Diagnosis of Multiple System Atrophy (MSA)
Multiple System Atrophy (MSA) is diagnosed through a combination of clinical evaluation of characteristic symptoms, neuroimaging findings, and autonomic function testing, with definitive diagnosis requiring neuropathological confirmation of alpha-synuclein-positive glial cytoplasmic inclusions at autopsy.
Clinical Diagnostic Criteria
The diagnosis of MSA relies on established consensus criteria that categorize patients into three levels of diagnostic certainty:
Definite MSA
- Requires neuropathological demonstration of CNS alpha-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures 1
Probable MSA
- Sporadic, progressive adult-onset disorder including:
- Rigorously defined autonomic failure (orthostatic hypotension)
- PLUS either:
- Poorly levodopa-responsive parkinsonism (MSA-P subtype)
- OR cerebellar ataxia (MSA-C subtype) 1
Possible MSA
- Sporadic, progressive adult-onset disease including:
- Parkinsonism or cerebellar ataxia
- PLUS at least one feature suggesting autonomic dysfunction (e.g., urinary incontinence)
- PLUS one other supporting feature (clinical or neuroimaging) 1
Key Clinical Features to Evaluate
Motor Symptoms
- Parkinsonism: Bradykinesia, rigidity, postural instability, and resting tremor (less common than in Parkinson's disease)
- Cerebellar signs: Gait ataxia, limb ataxia, dysarthria, nystagmus
- Pyramidal signs: Hyperreflexia, extensor plantar responses
Autonomic Dysfunction
- Orthostatic hypotension (≥30 mmHg systolic or ≥15 mmHg diastolic drop within 3 minutes of standing)
- Urinary symptoms: Incontinence, retention, urgency
- Sexual dysfunction: Erectile dysfunction in males
- Constipation
- Anhidrosis or hyperhidrosis
Red Flags for MSA Diagnosis
- Poor or transient response to levodopa therapy
- Early falls and postural instability
- Rapid disease progression
- Early and severe autonomic failure
- Stridor (particularly during sleep)
Diagnostic Investigations
Neuroimaging
- MRI Brain: The optimal imaging modality for MSA diagnosis 2
- MSA-P: Putaminal atrophy, hypointensity on T2-weighted images, "hot cross bun" sign
- MSA-C: Cerebellar and pontine atrophy, middle cerebellar peduncle hyperintensity
- 3T MRI is preferable over 1.5T for better resolution 2
Autonomic Function Testing
- Cardiovascular autonomic testing to document orthostatic hypotension
- Urodynamic studies to evaluate bladder dysfunction
- Sudomotor function tests
Nuclear Medicine Imaging
- Ioflupane SPECT/CT (DaTscan): Demonstrates decreased radiotracer uptake in the striatum, but cannot differentiate MSA from other parkinsonian syndromes 2
- Cardiac sympathetic imaging: MIBG scintigraphy may help differentiate MSA from Parkinson's disease
Other Supporting Tests
- Polysomnography to detect REM sleep behavior disorder and sleep-disordered breathing
- Neurophysiological studies (e.g., sphincter EMG)
Differential Diagnosis
The main differential diagnoses to consider include:
- Parkinson's disease
- Progressive supranuclear palsy (PSP)
- Corticobasal degeneration (CBD)
- Pure autonomic failure
- Spinocerebellar ataxias
- Vascular parkinsonism
Diagnostic Challenges and Pitfalls
Early diagnosis is difficult: Patients may initially present with isolated autonomic failure or motor symptoms, making early diagnosis challenging 3
Misdiagnosis is common: Up to 20-30% of patients diagnosed with MSA in life have a different pathology at autopsy
Atypical features: Some patients may present with features not typically associated with MSA, such as dementia, hallucinations, or vertical gaze palsy 3
Variable levodopa response: While often described as "poorly levodopa-responsive," approximately 40-60% of MSA patients with predominant parkinsonian features may show some response to levodopa, especially early in the disease course 4
Emerging Diagnostic Approaches
- Advanced MRI techniques: Diffusion tensor imaging, voxel-based morphometry
- Fluid biomarkers: Alpha-synuclein in cerebrospinal fluid
- Skin biopsy: Detection of phosphorylated alpha-synuclein deposits
- Retinal imaging biomarkers
By systematically evaluating clinical features and using appropriate diagnostic tests, clinicians can improve the accuracy of MSA diagnosis, which is crucial for proper management, counseling, and potential enrollment in clinical trials.