Chorea: A Comprehensive Overview

Definition and Etymology

• Adams and Victor's Principles of Neurology, p. 92
• Localization in Clinical Neurology, p. 1101

Clinical Features

Core Motor Characteristics

• Movements are arrhythmic, rapid, and jerky, variable in distribution across body regions
• Often semi-purposeful in appearance: patients may incorporate involuntary movements into deliberate acts (termed parakinesia) to make them less conspicuous
• Movements cease during sleep, worsen with stress or anxiety, and typically do not interfere with voluntary movement during quiet periods
• Associated with hypotonia: limbs are slack, and knee jerks are pendular (the leg swings several times rather than once on patellar tendon tap)

Distribution Patterns

• Truncal predominance: characteristic of Huntington disease
• Distal appendicular predominance: characteristic of Sydenham chorea
• Hemichorea: unilateral involvement, usually due to structural lesions (stroke, tumor)
• Generalized chorea: bilateral, seen in most metabolic and hereditary causes

Associated Signs

• Milkmaid's grip: inability to sustain a tight handgrip; the grip alternately tightens and relaxes
• Trombone tongue (flycatcher tongue): the tongue cannot remain protruded steadily and darts irregularly in and out
• Facial grimacing and abnormal respiratory sounds
• Motor impersistence: inability to maintain sustained voluntary movements (e.g., prolonged eye closure, sustained mouth opening)

Distinguishing Chorea from Related Disorders

Pathophysiology

Normal Basal Ganglia Circuit

• Direct pathway (striatum → GPi/SNr): inhibits the thalamus less, promoting movement
• Indirect pathway (striatum → GPe → STN → GPi/SNr): increases inhibition of the thalamus, suppressing unwanted movements

Mechanism of Chorea

1. Reduced inhibition of GPe → GPe becomes overactive
2. Overactive GPe inhibits the subthalamic nucleus (STN)
3. Reduced STN activity leads to less excitation of GPi/SNr
4. GPi/SNr (the output nuclei) become under-active
5. Result: disinhibition of the thalamus → thalamocortical circuits are released from inhibitory control → involuntary, excessive motor output

• Eric Kandel, Principles of Neural Science, 6th Edition, p. 995-996
• Localization in Clinical Neurology, p. 1101

Etiology and Classification

1. Inherited / Hereditary Causes

Autosomal Dominant

• Huntington disease (HD): the most common hereditary cause; CAG trinucleotide repeat expansion in the HTT gene on chromosome 4p; normal: 10-29 repeats; pathological: >36 repeats; longer repeats = earlier onset
• Huntington disease-like disorders (HDL 1, 2, 4):
  • HDL-2: CTG/CAG expansion in junctophilin-3 gene; predominantly in patients of African descent; presents with chorea, dystonia, acanthocytosis
  • HDL-4/SCA17: expansion in the TBP gene (TATA box-binding protein)
  • HDL-1: octapeptide repeat in PRNP (a prion disease)
• Dentatorubropallidoluysian atrophy (DRPLA)
• Spinocerebellar ataxias (SCA3/Machado-Joseph disease, SCA17)
• Neuroferritinopathy
• Benign hereditary chorea (BHC / NKX2-1 disease): mutations in the NKX2-1 (TITF1) gene; childhood-onset, non-progressive, associated with thyroid and pulmonary abnormalities ("brain-thyroid-lung / BLT syndrome")
• ADCY5 mutations: episodic and fluctuating chorea, dystonia, myoclonus; frequently misdiagnosed as dyskinetic cerebral palsy

Autosomal Recessive

• Neuroacanthocytosis (chorea-acanthocytosis): mutations in VPS13A (chorein); chorea with orolingual dystonia, self-mutilation, seizures, peripheral neuropathy, acanthocytes on blood smear
• Wilson disease: copper metabolism disorder (ATP7B mutations); chorea, dystonia, Kayser-Fleischer rings
• Lesch-Nyhan syndrome: HGPRT deficiency; chorea, self-mutilation, hyperuricemia
• Ataxia telangiectasia
• Pantothenate kinase-associated neurodegeneration (PKAN)
• Lysosomal disorders (Niemann-Pick, etc.)
• Organic acidurias (glutaric aciduria type 1, propionic acidemia, methylmalonic acidemia)
• Porphyria, urea cycle disorders, Leigh syndrome

X-linked

• McLeod syndrome: XK gene mutations; chorea, axonal neuropathy, cardiomyopathy, hemolytic anemia; onset ~age 50; related to Kell blood group antigens

2. Immune-Mediated Chorea

• Sydenham chorea (SC): post-group A streptococcal infection; most common acquired chorea in children (see dedicated section below)
• PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections)
• Systemic lupus erythematosus (SLE): the most common systemic disorder associated with chorea
• Antiphospholipid syndrome (APS): may occur with or without SLE
• NMDA receptor antibody encephalitis: chorea is a prominent feature
• Paraneoplastic syndromes: anti-CRMP-5 or anti-Hu antibodies; associated with lung carcinoma
• Sjögren's syndrome

3. Drug-Induced Chorea

• Levodopa / dopamine agonists: levodopa-induced dyskinesia is the most common drug cause in adults
• Neuroleptics (phenothiazines, haloperidol, metoclopramide): acute or tardive dyskinesia
• Anticonvulsants: phenytoin, carbamazepine, valproate (rare)
• Oral contraceptives / estrogens
• Stimulants: cocaine, amphetamines
• Lithium, digoxin, tricyclic antidepressants, pemoline
• Antiparkinsonian medications

4. Metabolic / Toxic Causes

• Thyrotoxicosis (hyperthyroidism)
• Hyperosmolar non-ketotic hyperglycemia: hemichorea-hemiballismus is a well-recognized presentation
• Hypoglycemia
• Polycythemia vera (rubra)
• Hypo- and hypernatremia
• Hypoparathyroidism / hypocalcemia
• Hepatic failure (acquired hepatocerebral degeneration)
• Alcohol, carbon monoxide poisoning, heavy metal poisoning

5. Structural / Vascular Causes (Hemichorea)

• Stroke (ischemic or hemorrhagic): especially subthalamic nucleus lesions cause hemiballismus
• Tumor
• Vascular malformation
• Hyperglycemic hemichorea: characteristic MRI showing T1 hyperintensity in the putamen

6. Infectious Causes

• Sydenham chorea (post-streptococcal)
• HIV/AIDS: toxoplasmosis; HIV encephalopathy
• Creutzfeldt-Jakob disease
• Herpes simplex encephalitis (post-encephalitic chorea)

7. Special Clinical Contexts

• Chorea gravidarum: any chorea developing during pregnancy; historically associated with rheumatic fever; currently most strongly linked to antiphospholipid syndrome and SLE; may also be caused by Huntington disease, neuroacanthocytosis, or medications; typically resolves postpartum; recurs in subsequent pregnancies
• Senile chorea: chorea of late onset without the other features of Huntington disease; requires careful exclusion of HD and other hereditary causes
• Post-cardiac surgery chorea: especially in the pediatric population after open-heart surgery

Major Individual Conditions

Huntington Disease (HD)

• Motor: Chorea is the hallmark early symptom in ~60% of patients at onset; bradykinesia, dystonia, and motor impersistence also present; gait is irregular and dance-like, described as "marionette-like"; eventual dysphagia, dysarthria; wheelchair-bound state in late disease
• Psychiatric: Behavioral changes in 98% of patients; irritability (most common early feature), anxiety, depression (~30% meet criteria for major depressive disorder); mania (less common); risk of suicide is increased
• Cognitive: Progressive subcortical dementia; executive dysfunction, mental inflexibility, impaired attention; eventually severe dementia
• Ocular: Slow saccades (often the earliest sign); impaired smooth pursuit

• VMAT2 inhibitors (drugs of choice for chorea suppression):
  • Tetrabenazine: depletes presynaptic monoamines; effective for chorea; risk of depression, parkinsonism
  • Deutetrabenazine: deuterated form; approved by FDA; 6 mg/day titrated to max 24 mg twice daily; fewer side effects; contraindicated with MAOIs
  • Valbenazine: also FDA-approved for HD chorea
• Haloperidol / other dopamine-blockers: effective but now rarely first-line
• Investigational: antisense oligonucleotides (targeting mutant HTT mRNA), CRISPR gene editing, pridopidine (sigma-1 receptor agonist), stem cell therapy
• Supportive: genetic counseling (1st-degree relatives should be offered testing), speech therapy, occupational therapy, physical therapy, dysphagia management, social services

Sydenham Chorea (SC)

• Acute onset of generalized choreiform movements, usually asymmetric; hemichorea in some cases
• Characteristic tongue movements ("flycatcher/trombone tongue")
• Hypotonia
• Behavioral changes: irritability, emotional lability, obsessive-compulsive traits (may outlast the chorea)
• More than 50% of patients have carditis - echocardiography is mandatory
• Usually self-limited: resolves within 6 months (often 6 weeks); ~20% recurrence rate
• Mild basal ganglia enlargement may be seen on MRI

• Often self-limited; treat only when chorea is severe/disabling
• VMAT2 inhibitors (tetrabenazine, deutetrabenazine, valbenazine): currently considered drugs of choice
• Valproic acid: comparative trials suggest it is the most effective agent among traditional drugs
• Carbamazepine: second-line
• Haloperidol: effective but now rarely used due to side effects
• Intravenous methylprednisolone followed by oral prednisone: for refractory cases
• Secondary prophylaxis: penicillin prophylaxis to prevent recurrent streptococcal infections
• IVIG and plasmapheresis: reported in severe/refractory cases

Diagnosis

Clinical Assessment

• Detailed history: onset, progression, family history (mandatory for hereditary causes), medications, prior infections, pregnancy
• Characterize the chorea: unilateral vs. bilateral, distribution, associated features
• Neurological examination: look for associated features (cognitive changes, psychiatric symptoms, eye movement abnormalities, dystonia, pyramidal signs)

Investigations

MRI Findings

• HD: caudate atrophy, compensatory enlargement of lateral ventricles ("box-car" appearance on axial sections)
• Sydenham chorea: mild basal ganglia enlargement acutely
• Hyperglycemic hemichorea: T1 hyperintensity in contralateral putamen
• Neuroacanthocytosis/McLeod: caudate and putaminal atrophy; T2 signal changes in lateral putamen

Management Principles

Symptomatic Pharmacotherapy

1. VMAT2 inhibitors (first-line):
   • Tetrabenazine, deutetrabenazine, valbenazine
   • Work by depleting presynaptic dopamine and other monoamines
2. Dopamine receptor blockers:
   • Haloperidol, clonazepam, risperidone
   • Effective but risk of tardive dyskinesia with long-term use
3. Atypical antipsychotics: olanzapine, quetiapine
4. Valproic acid: especially for Sydenham chorea and hemichorea
5. Clonazepam: useful adjunct
6. Amantadine: may help in HD

Cause-Specific Treatments

• Hyperthyroidism: antithyroid therapy
• SLE/APS: immunosuppression, anticoagulation (for APS)
• Drug-induced: discontinue offending agent
• Wilson disease: penicillamine or trientine (copper chelation)
• Paraneoplastic: treat underlying malignancy, immunotherapy
• NMDA receptor encephalitis: immunotherapy (steroids, IVIG, plasmapheresis)

Non-Pharmacological

• Multidisciplinary team care
• Speech and language therapy (for dysarthria/dysphagia)
• Occupational and physical therapy
• Genetic counseling (for hereditary causes)
• Psychological support and psychiatry (mood disorders, OCD, behavior changes)
• Deep brain stimulation (DBS) of the globus pallidus interna (GPi): effective in refractory cases, including HD and neuroacanthocytosis

Summary Table: Key Chorea Syndromes

• Localization in Clinical Neurology, 8th Edition, pp. 1101-1109
• Adams and Victor's Principles of Neurology, 12th Edition, pp. 92-93
• Bradley and Daroff's Neurology in Clinical Practice, pp. 2968-3076
• Harrison's Principles of Internal Medicine, 22nd Edition (2025), pp. 2052-2286
• Katzung's Basic and Clinical Pharmacology, 16th Edition, p. 791-794
• Eric Kandel, Principles of Neural Science, 6th Edition, pp. 995-996
• Moore KPL. "Huntington Disease and Chorea." Continuum, 2025 Aug [PMID: 40748130]
• Brooker SM et al. "Movement Disorders Associated with SLE." Curr Neurol Neurosci Rep, 2024 [PMID: 39576409]