Atypical Parkinsonism
Atypical Parkinsonism
What You'll Learn
- MSA: Cerebellar ataxia + autonomic failure (MSA-C) or parkinsonism + autonomic failure (MSA-P); glial cytoplasmic inclusions (GCIs) with α-synuclein; hot cross bun sign and putaminal rim sign; mean survival 6–10 years
- PSP: Vertical supranuclear gaze palsy (downgaze first) + early backward falls within the first year + axial rigidity; hummingbird sign and morning glory sign; 4R tauopathy
- CBD: Asymmetric rigidity + apraxia + alien limb phenomenon + cortical sensory loss + myoclonus; asymmetric frontoparietal atrophy; 4R tauopathy; CBS ≠ CBD
- DLB: Fluctuating cognition + visual hallucinations + parkinsonism + REM sleep behavior disorder; neuroleptic sensitivity; DaTscan abnormal; the “1-year rule” separates DLB from PDD
- Common theme: All show poor or absent sustained levodopa response (except DLB with modest benefit); early red flags distinguish these from idiopathic PD
HighYield Pearls
- Vertical supranuclear gaze palsy + early backward falls (within year 1) = PSP. Single most tested PSP stem — "patient cannot look down at the plate"
- Cerebellar ataxia + autonomic failure = MSA-C; akinetic-rigid parkinsonism + autonomic failure = MSA-P. Per MDS 2022: clinically established MSA requires autonomic dysfunction plus poorly levodopa-responsive parkinsonism or cerebellar syndrome, supportive features, and an MRI marker; clinically probable MSA requires at least two of autonomic dysfunction, parkinsonism, and cerebellar syndrome, plus at least one supportive feature (MRI not required)
- Alien limb + asymmetric apraxia + cortical sensory loss = CBS (clinical). Only ~25–50% of CBS patients have CBD pathology at autopsy — CBS ≠ CBD
- Fluctuating cognition + visual hallucinations + RBD + parkinsonism = DLB. Probable DLB = ≥2 core clinical features OR 1 core feature + ≥1 indicative biomarker; well-formed visual hallucinations are the single biggest distinguisher from AD
- NEVER give haloperidol/typical antipsychotics in DLB. Severe neuroleptic sensitivity → NMS → death; use quetiapine or pimavanserin if absolutely needed
- Levodopa response is the key initial filter: excellent + sustained = PD; modest = DLB; poor/transient = MSA-P; absent = PSP/CBD
- MIBG cardiac scintigraphy: reduced uptake in PD/DLB (postganglionic denervation); preserved in MSA (preganglionic) — can support the distinction between MSA and PD/DLB (performance imperfect; US availability variable)
- DBS is NOT indicated in MSA, PSP, CBD, or DLB — robust sustained levodopa response is required for PD DBS candidacy
- 1-year rule: dementia onset ≤1 year of parkinsonism = DLB; >1 year after = PDD (same pathology, clinical distinction)
- Inspiratory stridor in a parkinsonian patient = MSA until proven otherwise (sudden death risk; ~30% of MSA)
🔍 Quick ReferenceImaging · Clinical · Pathology
Imaging signs
- Hummingbird sign / penguin sign (sagittal midbrain atrophy) → PSP
- Morning glory sign (axial midbrain — concave lateral margin) → PSP
- Midbrain-to-pons ratio <0.52 on midsagittal MRI → PSP (normal ≈0.6)
- Hot cross bun sign (cruciform pontine T2 hyperintensity) → MSA-C (also seen in SCA2/3/7)
- Putaminal rim sign (hyperintense lateral putaminal margin on T2) → MSA-P (1.5T more specific)
- Putaminal atrophy + T2 hypointensity → MSA-P
- Cingulate island sign on FDG-PET (cingulate preservation amid posterior hypometabolism) → DLB
- Asymmetric frontoparietal atrophy contralateral to affected limb → CBD
- Hippocampal preservation on MRI (relative to AD) → DLB
Clinical signs
- Applause sign (cannot stop clapping after 3 claps) → PSP frontal dysfunction
- Rocket sign (recklessly rising from chair without checking environment) → PSP
- "Surprised facies" / frontalis overactivity → PSP (compensating for limited upgaze)
- Retrocollis (extended neck) → PSP (vs. flexed posture of PD)
- Square wave jerks on primary gaze fixation → PSP
- Doll’s eyes intact despite gaze palsy → PSP supranuclear lesion (VOR bypasses supranuclear pathways)
- Alien limb phenomenon (limb “acts on its own”) → CBS
- Pisa syndrome (sustained lateral truncal lean) → MSA, PD
- Inspiratory stridor → MSA (vocal cord abductor paralysis)
- Neuroleptic sensitivity (severe reaction to low-dose antipsychotic) → DLB
- REM sleep behavior disorder preceding parkinsonism by years → α-synucleinopathy (DLB, PD, MSA)
Pathology hallmarks
- Glial cytoplasmic inclusions (GCIs) in oligodendrocytes (α-synuclein) → MSA
- Tufted astrocytes + 4R NFTs + coiled bodies → PSP
- Astrocytic plaques + ballooned neurons (4R tau) → CBD
- Cortical Lewy bodies (neuronal α-synuclein) → DLB
- Brainstem Lewy bodies in SN pars compacta → PD
Red Flags for Atypical Parkinsonism
When to Suspect “Parkinson-Plus”
- Early falls (within first year) — especially backward falls (PSP)
- Poor or absent levodopa response after adequate trial (up to 1000 mg/day, or maximum tolerated dose, for ≥1 month)
- Symmetric onset — PD is classically asymmetric, but both MSA and PSP can also present asymmetrically; symmetric onset should raise suspicion but does not exclude PD
- Early severe autonomic failure — orthostatic hypotension, urinary retention/incontinence, erectile dysfunction (MSA)
- Vertical gaze palsy — especially downgaze limitation (PSP)
- Alien limb phenomenon — involuntary purposeful movements of a limb (CBD)
- Early dementia (<1 year from motor onset) with visual hallucinations (DLB)
- Rapid progression — wheelchair-bound within 5 years
- Cerebellar signs (gait ataxia, dysarthria, nystagmus) — MSA-C
Red Flags Summary Table
| Red Flag | Most Suggestive Of |
|---|---|
| Early backward falls | PSP |
| Vertical supranuclear gaze palsy | PSP |
| Severe early autonomic failure | MSA |
| Cerebellar ataxia + parkinsonism | MSA-C |
| Alien limb phenomenon | CBD |
| Asymmetric apraxia + cortical sensory loss | CBD |
| Early visual hallucinations + fluctuating cognition | DLB |
| REM sleep behavior disorder + parkinsonism | DLB (also MSA, PD) |
| Symmetric akinetic-rigid syndrome | MSA-P or PSP |
| Inspiratory stridor | MSA |
💎 Board Pearl
- Falls within the first year + poor levodopa response = not PD. In PD, falls typically occur ≥5 years into the disease. Early falls are the single strongest predictor of atypical parkinsonism, especially PSP
Multiple System Atrophy (MSA)
Overview & Subtypes
- α-Synucleinopathy — deposits in oligodendrocytes (GCIs), not neurons
- Mean onset: 50–60 years; no sex predominance; mean survival 6–10 years
| Feature | MSA-C (Cerebellar) | MSA-P (Parkinsonian) |
|---|---|---|
| Motor phenotype | Cerebellar ataxia (gait > limb), scanning dysarthria, nystagmus | Akinetic-rigid parkinsonism, often symmetric; jerky postural/action tremor with a myoclonic component — classic pill-rolling rest tremor is uncommon |
| Prevalence | More common in East Asian populations | More common in Western populations |
| Key MRI finding | Hot cross bun sign (cruciform pontine hyperintensity on T2) | Putaminal atrophy with T2/iron-related hypointensity and a hyperintense lateral putaminal rim (best at 1.5T; rim alone can be a normal finding at 3T) |
| Levodopa response | Poor or absent | Transient modest response possible; never sustained |
Autonomic Failure
- Required for clinically established MSA (MDS 2022); for clinically probable MSA, autonomic dysfunction is one of three core domains (with parkinsonism and cerebellar syndrome) and only two of three need be present
- Orthostatic hypotension: ≥20 mmHg systolic or ≥10 mmHg diastolic drop within 3 min of standing (threshold for clinically probable MSA); ≥30/≥15 within 3 min for clinically established MSA
- Supine hypertension — frequently coexists with OH in MSA; complicates pharmacologic management of orthostasis
- Urogenital dysfunction: Urinary incontinence/retention (early), erectile dysfunction in men (often presenting symptom)
- Inspiratory stridor: Vocal cord abductor paralysis; ~30% of MSA; risk of sudden death
Diagnostic Criteria (MDS 2022)
- Clinically established MSA: Autonomic failure (OH ≥30/15 mmHg within 3 min OR unexplained urinary incontinence with erectile dysfunction in males <60) + poorly levodopa-responsive parkinsonism (MSA-P) or cerebellar syndrome (MSA-C) + ≥2 supportive clinical/imaging features
- Clinically probable MSA: at least two of three core domains — autonomic dysfunction (lower OH threshold ≥20/10 mmHg within 3 min, or other autonomic feature), parkinsonism, and cerebellar syndrome — plus at least one supportive clinical feature (e.g., stridor, rapid progression). MRI marker is NOT required for clinically probable MSA.
- Neuropathologically confirmed: GCIs with α-synuclein in widespread CNS distribution
💎 Board Pearl
- GCIs (glial cytoplasmic inclusions) = MSA. α-Synuclein in oligodendrocytes, not neurons — the defining pathological distinction from PD/DLB (neuronal Lewy bodies)
- Hot cross bun sign = MSA-C; putaminal rim sign = MSA-P — the hot cross bun sign is highly suggestive of MSA-C but is also seen in some spinocerebellar ataxias (SCA2, SCA3, SCA7)
- Inspiratory stridor in a parkinsonian patient = MSA until proven otherwise
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