Last Minute Review
Movement Disorders — Last Minute Review
A last-minute review of high-yield facts — dense tables and one-liners for RITE/Board prep. Not a substitute for the full notes.
Parkinsonism — PD vs Atypical
| Disorder | Key Features | Red Flags / Distinguishing Clues | Pathology | Treatment |
|---|---|---|---|---|
| Parkinson Disease (PD) | Asymmetric rest tremor (4–6 Hz), bradykinesia, rigidity; non-motor prodrome (RBD, anosmia, constipation) | Excellent sustained levodopa response; asymmetric onset; levodopa-induced dyskinesias support diagnosis | α-synuclein Lewy bodies; Braak staging (dorsal motor nucleus of vagus → substantia nigra → cortex) | Levodopa/carbidopa (gold standard); DA agonists; MAO-B inhibitors; DBS (STN or GPi) |
| MSA-P (striatonigral degeneration) | Symmetric parkinsonism + early severe autonomic failure (OH, urinary retention); poor levodopa response | Stridor (laryngeal dystonia); anterocollis; early falls; wheelchair ≤5 yr; putaminal slit sign on MRI | α-synuclein glial cytoplasmic inclusions (GCIs) in oligodendrocytes | Levodopa trial (transient benefit ~30%); midodrine/droxidopa for OH; no disease-modifying therapy |
| MSA-C (olivopontocerebellar atrophy) | Cerebellar ataxia + autonomic failure ± parkinsonism | “Hot cross bun” sign (pons) on MRI; cerebellar/pontine atrophy | α-synuclein GCIs (same as MSA-P) | Supportive; PT/OT; autonomic management |
| PSP (Richardson syndrome) | Early postural instability + falls (backward); vertical supranuclear gaze palsy (downgaze > upgaze); axial rigidity > limb; “surprised” facies | Vertical gaze palsy (downgaze first); “hummingbird” / “penguin” sign on MRI (midbrain atrophy); applause sign | 4R tauopathy; globose neurofibrillary tangles | No effective therapy; levodopa trial (poor response); PT for fall prevention |
| CBS / CBD | Markedly asymmetric rigidity + limb apraxia; cortical sensory loss; alien limb phenomenon; myoclonus | Asymmetric cortical atrophy (parietal); “alien limb”; apraxia of speech; CBD is a pathologic diagnosis | 4R tauopathy; astrocytic plaques; ballooned (achromatic) neurons | Supportive; botulinum toxin for dystonia; clonazepam for myoclonus |
| DLB | Fluctuating cognition; recurrent visual hallucinations; parkinsonism; RBD | Visual hallucinations early; neuroleptic sensitivity (avoid typical antipsychotics!); low DAT uptake on SPECT; Capgras delusion | α-synuclein Lewy bodies (cortical predominant) | Cholinesterase inhibitors (rivastigmine); pimavanserin or quetiapine for hallucinations; carbidopa/levodopa cautiously |
💎 Board Pearl
- 1-year rule: Dementia within 1 year of parkinsonism onset = DLB; dementia ≥1 year after established PD = PDD. Same α-synuclein pathology, different temporal profile.
- Protein cheat sheet: PD/DLB/MSA = α-synuclein; PSP/CBD = 4R tau. GCIs (oligodendrocytes) = MSA; Lewy bodies (neurons) = PD/DLB.
- DaTscan is abnormal in ALL degenerative parkinsonisms (PD, MSA, PSP, DLB) but normal in ET, drug-induced parkinsonism, and functional tremor — it does NOT distinguish PD from atypical syndromes.
PD Medications
| Drug / Class | MOA | Key Points |
|---|---|---|
| Levodopa/Carbidopa (Sinemet) | DA precursor + peripheral decarboxylase inhibitor | Most effective PD drug; gold standard; motor fluctuations with chronic use; carbidopa blocks peripheral conversion (reduces nausea) |
| DA Agonists (pramipexole, ropinirole, rotigotine) | Direct D2/D3 receptor stimulation | Monotherapy in young-onset PD to delay levodopa; impulse control disorders (gambling, hypersexuality, shopping); daytime somnolence; leg edema |
| MAO-B Inhibitors (selegiline, rasagiline, safinamide) | Block MAO-B → ↓ DA degradation | Mild symptomatic benefit; adjunct to levodopa; selegiline metabolized to amphetamine; avoid with meperidine/SSRIs (serotonin syndrome risk) |
| COMT Inhibitors (entacapone, opicapone, tolcapone) | Block COMT → prolong levodopa half-life | Always used WITH levodopa; extend “on” time; tolcapone = hepatotoxicity (requires LFT monitoring); entacapone = orange urine |
| Amantadine | NMDA antagonist + ↑ DA release | Only FDA-approved drug for levodopa-induced dyskinesias; also mild antiparkinsonian; livedo reticularis; hallucinations in elderly |
| Anticholinergics (trihexyphenidyl, benztropine) | Block muscarinic receptors (restore DA/ACh balance) | Best for tremor-predominant PD in young patients only; avoid in elderly (confusion, urinary retention, constipation, cognitive worsening) |
| Apomorphine | Potent non-selective DA agonist | SC injection for acute “off” rescue; severe nausea (pretreat with trimethobenzamide, NOT ondansetron — hypotension risk); continuous infusion (pump) available |
| DBS (STN or GPi) | High-frequency stimulation modulates basal ganglia circuits | STN: allows medication reduction; GPi: better for dyskinesias + mood/behavior concerns; requires good levodopa response; no significant cognitive impairment |
PD Treatment Side Effects & Management
| Side Effect | Management |
|---|---|
| Wearing off | Add COMT inhibitor (entacapone) or MAO-B inhibitor; increase levodopa frequency (smaller, more frequent doses); switch to extended-release; add DA agonist |
| Peak-dose dyskinesias | Add amantadine (first-line, only FDA-approved); reduce individual levodopa dose; consider GPi DBS |
| Diphasic dyskinesias | Increase levodopa dose (counter-intuitive — need to reach peak faster); more frequent dosing; consider continuous infusion or DBS |
| “Off” dystonia (early morning foot) | Bedtime long-acting levodopa or DA agonist; early morning rescue dose; botulinum toxin for focal dystonia |
| Impulse control disorders | Reduce or stop DA agonist (most common cause); screen regularly (gambling, hypersexuality, compulsive shopping/eating); can occur with any dopaminergic drug |
| Hallucinations / psychosis | First: stop anticholinergics → then reduce/stop DA agonists → then reduce MAO-B/COMT inhibitors → keep levodopa as last drug standing (most effective). Add pimavanserin (5-HT2A inverse agonist, FDA-approved for PD psychosis) or quetiapine (low-dose). Never use typical antipsychotics or most atypicals (worsen parkinsonism). Clozapine is effective but requires ANC monitoring. |
| Orthostatic hypotension | Reduce antihypertensives; fludrocortisone; midodrine; droxidopa (FDA-approved for neurogenic OH); compression stockings; increase salt/fluid intake |
| Nausea | Take levodopa with food (reduces absorption slightly); add extra carbidopa; trimethobenzamide; domperidone (does not cross BBB). Avoid metoclopramide/ondansetron |
| Freezing of gait | Optimize levodopa timing; visual/auditory cues (laser pointer, metronome); PT for gait training; consider DBS if levodopa-responsive freezing |
💎 Board Pearl
- PD psychosis drug removal order: anticholinergics → DA agonists → MAO-B/COMT inhibitors → amantadine. Levodopa is the last drug to reduce (most effective, most needed).
- Pimavanserin = only FDA-approved drug for PD psychosis (no D2 blockade, won’t worsen parkinsonism).
- Never use haloperidol in PD (severe rigidity, NMS risk). Quetiapine and clozapine are the safest antipsychotics in PD.
Tremor Classification
| Type | Frequency | Activation | Key Features | Etiology / Notes |
|---|---|---|---|---|
| Essential Tremor | 4–12 Hz | Action (postural + kinetic) | Bilateral upper limbs; head tremor common; alcohol-responsive; ≥3 yr duration; no other neuro signs | AD family history ~50%; propranolol or primidone first-line; DBS (VIM thalamus) or MRgFUS for refractory |
| Enhanced Physiologic | 8–12 Hz | Postural | Fine, low-amplitude; worsened by anxiety, caffeine, hyperthyroidism, β-agonists, withdrawal | Remove offending cause; beta-blockers if needed |
| Parkinsonian | 4–6 Hz | Rest (pill-rolling); re-emergent postural | Asymmetric; suppressed by movement; re-emerges after latency with arms outstretched; worsens with contralateral distraction | PD, MSA-P; abnormal DaTscan; levodopa-responsive |
| Cerebellar (Intention) | 3–5 Hz | Intention (terminal kinetic) | Worsens approaching target; absent at rest; associated dysmetria/dysdiadochokinesia | Cerebellar lesion (MS, stroke, tumor, alcohol); ipsilateral to lesion |
| Holmes (Rubral/Midbrain) | <5 Hz | Rest + postural + intention (all three) | Large-amplitude; irregular; delayed onset (weeks–months after lesion) | Midbrain/thalamic lesion (stroke, MS); disrupts cerebello-thalamo-cortical + nigrostriatal circuits; often refractory |
| Dystonic Tremor | Variable (4–7 Hz) | Postural/kinetic; position-specific | Irregular, jerky; occurs in body part affected by dystonia; “null point” (position where tremor stops); DaTscan normal | Botulinum toxin; sensory tricks may reduce; often misdiagnosed as ET |
| Orthostatic Tremor | 13–18 Hz | Standing only | Subjective unsteadiness on standing; disappears sitting/walking; highest-frequency tremor on boards; diagnosed by surface EMG (pathognomonic) | Clonazepam or gabapentin first-line; often refractory |
| Palatal Tremor | 1–3 Hz | Continuous (persists in sleep) | Essential: tensor veli palatini, ear click, no olivary hypertrophy. Symptomatic: levator veli palatini, olivary hypertrophy on MRI (Guillain-Mollaret triangle lesion) | Persists in sleep (unique among tremors); botulinum toxin for symptomatic relief |
| Functional (Psychogenic) | Variable | Variable (rest, action, or both) | Entrainment (matches frequency of contralateral tapping); distractibility; sudden onset; variable frequency/direction; coactivation sign | DaTscan normal; PT + CBT; avoid unnecessary medications |
💎 Board Pearl
- DaTscan abnormal: PD, MSA, PSP, CBD, DLB. DaTscan normal: ET, enhanced physiologic, dystonic, drug-induced, functional.
- Orthostatic tremor (13–18 Hz) is the highest-frequency tremor — diagnosed by EMG, not visible to the eye.
- Holmes tremor is the only tremor present at rest AND posture AND intention (all three components).
- Guillain-Mollaret triangle: dentate nucleus → red nucleus → inferior olive. Lesion causes symptomatic palatal tremor + inferior olivary pseudohypertrophy on MRI.
Dystonia — Genetics & Classification
| Gene | Name / Syndrome | Inheritance | Age Onset | Distribution | Key Feature |
|---|---|---|---|---|---|
| DYT-TOR1A (DYT1) | Early-onset generalized dystonia | AD (30% penetrance) | Childhood (mean ~12 yr) | Limb → generalized | Most common hereditary dystonia; GAG deletion in TOR1A; Ashkenazi Jewish predilection |
| DYT-THAP1 (DYT6) | Adolescent-onset mixed dystonia | AD | Adolescence | Craniocervical + limb | Prominent laryngeal/oromandibular involvement; Amish-Mennonite |
| DYT-KMT2B (DYT28) | Childhood-onset generalized dystonia | AD (often de novo) | Childhood | Lower limb → generalized | Short stature; microcephaly; intellectual disability; excellent GPi-DBS response |
| DYT-SGCE (DYT11) | Myoclonus-dystonia | AD (maternal imprinting) | Childhood–teens | Upper body myoclonus + dystonia | Alcohol-responsive; psychiatric comorbidity (OCD, anxiety); disease only manifests when inherited from father |
| DYT-GCH1 (DYT5a) | Dopa-responsive dystonia (Segawa disease) | AD (higher penetrance in females) | Childhood (mean ~6 yr) | Lower limb → gait dystonia | Diurnal fluctuation (worse PM, better AM); dramatic sustained levodopa response at LOW doses; normal DaTscan |
| DYT-ATP1A3 (DYT12) | Rapid-onset dystonia-parkinsonism | AD | Teens–young adult | Rostrocaudal gradient (face > arm > leg) | Abrupt onset (hours–weeks) triggered by stress/fever; poor levodopa response; Na+/K+-ATPase α3 subunit |
| DYT-PRKRA (DYT16) | Young-onset dystonia-parkinsonism | AR | Childhood–teens | Generalized; prominent oromandibular/laryngeal | Brazilian families; progressive; poor levodopa response |
Clinical Pearl
Any child with limb dystonia and diurnal fluctuation deserves a levodopa trial. Dopa-responsive dystonia (GCH1) is treatable, progressive if missed, and can mimic cerebral palsy. Low-dose levodopa produces a dramatic, sustained response with NO dyskinesias.
💎 Board Pearl
- DYT-TOR1A (DYT1): Most common hereditary dystonia. Only 30% penetrance — GAG deletion, NOT a trinucleotide repeat expansion.
- DYT-SGCE: Maternal imprinting means disease only manifests when inherited from father (maternal allele silenced). Alcohol-responsive myoclonus-dystonia.
- GPi DBS for dystonia: benefit takes weeks to months (unlike STN DBS for PD which works immediately). Best response: DYT-TOR1A and DYT-KMT2B.
Chorea — Differential Diagnosis
| Cause | Key Clue | Test / Marker |
|---|---|---|
| Huntington Disease | AD; chorea + psychiatric + cognitive decline; caudate atrophy (→ ex vacuo hydrocephalus); onset 30–50 yr; medium spiny neurons lost | HTT gene CAG repeat ≥36 (full penetrance ≥40); genetic testing is diagnostic |
| Sydenham Chorea | Post-streptococcal (rheumatic fever); children; self-limited; “milkmaid grip”; darting tongue; emotional lability | ASO titer; anti-DNase B; anti-basal ganglia antibodies; part of Jones criteria |
| SLE / Antiphospholipid Chorea | Young woman; may be presenting feature of SLE; bilateral or unilateral | Antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, anti-β2GP1) |
| Wilson Disease | Age <40; liver disease + neuropsychiatric; wing-beating tremor; Kayser-Fleischer rings | Low ceruloplasmin (<20 mg/dL); high 24-hr urine copper (>100 µg); ATP7B genetic testing |
| Neuroacanthocytosis (ChAc) | Lip/tongue biting (self-mutilation); orofacial dyskinesias; seizures; myopathy; AR (VPS13A/chorein) | Acanthocytes on peripheral blood smear (fresh wet prep); elevated CK; caudate atrophy |
| McLeod Syndrome | X-linked (XK gene); chorea + cardiomyopathy + hemolytic anemia; late-onset (40s–60s); transfusion reaction risk | Weak Kx antigen / absent Kell; acanthocytes; elevated CK |
| Benign Hereditary Chorea | AD; childhood onset; non-progressive; thyroid + lung involvement (“brain-thyroid-lung” syndrome) | NKX2-1 (TITF1) gene mutation |
| Chorea Gravidarum | Chorea in pregnancy (usually 1st trimester); often history of Sydenham or APS; estrogen-mediated | Check antiphospholipid antibodies; self-resolves post-partum |
| Drug-Induced Chorea | Levodopa dyskinesias; neuroleptic withdrawal; OCP; stimulants; phenytoin | Temporal relationship to medication; resolves with dose adjustment |
| Hemiballismus | Sudden unilateral large-amplitude flinging; contralateral STN lesion (lacunar stroke most common); hyperglycemia in elderly diabetics | MRI brain (STN infarct); nonketotic hyperglycemia → T1 hyperintense contralateral putamen/caudate |
💎 Board Pearl
- Huntington CAG thresholds: <27 normal; 27–35 intermediate (no disease but unstable — may expand in offspring); 36–39 reduced penetrance; ≥40 full penetrance. Anticipation = earlier onset in successive generations (paternal transmission → larger expansions).
- Lip/tongue biting + chorea + elevated CK = neuroacanthocytosis. Order peripheral smear for acanthocytes (need fresh wet prep).
- Hemiballismus + T1-bright striatum on MRI = nonketotic hyperglycemia until proven otherwise — classic board vignette in elderly diabetic.
- Neuroacanthocytosis vs. McLeod: both have acanthocytes + chorea; McLeod = X-linked, cardiomyopathy, weak Kell antigens.
Myoclonus Classification
| Type | Origin | Distribution | Key Features | Example |
|---|---|---|---|---|
| Cortical | Sensorimotor cortex | Focal/multifocal; distal > proximal | Stimulus-sensitive; brief (<50 ms EMG burst); giant SEPs; EEG back-averaging shows cortical spike preceding jerk; enhanced C-reflex | Post-hypoxic myoclonus (Lance-Adams); PMEs (Unverricht-Lundborg, Lafora); CBD |
| Subcortical (Reticular) | Brainstem reticular formation | Generalized; proximal > distal; axial | Startle-sensitive; upward spread (legs → trunk → arms); no cortical correlate; EMG burst 50–100 ms | Hyperekplexia (glycine receptor mutations); reticular reflex myoclonus |
| Spinal (Segmental) | Spinal cord segment | Segmental (1–2 myotomes) | Rhythmic; persists in sleep; not stimulus-sensitive; no cortical correlate | Spinal cord lesion (tumor, myelitis, syrinx) |
| Propriospinal | Propriospinal pathways | Axial (trunk flexion) | Slow propagation; flexion jerks; prominent at rest/supine; often functional when no structural lesion found | Idiopathic/functional; spinal cord lesions |
| Opsoclonus-Myoclonus | Brainstem (omnipause neuron dysfunction) | Trunk/limb myoclonus + chaotic saccadic eye movements + ataxia | Paraneoplastic or post-infectious; “dancing eyes, dancing feet” | Children: neuroblastoma (~50%); Adults: breast, lung, ovarian (anti-Ri, anti-ANNA-2) |
Clinical Pearl
Opsoclonus-myoclonus in a child mandates workup for neuroblastoma — urine catecholamines, CT/MRI abdomen, MIBG scan. ~50% of pediatric cases are paraneoplastic. In adults, consider breast, lung, or ovarian malignancy.
💎 Board Pearl
- Giant SEPs = cortical myoclonus — pathognomonic finding on neurophysiology.
- Lance-Adams syndrome: post-hypoxic action myoclonus (cortical) after cardiac arrest survivors regain consciousness. Treat with levetiracetam, valproate, or clonazepam.
- Spinal myoclonus persists in sleep (unlike cortical) — key differentiator.
- Negative myoclonus: sudden loss of muscle tone = asterixis (hepatic encephalopathy, uremia).
- Lafora body disease: PME + PAS-positive polyglucosan inclusions on skin biopsy = diagnostic.
Wilson Disease & NBIA
| Disorder | Gene | Protein / Pathway | Key Lab / MRI Finding | Treatment |
|---|---|---|---|---|
| Wilson Disease | ATP7B (AR) | Copper-transporting ATPase → impaired biliary copper excretion | Low ceruloplasmin (<20 mg/dL); high 24-hr urine Cu (>100 µg); KF rings (slit lamp in >95% neuro Wilson); MRI: “face of the giant panda” (midbrain), T2 putaminal hyperintensity | Trientine (preferred for neuro Wilson) or penicillamine (chelators); zinc (blocks GI absorption, maintenance); liver transplant for fulminant hepatic failure |
| PKAN (NBIA1) | PANK2 (AR) | Pantothenate kinase 2 → CoA synthesis → iron accumulation in globus pallidus | MRI: “Eye of the tiger” sign — T2 hypointense GP with central hyperintensity (gliosis/edema) | No disease-modifying therapy; GPi DBS for dystonia; baclofen; botulinum toxin |
| PLA2G6-associated (NBIA2 / PLAN) | PLA2G6 (AR) | Phospholipase A2 → membrane phospholipid metabolism | MRI: cerebellar atrophy (early); GP iron; no eye of the tiger; infantile neuroaxonal dystrophy (INAD) in severe form | Supportive; no specific therapy |
| Neuroferritinopathy | FTL (AD — only AD form of NBIA) | Ferritin light chain → iron aggregation in basal ganglia | Low serum ferritin (unique clue); MRI: cystic cavitation of basal ganglia with iron deposition | Supportive |
| Aceruloplasminemia | CP (AR) | Ceruloplasmin → ferroxidase deficiency → iron accumulation (brain + liver + retina) | Absent serum ceruloplasmin; low serum iron + high ferritin; diabetes; retinal degeneration; MRI: diffuse iron (basal ganglia + dentate + thalami) | Iron chelation (desferrioxamine); fresh frozen plasma (ceruloplasmin source) |
| BPAN | WDR45 (X-linked dominant) | Autophagy pathway | MRI: T1 hyperintense “halo” surrounding SN + cerebral peduncles; iron in GP + SN | Supportive; predominantly affects females (de novo); childhood stagnation → adult-onset parkinsonism-dystonia-dementia |
💎 Board Pearl
- “Eye of the tiger” on MRI = PKAN (PANK2). T2-weighted: hypointense GP (iron) with central hyperintensity (gliosis). Pathognomonic.
- Wilson disease: Screen any patient <50 with unexplained movement disorder + liver disease or psychiatric symptoms. KF rings present in >95% with neurologic Wilson.
- Neuroferritinopathy = only AD NBIA. All others are AR or X-linked. Low serum ferritin is the clue.
- Penicillamine can worsen neurological Wilson initially (10–50%) — trientine is preferred for neurological presentations.
Hereditary Ataxias
| Disorder | Gene / Repeat | Inheritance | Key Features | Distinguishing Clue |
|---|---|---|---|---|
| Friedreich Ataxia | FXN (GAA repeat, intron 1) | AR | Onset <25 yr; gait/limb ataxia; absent DTRs + Babinski; hypertrophic cardiomyopathy; scoliosis; pes cavus; diabetes | Most common hereditary ataxia; GAA in intron (gene silencing, NOT toxic protein); no anticipation; cardiomyopathy = #1 COD; omaveloxolone (FDA-approved) |
| SCA1 | ATXN1 (CAG) | AD | Cerebellar ataxia; pyramidal signs; early bulbar; cognitive decline | Prominent pyramidal signs (hyperreflexia); faster progression than other SCAs |
| SCA2 | ATXN2 (CAG) | AD | Cerebellar ataxia; slow saccades; hyporeflexia; peripheral neuropathy | Slow saccades (most prominent among SCAs); may present as parkinsonism; ATXN2 intermediate expansions = ALS risk factor |
| SCA3 / MJD | ATXN3 (CAG) | AD | Ataxia; spasticity; dystonia; bulging eyes; faciolingual fasciculations | Most common AD SCA worldwide; Portuguese/Azorean heritage; wide phenotypic spectrum |
| SCA6 | CACNA1A (CAG, small ~20–33) | AD | Pure cerebellar ataxia; late onset (>50 yr); very slow progression | Allelic with EA2 and FHM1 (all CACNA1A); smallest pathogenic CAG expansion; pure cerebellar |
| SCA7 | ATXN7 (CAG) | AD | Cerebellar ataxia + progressive visual loss (cone-rod dystrophy) | Only SCA with retinal degeneration; severe anticipation (infantile cases from paternal transmission) |
| Ataxia-Telangiectasia | ATM (loss-of-function) | AR | Onset 1–3 yr; ataxia; oculomotor apraxia; conjunctival telangiectasias; immunodeficiency (low IgA) | Elevated AFP; radiosensitivity; lymphoma/leukemia risk; ATM heterozygotes → increased breast cancer risk |
| AOA1 | APTX (aprataxin) | AR | Ataxia + oculomotor apraxia; peripheral neuropathy; chorea early | Low albumin; high cholesterol; AFP normal (unlike AT) |
| AOA2 | SETX (senataxin) | AR | Ataxia + oculomotor apraxia; later onset than AOA1 (teens); neuropathy | Elevated AFP (like AT but no telangiectasias, no immunodeficiency); SETX also linked to ALS4 |
| Episodic Ataxia 1 | KCNA1 (K+ channel) | AD | Brief attacks (seconds–minutes); myokymia between attacks | Interictal myokymia (continuous muscle rippling); carbamazepine effective |
| Episodic Ataxia 2 | CACNA1A (Ca2+ channel) | AD | Longer attacks (hours); interictal downbeat nystagmus; triggered by stress/exercise | Allelic with SCA6 and FHM1; acetazolamide-responsive |
| MSA-C | Sporadic (α-synuclein) | Sporadic | Progressive cerebellar ataxia + autonomic failure; older adult | Hot cross bun sign on MRI; no family history; autonomic failure distinguishes from genetic SCAs |
| FXTAS | FMR1 premutation (55–200 CGG) | X-linked | Males >50; intention tremor + gait ataxia + cognitive decline | FMR1 premutation carriers (NOT full mutation); MRI: MCP sign (T2 hyperintense middle cerebellar peduncles); grandfathers of fragile X children |
💎 Board Pearl
- Friedreich ataxia: AR, most common hereditary ataxia. Absent DTRs + Babinski + cardiomyopathy + diabetes + scoliosis in a teenager. GAA repeat in intron (gene silencing) — no anticipation.
- SCA6 / EA2 / FHM1 are all CACNA1A — allelic disorders. Classic board association.
- SCA7 = only SCA with vision loss (retinal degeneration). SCA2 = slow saccades. SCA3 = most common worldwide.
- Elevated AFP in ataxia: AT (+ telangiectasias + immunodeficiency) or AOA2 (no telangiectasias, no immunodeficiency).
- FXTAS vs Fragile X: Premutation (55–200) = tremor/ataxia in older adults. Full mutation (>200) = intellectual disability in children.
Drug-Induced Movement Disorders
| Drug / Class | Movement Disorder | Mechanism | Treatment |
|---|---|---|---|
| Typical antipsychotics (haloperidol, chlorpromazine) | Acute dystonia; parkinsonism; akathisia; tardive dyskinesia; NMS | D2 receptor blockade (striatal) | Dystonia: IV diphenhydramine/benztropine. Parkinsonism: amantadine/anticholinergics. Akathisia: propranolol. TD: VMAT2 inhibitors. NMS: dantrolene + bromocriptine |
| Atypical antipsychotics | Lower but NOT zero EPS/TD risk; clozapine & quetiapine = lowest risk | D2 + 5-HT2A blockade | Switch to quetiapine/clozapine if EPS develop |
| Metoclopramide | Acute dystonia; parkinsonism; akathisia; tardive dyskinesia (all four) | D2 blockade (crosses BBB) | Avoid prolonged use (>12 weeks); VMAT2 inhibitors for TD |
| SSRIs / SNRIs | Tremor; akathisia; serotonin syndrome; bruxism; myoclonus | Increased serotonergic tone | Dose reduction; switch agents; cyproheptadine for serotonin syndrome |
| Valproate | Postural tremor (dose-dependent); parkinsonism (reversible) | Unknown; possibly GABAergic | Dose reduction; propranolol for tremor; discontinue if parkinsonism |
| Lithium | Postural/action tremor (common); myoclonus; cerebellar ataxia (toxicity) | Enhanced physiologic tremor | Dose reduction; propranolol; check levels (ataxia = toxicity) |
| Levodopa | Peak-dose dyskinesias (choreiform); diphasic dyskinesias; wearing-off dystonia (foot) | Pulsatile dopaminergic stimulation → receptor sensitization | Amantadine (only FDA-approved for levodopa dyskinesias); COMT/MAO-B inhibitors; DBS |
| Amiodarone | Action tremor; cerebellar ataxia; peripheral neuropathy | Direct neurotoxicity (iodinated; half-life ~40–55 days) | Discontinue; may persist due to extremely long half-life |
Clinical Pearl
NMS = rigidity + fever + AMS + elevated CK. Mortality 10–20%. Stop offending agent immediately. Treat with dantrolene (muscle relaxant) + bromocriptine (DA agonist) + aggressive cooling/hydration. Watch for rhabdomyolysis → acute renal failure. NMS can also occur from abrupt levodopa withdrawal in PD patients — never stop dopaminergic drugs suddenly.
💎 Board Pearl
- Anticholinergics worsen TD but help acute dystonic reactions and tardive dystonia — critical board distinction.
- Amantadine is the only FDA-approved drug for levodopa-induced dyskinesias.
- Drug-induced parkinsonism: bilateral, symmetric, DaTscan normal, resolves after drug withdrawal (may take months).
- Apomorphine + ondansetron = contraindicated (severe hypotension). Use trimethobenzamide for nausea.
Serotonin Syndrome vs NMS vs Malignant Hyperthermia
| Feature | NMS | Serotonin Syndrome | Malignant Hyperthermia |
|---|---|---|---|
| Cause | D2 blockers (antipsychotics, metoclopramide) or abrupt dopamine drug withdrawal | Serotonergic drugs (SSRIs + MAOIs, tramadol + SSRI, linezolid + SSRI) | Volatile anesthetics (halothane, sevoflurane) or succinylcholine |
| Onset | Days to weeks (slow) | Hours (rapid, within 24 hr of drug change) | Minutes to hours (intraoperative) |
| Rigidity type | Lead-pipe rigidity (severe, generalized) | Rigidity + clonus (especially lower extremity) + hyperreflexia | Generalized muscle rigidity (masseter spasm early) |
| Reflexes | Normal to decreased | Hyperreflexia + clonus (key distinguishing feature) | Decreased (late) |
| Pupils | Normal | Mydriasis (dilated) | Normal |
| Diaphoresis | Present | Profuse | Present |
| CK | Markedly elevated (often >1000; rhabdomyolysis) | Mildly elevated (usually <1000) | Markedly elevated |
| Treatment | Dantrolene + bromocriptine; stop offending agent; cooling; IV fluids | Cyproheptadine (5-HT2A antagonist); stop serotonergic agents; benzodiazepines; cooling | Dantrolene (first-line); stop volatile anesthetic; cooling; hyperventilate |
| Genetics | None (idiosyncratic) | None (pharmacologic) | RYR1 mutation (AD); ryanodine receptor; caffeine-halothane contracture test |
💎 Board Pearl
- Clonus + hyperreflexia = serotonin syndrome. Lead-pipe rigidity + bradyreflexia = NMS. This is the #1 differentiator on boards.
- Onset speed: MH = minutes (intraoperative); serotonin syndrome = hours; NMS = days to weeks.
- Dantrolene works for NMS and MH (both involve muscle rigidity). Cyproheptadine is specific to serotonin syndrome.
- Bowel sounds: Increased in serotonin syndrome (diarrhea); decreased in NMS.
Key Numbers & Board Traps
| Fact | Value / Detail |
|---|---|
| PD motor diagnostic criteria | Bradykinesia (mandatory) + rest tremor OR rigidity |
| PD rest tremor frequency | 4–6 Hz |
| Hoehn-Yahr stages | 1 = unilateral; 2 = bilateral, no balance impairment; 3 = bilateral + postural instability; 4 = severe disability, can still stand/walk; 5 = wheelchair/bedridden |
| Huntington CAG — normal | <27 repeats |
| Huntington CAG — intermediate | 27–35 (no disease, may expand in offspring) |
| Huntington CAG — reduced penetrance | 36–39 |
| Huntington CAG — full penetrance | ≥40 repeats |
| Wilson ceruloplasmin cutoff | <20 mg/dL (suggestive); 24-hr urine copper >100 µg/day |
| Friedreich GAA repeat | Normal ≤33; pathologic ≥66 (typically 600–1200) |
| Essential tremor criteria | Bilateral action tremor of upper limbs; ≥3 years duration; ± head tremor without dystonia |
| Tardive dyskinesia definition | D2 blocker exposure ≥3 months (or ≥1 month if age >60) |
| Orthostatic tremor frequency | 13–18 Hz (highest-frequency tremor on boards) |
| DBS target — PD | STN (most common; allows medication reduction) or GPi (better for dyskinesias; preferred if cognitive/behavioral concerns) |
| DBS target — Essential Tremor | VIM (ventral intermediate nucleus of thalamus); also MRgFUS |
| DBS target — Dystonia | GPi (globus pallidus internus); best response in DYT-TOR1A and DYT-KMT2B; delayed benefit (weeks–months) |
| PDD vs DLB — 1-year rule | Dementia within 1 yr of parkinsonism = DLB; dementia ≥1 yr after established motor PD = PDD |
| LRRK2 | Most common genetic cause of familial PD (AD); Ashkenazi Jewish and North African Berber |
| GBA (glucocerebrosidase) | Most common genetic risk factor for PD (not fully penetrant); linked to Gaucher disease |
| Parkin (PARK2) | Most common cause of AR young-onset PD (<40 yr); slow progression; dystonia at onset |
| SCA3 (MJD) | Most common AD SCA worldwide |
| CACNA1A allelic disorders | SCA6 + EA2 + FHM1 — same gene, three diseases |
| VMAT2 inhibitors for TD | Valbenazine (Ingrezza, once daily) and deutetrabenazine (Austedo, requires CYP2D6 genotyping) — FDA-approved |
| Tetrabenazine vs deutetrabenazine | Tetrabenazine = Huntington chorea (FDA). Deutetrabenazine = TD + Huntington (FDA). Valbenazine = TD only (FDA). |
💎 Board Pearl
- DBS targets: STN/GPi for PD, VIM for ET, GPi for dystonia.
- Board trap: DaTscan cannot distinguish PD from MSA/PSP/CBD — it only separates degenerative parkinsonism from non-degenerative (ET, drug-induced, functional).
- Board trap: Anticholinergics help acute dystonia and tardive dystonia but worsen tardive dyskinesia.
- Board trap: Friedreich ataxia has absent DTRs (sensory neuropathy) but upgoing toes (corticospinal degeneration) — mixed upper + lower motor neuron signs.
- Board trap: GPi DBS benefit in dystonia takes weeks to months (unlike PD DBS which works immediately).
- Board trap: Never abruptly stop levodopa/DA agonists in PD patients — risk of NMS / parkinsonism-hyperpyrexia syndrome.