs from Parkinson's disease and dementia with Lewy bodies because the pathologic α-synuclein aggregates accumulate in oligodendrocytes rather than neurons 4, 3.
Clinical Subtypes and Presentation
MSA manifests in three recognized clinical variants based on predominant motor features 1:
- MSA-P (parkinsonian type): Characterized by striatonigral degeneration with parkinsonism present in 87% of cases, featuring bradykinesia and rigidity with characteristically poor response to levodopa 1
- MSA-C (cerebellar type): Marked by olivopontocerebellar atrophy with cerebellar ataxia in 64% of patients, manifesting as postural instability, dysarthria, and oculomotor dysfunction 1
- MSA-A (autonomic type/Shy-Drager syndrome): Dominated by autonomic failure 1
Cardinal Clinical Features
The disease presents with a characteristic triad 1, 2:
- Autonomic dysfunction (83% with urinary dysfunction, 75% with symptomatic orthostatic hypotension): This includes neurogenic bladder, erectile dysfunction, and severe orthostatic hypotension 1
- Motor impairment: Either parkinsonism or cerebellar ataxia as described above 1
- Additional features: REM sleep behavior disorder and isolated autonomic failure commonly precede motor symptoms 2
Distinguishing Features from Parkinson's Disease
Hyperreflexia is a key diagnostic clue that helps distinguish MSA from idiopathic Parkinson's disease, where deep tendon reflexes are typically normal or decreased 5. Early falls represent another red flag feature that should raise suspicion for MSA rather than Parkinson's disease 1.
Pathophysiology
The neuropathological hallmark consists of glial cytoplasmic inclusions containing misfolded α-synuclein in oligodendrocytes and neurons 4, 3. Selective neuronal loss and atrophy occur in striatonigral and olivopontocerebellar systems, with additional involvement of autonomic brain centers 2, 3. The pathogenic cascade involves myelin and iron dyshomeostasis, neuroinflammation, and mitochondrial dysfunction 3.
Disease Progression
Motor and non-motor symptoms progress rapidly, with significant worsening evident within 12-24 months 6. The UMSARS (Unified Multiple System Atrophy Rating Scale) scores increase by median values of 11-12.5 points over 24 months, with motor symptoms affecting basic daily activities showing the most pronounced deterioration 6. While non-motor symptoms like urinary dysfunction, sexual dysfunction, and sleep difficulties are prevalent and progress, other features such as mood dysfunction may not show clear progression on clinical scales 6.
Diagnostic Approach
Brain MRI is the optimal imaging modality, demonstrating characteristic patterns of regional atrophy that distinguish MSA from Parkinson's disease 1. Ioflupane SPECT/CT shows abnormal dopaminergic depletion patterns, though it cannot differentiate MSA from other parkinsonian syndromes including Parkinson's disease, progressive supranuclear palsy, or corticobasal degeneration 1.
Prognosis and Treatment Landscape
No disease-modifying therapies currently exist, and treatment remains purely symptomatic 4, 7. The multisystem nature of symptoms—particularly motor dysfunction, autonomic failure, and depression—drives quality of life assessments and requires coordinated multidisciplinary management 4. Deep brain stimulation is contraindicated in MSA, as it is only effective in Parkinson's disease patients with good levodopa response 1.
For orthostatic hypotension management, non-pharmacological measures include compression garments, physical counter-pressure maneuvers, acute water ingestion, and increased salt intake 1. Pharmacological options include midodrine, droxidopa, and fludrocortisone, though supine hypertension must be monitored 1.
Research into disease-modifying therapies focuses primarily on synuclein-targeted interventions 4, 7.