Chorea

Feature

Detail

Origin

Greek word for “dance”

Definition

Hyperkinetic involuntary movement — non-rhythmic, jerky, semi-purposeful, random and flowing in nature

Site of lesion

Caudate nucleus (striatum)

Hemiballism → contralateral subthalamic nucleus (STN)

Parakinesia

Chorea camouflaged by blending it into seemingly voluntary gestures (touching face, adjusting glasses)

Motor impersistence

Cannot sustain a movement — forced eye closure, mouth open, tongue protrusion

Chorea vs ballism

Overlap and coexist; ballism = high-amplitude, proximal, flinging; often evolves into chorea

Category

Examples

Structural lesion

Vascular: ischemic and hemorrhagic stroke, vascular malformation (e.g., Moyamoya)

Tumors

Demyelinating lesions

Metabolic / endocrine

Nonketotic hyperglycemia

Hypoglycemia

Hypocalcemia

Hyponatremia / hypernatremia

Uremia

Acquired hepatocerebral degeneration

Hyperthyroidism

Hypo- / hyperparathyroidism

Infectious

Toxoplasmosis

HIV encephalopathy

Prion diseases

Drug-induced

Levodopa

Cocaine (“crack-dancing”)

Amphetamine

Anticonvulsants

Lithium

Anticholinergics

Neuroleptic withdrawal; tardive chorea

Autoimmune / paraneoplastic

Sydenham chorea

SLE, antiphospholipid antibody syndrome, systemic sclerosis

Autoimmune neurologic syndromes: anti-CRMP-5, anti-NMDA, anti-Hu (ANNA-1), anti-Yo, anti-LGI1, anti-CASPR2, anti-GAD65, anti-IgLON5

Other

Polycythemia vera

Chorea gravidarum (pregnancy), estrogen / oral contraceptives

Disorder

Gene / inheritance

Key clue

Huntington disease

HTT (IT15), chr 4p; CAG; AD

Most common adult genetic cause; chorea + psychiatric + subcortical dementia

C9orf72 disease

GGGGCC hexanucleotide; AD

Most common HD phenocopy; can mimic HD on MRI

SCA17 (HDL4)

TBP; CAG; AD

Chorea + ataxia + dementia

HDL1 / HDL2 / HDL3

PRNP / Junctophilin-3 (CTG/CAG) / rare

HD-like syndromes

DRPLA

ATN1, chr 12; CAG; AD

Chorea, ataxia, myoclonic epilepsy; Japan; Haw River

Chorea-acanthocytosis

VPS13A (CHAC), chr 9; AR

Feeding dystonia, lip/tongue biting, ↑CK, acanthocytes

McLeod syndrome

XK gene; X-linked recessive

Kell antigen; neuropathy, cardiomyopathy, hemolysis, ↑CK

Benign hereditary chorea

NKX2-1 (TITF1); AD

Most common genetic chorea in children; brain-lung-thyroid

ADCY5-related

ADCY5

Episodic fluctuating chorea; misdiagnosed as dyskinetic CP

PDE2A-related

PDE2A; AR (homozygous LoF)

Early-onset hereditary chorea

PKAN (NBIA)

PANK2; AR

Pantothenate kinase-associated neurodegeneration; NBIA; “eye-of-the-tiger” MRI; orobuccolingual dystonia

Lesch-Nyhan

HPRT1; X-linked

Orobuccolingual dystonia, self-injury

Time course

Group

Age

Think first

Acute / subacute

Sporadic

Adult

Structural, metabolic, autoimmune, infection, drugs

Acute / subacute

Sporadic

Children

Sydenham chorea → others

Chronic (>1 year)

Genetic

Adult

1. Huntington disease

2. C9orf72 disease

3. SCA17

→ others

Chronic (>1 year)

Genetic

Children

Benign hereditary chorea (most common genetic cause in children) → others

Point

Detail

Best test for suspected HD

Genetic testing (CAG repeat analysis) — most cost-effective

Negative family history

Early parental death, misdiagnosis, denial, non-paternity, new mutation from intermediate allele

Region

Suggests

Forehead

Huntington disease

Orobuccolingual

Tardive chorea

Acquired hepatocerebral degeneration

Chorea-acanthocytosis (feeding chorea)

Lesch-Nyhan syndrome (dystonia)

PKAN (dystonia)

Lubag (dystonia)

Hemichorea

Structural lesion on the contralateral side

Nonketotic hyperglycemia

Polycythemia vera

Sydenham chorea

Other

Feature

Detail

First described

George Huntington (1872), Long Island, New York

Prevalence

~10/100,000 (Harrison: 2–8/100,000); common in Scotland, Venezuela; rare in Finland, China, Japan, Black South Africans

Onset

30–55 years (Harrison: 25–45; range 2–92); ~5% before age 21

Mutation

Unstable CAG repeat, exon 1 of HTT, tip of short arm chr 4; AD, high penetrance

Anticipation

Paternal — instability greater in spermatogenesis; juvenile HD almost always from father

Mechanism

Homozygotes not more severe → toxic gain of function

Predictive value

CAG length explains only 50–70% of onset variance — poor individual predictor

CAG repeats

Interpretation

<27

Normal

27–36

Intermediate — may expand into disease range in offspring; rare clinical cases

36–41

Very late-onset disease

≥37

Pathogenic

≥60

Juvenile onset

≥80

Onset within the first decade

Feature

Detail

Presentation

Motor alone ~60%, behavioural alone ~15%, both ~25% (onset is a “zone”)

Earliest sign

Impaired saccade generation (initiation, speed); later blink/head thrust; smooth-pursuit intrusions, impaired convergence

Early motor

Clumsiness, fidgetiness → chorea; focal/segmental → generalised

Late motor

Chorea lessens; dystonia, rigidity, bradykinesia, myoclonus

Gait

“Marionette” — lurching, swaying, dipping, bobbing; tandem impossible

Systemic

Progressive weight loss predicts decline; NIDDM

Outcome

Death from pneumonia, head injury; mean survival ~17 years

Westphal variant

Juvenile (~10%): akinetic-rigid parkinsonism, dystonia, myoclonus, seizures, cognitive decline

Feature

Detail

Frequency

98% have ≥1 behavioural symptom; may precede motor HD by up to a decade

Early

Irritability, anxiety, mood disturbance

Mood / psychosis

Major depression ~30%; mania less common; psychosis rare; OCD; apathy near-universal late

Suicide

~6-fold — unmarried, childless, living alone, depressed, family history of suicide

Cognition

Subcortical dementia — attention, motivation, insight, judgement, problem-solving; no aphasia/apraxia

Feature

Detail

MRI / CT

Caudate + putamen atrophy — not specific; volume falls even presymptomatically

PET

[¹¹C]-Raclopride: progressive loss of D2-bearing striatal neurons; ↓ glucose metabolism

SSEP

Abnormal in ~94%

Gross pathology

Caudate/putamen neuronal loss + gliosis; ~20% brain weight loss; cortex layer VI, thalamus, SNr, hypothalamus

Neurons lost

Indirect-pathway GABAergic MSNs first → chorea; direct later → parkinsonism; juvenile = both from start

Mechanisms

Mutant HTT aggregates, mitochondrial complex II–IV dysfunction, indirect excitotoxicity (NMDA, loss of Mg²⁺ block), ↓ BDNF, apoptosis

Feature

Detail

Counselling

Genetic + psychological, before and after; asymptomatic minors not tested

Risks

Severe adverse outcome <1%; “survivor guilt” after negative result

Agent

Detail

Disease-modifying

None proven; CoQ10 and remacemide not significant

VMAT2 inhibitors

Tetrabenazine, deutetrabenazine — FDA-approved; drowsiness, parkinsonism, depression, akathisia; no tardive dyskinesia

Amantadine

Up to 400 mg — may improve chorea

Neuroleptics

Reduce chorea, no functional benefit; quetiapine for irritability/aggression

SSRIs / carbamazepine

Irritability, aggression, depression, OCD

Tominersen (ASO)

Phase 1–2a: up to 38% ↓ CSF mutant HTT; phase 3 (GENERATION HD1) halted 2021 for lack of benefit

Feature

Detail

Distribution

Mainly Japan; also North Carolina — “Haw River syndrome”

Genetics

CAG expansion, chromosome 12 (ATN1); normal 7–23, DRPLA 49–75; AD with paternal anticipation

Clinical

Chorea, ataxia, myoclonic epilepsy, dystonia, parkinsonism, psychosis, dementia

Age-dependent

Younger onset → progressive myoclonic epilepsy

Older onset → ataxia + chorea(-athetosis) + dementia

Course

Onset in the 20s; death ~20 years later

Pathology

Dentate and red nuclei, GP, STN; ubiquitin / atrophin-1 nuclear inclusions

Haw River variant

Same expansion; no myoclonic epilepsy; white-matter demyelination, BG calcification, neuroaxonal dystrophy

Treatment

Symptomatic, as in HD

Feature

Detail

Acanthocyte

Greek “thorn” — contracted RBC with uneven thorny projections

Seen in

Abetalipoproteinemia, neuroacanthocytosis, McLeod syndrome

Feature

Chorea-acanthocytosis

McLeod syndrome

Inheritance / gene

AR; VPS13A (CHAC), chr 9 → chorein

X-linked recessive; XK gene (Kell antigen)

Onset

~35 years

~50 years; slowly progressive

Movement

Chorea, dystonia, tics; parkinsonism later

“Feeding dystonia” (tongue protrusion), lip/tongue biting, dysarthria, dysphagia

Limb chorea; facial tics; oral movements less common; some dystonia

Neuromuscular

Myopathy or axonal neuropathy; ↑CK

Axonal neuropathy (commonest); myopathy; CK always ↑

Other

HD-like behaviour; seizures ~50%; late dementia; acanthocytes 5–20%

Seizures; subcortical dementia ~50%; cardiomyopathy, hemolytic anemia

Imaging / pathology

Atrophy of caudate, putamen, GP, SN; cortex spared

Caudate atrophy; T2 ↑ lateral putamen

Feature

Detail

Association

Major manifestation of rheumatic fever; months after streptococcal infection

Who

Children, mainly girls 5–15 y (mean 8.4 y); rare in developed countries

Course

Insidious, progresses over weeks, resolves ~6 months; ~20% recur

Distribution

Generalised; asymmetric or hemichorea possible

Accompaniments

Restlessness, irritability, obsessive-compulsive traits

Investigations

MRI: mild BG enlargement; anti-basal ganglia antibodies (ELISA, Western blot)

Mechanism

Molecular mimicry — streptococcal antibodies cross-react with striatum

Treatment

Valproate best → carbamazepine → haloperidol; VMAT2 inhibitors now drug of choice; IV methylprednisolone → oral prednisone if refractory; wean periodically

Recurrence

Chorea gravidarum, estrogen / OCP

Type

Examples

Systemic

SLE, antiphospholipid antibody syndrome

Paraneoplastic

Anti-CRMP-5, anti-Hu, etc.

Encephalitis

Anti-NMDAR encephalitis

Disorder

Key points

Benign hereditary chorea (NKX2-1 disease)

AD; NKX2-1 (TITF1) → “brain-lung-thyroid syndrome”

Childhood onset; originally thought non-progressive

Hypotonia, delayed walking, dystonia, myoclonus, tics, ADHD

ADCY5-related

Episodic, fluctuating chorea; dystonia, myoclonus

Cognitive decline, delayed milestones, hypotonia, ataxia, falls, myopathy-like facies

Misdiagnosed as dyskinetic cerebral palsy

PDE2A-related

Homozygous loss-of-function → early-onset hereditary chorea

Feature

Detail

Definition

High-amplitude, proximal, flinging limb movements; hemiballism / paraballism / biballism

Evolution

Acute ballism often replaced by chorea

Lesion

Contralateral STN ~20%; no MRI lesion ~20%; else STN afferent/efferent; rarely ipsilateral

Age clue

Elderly → cerebrovascular; younger → infectious / inflammatory

Mechanism

↓ STN excitation of GPi → ↓ thalamic inhibition → excess movement

Onset

Stroke: sudden, or emerges in recovering plegic limb

Prognosis

Regresses or becomes choreic over months

Treatment

Dopamine antagonists, VMAT2 inhibitors, gabapentin, valproate

Category

Causes

Cerebrovascular

Infarction, TIA, hemorrhage, AVM, SAH, subclavian steal

Infection

Syphilis, tuberculoma, toxoplasmosis, AIDS, influenza A

Tumor

Pituitary microadenoma, metastasis

Immune-mediated

SLE, Sydenham chorea, Behçet disease, scleroderma

Metabolic

Nonketotic hyperosmolar hyperglycemia

Drug-induced

Phenytoin and other anticonvulsants, oral contraceptives, neuroleptics (tardive)

Other

Static encephalopathy, head injury, demyelination, thalamotomy, heredodegenerative disease

Approach

Detail

Treat the cause

Correct metabolic derangement, withdraw offending drug, treat autoimmune disease

VMAT2 inhibitors (first line)

Tetrabenazine, deutetrabenazine, valbenazine — no TD; watch depression/suicidality, parkinsonism, akathisia, drowsiness

Neuroleptics

Effective but rarely used — parkinsonism, TD; no functional benefit in HD

Amantadine

Up to 400 mg/day in HD

Antiepileptics

Valproate (best in Sydenham), carbamazepine; gabapentin / valproate in ballism

Immunotherapy

Steroids for refractory Sydenham; autoimmune / paraneoplastic chorea

Domain

Practical point

Definition

Non-rhythmic, jerky, semi-purposeful, flowing; caudate; parakinesia, motor impersistence

First step

Time course: acute/subacute = sporadic; chronic >1 year = genetic

Adult genetic

HD → C9orf72 → SCA17

Child

Acute → Sydenham; chronic → benign hereditary chorea (NKX2-1)

Distribution

Forehead = HD; orobuccolingual = tardive, AHD, chorea-acanthocytosis; hemichorea = contralateral lesion, NKH, PV

HD

CAG ≥37 pathogenic, ≥60 juvenile; paternal anticipation; earliest = impaired saccades; survival ~17 y; suicide ×6

DRPLA

CAG chr 12; chorea + ataxia + myoclonic epilepsy; Japan / Haw River

Acanthocytes

Chorea-acanthocytosis (AR, VPS13A, feeding dystonia) vs McLeod (XLR, XK, cardiomyopathy, hemolysis); both ↑CK

Sydenham

Girls 5–15; months after strep; resolves ~6 months; valproate best; chorea gravidarum

Hemiballism

Contralateral STN (~20%); stroke in elderly; NKH

Treatment

VMAT2 inhibitors first line — no TD, monitor mood; treat cause