How should multiple system atrophy be diagnosed in a middle‑aged (≈50‑70 yr) adult with progressive autonomic failure (orthostatic hypotension, urinary urgency, erectile dysfunction, constipation), parkinsonism with poor levodopa response, and/or cerebellar ataxia?

Diagnosis of Multiple System Atrophy

Core Diagnostic Framework

Multiple system atrophy (MSA) should be diagnosed using the Movement Disorder Society criteria, which require the presence of autonomic failure (orthostatic hypotension or urinary dysfunction) combined with either poorly levodopa-responsive parkinsonism or cerebellar ataxia, supported by characteristic MRI findings and clinical "red flags." 1, 2, 3

Clinical Diagnostic Categories

The diagnosis operates on three levels of certainty 2, 3:

Clinically Established MSA

• Requires cardiovascular or urological autonomic failure 2
• Plus poorly L-dopa-responsive parkinsonism or cerebellar syndrome 2
• Plus characteristic brain MRI markers (see imaging section below) 2
• Plus supportive MSA red flags 2
• Plus absence of exclusion criteria 2

Clinically Probable MSA

• Requires autonomic failure (orthostatic hypotension with ≥30 mmHg systolic or ≥15 mmHg diastolic drop, or urinary incontinence/urgency) 3, 4
• Plus poorly levodopa-responsive parkinsonism (bradykinesia with rigidity) or cerebellar ataxia 3, 4
• Does not require MRI confirmation 3

Possible MSA

• Requires parkinsonism or cerebellar ataxia 3, 4
• Plus at least one feature suggesting autonomic dysfunction 3
• Plus one additional clinical or neuroimaging abnormality 3

Essential Clinical Features to Document

Autonomic Dysfunction (Present in 83% with urinary symptoms, 75% with orthostatic hypotension) 5

• Orthostatic hypotension: Document blood pressure drop ≥30 mmHg systolic or ≥15 mmHg diastolic within 3 minutes of standing 3
• Urinary dysfunction: Urgency, frequency, incomplete bladder emptying, or incontinence occurring in 83% of cases 5
• Erectile dysfunction in men (often an early feature) 6
• Constipation (less specific but supportive) 6

Motor Features

• Parkinsonism: Bradykinesia and rigidity present in 87% of MSA cases 1
• Poor levodopa response: Less than 30% improvement or transient response only 2, 3
• Cerebellar ataxia: Gait ataxia, limb ataxia, ataxic dysarthria, or cerebellar oculomotor dysfunction 2, 3

MSA "Red Flags" (High Specificity Features)

When two or more of the following six red flag categories are present, specificity is 98.3% and sensitivity is 84.2% for MSA-P diagnosis 7:

• Rapid progression: Disease duration less than 3 years to wheelchair dependence 7
• Poor levodopa response: Less than 30% improvement or benefit lasting less than 1 year 7
• Early postural instability: Falls within the first 3 years 7
• Early bulbar dysfunction: Dysarthria or dysphagia within the first 3 years 7
• Inspiratory sighs or stridor: Respiratory dysfunction 7
• Severe autonomic failure: Early and prominent orthostatic hypotension or urinary incontinence 7

Essential Imaging Studies

MRI Brain Without Contrast (First-Line Imaging)

MRI is the optimal imaging modality and is required for clinically established MSA diagnosis 6, 1, 2:

• MSA-P (parkinsonian variant): Look for putaminal atrophy, T2 hypointensity in the putamen, and hyperintense putaminal rim ("putaminal rim sign") 6
• MSA-C (cerebellar variant): Look for pontine and middle cerebellar peduncle atrophy, T2 hyperintensity in the middle cerebellar peduncles, and the "hot cross bun sign" (cruciform T2 hyperintensity in the pons) 6
• General findings: Disproportionate atrophy of the neostriatum, pons, and cerebellum 6

Dopamine Transporter Imaging (DaTscan/Ioflupane SPECT)

• Abnormal DaTscan shows decreased striatal uptake, confirming nigrostriatal degeneration in MSA 1
• Normal DaTscan essentially excludes MSA and all other parkinsonian syndromes 1
• Critical limitation: Cannot distinguish MSA from Parkinson's disease, PSP, or CBD—all show abnormal uptake patterns 1
• Use when: Clinical diagnosis is uncertain or to exclude non-degenerative causes of parkinsonism 1

CT Head

• Not preferred due to limited soft-tissue characterization compared to MRI 6
• Can demonstrate patterns of regional volume loss but is less sensitive 6
• Reserve for patients who cannot undergo MRI 6

FDG-PET/CT Brain

• Limited evidence for routine use in MSA diagnosis 6
• May show hypometabolism in striatum, brainstem, and cerebellum but not required for diagnosis 6

Diagnostic Algorithm

Step 1: Establish Core Clinical Syndrome

• Document presence of autonomic failure (orthostatic BP measurements, urinary symptoms) 3
• Document presence of parkinsonism (bradykinesia + rigidity) or cerebellar ataxia 3
• Assess levodopa response (trial of carbidopa/levodopa up to 1000-1500 mg/day for at least 3 months) 2, 3

Step 2: Count MSA Red Flags

• Systematically assess all six red flag categories 7
• If ≥2 red flag categories present: High specificity (98.3%) for MSA-P 7

Step 3: Obtain MRI Brain Without Contrast

• Look for characteristic patterns of atrophy and signal abnormalities specific to MSA subtype 6, 1, 2
• If characteristic MRI findings present with autonomic failure + poor levodopa response/cerebellar signs: Diagnosis of clinically established MSA 2

Step 4: Consider DaTscan If Diagnosis Uncertain

• If DaTscan is normal: MSA is excluded 1
• If DaTscan is abnormal: Confirms nigrostriatal degeneration but does not distinguish MSA from PD, PSP, or CBD 1
• If clinical suspicion remains high despite normal DaTscan: Reassess for true bradykinesia/rigidity versus other movement abnormalities, or consider repeat imaging in 6-12 months 1

Step 5: Exclude Alternative Diagnoses

If cerebellar ataxia predominates without true parkinsonism 1:

• Test for coeliac antibodies, anti-GQ1b, vitamin E levels (autoimmune/nutritional causes) 1
• Consider genetic testing for spinocerebellar ataxias (SCA) 1
• Evaluate for paraneoplastic cerebellar degeneration (anti-Yo, anti-Hu antibodies) 6

If symptoms are inconsistent or atypical 1:

• Consider functional neurological disorder 1

Clinical Subtypes and Their Presentations

MSA-P (Parkinsonian/Striatonigral Degeneration)

• Extrapyramidal features predominate: Bradykinesia, rigidity, postural instability 6
• Most common subtype: Majority of MSA cases exhibit parkinsonian symptoms at some stage 6
• Key distinguishing feature: Poor or absent levodopa response 6, 2

MSA-C (Cerebellar/Olivopontocerebellar Atrophy)

• Cerebellar ataxia predominates: Gait ataxia, limb ataxia, dysarthria 6
• MRI findings: Pontine and cerebellar atrophy, "hot cross bun sign" 6

MSA-A (Autonomic/Shy-Drager Syndrome)

• Autonomic dysfunction predominates: Severe orthostatic hypotension, urinary incontinence 6
• Less common subtype 6

Pathological Confirmation (Definite MSA)

• Gold standard: Neuropathologic demonstration of α-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures 3
• MSA is a synucleinopathy with abnormal cytoplasmic inclusions of ubiquitin and α-synuclein in oligodendroglia (not neurons as in Parkinson's disease) 6, 8
• Distinguishes MSA from tauopathies (PSP and CBD) which have tau protein accumulation 6, 5

Critical Diagnostic Pitfalls

Common Misdiagnoses

• Parkinson's disease: MSA has earlier and more prominent autonomic failure, poor levodopa response, and more rapid progression 6, 2, 3
• Progressive supranuclear palsy: PSP has vertical supranuclear gaze palsy and axial rigidity predominance 6
• Corticobasal degeneration: CBD has asymmetric presentation with cortical features (apraxia, alien limb) 6

Age and Progression Considerations

• Typical onset: 55-65 years of age 6
• Mean disease duration: Approximately 6 years from diagnosis (shorter than Parkinson's disease) 6, 5
• Rapid progression is a red flag: Wheelchair dependence within 3 years suggests MSA over PD 7

Levodopa Trial Interpretation

• Adequate trial required: Carbidopa/levodopa up to 1000-1500 mg/day for at least 3 months 2, 3
• Poor response defined as: Less than 30% improvement or benefit lasting less than 1 year 7
• Some MSA patients may have transient modest response initially, but this wanes over time 2