Pathophysiology and Cardinal Features
Parkinson's pathophysiology: degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) → reduced dopamine in the nigrostriatal pathway → loss of inhibitory control over indirect pathway → increased inhibitory output from basal ganglia → suppression of thalamo-cortical motor circuits → bradykinesia. Lewy bodies (alpha-synuclein aggregates): pathological hallmark; found in remaining SNpc neurons. Cardinal features (TRAP): Tremor (resting, 4–6 Hz, 'pill-rolling' — disappears with movement, worse at rest), Rigidity (cogwheel or lead-pipe; present throughout passive range of motion), Akinesia/Bradykinesia (slowness of movement, reduced arm swing, micrographia, hypomimia 'masked facies'), Postural instability (late feature — falls, festinating gait). Non-motor features: anosmia (often precedes motor symptoms by years), REM sleep behavior disorder (acts out dreams — early marker), autonomic dysfunction (orthostatic hypotension, constipation, seborrhea), depression, dementia (Lewy body dementia).
Parkinson's vs Essential Tremor
Essential tremor: most common movement disorder. Action/postural tremor (worse with movement, better at rest) — opposite of Parkinson's. Most commonly affects hands and head; voice tremor common. Family history in 50%+ (autosomal dominant pattern). No rigidity, no bradykinesia. Treatment: propranolol (first-line), primidone, gabapentin; deep brain stimulation for refractory cases. Parkinson's: resting tremor (improves with movement), pill-rolling quality, associated with rigidity and bradykinesia. Drug-induced parkinsonism: dopamine antagonists (antipsychotics — haloperidol, metoclopramide) block D2 receptors → parkinsonian features. Fully reversible on drug discontinuation. Wilson's disease: liver disease + neuropsychiatric symptoms + Kayser-Fleischer rings + low ceruloplasmin → presents with tremor + dysarthria in young (<40); copper deposition.
Treatment: Levodopa and Adjuncts
Levodopa + carbidopa (Sinemet): most effective treatment. Levodopa crosses BBB → decarboxylated to dopamine in brain. Carbidopa inhibits peripheral decarboxylation (prevents levodopa conversion to dopamine outside CNS, reducing nausea and increasing CNS delivery). Start later in disease for young patients (delay motor fluctuations). Side effects: nausea (first few weeks), orthostatic hypotension, dyskinesias (involuntary movements — late complication of long-term use), 'on-off' fluctuations (unpredictable motor oscillations between functional ('on') and immobile ('off') states with prolonged use), dopamine dysregulation syndrome (compulsive behaviors). Dopamine agonists (pramipexole, ropinirole, rotigotine): directly stimulate D2/D3 receptors. Used as initial therapy in younger patients to delay levodopa. Side effects: compulsive behaviors (gambling, hypersexuality), hallucinations, orthostatic hypotension, somnolence. MAO-B inhibitors (selegiline, rasagiline): inhibit dopamine breakdown, mild symptomatic benefit + possible neuroprotection. COMT inhibitors (entacapone, tolcapone): inhibit catecholamine degradation, extend levodopa duration, reduce 'wearing off'. Deep brain stimulation (DBS): subthalamic nucleus stimulation — most effective for refractory motor symptoms and dyskinesias in advanced disease.