Parkinson Disease

Risk factors

• Advancing age (strongest)
• Male sex
• Family history; LRRK2, GBA, SNCA, PARK7, PINK1 mutations (most cases sporadic)
• Pesticide and herbicide exposure (paraquat, rotenone)
• Rural living, well-water consumption (epidemiologic association)
• History of repetitive head trauma

Pathophysiology

Progressive loss of dopaminergic neurons in the substantia nigra pars compacta reduces dopaminergic input to the striatum. The resulting imbalance of the direct and indirect basal ganglia pathways produces a hypokinetic movement disorder. Intracellular alpha-synuclein aggregates (Lewy bodies and Lewy neurites) are the pathologic hallmark and also affect the brainstem, olfactory bulb, and autonomic neurons (explaining hyposmia, REM behavior disorder, and dysautonomia, which often precede motor symptoms).

Clinical presentation

Differential diagnosis

• Essential tremor — Bilateral action/postural tremor of hands and head, family history, improves with alcohol, no bradykinesia or rigidity
• Drug-induced parkinsonism — Antipsychotics (typical and atypical), metoclopramide, prochlorperazine; usually symmetric, no rest tremor, resolves weeks-months after offending drug stopped
• Multiple system atrophy (MSA) — Parkinsonism + early autonomic failure (orthostasis, urinary), cerebellar signs (MSA-C); poor levodopa response; 'hot cross bun' sign on pons MRI
• Progressive supranuclear palsy (PSP) — Early postural instability with backward falls, vertical supranuclear gaze palsy (downgaze first), axial rigidity, hummingbird sign on midbrain MRI
• Corticobasal degeneration — Asymmetric rigidity, apraxia, alien limb phenomenon, cortical sensory loss
• Lewy body dementia (DLB) — Dementia precedes or appears within 1 year of parkinsonism; fluctuating cognition, visual hallucinations, REM behavior disorder, neuroleptic sensitivity
• Vascular parkinsonism — Lower-body predominant ('lower-half parkinsonism'), gait apraxia, vascular risk factors, white matter disease on MRI, poor levodopa response
• Normal pressure hydrocephalus — Magnetic gait, urinary incontinence, cognitive impairment; ventriculomegaly out of proportion to atrophy

Diagnostic workup

Diagnostic algorithm

Treatment

Complications

• Levodopa-induced dyskinesia (chorea, dystonia) with chronic use
• Motor fluctuations: wearing-off, on-off phenomenon, delayed-on, no-on
• Freezing of gait and falls
• Parkinson disease dementia (occurs in >1 year after motor onset; if cognitive features precede motor by ≥1 year, classified as DLB)
• Psychosis and hallucinations (often dopamine-agonist or levodopa-related)
• Autonomic failure: orthostatic hypotension, constipation, urinary dysfunction
• Dysphagia and aspiration pneumonia (leading cause of death)
• Impulse control disorders with dopamine agonists
• Neuroleptic malignant-like syndrome with abrupt levodopa withdrawal

PANCE pearls

• NEVER abruptly stop levodopa — risk of neuroleptic malignant-like syndrome (fever, rigidity, autonomic instability).
• Asymmetric onset is a key clue — symmetric parkinsonism suggests an atypical or drug-induced cause.
• Rest tremor is the most specific sign for idiopathic PD; absence of rest tremor does NOT exclude PD (akinetic-rigid variant).
• If a patient develops parkinsonism plus early dementia, hallucinations, or autonomic failure, think Lewy body dementia, MSA, or PSP — NOT idiopathic PD.
• Avoid dopamine-blocking antiemetics (metoclopramide, prochlorperazine) — use ondansetron or trimethobenzamide instead.
• Avoid first-generation antipsychotics for PD-related psychosis; pimavanserin (5-HT2A inverse agonist) is FDA-approved without worsening motor symptoms.

References

• AAN 2021 — Practice Guideline Update: Treatment of Motor Symptoms of Parkinson Disease (Pringsheim et al., Neurology 2021)
• MDS 2015 — MDS Clinical Diagnostic Criteria for Parkinson Disease (Postuma et al., Mov Disord 2015)
• EARLYSTIM Trial — Neurostimulation for Parkinson Disease with Early Motor Complications (Schuepbach et al., NEJM 2013)