What is the appropriate diagnostic workup and symptomatic treatment plan for a middle‑aged patient with suspected multiple system atrophy presenting with orthostatic hypotension, neurogenic bladder, parkinsonian features, cerebellar ataxia, depression, and mild cognitive impairment?

Multiple System Atrophy: Diagnostic Workup and Symptomatic Management

Diagnostic Workup

The diagnostic evaluation must distinguish MSA from Pure Autonomic Failure, Parkinson's disease, and other synucleinopathies through systematic assessment of motor, autonomic, and imaging features. 1, 2

Clinical Examination Priorities

• Confirm true parkinsonism by documenting bradykinesia and rigidity (present in 87% of MSA cases), distinguishing this from other movement abnormalities that may mimic parkinsonism 2
• Document orthostatic hypotension with sustained drop in systolic BP ≥20 mmHg or diastolic BP ≥10 mmHg within 3 minutes of standing 1
• Assess for cerebellar signs including ataxia, dysmetria, and intention tremor, which define MSA-cerebellar subtype 2, 3
• Evaluate for pyramidal signs (hyperreflexia, extensor plantar responses) which support MSA diagnosis 1, 4

Neuroimaging Strategy

Brain MRI without contrast is the preferred initial imaging modality and should be obtained in all suspected MSA cases 2, 3

• Look for olivopontocerebellar atrophy with predominant cerebellar and brainstem volume loss characteristic of MSA-C 3
• Assess for putaminal atrophy and signal changes on T2-weighted sequences 2
• MRI provides superior posterior fossa visualization compared to CT and can detect subtle atrophy patterns 3

Dopamine transporter (DaT) SPECT imaging should be obtained when parkinsonism is present 2

• Abnormal DaTscan showing decreased striatal uptake supports MSA diagnosis but cannot distinguish MSA from Parkinson's disease, PSP, or CBD 2
• A normal DaTscan essentially excludes all parkinsonian syndromes including MSA 2
• If DaTscan is normal but clinical suspicion remains high, reassess for true bradykinesia versus other movement abnormalities and consider repeat imaging in 6-12 months 2

Autonomic Function Testing

Referral for formal autonomic evaluation is reasonable (Class IIa recommendation) in patients with suspected neurodegenerative disease presenting with orthostatic hypotension to improve diagnostic and prognostic accuracy 1

Excluding Alternative Diagnoses

• Test for autoimmune cerebellitis if cerebellar ataxia is prominent: obtain coeliac antibodies, anti-GQ1b, and vitamin E levels 2
• Consider genetic testing for spinocerebellar ataxias if cerebellar predominance exists without true parkinsonism 2
• Exclude secondary causes including diabetes mellitus, amyloidosis, kidney/liver failure, alcohol abuse, and medication effects (antihypertensives, diuretics, tricyclic antidepressants, phenothiazines, levodopa) 1
• Always exclude posterior fossa mass lesions, tumors, and paraneoplastic syndromes before attributing atrophy to primary degenerative disease, as these are treatable and directly impact mortality 3

Symptomatic Treatment Plan

Orthostatic Hypotension Management

The therapeutic goal is to minimize postural symptoms rather than restore normotension. 5

Non-pharmacologic measures (implement first): 5, 6

• Ensure adequate salt intake (6-10 grams daily) 6
• Use compressive garments over legs and abdomen 5
• Encourage physical activity and exercise to avoid deconditioning 5
• Volume repletion with fluids (2-2.5 liters daily) 6
• Elevate head of bed 30-45 degrees to reduce nocturnal hypertension 6
• Avoid medications that aggravate hypotension 5

Pharmacologic treatment: 5, 6

• Midodrine (FDA-approved): Start 2.5-5 mg three times daily, titrate to 10 mg three times daily 5, 6
• Droxidopa (FDA-approved): Alternative agent for orthostatic hypotension 5
• Fludrocortisone 0.1-0.2 mg daily may be added if midodrine insufficient 6

Parkinsonian Features

Trial levodopa/carbidopa despite limited expectations, as 40-60% of MSA patients with predominant parkinsonian features show some response. 7, 6

• Start carbidopa/levodopa 25/100 mg three times daily, titrate to 25/250 mg three to four times daily 6
• Response is typically partial and diminishes over time due to striatal degeneration 8, 7
• Critical caveat: Levodopa may worsen orthostatic hypotension, requiring careful balance between motor and autonomic management 6, 7
• Dopamine agonists and amantadine are not more effective than levodopa 7

Neurogenic Bladder

Urinary symptoms require staged approach based on predominant dysfunction: 6, 4

• For urinary urgency/frequency: Oxybutynin 5 mg twice daily or tolterodine 2 mg twice daily 6
• For urinary retention: Intermittent self-catheterization is preferred over indwelling catheter to reduce infection risk 6
• For nocturia: Desmopressin 0.1-0.2 mg at bedtime (monitor sodium levels) 6
• Urology consultation for complex cases or consideration of suprapubic catheter 6

Cerebellar Ataxia

No effective pharmacologic treatment exists for cerebellar symptoms in MSA. 8, 9

• Focus on physical therapy to maintain mobility and prevent falls 6, 9
• Assistive devices (walker, wheelchair) as disease progresses 6
• Occupational therapy for activities of daily living adaptations 6

Depression and Cognitive Impairment

Treat depression with SSRIs as first-line agents: 6

• Sertraline 50-200 mg daily or citalopram 20-40 mg daily 6
• Avoid tricyclic antidepressants as they worsen orthostatic hypotension 1

For mild cognitive impairment: 5

• Cognitive impairment in MSA is typically mild and does not require cholinesterase inhibitors 6
• If cognitive symptoms are prominent, reconsider diagnosis (Lewy body dementia or Alzheimer's disease may be present) 1

Critical Management Pitfalls

• Monitor for supine hypertension when treating orthostatic hypotension; elevating head of bed and avoiding late-day doses of pressor agents helps 6
• Balance motor and autonomic treatments: Levodopa improves parkinsonism but worsens orthostatic hypotension 6, 7
• Recognize that MSA has mean disease duration of 6 years with progressive disability; early palliative care discussions are appropriate 3
• Multidisciplinary team approach involving neurology, urology, physical therapy, and primary care optimizes symptom management throughout disease course 6, 9