Parkinson Disease
Parkinson Disease
What Do You Need to Know?
- MDS Criteria: bradykinesia + rest tremor OR rigidity; asymmetric onset is typical and strongly supportive (symmetric onset is a red flag but does not by itself exclude PD)
- Braak Staging: α-synuclein pathology begins in olfactory bulb/dorsal motor nucleus of vagus → non-motor symptoms precede motor by years
- Levodopa response: robust, sustained response is the strongest supportive criterion; poor response is a red flag
- Non-motor prodrome: RBD, anosmia, constipation appear 10–20 years before motor onset; RBD converts to α-synucleinopathy in >80%
- DBS: indicated for motor fluctuations/dyskinesias refractory to medical optimization; STN vs. GPi both effective
- PDD vs. DLB: 1-year rule — dementia within 1 year of parkinsonism = DLB; ≥1 year after = PDD
- Genetics: LRRK2 (AD, most common genetic cause), GBA (most common risk factor), PARK2/Parkin (AR, young-onset)
🚩 Don’t Miss — Test-Day Priorities
- Asymmetric onset + sustained levodopa response: hallmark of idiopathic PD; absent levodopa response despite high dose is an absolute exclusion
- Bradykinesia is mandatory (MDS 2015): must show decrement in speed AND amplitude on repetitive tapping — not just slowness
- Postural instability is NO LONGER a core feature — early falls/postural instability is a red flag for PSP/MSA
- RBD + parkinsonism = α-synucleinopathy (PD, DLB, MSA); >80% of isolated RBD converts within ~14 yr
- 1-year rule (DLB vs PDD): dementia within 1 yr of motor onset → DLB; ≥1 yr after → PDD
- DaTscan: abnormal in PD/MSA/PSP/CBD/DLB; normal in essential tremor, drug-induced, dystonic, functional tremor — cannot separate PD from atypical
- Hallucinations: first reduce DA agonists/anticholinergics → pimavanserin (5HT2A inverse agonist) or quetiapine; AVOID typical antipsychotics + risperidone/olanzapine
- DA agonist red flags: impulse control disorders (gambling, hypersexuality, shopping, binge eating); pergolide/cabergoline → valvulopathy (off-market)
- DBS candidacy: robust levodopa response + motor fluctuations/dyskinesias; contraindicated if cognitive impairment, severe axial/gait-freezing, or no levodopa response
- LRRK2 = most common monogenic (AD, Ashkenazi + North African Berber); GBA = strongest risk factor, faster cognitive decline + earlier dementia; PARK2/Parkin = juvenile AR
🔍 Buzzwords & Pathognomonic FindingsClinical · Imaging / biomarkers · Genetics / pathology
Clinical phenotype
- Asymmetric pill-rolling rest tremor (4–6 Hz), re-emergent on posture → Parkinson disease
- Bradykinesia with decrement/sequence effect on finger tapping → PD (mandatory feature)
- Cogwheel rigidity, enhanced by Froment maneuver → PD
- Masked facies, hypomimia, hypophonia, micrographia → PD
- Festinating gait, retropulsion, freezing of gait (late) → PD (PIGD subtype)
- RBD, hyposmia, constipation, depression years before motor onset → PD non-motor prodrome (α-synucleinopathy)
- Sialorrhea, orthostatic hypotension (late), urinary urgency → PD autonomic features
- Impulse control disorder (gambling/hypersexuality) on new dopamine agonist → DA agonist side effect
- Visual hallucinations + parkinsonism + fluctuating cognition (early) → DLB (1-yr rule)
Imaging / biomarkers
- Normal structural MRI → typical PD (vs structural mimics)
- DaTscan: asymmetric reduced putaminal uptake (posterior > anterior) → PD
- Normal DaTscan → essential tremor, drug-induced, dystonic, or functional tremor (NOT PD)
- Reduced MIBG cardiac scintigraphy (postganglionic) → PD (preserved in MSA — preganglionic)
- Skin biopsy phosphorylated α-synuclein → emerging adjunctive biomarker for α-synucleinopathy (not a core board criterion)
- CSF α-synuclein seed amplification (RT-QuIC/SAA) → emerging adjunctive biomarker for α-synucleinopathy (not a standalone diagnostic criterion)
- Neuromelanin loss in substantia nigra pars compacta on imaging/pathology → PD
Genetics / pathology / treatment pearls
- Brainstem Lewy bodies with α-synuclein neuronal inclusions in SN → Parkinson disease
- LRRK2 (PARK8), autosomal dominant, Ashkenazi Jewish + North African Berber → most common monogenic PD (resembles sporadic)
- GBA mutation, Gaucher heterozygote, 5–10× PD risk → faster cognitive decline + earlier dementia
- SNCA (PARK1/4) duplication or triplication → familial PD (gene dosage effect)
- PARK2/Parkin, PINK1, DJ-1 — autosomal recessive, juvenile onset → young-onset PD
- Pimavanserin (5HT2A inverse agonist, no D2 block) → PD psychosis (doesn’t worsen motor)
- DBS STN > GPi for medication reduction; GPi better for axial/dyskinesia → advanced PD with fluctuations
- Levodopa-carbidopa intestinal gel (Duopa) → advanced PD wearing-off
- Apomorphine subcutaneous → rescue therapy for sudden off periods
- Amantadine → levodopa-induced dyskinesias
- Pergolide / cabergoline (ergot DA agonists) → cardiac valvulopathy — AVOID
Diagnosis & MDS Clinical Diagnostic Criteria
Core Diagnostic Features
- Parkinsonism: bradykinesia (progressive reduction in speed AND amplitude of repetitive movements) PLUS at least one of:
- Rest tremor (4–6 Hz)
- Rigidity (lead-pipe or cogwheel)
- Parkinsonism is the entry criterion; bradykinesia is mandatory
MDS Criteria: Clinically Established PD
| Category | Criteria |
|---|---|
| Supportive Criteria | Clear, dramatic beneficial response to dopaminergic therapy; levodopa-induced dyskinesias; rest tremor of a limb; olfactory loss or cardiac sympathetic denervation on MIBG |
| Absolute Exclusion | Cerebellar signs; downward vertical gaze palsy; behavioral variant FTD or primary progressive aphasia within 5 yr; parkinsonism restricted to lower limbs >3 yr; dopamine-receptor blocker exposure consistent with drug-induced; absent response to high-dose levodopa despite moderate severity; cortical sensory loss, limb apraxia, or progressive aphasia; normal functional neuroimaging of the presynaptic dopaminergic system (normal DaTscan) |
| Red Flags | Rapid gait impairment (wheelchair ≤5 yr); no progression over 5 yr; early bulbar dysfunction; inspiratory stridor; severe early autonomic failure within the first 5 years; early recurrent (>1/yr) falls from balance impairment within 3 years of onset; anterocollis; absent non-motor features despite 5 yr; unexplained pyramidal signs; bilateral symmetric throughout |
- Clinically established PD: absence of absolute exclusion criteria; ≥2 supportive criteria; no red flags
- Clinically probable PD: absence of absolute exclusion criteria; up to 2 red flags, each counterbalanced by ≥1 supportive criterion
DaTscan (Ioflupane SPECT)
- Binds dopamine transporter (DAT) in presynaptic striatal terminals
- Abnormal (reduced uptake): PD, MSA, PSP, CBD, DLB — all presynaptic dopaminergic degenerations
- Normal: essential tremor, drug-induced parkinsonism, dystonic tremor, functional tremor
- Cannot distinguish PD from other parkinsonian syndromes (MSA, PSP, CBD)
- Asymmetric putaminal loss (posterior > anterior) is characteristic of PD
💎 Board Pearl
- DaTscan differentiates degenerative parkinsonism from non-degenerative (ET, drug-induced, functional) but does NOT distinguish PD from MSA/PSP/CBD
- Absent response to high-dose levodopa despite moderate severity is an absolute exclusion for PD
Motor Features
Cardinal Motor Features (TRAP)
| Feature | Key Characteristics | Board-Relevant Details |
|---|---|---|
| Tremor | 4–6 Hz rest tremor; "pill-rolling"; re-emergent on posture | Asymmetric onset; suppressed by voluntary movement; worse with distraction (mental subtraction); absent during sleep |
| Rigidity | Lead-pipe; cogwheel (rigidity + superimposed tremor) | Velocity-independent (vs. spasticity = velocity-dependent); enhanced by contralateral activation (Froment maneuver) |
| Akinesia / Bradykinesia | Progressive reduction in speed AND amplitude; decrement pattern | Must show decrement (not just slowness); test: finger tapping, hand opening/closing, toe tapping; most strongly correlated with striatal dopamine loss; mandatory feature for diagnosis |
| Postural Instability (no longer a core feature) | Impaired postural reflexes; retropulsion | Under MDS 2015, postural instability is NO LONGER a core diagnostic feature (it was in UKPDS Brain Bank criteria); early postural instability is now a RED FLAG suggesting PSP/MSA; tested with pull test |
PD Motor Subtypes
| Subtype | Features | Prognosis |
|---|---|---|
| Tremor-dominant | Prominent rest tremor; relatively preserved gait/balance early | Slower progression; less cognitive decline |
| Akinetic-rigid | Bradykinesia and rigidity dominate; less prominent tremor | Intermediate progression |
| PIGD (Postural Instability/Gait Disorder) | Predominant gait dysfunction, postural instability, freezing | Fastest progression; worst cognitive outcomes; more falls; higher PDD risk |
Other Motor Signs
- Freezing of gait (FOG): transient inability to initiate or continue stepping; triggered by doorways, turns, dual-tasking; occurs in advanced disease
- Micrographia: progressively smaller handwriting; decrement pattern mirrors bradykinesia
- Hypomimia: masked facies; reduced blink rate
- Hypophonia: soft, monotone voice; loss of prosody
- Festinating gait: short, shuffling steps with forward flexed posture
- Asymmetric onset: typical and strongly supportive of PD; symmetric onset from the start is a red flag but does not by itself exclude PD
Clinical Pearl
- Cogwheel rigidity = lead-pipe rigidity + tremor superimposed on the resistance; rigidity alone (without tremor) is lead-pipe only
- Bradykinesia requires progressive decrement in amplitude AND speed — simply slow movement alone is not bradykinesia
Non-Motor Features
Non-Motor Symptoms by System
| System | Symptoms | Key Details |
|---|---|---|
| Sleep | RBD, insomnia, excessive daytime sleepiness, restless legs | RBD may precede motor onset by 10–20 yr; >80% convert to α-synucleinopathy; loss of REM atonia on PSG |
| Olfactory | Anosmia / hyposmia | Present in >90% of PD; often unnoticed; precedes motor by years; UPSIT testing; absent in PSP (useful differential) |
| Autonomic | Constipation, orthostatic hypotension, urinary urgency, erectile dysfunction, sialorrhea | Constipation is the earliest autonomic feature (may precede motor by >10 yr); severe early autonomic failure = red flag for MSA |
| Neuropsychiatric | Depression, anxiety, apathy, psychosis, impulse control disorders (ICDs) | Depression in 40–50%; ICDs (gambling, hypersexuality, binge eating, compulsive shopping) — associated with dopamine agonists |
| Cognitive | PD-MCI, PDD | Executive dysfunction earliest; PDD prevalence ≥80% at 20 yr; subcortical pattern (attention, visuospatial > memory) |
| Sensory | Pain, paresthesias | Shoulder pain may be presenting complaint; often misdiagnosed as musculoskeletal |
MDS Prodromal PD Research Criteria (Berg 2015)
- Probability calculator combining risk markers and prodromal markers to estimate likelihood of prodromal PD
- Risk markers: age, male sex, pesticide exposure, family history of PD, non-smoker status
- Prodromal markers (by likelihood ratio):
- RBD — highest LR (single strongest predictor)
- Hyposmia
- Constipation
- Depression
- Orthostatic hypotension
- Abnormal DaTscan
- Research tool — not used for clinical diagnosis; informs cohort selection for neuroprotection trials
PDD vs. DLB: The 1-Year Rule
- DLB: dementia within 1 year of parkinsonism (or before motor); PDD: dementia ≥1 year after established motor PD
- Same underlying α-synuclein pathology — spectrum concept; both feature visual hallucinations, fluctuating cognition, RBD, neuroleptic sensitivity
- DLB: less asymmetric, less tremor-dominant, more early visual hallucinations
💎 Board Pearl
- RBD is the strongest prodromal predictor of α-synucleinopathy — >80% conversion to PD, DLB, or MSA within 10–15 years
- PDD vs. DLB = 1-year rule: dementia before or within 1 yr of motor = DLB; ≥1 yr after motor = PDD
- ICDs (gambling, hypersexuality) are specifically associated with dopamine agonists, not levodopa
Pathology & Braak Staging
Neuropathology
- α-synuclein: misfolded, aggregated protein; main component of Lewy bodies and Lewy neurites
- Lewy bodies: eosinophilic, spherical intracytoplasmic inclusions with dense core and pale halo
- Substantia nigra pars compacta (SNpc): loss of dopaminergic neurons; visible depigmentation at autopsy
- Motor symptoms appear when ≥50–60% of SNpc neurons and ~80% of striatal dopamine is lost
- α-synuclein propagates in a prion-like manner (cell-to-cell transmission; host-to-graft spread in transplant studies)
Braak Staging
| Stage | Anatomic Region | Clinical Correlate |
|---|---|---|
| 1 | Olfactory bulb, dorsal motor nucleus of vagus (medulla) | Anosmia, constipation |
| 2 | Locus coeruleus, raphe nuclei (pons) | RBD, depression, anxiety, sleep disturbance |
| 3 | Substantia nigra pars compacta (midbrain) | Motor symptom onset (tremor, rigidity, bradykinesia) |
| 4 | Basal forebrain, amygdala, mesocortex (temporal) | Cognitive decline, emotional changes, olfactory worsening |
| 5 | Prefrontal and association neocortex | Executive dysfunction, visuospatial deficits |
| 6 | Primary motor and sensory neocortex | Severe dementia, widespread cortical dysfunction |
💎 Board Pearl
- Braak stage 1–2 = preclinical/prodromal (non-motor symptoms); stage 3 = motor onset; stages 5–6 = dementia
- Motor symptoms do NOT appear until stage 3 (≥50–60% SNpc neuron loss) — explains why non-motor precede motor by years
- Prion-like α-synuclein spread: demonstrated by Lewy body formation in fetal grafts transplanted into PD patients 10–15 years earlier
Genetics
Genetic Forms of Parkinson Disease
| Gene | Locus | Inheritance | Key Features |
|---|---|---|---|
| LRRK2 | PARK8 | AD | Most common genetic cause; G2019S mutation; late-onset, clinically indistinguishable from idiopathic PD; Ashkenazi Jewish & North African Berber populations; incomplete penetrance |
| GBA | — | AD (reduced penetrance) for PD risk; AR for Gaucher | Most common genetic risk factor for PD; encodes glucocerebrosidase; homozygous = Gaucher disease; heterozygous carriers have 5–10× ↑ PD risk. GBA-PD: earlier onset, faster cognitive decline, more RBD; worse cognitive outcome after STN-DBS |
| PARK2 (Parkin) | PARK2 | AR | Most common cause of young-onset PD (<40 yr); slow progression; excellent levodopa response; early dyskinesias; Lewy bodies often absent |
| PINK1 | PARK6 | AR | Young-onset; mitochondrial kinase; slow progression; good levodopa response |
| SNCA (α-synuclein) | PARK1/4 | AD | First PD gene discovered; point mutations (rare) or duplications/triplications; triplications → aggressive course with early dementia; gene dose effect |
| DJ-1 | PARK7 | AR | Rare; young-onset; oxidative stress response protein |
💎 Board Pearl
- LRRK2 G2019S: most common genetic cause of PD; Ashkenazi Jewish; looks like typical PD; incomplete penetrance
- GBA: most common genetic risk factor; heterozygous carriers (not Gaucher) have 5–10× PD risk and faster cognitive decline
- Parkin (PARK2): most common cause of young-onset PD; AR; Lewy bodies often absent; excellent levodopa response
- SNCA triplications > duplications > point mutations in severity (gene dose effect)
Medical Treatment
Pharmacotherapy Overview
| Drug Class | Examples | Mechanism | Clinical Use | Key Side Effects |
|---|---|---|---|---|
| Levodopa/Carbidopa | Sinemet, Rytary (ER), Inbrija (inhaled) | DA precursor + peripheral DDC inhibitor | Gold standard; most effective for motor symptoms | Nausea, dyskinesias, motor fluctuations, hallucinations (long-term) |
| Dopamine Agonists | Pramipexole, ropinirole, rotigotine (patch), apomorphine (SC/SL) | Direct D2/D3 receptor stimulation | Monotherapy in young-onset; adjunct to levodopa | ICDs (gambling, hypersexuality), daytime somnolence, edema, hallucinations; ergot types (bromocriptine, cabergoline) → fibrosis |
| MAO-B Inhibitors | Selegiline, rasagiline, safinamide | Inhibit monoamine oxidase-B → ↓DA metabolism | Early monotherapy (mild disease); adjunct for fluctuations | Insomnia (selegiline metabolized to amphetamine); SSRI serotonin syndrome risk is theoretical/rare. Real contraindications: meperidine, tramadol, linezolid, methylene blue, other MAOIs → serotonin syndrome. Dose-dependent MAO-B selectivity loss at higher doses (selegiline >10 mg/d) |
| COMT Inhibitors | Entacapone, opicapone, tolcapone | Block catechol-O-methyltransferase → ↑levodopa half-life | Motor fluctuations (wearing off); always given WITH levodopa | Dyskinesias, diarrhea; tolcapone: hepatotoxicity (monitor LFTs) |
| Amantadine | Amantadine IR, Gocovri (ER) | NMDA antagonist + mild DA release | Only proven treatment for levodopa-induced dyskinesias | Livedo reticularis, ankle edema, hallucinations, confusion |
| Anticholinergics | Trihexyphenidyl, benztropine | Muscarinic antagonist | Tremor-dominant PD in young patients only | Cognitive impairment, confusion, urinary retention, dry mouth; avoid in elderly |
Motor Complications
- Wearing off: end-of-dose deterioration; predictable; most common motor complication
- On-off fluctuations: unpredictable swings between mobile ("on") and immobile ("off") states
- Peak-dose dyskinesias: choreiform movements at peak levodopa levels; most common dyskinesia type
- Diphasic dyskinesias: during rising/falling levodopa levels; dystonic; legs > arms
- Off dystonia: painful early morning foot dystonia; give first dose earlier
- Motor complications in ~50% within 5 years of levodopa; risk: younger onset, higher doses
Initial Therapy — Landmark Trials
- LEAP trial (2019, NEJM): early vs delayed levodopa in newly diagnosed PD — no difference in UPDRS at 80 weeks → levodopa is not neurotoxic; do NOT delay levodopa for fear of disease progression
- PD-MED (2014, Lancet): levodopa-first improved long-term quality of life vs DA-first or MAO-B-first → benefit-risk favors early levodopa, particularly in older patients
- Practical implication: start levodopa when patient is functionally impaired, regardless of age; reserve DA monotherapy primarily for very young patients accepting higher ICD risk
Management of Motor Fluctuations
- Wearing off: add COMT inhibitor (entacapone, opicapone); add MAO-B inhibitor; switch to extended-release levodopa; shorten dosing intervals
- Dyskinesias: reduce levodopa dose; add amantadine (Gocovri); consider DBS
- Off periods: on-demand options — subcutaneous apomorphine injection and inhaled levodopa (Inbrija) for rescue. Sublingual apomorphine (Kynmobi) was discontinued in the US in 2023.
Apomorphine SC — Practical Pearls
- Requires test dose under BP monitoring before initiation (significant orthostasis risk)
- Common AEs: orthostatic hypotension, severe nausea/vomiting, injection-site nodules
- Avoid concurrent 5-HT3 antagonists (ondansetron, granisetron) — risk of severe hypotension and loss of consciousness
- Trimethobenzamide (historically used as antiemetic premedication) is no longer US-available; counsel patients on slow dose escalation
PD Psychosis — Pharmacotherapy
- Pimavanserin (Nuplazid): selective 5-HT2A inverse agonist; FDA-approved 2016 for PD psychosis; first agent without dopamine receptor blockade
- BOXED WARNING: increased mortality in elderly patients with dementia-related psychosis (class effect for all atypical antipsychotics)
- No worsening of motor symptoms (no D2 blockade)
- QT prolongation — check baseline ECG; avoid with other QT-prolonging drugs
- Quetiapine: low D2 affinity; widely used off-label; less robust evidence but better tolerated than other atypicals
- Clozapine: strongest evidence for efficacy; requires weekly CBC monitoring (agranulocytosis risk); reserved for refractory psychosis
- AVOID: typical antipsychotics (haloperidol), risperidone, olanzapine — worsen parkinsonism via D2 blockade
- AVOID antiemetics with D2 blockade: metoclopramide, prochlorperazine, promethazine — precipitate parkinsonism. Use ondansetron or trimethobenzamide (where available) for nausea
PD Dementia (PDD) — Pharmacotherapy
- Rivastigmine (oral capsule or transdermal patch): cholinesterase inhibitor; FDA-approved for PDD based on the EXPRESS trial (NEJM 2004); modest improvement in cognition and ADLs
- Donepezil: off-label; reasonable alternative with similar efficacy in trials
- Memantine: off-label; modest benefit in PDD/DLB; consider in moderate–severe disease
- Cholinesterase inhibitors may modestly worsen tremor; weigh against cognitive benefit
Advanced PD — Device-Aided Therapies
- Foslevodopa/foscarbidopa (Vyalev): continuous 24-hr subcutaneous infusion; FDA-approved 2024 for advanced PD with motor fluctuations
- Soluble prodrug delivers steady-state levodopa — reduces "off" time without requiring PEG-J tube
- Alternative to LCIG (Duopa) without GI surgery; common AE = infusion-site reactions (nodules, erythema)
- LCIG (Duopa): continuous jejunal infusion via PEG-J (see DBS section)
- Apomorphine SC pump: continuous infusion alternative for advanced PD; Onapgo (continuous SC apomorphine; FDA-approved 2025) added as an on-label US continuous SC apomorphine option
Non-Motor Symptom Pharmacotherapy
| Symptom | First-Line | Alternatives / Notes |
|---|---|---|
| Neurogenic OH | Midodrine (α1 agonist; 2.5–10 mg TID, dose 4h apart, avoid evening); Droxidopa (Northera) (norepinephrine precursor; FDA-approved for neurogenic OH) | Fludrocortisone (mineralocorticoid — volume expansion; watch hypokalemia, supine HTN); pyridostigmine for mild OH (lower supine HTN risk) |
| OH — non-pharm | Increased salt and fluid intake (2–3 L/day, 6–10 g salt); compression stockings (waist-high); head-of-bed elevation 30° | Counter-maneuvers (leg crossing, squatting); slow positional changes |
| Sialorrhea | Botulinum toxin injection into parotid/submandibular glands | Glycopyrrolate (peripheral anticholinergic); avoid centrally-acting anticholinergics |
| Constipation | Polyethylene glycol (PEG); increased fiber and hydration | Lubiprostone (FDA-approved for chronic idiopathic constipation; evidence in PD) |
| Urinary urgency | Mirabegron (β3 agonist; avoids anticholinergic burden) | Oxybutynin/tolterodine — avoid in cognitively impaired |
REM Sleep Behavior Disorder (RBD) Treatment
- Melatonin 3–12 mg qHS: conditional first-line option per AASM 2023; favorable safety profile (often preferred in older PD/DLB/MSA patients given lower cognitive/fall risk)
- Clonazepam 0.25–2 mg qHS: also a conditional first-line option per AASM 2023; long-standing efficacy; caution in elderly, OSA, dementia, and fall-risk patients
- Bed safety counseling: remove sharp/heavy objects from nightstand; consider padded bed rails or mattress on floor; partner sleeps separately or with barrier; lock weapons away
- Counsel patient and partner on RBD as prodromal α-synucleinopathy marker (sensitive disclosure)
💎 Board Pearl
- Levodopa remains the gold standard — most effective drug for PD motor symptoms at any stage
- LEAP trial: early vs delayed levodopa → no difference at 80 wk → levodopa is not neurotoxic; don't delay
- Amantadine is the only proven pharmacotherapy for levodopa-induced dyskinesias (EASE LID trials)
- Dopamine agonists → ICDs (gambling, hypersexuality, shopping, binge eating); screen at every visit; treatment = reduce/stop agonist
- Pimavanserin = first FDA-approved drug for PD psychosis (5-HT2A inverse agonist); boxed warning for elderly dementia-related psychosis
- Rivastigmine = only FDA-approved drug for PDD (EXPRESS trial)
- Droxidopa = FDA-approved norepinephrine precursor for neurogenic OH
- Melatonin and clonazepam are both conditional first-line options for RBD per AASM 2023 — melatonin often preferred in older PD/DLB/MSA patients for safety (less cognitive/fall risk than clonazepam)
- Tolcapone requires LFT monitoring (hepatotoxicity); entacapone and opicapone do not
Surgical Treatment
Deep Brain Stimulation (DBS)
| Feature | STN DBS | GPi DBS |
|---|---|---|
| Motor benefit | Comparable | Comparable |
| Medication reduction | ↓Levodopa by 30–50% | Minimal change |
| Dyskinesia suppression | Indirect (via ↓levodopa) | Direct antidyskinetic effect |
| Cognitive/mood risk | Higher risk of depression, impulsivity | Possibly lower cognitive risk |
| Battery life | Longer (lower stimulation needed) | Shorter (higher stimulation needed) |
Indications & Contraindications
- Indications: motor fluctuations/dyskinesias refractory to medical optimization; medication-refractory tremor; confirmed levodopa-responsive PD; disease duration ≥4 yr (or earlier per EARLY-STIM)
- Contraindications:
- Dementia — formal neuropsychological testing is preferred over a single MoCA cutoff; MoCA <21 raises concern but does not replace neuropsych evaluation
- Active uncontrolled psychiatric illness (depression, psychosis)
- Atypical parkinsonism (MSA, PSP, CBD)
- Poor levodopa response (except for medication-refractory tremor)
- Selection framework: follow CAPSIT-PD criteria (Core Assessment Program for Surgical Interventional Therapies in PD) — multidisciplinary evaluation including levodopa-challenge UPDRS, neuropsychology, psychiatry, MRI
EARLY-STIM Trial (NEJM 2013)
- STN-DBS superior to best medical therapy in patients with early motor complications (avg disease duration ~7.5 yr; mean age ~52)
- Improved quality of life, motor symptoms, and ADLs at 2 years
- Supports earlier DBS consideration once motor fluctuations emerge — do not wait until advanced disease
MRgFUS (MR-Guided Focused Ultrasound)
- Incisionless ablation using transcranial focused ultrasound under real-time MRI thermometry — no implanted hardware
- FDA-approved indications:
- Unilateral VIM thalamotomy for tremor-dominant PD (2018)
- Unilateral GPi pallidotomy for PD with motor complications (2021)
- Option for patients who cannot undergo DBS (anticoagulation, infection risk, surgical aversion, hardware concerns)
- Limitations: unilateral only (bilateral lesioning carries unacceptable speech/bulbar risk); non-reversible (vs reversible/adjustable DBS); skull density ratio affects candidacy
Advanced Continuous Infusion Options: LCIG (Duopa), Foslevodopa (Vyalev), Apomorphine (Onapgo)
- LCIG (Duopa): continuous jejunal infusion via PEG-J tube → steady-state levodopa → reduces motor fluctuations. Complications: tube dislodgement, infection, peripheral neuropathy (monitor B12)
- Foslevodopa/foscarbidopa (Vyalev): continuous 24-hr SC infusion (FDA-approved 2024); achieves similar steady-state pharmacokinetics without GI tube
- Continuous SC apomorphine (Onapgo): FDA-approved 2025 on-label US wearable pump for continuous SC apomorphine delivery in advanced PD with motor fluctuations
💎 Board Pearl
- Best predictor of DBS outcome = levodopa responsiveness — DBS does not improve symptoms beyond what levodopa achieves in "best on" state
- STN allows medication reduction; GPi directly suppresses dyskinesias — both targets have equivalent motor benefit
- Dementia is the most important contraindication to DBS — always screen cognition
Differential Diagnosis
Parkinsonism Differential: Key Comparisons
| Feature | PD | MSA | PSP | Drug-Induced | Vascular | NPH |
|---|---|---|---|---|---|---|
| Onset | Asymmetric | Asymmetric or symmetric | Symmetric, axial | Symmetric | Lower body | Symmetric, lower body |
| Tremor | 4–6 Hz rest, pill-rolling | Irregular, jerky, postural | Rare | Symmetric rest/postural | Rare | Rare |
| Key Feature | Levodopa-responsive | Early severe autonomic failure; cerebellar signs | Vertical gaze palsy (down > up); early falls | Temporal relationship to offending drug | Lower-body parkinsonism; vascular risk factors | Gait apraxia, urinary incontinence, dementia (triad) |
| DaTscan | Abnormal (asymmetric) | Abnormal | Abnormal | Normal | Abnormal or normal | Normal |
| L-dopa Response | Robust, sustained | Poor or transient | Poor or absent | N/A (withdraw drug) | Poor | Poor (CSF drainage test) |
PD Tremor vs. Essential Tremor
| Feature | PD Tremor | Essential Tremor |
|---|---|---|
| Type | Rest tremor (4–6 Hz) | Action/postural (4–12 Hz, typically 6–8 Hz) |
| Onset | Unilateral, asymmetric | Bilateral |
| Distribution | Hands, jaw, legs | Hands, head, voice |
| Re-emergent | Yes (after latency on posture) | Immediate postural tremor |
| Alcohol | No improvement | Marked improvement (50–70%) |
| DaTscan | Abnormal | Normal |
Drug-Induced Parkinsonism
- Culprits: typical antipsychotics (haloperidol), metoclopramide, prochlorperazine; symmetric; DaTscan normal
- Treatment: withdraw offending agent; may take months to resolve
- If antipsychotic needed in PD: quetiapine or clozapine (pimavanserin for PD psychosis)
Clinical Pearl
- NPH triad: "wet, wacky, and wobbly" — gait apraxia (magnetic gait) is first and most responsive to shunting
- PSP: early falls (first year), vertical supranuclear gaze palsy (downgaze > upgaze), axial rigidity > limb rigidity, "surprised" facies
- MSA: early severe autonomic failure + poor levodopa response; cerebellar (MSA-C) or parkinsonian (MSA-P) subtypes
References
- Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. 2015;30(12):1591-1601.
- Braak H, Del Tredici K, Rüb U, et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003;24(2):197-211.
- Kalia LV, Lang AE. Parkinson's disease. Lancet. 2015;386(9996):896-912.
- Armstrong MJ, Okun MS. Diagnosis and treatment of Parkinson disease: a review. JAMA. 2020;323(6):548-560.
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