Parkinson disease

Epidemiology

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Etiology

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Parkinson disease

• Idiopathic
• Contributing genetic factors include:
  • α-Synuclein (SNCA)
    • α-Synuclein constitutes the major component of Lewy bodies. In addition to mutations, duplication/triplication of the wild-type gene can also cause PD (due to increased production of the normal protein).

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Pathophysiology

Mnemonic

PArkinson’s Disease = doPAmine Down Alzheimer Disease = Acetylcholine Down

• Progressive dopaminergic neuron degeneration in the substantia nigra (part of the basal ganglia) and the locus coeruleus → dopamine deficiency at the respective receptors of the striatum with interrupted transmission to the thalamus and motor cortex → motor symptoms of PD
• Serotonin and noradrenaline depletion (in the raphe nuclei): likely cause of depressive symptoms
• Acetylcholine surplus (in the nucleus basalis of Meynert): likely cause of dyskinesia

Clinical features

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• Cardinal Motor Signs (TRAP - asymmetric onset):
  • T - Tremor: Resting tremor (4–6 Hz, “pill-rolling”), improves with voluntary movement.
    • Often the initial presenting sign and can remain the only symptom for years (ie, tremor-dominant PD) c
  • R - Rigidity: Cogwheel or lead-pipe resistance.
  • A - Akinesia/Bradykinesia: Micrographia, masked facies, shuffling gait with ↓ arm swing.
  • P - Postural Instability: Late feature; impaired balance, positive pull test, frequent falls.
• Non-Motor Signs: REM sleep behavior disorder (RBD), anosmia, severe constipation, orthostatic hypotension, depression c , dementia.

Diagnostics

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Pathology

• Lewy bodies
  • Aggregates of misfolded α-synuclein and other proteins, such as ubiquitin and neurofilament protein within the neural cell bodies
  • Appear histologically as intracellular hyaline eosinophilic globules
  • May be found in brainstem, substantia nigra, and cortex
  • Also seen in Lewy body dementia

• Image A: An eosinophilic cytoplasmic inclusion (Lewy body; blue overlay) is visible inside a neuron. There is a large accumulation of neuromelanin (brown granules; green overlay).
• Image B: A neurite staining positive for α-synuclein is visible in the center of the image (Lewy neurite; yellow overlay).

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Differential diagnostics

• Drug-Induced Parkinsonism (DIP):
  • Diff by history of D2 receptor blockers (typical/atypical antipsychotics, Metoclopramide, Prochlorperazine); typically symmetric, rapid onset, lack of tremor; unresponsive to levodopa; Tx: discontinue offending agent, switch to low-D2 drug (e.g., Quetiapine), or use Benztropine. c

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Treatment

• Initial Pharmacotherapy (Motor Symptoms):
  • Age $\ge 65$ yo OR Severe functional impairment:
    • First-line: Carbidopa-Levodopa (most potent agent).
    • Mechanism: Levodopa crosses blood-brain barrier (BBB) and converts to DA; Carbidopa is a peripheral DOPA decarboxylase inhibitor that prevents peripheral conversion (reduces nausea, vomiting, orthostasis, and cardiac arrhythmias).
  • Age $<65$ yo AND Mild/Moderate symptoms:
    • First-line: Dopamine Agonists (Pramipexole, Ropinirole) to delay long-term motor complications of levodopa.
    • Side effects: Excessive daytime sleepiness, impulse control disorders (pathological gambling, hypersexuality, compulsive shopping).
  • Younger patients with Tremor-predominant disease:
    • Anticholinergics: Trihexyphenidyl or Benztropine.
    • Caution: Strictly avoid in elderly or cognitively impaired pts due to risk of delirium, urinary retention, and glaucoma.
  • Mild, early symptoms:
    • MAO-B Inhibitors: Selegiline, Rasagiline (inhibits central DA breakdown).
• Management of Treatment Complications:
  • “Wearing-off” Phenomenon / Motor Fluctuations:
    • Add COMT inhibitors (Entacapone, Tolcapone) to prolong Levodopa half-life.
    • Add long-acting DA agonists or MAO-B inhibitors; fractionate Levodopa dosing (smaller, more frequent doses).
  • Peak-Dose Dyskinesia (choreiform movements):
    • Reduce individual Levodopa doses.
    • Add Amantadine (NMDA receptor antagonist; watch for livedo reticularis and peripheral edema).
• Management of Non-Motor Complications:
  • Psychosis / Visual Hallucinations:
    • First step: Reduce antiparkinsonian medications in step-wise fashion (anticholinergics $\to$ amantadine $\to$ MAO-B inhibitors $\to$ DA agonists $\to$ levodopa).
    • Second step (if persistent): Pimavanserin (5-HT2A inverse agonist; no D2 blockade) or low-dose Quetiapine / Clozapine. c
  • PD Dementia (PDD):
    • Cholinesterase inhibitors (Rivastigmine, Donepezil).
  • REM Sleep Behavior Disorder (RBD):
    • Melatonin (first-line) or low-dose Clonazepam.
  • Orthostatic Hypotension:
    • Conservative measures (compression stockings, hydration); if refractory: Fludrocortisone, Midodrine, or Droxidopa.
• Refractory / Advanced Disease:
  • Deep Brain Stimulation (DBS):
    • Targets: Subthalamic Nucleus (STN) or Globus Pallidus internus (GPi).
    • Indication: Severe motor fluctuations or medication-induced dyskinesias refractory to medical optimization in pts without cognitive impairment/dementia.
  • Continuous Levodopa-Carbidopa Enteral Suspension (LCIG): Via percutaneous endoscopic gastrojejunostomy (PEG-J).

Tip

• Ergot dopamine agonists (cabergoline and bromocriptine) are not recommended in Parkinson disease or restless leg syndrome, but are first-line treatment in Prolactinoma and Hyperprolactinemia.
  • Primarily due to a higher risk of serious side effects, specifically fibrotic reactions affecting the heart valves and lungs.
  • The doses used for Prolactinoma and Hyperprolactinemia are generally lower than for Parkinson’s, leading to a lower risk of fibrotic side effects, making the benefit-risk balance more favorable.

Deep brain stimulation (DBS)

• In PD, the lack of dopamine leads to overactivity in the indirect pathway. Key players here are the STN and the GPi.
• Indications
  • Severe motor symptoms or refractory tremor
  • Decrease in dosage of medication because of adverse effects
• Procedure
  • Stereotactic implantation of stimulating electrode(s) targeting the subthalamic nucleus or internal globus pallidus
  • Controlled remotely

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Complications

• Aspiration Pneumonia: Leading cause of death (oropharyngeal dysphagia).
• Major Depressive Disorder (MDD): Affects up to 40–50% of pts; often underdiagnosed due to symptom overlap with psychomotor retardation and masked facies; Tx: SSRIs, SNRIs, or dopamine agonists (Pramipexole). c
• Traumatic Falls: Hip fractures and subdural hematomas secondary to postural instability.
• Parkinsonism-Hyperpyrexia Syndrome: Life-threatening condition caused by abrupt cessation of dopaminergic therapy (mimics NMS).

Parkinson-plus syndromes

Epidemiology & Risk Factors

• Age > 50 yo; rapid progression and short survival vs idiopathic PD.
• Pathologic classification:
  • $\alpha$-Synucleinopathies: Multiple System Atrophy (MSA), Dementia with Lewy Bodies (DLB).
  • Tauopathies: Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD).

Clinical Features

• Hallmark Shared Feature: Parkinsonism w/ poor or absent response to L-DOPA and absence of classic resting tremor.
• Multiple System Atrophy (MSA):
  • Autonomic failure: Severe orthostatic hypotension, urinary incontinence/retention. c
  • Motor subtypes: Cerebellar ataxia (MSA-C) or symmetric parkinsonism (MSA-P).
  • Key sign: Laryngeal stridor (vocal cord paresis).
• Progressive Supranuclear Palsy (PSP):
  • Vertical supranuclear gaze palsy (impaired downward > upward voluntary saccades).
  • Early unexplained backward falls (within 1–2 yrs of onset).
  • Axial rigidity > limb rigidity; “surprised/staring” facies.
• Corticobasal Degeneration (CBD):
  • Marked asymmetry w/ limb dystonia and focal myoclonus.
  • Ideomotor apraxia and cortical sensory loss.
  • Alien limb phenomenon.
• Dementia with Lewy Bodies (DLB):
  • Dementia $\le$ 1 yr of motor onset (1-year rule).
  • Recurrent vivid visual hallucinations + episodic impairment cognition (Fluctuations). c2
  • Extreme neuroleptic sensitivity (lethal rigidity/catatonia w/ DA antagonists).

Diagnosis

• Initial / Clinical: Clinical diagnosis based on red flags (early falls, dysautonomia, gaze palsy, apraxia) and negative L-DOPA challenge.
• Key Labs: TSH, B12, RPR (exclude reversible mimics).
• Brain MRI (Key Findings):
  • MSA: “Hot cross bun” sign (cruciform T2 pontine hyperintensity).
  • PSP: “Hummingbird / Penguin” sign (midbrain tegmentum atrophy w/ preserved pons).
  • CBD: Asymmetric frontoparietal atrophy.
  • DLB: Generalized cortical atrophy w/ relative hippocampal preservation.
• Confirmatory / Gold Standard: Post-mortem neuropathology.

Differential Diagnostics

• Idiopathic PD: Diff by robust L-DOPA response, 4–6 Hz resting tremor, unilateral onset, dementia late (>1 yr).
• NPH: Diff by classic triad (“wet, wacky, wobbly”), ventriculomegaly on MRI, gait improvement post-lumbar puncture.
• Vascular Parkinsonism: Diff by “lower-body” predominance (legs > arms), subcortical white matter infarcts on MRI.
• Drug-Induced Parkinsonism: Diff by DA antagonist exposure (neuroleptics, metoclopramide), symmetric presentation, reversibility.

Management

• Symptomatic Pharmacotherapy:
  • L-DOPA trial: High-dose trial; taper/stop if ineffective.
  • MSA Dysautonomia: Waist-high compression stockings $\to$ Fludrocortisone, Midodrine, or Droxidopa.
  • DLB Cognition/Psychosis: Cholinesterase inhibitors (Donepezil); low-dose Quetiapine or Pimavanserin (avoid typical neuroleptics).
  • RBD: Melatonin or low-dose Clonazepam.
• Supportive:
  • PT/OT (weighted walkers for PSP falls).
  • Early swallow eval $\to$ PEG tube placement for high aspiration risk.
• Surgical / Refractory:
  • DBS: Contraindicated / Ineffective.
  • Tracheostomy / CPAP: For severe nocturnal stridor in MSA.