380.1 🎓 醫孞生版

380.1.0.1 📌 䞀頁重點

380.1.0.1.1 Epidemiology
  • 2nd most common neurodegenerative
  • ~ 1% > 60 yo, 5% > 85 yo
  • Slight male predominance
  • Mean onset 60 yo
  • Early-onset PD (< 50) and juvenile PD (< 21) exist
  • Genetic factors in 10-15% (LRRK2 most common autosomal dominant, GBA risk)
380.1.0.1.2 Pathology
  • α-synuclein aggregation (Lewy bodies)
  • Loss of dopaminergic neurons in substantia nigra pars compacta (SNpc)
  • Braak staging: lower brainstem (dorsal motor nucleus vagus, olfactory) → midbrain (SN) → cortex
  • Non-dopaminergic systems also affected (cholinergic, noradrenergic, serotonergic)
380.1.0.1.3 Clinical Features (Cardinal Motor — TRAP)

380.1.1 Tremor

  • Rest (most characteristic)
  • Asymmetric onset
  • 4-6 Hz
  • “Pill-rolling”
  • Worse with stress, distraction (counting backwards)
  • ~ 30% never have tremor

380.1.2 Rigidity

  • Increased tone
  • Cogwheel (combined with tremor)
  • Lead-pipe

380.1.3 Akinesia/Bradykinesia

  • Slowness + decreased amplitude
  • Decreased automatic movements (arm swing, blinking)
  • Masked facies (hypomimia)
  • Micrographia
  • Hypophonia
  • Festinating gait (small shuffling steps)

380.1.4 Postural Instability (Later)

  • Loss of righting reflexes
  • Falls
  • Pull test positive

380.1.5 Other Motor

  • Freezing of gait
  • Dystonia (especially foot)
  • Stooped posture
  • En bloc turning
380.1.5.0.1 Non-Motor Features (Critical!)

380.1.6 Prodromal (Years Before Motor)

  • REM behavior disorder (RBD) — acting out dreams; 80% develop synucleinopathy within 15 years
  • Hyposmia/anosmia — very early
  • Constipation
  • Depression, anxiety
  • Daytime sleepiness

380.1.7 During Disease

  • Autonomic: orthostatic hypotension, urinary urgency, sexual dysfunction, sialorrhea, sweating abnormalities
  • Cognitive: mild cognitive impairment (MCI) → PD dementia (~ 80% over time)
  • Neuropsychiatric: depression, anxiety, apathy, ICDs (impulse control disorders), psychosis
  • Sleep: insomnia, RLS, RBD, EDS
  • Pain: musculoskeletal, dystonic, central, neuropathic
  • Fatigue
380.1.7.0.1 Diagnosis

380.1.8 MDS Clinical Diagnostic Criteria (2015)

Bradykinesia + at least one of: - Rest tremor - Rigidity

Plus supportive criteria (good response to levodopa, levodopa-induced dyskinesia, rest tremor of limb, MIBG-cardiac sympathetic denervation)

No absolute exclusion criteria (cerebellar abnormalities, supranuclear gaze palsy, frontotemporal dementia first, parkinsonism restricted to legs, etc.)

No red flags for atypical parkinsonism (rapid progression, early falls, severe autonomic failure, severe bulbar dysfunction, inspiratory stridor, etc.)

380.1.9 Imaging

  • MRI: usually normal
  • DaT-SCAN (123I-FP-CIT SPECT): dopamine transporter
    • Abnormal in PD, MSA, PSP, DLB
    • Normal in essential tremor, vascular parkinsonism, drug-induced, psychogenic
  • Genetic testing for selected (early onset, family history)
  • Skin biopsy for synuclein (emerging)
  • CSF synuclein RT-QuIC (emerging biomarker)
380.1.9.0.1 Treatment

380.1.10 Levodopa (Gold Standard)

  • Levodopa + carbidopa (decarboxylase inhibitor) — Sinemet
  • Most effective for motor symptoms
  • Dose-titrate to clinical response
  • Wearing off and dyskinesias after years
  • Available IR, CR, ER (Rytary), ODT
  • Foslevodopa-foscarbidopa (Vyalev) SC infusion FDA 2024 — continuous SC delivery for advanced PD

380.1.11 Dopamine Agonists

  • Pramipexole (Mirapex)
  • Ropinirole (Requip)
  • Rotigotine transdermal patch (Neupro)
  • Apomorphine SC (rescue for OFF periods)
  • Useful as initial monotherapy or adjunct
  • Side effects: ICDs (gambling, hypersexuality, eating, shopping) — counsel patients + family!, sleep attacks, edema, hallucinations
  • Less dyskinesia initially but less effective for motor

380.1.12 MAO-B Inhibitors

  • Selegiline (older)
  • Rasagiline (Azilect)
  • Safinamide (Xadago) — also glutamate modulator
  • Mild benefit
  • Possible neuroprotection (unproven)

380.1.13 COMT Inhibitors

  • Entacapone (Comtan) — with each levodopa dose
  • Opicapone (Ongentys) — once daily, FDA 2020
  • Reduce wearing off
  • Side effect: dyskinesias, urine discoloration
  • Tolcapone (limited use — hepatotoxicity)

380.1.14 Amantadine

  • Mild benefit early disease
  • Reduces dyskinesias
  • Side effects: livedo reticularis, edema, hallucinations
  • Amantadine ER (Gocovri) FDA-approved for dyskinesias

380.1.15 Anticholinergics

  • Trihexyphenidyl, benztropine
  • Limited use (cognitive SEs in elderly)
  • May help tremor and dystonia in young
380.1.15.0.1 Non-Motor Treatment

380.1.16 Cognitive

  • Rivastigmine (cholinesterase inhibitor — only FDA-approved for PD dementia)
  • Donepezil off-label

380.1.17 Psychosis

  • Pimavanserin (Nuplazid) — selective 5HT-2A inverse agonist, FDA-approved
  • Quetiapine, clozapine (avoid typical antipsychotics)

380.1.18 Depression

  • SSRIs, SNRIs, TCAs (caution anticholinergic)

380.1.19 Orthostatic Hypotension

  • Salt + fluid + compression
  • Midodrine
  • Droxidopa (Northera) FDA-approved
  • Pyridostigmine

380.1.20 Sialorrhea

  • Botulinum toxin (parotid/submandibular)
  • Anticholinergic (glycopyrrolate)

380.1.21 REM Behavior Disorder

  • Melatonin, clonazepam

380.1.22 Constipation

  • Fiber + fluid + laxatives + lubiprostone, prucalopride
380.1.22.0.1 Advanced Therapies (Motor Fluctuations + Dyskinesias)

380.1.23 Deep Brain Stimulation (DBS)

  • STN (subthalamic nucleus) — most common
  • GPi (globus pallidus internus) — alternative
  • Vim (thalamic) — for tremor-predominant
  • Indications: motor fluctuations + dyskinesias not controlled medically; good levodopa response; reasonable cognition
  • Reduces medication needs
  • Side effects: bleeding, infection, speech, mood, cognition

380.1.24 Levodopa-Carbidopa Intestinal Gel (LCIG)

  • Duodenal infusion via PEG-J tube
  • For advanced PD with fluctuations
  • Reduces wearing off + dyskinesias

380.1.25 Foslevodopa-Foscarbidopa SC Infusion (Vyalev)

  • FDA 2024
  • Continuous SC pump
  • Alternative to LCIG
  • Less invasive

380.1.26 Apomorphine

  • SC rescue injection or pump
  • For OFF periods
  • Side effects: nausea (pretreat antiemetic)

380.1.27 Focused Ultrasound (MRgFUS)

  • Thalamotomy (tremor) FDA 2018 PD
  • Pallidotomy (dyskinesia) FDA 2021
  • Non-invasive
  • Unilateral typically

380.1.28 Other

  • Apomorphine sublingual film (Kynmobi) — OFF period rescue
  • Inhaled levodopa (Inbrija) — OFF period rescue
380.1.28.0.1 Disease-Modifying Therapy (None Yet)
  • Multiple trials of α-synuclein-targeted (passive antibodies prasinezumab, cinpanemab — disappointing)
  • GLP-1 agonists (exenatide trials promising — larger trial)
  • LRRK2 inhibitors trials
  • GBA-targeted approaches

380.1.28.1 🩺 床邊速查

  • TRAP: Tremor (rest) + Rigidity (cogwheel) + Akinesia + Postural instability
  • Non-motor critical: RBD (prodromal!), hyposmia, constipation, orthostatic, cognitive, mood
  • Diagnosis: clinical (MDS criteria); DaT-SCAN if uncertain
  • Treatment: levodopa gold standard + DA agonists + MAO-B + COMT inhibitor + amantadine
  • ICDs with DA agonists — counsel!
  • Pimavanserin for psychosis
  • Rivastigmine for PD dementia
  • DBS for motor fluctuations + dyskinesias
  • LCIG, Vyalev SC infusion (2024) for advanced