When to Suspect “Parkinson-Plus”

• Early falls (within first year) — especially backward falls (PSP)
• Poor or absent levodopa response after adequate trial (≥1000 mg/day for ≥3 months)
• Symmetric onset — PD is classically asymmetric; symmetric parkinsonism suggests MSA or PSP
• 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

Overview & Subtypes

• α-Synucleinopathy — deposits in oligodendrocytes (GCIs), not neurons
• Mean onset: 50–60 years; no sex predominance; mean survival 6–10 years

Autonomic Failure

• Required for diagnosis — core feature of both MSA-C and MSA-P
• Orthostatic hypotension: ≥30 mmHg systolic or ≥15 mmHg diastolic drop within 3 min of standing
• 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: Autonomic failure + poorly levodopa-responsive parkinsonism (MSA-P) OR cerebellar ataxia (MSA-C)
• Clinically probable: Parkinsonism or cerebellar ataxia + ≥1 autonomic feature + ≥1 additional feature (MRI changes, stridor, rapid progression)
• Neuropathologically confirmed: GCIs with α-synuclein in widespread CNS distribution

Overview

• 4R tauopathy — neurofibrillary tangles and tufted astrocytes with 4-repeat tau
• Most common atypical parkinsonian syndrome
• Mean onset: 60–70 years; slight male predominance; mean survival 5–8 years
• Key structures: midbrain, subthalamic nucleus, basal ganglia, frontal cortex

PSP Phenotypes

Vertical Supranuclear Gaze Palsy

• Downgaze affected first — then upgaze; horizontal gaze preserved until late
• Supranuclear = voluntary saccades impaired, but oculocephalic reflex (doll’s eyes) intact — brainstem nuclei are spared
• Slow vertical saccades precede frank gaze palsy — test with OKN strip
• Square wave jerks on primary gaze fixation
• Frontalis overactivity (“surprised” facies) — compensatory for limited upgaze

Imaging

• Hummingbird sign (penguin sign): Midbrain atrophy on sagittal MRI
• Morning glory sign: Midbrain atrophy on axial MRI — concavity of lateral midbrain margin
• Midbrain-to-pons ratio <0.52 supports PSP (normal ≈0.6)

Other Key Features

• Early backward falls within first year; reckless gait (“rocket sign” when rising from a chair)
• Axial rigidity > limb rigidity — extended neck (retrocollis), unlike flexed posture of PD
• Pseudobulbar affect — involuntary laughing/crying
• Frontal dysfunction — apathy, impulsivity; applause sign (cannot stop clapping after 3 claps)
• Early dysarthria/dysphagia — spastic > hypokinetic

Overview

• 4R tauopathy — astrocytic plaques (not tufted astrocytes) and ballooned neurons
• Mean onset: 60–70 years; mean survival 6–8 years
• Asymmetric frontoparietal cortical atrophy + basal ganglia degeneration

CBS vs. CBD: Critical Distinction

• Corticobasal syndrome (CBS) = clinical phenotype (bedside diagnosis)
• Corticobasal degeneration (CBD) = pathological diagnosis (autopsy)
• Only ~25–50% of CBS patients have CBD pathology; CBS can be caused by CBD, PSP, AD, FTLD-TDP, or CJD
• CBD pathology can present as CBS, PSP-like syndrome, bvFTD, or non-fluent PPA

Clinical Features of Corticobasal Syndrome

• Asymmetric rigidity + akinesia — markedly asymmetric, often one limb profoundly affected
• Limb apraxia — ideomotor apraxia (cannot pantomime tool use); often the most disabling feature
• Alien limb phenomenon — involuntary purposeful movements; the limb “acts on its own”; patient may physically restrain the limb
• Cortical sensory loss — agraphesthesia, astereognosis with intact primary sensation
• Myoclonus — cortical, stimulus-sensitive; may mimic tremor
• Dystonia — fixed dystonic posturing of affected hand/arm
• No significant levodopa response

Imaging

• Asymmetric frontoparietal cortical atrophy contralateral to the affected side
• FDG-PET: Asymmetric frontoparietal hypometabolism
• DaTscan: Abnormal (asymmetric); confirms dopaminergic deficit but does not differentiate from PD

Overview

• α-Synucleinopathy — cortical and brainstem Lewy bodies (neuronal, unlike GCIs in MSA)
• Second most common neurodegenerative dementia after AD
• Mean onset: 65–80 years; male predominance (~2:1)

Core Features (Need ≥2 for Probable DLB)

• Fluctuating cognition: Pronounced variations in attention/alertness; episodes of staring or unresponsiveness
• Recurrent visual hallucinations: Well-formed, detailed (people, animals); often one of the earliest features
• REM sleep behavior disorder (RBD): Dream enactment; may precede cognitive symptoms by decades
• Parkinsonism: Bradykinesia, rigidity, rest tremor; typically symmetric, less tremor-dominant than PD

Supportive & Indicative Features

• Indicative biomarkers: Abnormal DaTscan, PSG-confirmed RBD, reduced MIBG cardiac uptake
• Supportive: Neuroleptic sensitivity, postural instability, falls, syncope, autonomic dysfunction, hyposmia
• Neuroleptic sensitivity: Severe reactions even to atypical antipsychotics; may cause NMS or death — use quetiapine or pimavanserin if absolutely needed

The 1-Year Rule: DLB vs. PDD

• DLB: Dementia onset before or within 1 year of parkinsonism
• PDD: Dementia onset >1 year after well-established parkinsonism
• Same Lewy body pathology — distinction is clinical/temporal, not pathological

Diagnostic Workup

• DaTscan: Abnormal in DLB; normal in AD — key differentiator
• MIBG cardiac scintigraphy: Reduced in DLB/PD (postganglionic denervation); normal in MSA (preganglionic)
• MRI: Relative hippocampal preservation (unlike AD)
• EEG: Posterior slow-wave activity with periodic fluctuations

MSA vs. PSP vs. CBD vs. DLB vs. PD