Harvey's Garden

Parkinson disease

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tags—
aliasesDementia with Lewy bodies, Lewy body dementia, Parkinson's disease

5 min read

Epidemiology

Etiology

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).

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

Motor signs

  • Cardinal Motor Signs (TRAP - asymmetric onset):
    • T - Tremor: Resting tremor (4–6 Hz, “pill-rolling”), improves with voluntary movement.
    • R - Rigidity: Cogwheel or lead-pipe resistance.
    • A - Akinesia/Bradykinesia: Micrographia, masked facies, shuffling gait with \downarrow 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, dementia.

Diagnostics

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).

Treatment

Nonergot dopamine receptor agonists

  • Pramipexole, Ropinirole, Apomorphine
  • Consider as initial treatment in younger patients, especially those with risk factors for levodopa-induced dyskinesia.
  • Some patients develop impulse control disorders with compulsive gambling or hypersexuality. t

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.

Anticholinergic drugs (muscarinic antagonists)

  • Benztropine, Trihexyphenidyl, Biperiden
  • Beneficial regarding tremor and rigidity but does not improve bradykinesia

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

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:
    • -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 1 yr of motor onset (1-year rule).
    • Recurrent vivid visual hallucinations + fluctuating cognition. c
    • 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 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 PEG tube placement for high aspiration risk.
  • Surgical / Refractory:
    • DBS: Contraindicated / Ineffective.
    • Tracheostomy / CPAP: For severe nocturnal stridor in MSA.

Graph View

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