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

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 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

Overview

• 4R tauopathy — neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies with 4-repeat tau
• Most common Parkinson-plus syndrome (excluding DLB)
• 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 early — brainstem ocular motor nuclei are initially spared (may be lost late in the disease)
• 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 area ratio (midsagittal) <0.52 supports PSP (normal ≈0.6)
• MR Parkinsonism Index (MRPI) >13.55 also supports PSP-RS (combines pons/midbrain areas with middle and superior cerebellar peduncle widths)

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, FTLD-tau (Pick disease), DLB, and rarely 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 (Probable DLB: ≥2 core features, OR 1 core feature + ≥1 indicative biomarker; Possible DLB: 1 core feature without indicative biomarker, OR indicative biomarker without core features)

• 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 Biomarkers (2017 McKeith Criteria)

• Indicative biomarkers: Reduced striatal dopamine transporter uptake on DaTscan (SPECT/PET); PSG-confirmed REM sleep without atonia; reduced ¹²³I-MIBG cardiac scintigraphy uptake
• Supportive biomarkers: Relative preservation of medial temporal lobe on CT/MRI; generalized low uptake on SPECT/PET perfusion with reduced occipital activity (± cingulate island sign on FDG-PET); prominent posterior slow-wave EEG activity with periodic fluctuations in the pre-alpha/theta range
• Supportive clinical features: Neuroleptic sensitivity, postural instability, repeated falls, syncope/transient unresponsiveness, severe autonomic dysfunction, hypersomnia, hyposmia, hallucinations in other modalities, systematized delusions, apathy/anxiety/depression
• 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 (indicative biomarker): Abnormal in DLB; normal in AD — key differentiator
• MIBG cardiac scintigraphy (indicative biomarker): Reduced in DLB/PD (postganglionic denervation); normal in MSA (preganglionic)
• MRI (supportive biomarker): Relative hippocampal/medial temporal lobe preservation (unlike AD)
• EEG (supportive biomarker): Posterior slow-wave activity with periodic fluctuations in the pre-alpha/theta range

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

MSA

• Orthostatic hypotension: Non-pharmacologic first — compression stockings/abdominal binders, head-of-bed elevation (10–20°), increased salt/fluid intake, slow positional changes; pharmacologic — midodrine, droxidopa, fludrocortisone; manage coexisting supine hypertension
• Parkinsonism (MSA-P): Levodopa trial up to 1000 mg/day or maximum tolerated dose — transient/modest benefit in a subset
• Urinary symptoms: Intermittent self-catheterization for retention; antimuscarinics/mirabegron for overactive bladder (caution with cognitive/OH side effects)
• REM sleep behavior disorder: per AASM 2023, both melatonin and clonazepam are conditional first-line options; melatonin often preferred in MSA for safety (caution with clonazepam given falls/OH)
• Stridor: CPAP; tracheostomy in severe cases (sudden death risk)

PSP

• Falls/gait: Physical therapy, gait/balance training, assistive devices, home safety modifications — the cornerstone of management
• Dysphagia/dysarthria: Early speech and swallow evaluation; diet modification; consider PEG when aspiration risk is high
• Levodopa trial: Up to 1000 mg/day or maximum tolerated dose — usually limited benefit but worth a trial
• Pseudobulbar affect: Dextromethorphan-quinidine or SSRIs
• Ocular symptoms: Prism lenses, lubricating drops; botulinum toxin for blepharospasm/eyelid-opening apraxia

CBD

• Myoclonus: Levetiracetam or clonazepam
• Apraxia/limb dystonia: Occupational therapy; botulinum toxin for focal dystonia and painful posturing
• Parkinsonism: Levodopa trial usually disappointing but worth attempting
• Depression/behavioral symptoms: SSRIs; non-pharmacologic strategies for behavior

DLB

• Cognition: Cholinesterase inhibitors — rivastigmine has the strongest evidence; donepezil also effective; memantine adjunct
• Hallucinations/psychosis: Avoid typical antipsychotics (haloperidol) — risk of severe neuroleptic sensitivity reactions, NMS, death; quetiapine if needed; pimavanserin off-label for hallucinations
• REM sleep behavior disorder: per AASM 2023, both melatonin and clonazepam are conditional first-line options; melatonin often preferred in older DLB patients for safety (less cognitive/fall risk)
• Parkinsonism: Cautious levodopa (may worsen hallucinations); avoid dopamine agonists/anticholinergics
• Orthostatic hypotension: Same approach as MSA (midodrine, droxidopa, fludrocortisone)