Parkinson Disease
Medicine · Neurology · lean revision notes
Parkinson Disease
Parkinson disease (PD) is the second commonest neurodegenerative disorder after Alzheimer disease and the prototype akinetic-rigid (hypokinetic) movement disorder. The core lesion is progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) with intracytoplasmic Lewy bodies (aggregated alpha-synuclein). For NEET PG, the highest-yield themes are the TRAP tetrad, the pathology (Lewy body, alpha-synuclein, neuromelanin loss), levodopa pharmacology, and how PD is distinguished from "Parkinson-plus" syndromes.
Definition & classification
Parkinsonism is a clinical syndrome defined by bradykinesia plus at least one of rest tremor or rigidity. Parkinson disease is the commonest cause of parkinsonism (idiopathic, ~80% of cases).
Broad classification of parkinsonism:
| Category | Examples | Key discriminator |
|---|---|---|
| Primary (idiopathic) | Parkinson disease | Asymmetric onset, rest tremor, excellent levodopa response |
| Parkinson-plus (atypical) | PSP, MSA, CBD, DLB | Early falls/dementia/autonomic failure, poor levodopa response |
| Secondary | Drug-induced, vascular, post-encephalitic, toxin (MPTP, manganese, CO), NPH | History of offending drug/insult; often symmetric |
| Heredodegenerative | Wilson disease, Huntington (rigid/juvenile), SCA | Young patient, family history, systemic clues |
High-yield: The single most useful bedside feature separating idiopathic PD from Parkinson-plus syndromes is a sustained, dramatic response to levodopa along with asymmetric onset and a resting tremor. Parkinson-plus syndromes respond poorly.
Etiology & risk factors
PD is largely sporadic; aetiology is multifactorial (genetic susceptibility + environment + ageing).
- Age is the dominant risk factor (mean onset ~60 years).
- Environmental: pesticide/herbicide exposure (rotenone, paraquat), rural living, well-water, MPTP (a meperidine analogue contaminant that destroys SNpc neurons via MPP+ inhibiting complex I).
- Protective associations (classically tested): cigarette smoking and caffeine/coffee are inversely associated with PD risk.
- Genetic (young-onset/familial):
- SNCA (alpha-synuclein) — autosomal dominant.
- LRRK2 (dardarin) — commonest autosomal dominant; late onset, mimics sporadic PD.
- Parkin (PARK2), PINK1, DJ-1 — autosomal recessive, young-onset PD; Parkin-related PD often shows no Lewy bodies.
- GBA (glucocerebrosidase) mutations — important risk gene, link with Gaucher disease.
High-yield: LRRK2 is the commonest gene in autosomal dominant PD; Parkin is the commonest cause of autosomal recessive/young-onset PD.
Pathophysiology
The basal ganglia regulate movement through balanced direct (facilitatory) and indirect (inhibitory) pathways, both modulated by dopamine from the SNpc.
- Dopamine excites the direct pathway (via D1) and inhibits the indirect pathway (via D2).
- Loss of nigrostriatal dopamine → underactive direct + overactive indirect pathway → excess inhibitory output from GPi/SNr to the thalamus → reduced thalamocortical drive → hypokinesia/bradykinesia.
Stepwise cascade:
SNpc dopaminergic neuron loss → striatal dopamine depletion → ↓ direct + ↑ indirect pathway → ↑ GPi/SNr inhibitory output → ↓ thalamic excitation of motor cortex → bradykinesia, rigidity, tremor
Pathological hallmarks:
- Loss of pigmented (neuromelanin-containing) neurons in SNpc → gross pallor of the substantia nigra.
- Lewy bodies: eosinophilic intracytoplasmic inclusions with a dense core and pale halo; main component is alpha-synuclein (also ubiquitin). Lewy neurites in processes.
- Symptoms appear only after ~50–60% of SNpc neurons and ~70–80% of striatal dopamine are lost — hence the long preclinical phase.
High-yield: Lewy body = aggregated alpha-synuclein; PD is therefore an alpha-synucleinopathy (along with MSA and DLB). PSP and CBD are tauopathies.
Braak staging proposes that alpha-synuclein pathology ascends caudo-rostrally: olfactory bulb/medulla (premotor — anosmia, REM sleep behaviour disorder, constipation) → midbrain SNpc (motor stage) → neocortex (dementia stage).
Clinical features
Cardinal motor features — mnemonic TRAP
| Feature | Description / exam clue |
|---|---|
| Tremor | Rest tremor, 4–6 Hz, "pill-rolling", asymmetric, decreases with action, increases with stress/walking; classic first symptom |
| Rigidity | Increased tone throughout range; "cogwheel" (rigidity + tremor) or "lead-pipe"; reinforced by Froment manoeuvre |
| Akinesia/bradykinesia | Slowness + poverty of movement; the mandatory feature for diagnosis; decrementing amplitude on repetitive tasks |
| Postural instability | Loss of righting reflexes → falls; a late feature (early falls suggest PSP) |
Supportive/other features:
- Face & speech: masked facies (hypomimia), reduced blink, hypophonia, monotonous speech, drooling.
- Gait: stooped posture, reduced arm swing (early & asymmetric), short shuffling steps, festination, freezing of gait, en-bloc turning.
- Handwriting: micrographia.
- Glabellar tap (Myerson sign): failure to habituate to repeated tapping.
Non-motor features (often precede motor signs)
- Premotor: hyposmia/anosmia, REM sleep behaviour disorder (acting out dreams — strong predictor), constipation, depression.
- Autonomic: constipation, urinary urgency, orthostatic hypotension (milder than in MSA), seborrhoea.
- Neuropsychiatric: depression, anxiety, apathy; dementia in advanced disease; impulse-control disorders (especially with dopamine agonists).
- Sleep: insomnia, excessive daytime somnolence.
High-yield: PD tremor is a rest tremor that disappears on action; this contrasts with essential tremor (action/postural) and cerebellar tremor (intention).
Diagnosis & investigation of choice
PD is a clinical diagnosis (MDS clinical diagnostic criteria): establish parkinsonism (bradykinesia + rest tremor and/or rigidity), then look for supportive criteria, absolute exclusions, and red flags.
Supportive features: clear levodopa responsiveness, levodopa-induced dyskinesia, rest tremor, olfactory loss.
Red flags suggesting an alternative: early falls (<3 yr), early severe autonomic failure, rapid progression, symmetric onset, early dementia, supranuclear gaze palsy, poor levodopa response, cerebellar signs.
Investigations (mainly to exclude mimics, not to confirm PD):
| Investigation | Role / finding |
|---|---|
| Routine MRI brain | Usually normal in PD; used to exclude vascular parkinsonism, NPH, structural lesions |
| DaTscan (¹²³I-FP-CIT SPECT) | Reduced striatal presynaptic dopamine transporter uptake; separates degenerative parkinsonism (PD, MSA, PSP) from essential tremor / drug-induced parkinsonism (normal scan) |
| Serum ceruloplasmin, slit-lamp, 24-h urinary copper | Exclude Wilson disease in young-onset (<50 yr) |
| "Levodopa challenge" | Marked improvement supports PD |
| Olfactory testing | Hyposmia supports PD over Parkinson-plus |
High-yield: DaTscan cannot distinguish PD from Parkinson-plus (both show reduced uptake) but does distinguish degenerative parkinsonism from essential tremor and drug-induced parkinsonism (normal DaTscan).
MRI clues in Parkinson-plus:
- PSP: midbrain atrophy → "hummingbird"/penguin sign (sagittal); "Mickey Mouse" / morning-glory on axial.
- MSA: "hot cross bun" sign in pons; putaminal rim.
Management
Goals: symptomatic relief and quality of life. There is no proven neuroprotective/disease-modifying therapy yet. Treat when symptoms cause functional impairment.
Drug of choice & pharmacology
| Class / drug | Mechanism | Notes & exam points |
|---|---|---|
| Levodopa + carbidopa (DOC, most effective) | Dopamine precursor; carbidopa is a peripheral DOPA-decarboxylase inhibitor that ↓ peripheral conversion, ↓ nausea, allows more L-dopa into CNS | Most efficacious for bradykinesia/rigidity; motor fluctuations & dyskinesias with long-term use |
| Dopamine agonists — pramipexole, ropinirole (non-ergot); bromocriptine, cabergoline (ergot) | Direct D2/D3 stimulation | First-line in younger patients to delay levodopa; cause impulse-control disorders, somnolence, hallucinations; ergots → fibrosis/valvulopathy |
| MAO-B inhibitors — selegiline, rasagiline | ↓ central dopamine breakdown | Mild benefit; useful early/adjunct; selegiline metabolised to amphetamine |
| COMT inhibitors — entacapone, tolcapone | Block peripheral L-dopa breakdown → ↑ "on" time | Adjunct for wearing-off; tolcapone → hepatotoxicity; harmless orange urine |
| Anticholinergics — trihexyphenidyl, benztropine | Restore ACh–dopamine balance | Best for tremor-predominant young patients; avoid in elderly (confusion, glaucoma, retention) |
| Amantadine | NMDA antagonist + dopamine release | Useful for levodopa-induced dyskinesia; livedo reticularis, ankle oedema |
| Apomorphine (s.c.) | Potent dopamine agonist | Rescue for sudden "off" episodes; very emetogenic |
| Istradefylline | Adenosine A2A antagonist | Adjunct for off-time |
Practical age-based start (common teaching):
- Younger (<60–65 yr), milder disease → start dopamine agonist or MAO-B inhibitor to spare levodopa and delay dyskinesia.
- Older patients / significant disability / cognitive concern → start levodopa–carbidopa (best efficacy, lower neuropsychiatric/impulse-control risk).
- Tremor-predominant young → anticholinergic.
High-yield: Levodopa is the most effective symptomatic drug, but chronic use causes motor fluctuations (wearing-off, on-off) and dyskinesias; dopamine agonists are used early in the young to postpone this. Take levodopa on an empty stomach (protein/large neutral amino acids compete for absorption and the carrier).
Surgical / device therapy
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus interna (GPi) is the key surgical option.
Indications for DBS:
- Advanced PD with disabling motor fluctuations / dyskinesias despite optimal medical therapy.
- Levodopa-responsive disease (responsiveness predicts DBS benefit).
- Medication-refractory tremor.
- Absence of significant dementia or active psychiatric illness, reasonable general health.
High-yield: A good levodopa response is the best predictor of a good DBS outcome; STN-DBS allows reduction of drug dosage. DBS does not help levodopa-resistant features (gait freezing, postural instability, dementia, autonomic failure).
Other supportive care: physiotherapy, speech therapy (LSVT), occupational therapy, exercise; treat depression and constipation; manage orthostatic hypotension.
Complications
- Motor: wearing-off, unpredictable on-off phenomenon, peak-dose dyskinesias, freezing, falls/fractures.
- Neuropsychiatric: PD dementia (when dementia follows established motor PD, vs DLB where dementia is early), depression, psychosis/hallucinations (worsened by dopaminergic drugs — treat with quetiapine or clozapine, avoid typical antipsychotics), impulse-control disorders.
- Autonomic: orthostatic hypotension, constipation, urinary dysfunction.
- Dopamine agonist withdrawal syndrome; Parkinsonism-hyperpyrexia syndrome (NMS-like) on abrupt withdrawal of dopaminergic drugs.
- Aspiration pneumonia (leading cause of death), immobility complications.
High-yield: For drug-induced psychosis in PD use quetiapine or clozapine (low D2 affinity). Never give typical antipsychotics (haloperidol) or metoclopramide — they worsen parkinsonism.
Key differentials
Parkinson-plus syndromes
| Disorder | Distinguishing features | Pathology |
|---|---|---|
| PSP (Steele-Richardson-Olszewski) | Vertical supranuclear gaze palsy (down-gaze), early backward falls, axial rigidity, "surprised" facies; hummingbird sign | Tauopathy |
| MSA | Early autonomic failure (orthostatic hypotension, urinary), cerebellar (MSA-C) or parkinsonian (MSA-P) signs; hot-cross-bun sign | Alpha-synucleinopathy (glial cytoplasmic inclusions) |
| CBD | Marked asymmetry, apraxia, alien limb, cortical sensory loss, myoclonus | Tauopathy |
| DLB | Dementia early/within 1 yr of motor signs, fluctuating cognition, visual hallucinations, neuroleptic sensitivity; REM sleep behaviour disorder | Alpha-synucleinopathy |
High-yield mnemonic for Parkinson-plus pathology: "PSP & CBD = Tau; PD, MSA, DLB = synuclein."
Other tremor/parkinsonism mimics
- Essential tremor: bilateral action/postural tremor, head/voice involvement, family history, improves with alcohol and propranolol/primidone; normal DaTscan.
- Drug-induced parkinsonism: symmetric, offending drugs = antipsychotics, metoclopramide, prochlorperazine, sodium valproate, flunarizine; normal DaTscan; reversible.
- Vascular ("lower-body") parkinsonism: gait-predominant, stepwise, poor levodopa response, vascular risk factors.
- Normal pressure hydrocephalus: Hakim triad = gait apraxia + dementia + incontinence ("wet, wacky, wobbly").
- Wilson disease: young, Kayser-Fleischer rings, hepatic/psychiatric features, low ceruloplasmin.
Tremor comparison
| Type | When present | Frequency | Classic cause |
|---|---|---|---|
| Rest | At rest, abolished by action | 4–6 Hz | Parkinson disease |
| Postural/action | Limb held against gravity / movement | 5–10 Hz | Essential tremor, physiological |
| Intention | Worsens approaching target | Variable | Cerebellar disease |
Recently asked / exam angle
- Image-based: Lewy body histology (eosinophilic inclusion, halo) → "alpha-synuclein"; midbrain hummingbird sign → PSP; hot-cross-bun sign → MSA.
- Pharmacology one-liners: role of carbidopa (peripheral DOPA-decarboxylase inhibitor, doesn't cross BBB), entacapone (COMT inhibitor) for wearing-off, amantadine for dyskinesia, take levodopa on empty stomach.
- MPTP mechanism (MPP+ → complex I inhibition → selective SNpc toxicity) — classic toxicology link.
- DaTscan: normal in essential tremor & drug-induced; abnormal in degenerative parkinsonism.
- DBS target = STN (most common) / GPi; best predictor of outcome = levodopa responsiveness.
- Genetics: LRRK2 (AD), Parkin (AR/young-onset), alpha-synuclein/SNCA, GBA.
- "Antipsychotic safe in PD psychosis" → quetiapine/clozapine; avoid haloperidol.
- Drug-induced parkinsonism culprits, especially metoclopramide and flunarizine.
- Differentiating early dementia (DLB) vs early gaze palsy/falls (PSP) vs early autonomic failure (MSA).
Rapid revision
- PD = degeneration of SNpc dopaminergic neurons + Lewy bodies (alpha-synuclein); an alpha-synucleinopathy.
- Cardinal features = TRAP: Tremor (rest, 4–6 Hz, pill-rolling), Rigidity (cogwheel), Akinesia/bradykinesia (mandatory), Postural instability (late).
- Symptoms appear after ~50–60% SNpc neuron / ~80% striatal dopamine loss.
- Bradykinesia is essential for diagnosing parkinsonism; PD is asymmetric and levodopa-responsive.
- Levodopa + carbidopa = most effective drug; long-term → motor fluctuations + dyskinesias; give on empty stomach.
- Dopamine agonists (pramipexole/ropinirole) first-line in the young to delay levodopa; cause impulse-control disorders.
- Amantadine treats levodopa-induced dyskinesia; COMT inhibitors (entacapone) treat wearing-off.
- DaTscan normal in essential tremor & drug-induced parkinsonism; abnormal in degenerative PD.
- PSP = vertical gaze palsy + early falls (hummingbird sign); MSA = autonomic failure (hot-cross-bun); CBD = alien limb; DLB = early dementia + hallucinations.
- Tau = PSP, CBD; synuclein = PD, MSA, DLB.
- DBS target STN/GPi; works only if levodopa-responsive; useless for freezing, dementia, autonomic failure.
- PD psychosis → quetiapine/clozapine; never haloperidol or metoclopramide (worsen parkinsonism).