Parkinson Disease
Parkinson Disease
What Do You Need to Know?
- MDS Criteria: bradykinesia + rest tremor OR rigidity; asymmetric onset is the hallmark
- 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)
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 |
| Red Flags | Rapid gait impairment (wheelchair ≤5 yr); no progression over 5 yr; early bulbar dysfunction; inspiratory stridor; severe early autonomic failure (≤5 yr); early recurrent falls (≤3 yr); anterocollis; absent non-motor features despite 5 yr; unexplained pyramidal signs; bilateral symmetric throughout |
- Clinically established PD: ≥2 supportive criteria, no absolute exclusion, no red flags
- Clinically probable PD: ≥1 supportive criteria, no absolute exclusion; red flags counterbalanced by supportive criteria
DaTscan (Ioflupane SPECT)
- Binds dopamine transporter (DAT) in presynaptic striatal terminals
- Abnormal (reduced uptake): PD, MSA, PSP, 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 disabling cardinal feature |
| Postural Instability | Impaired postural reflexes; retropulsion | Late feature (>5 yr); early falls (≤3 yr onset) = red flag for PSP; tested with pull test |
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: virtually universal; bilateral symmetric from start = red flag
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 |
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 | — | Risk factor | Most common genetic risk factor for PD; encodes glucocerebrosidase; homozygous = Gaucher disease; heterozygous carriers have 5–10× ↑ PD risk; associated with earlier cognitive decline |
| 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); serotonin syndrome risk with SSRIs (theoretical, rare in practice) |
| 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
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: subcutaneous apomorphine; sublingual apomorphine (Kynmobi); inhaled levodopa (Inbrija) for rescue
💎 Board Pearl
- Levodopa remains the gold standard — most effective drug for PD motor symptoms at any stage
- 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
- 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
- Contraindications: dementia (MoCA <22–24); active psychiatric illness; atypical parkinsonism; poor levodopa response (except tremor)
LCIG (Duopa)
- Continuous jejunal infusion via PEG-J tube → steady-state levodopa levels → reduces motor fluctuations
- Complications: tube dislodgement, infection, peripheral neuropathy (monitor B12)
💎 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 (6–12 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.
- Deuschl G, Schade-Brittinger C, Krack P, et al. A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med. 2006;355(9):896-908.
- Follett KA, Weaver FM, Stern M, et al. Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease (CSP 468). N Engl J Med. 2010;362(22):2077-2091.
- Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and Movement Disorder Society evidence-based medicine review: update on treatments for the motor symptoms of PD. Mov Disord. 2018;33(8):1248-1266.
- Seppi K, Ray Chaudhuri K, Coelho M, et al. Update on treatments for nonmotor symptoms of PD — MDS evidence-based medicine review. Mov Disord. 2019;34(2):180-198.
- Schneider SA, Alcalay RN. Neuropathology of genetic synucleinopathies with parkinsonism: review of the literature. Mov Disord. 2017;32(6):801-811.
- McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report. Neurology. 2017;89(1):88-100.