Chorea

Chorea
ICD-10	G25.5
ICD-9	333.5
DiseasesDB	16662
MeSH	D002819

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Muzamil Akhtar [2]

Overview

Chorea is a hyperkinetic movement disorder—a clinical sign with a broad differential—defined by abrupt, involuntary, irregular, nonrhythmic movements that flow unpredictably from one body part to another. It is not a disease itself but a syndrome produced by autoimmune, hereditary, vascular, metabolic, drug-induced, infectious, paraneoplastic, and functional causes. The two clinical anchors are Huntington disease (HD), the most common inherited cause of chorea in adults, and Sydenham chorea, the most common acquired chorea of childhood worldwide.

Contemporary practice has shifted meaningfully since legacy teaching: vesicular monoamine transporter 2 (VMAT2) inhibitors (tetrabenazine, deutetrabenazine, valbenazine) are now the evidence-based, FDA-approved symptomatic therapy for HD chorea, and corticosteroids plus antibiotics are supported as disease-modifying therapy in Sydenham chorea. The clinical priority is to identify treatable or reversible causes rapidly.

Definition and Phenomenology

Chorea consists of irregular, purposeless, abrupt, rapid, brief, unsustained movements that flow randomly between body regions. Its unpredictable, non-stereotyped, non-suppressible quality distinguishes it from other hyperkinetic disorders. Key bedside signs reflect motor impersistence (the inability to maintain a sustained muscle contraction), which produces the characteristic "milkmaid grip" and the inability to keep the tongue protruded.

Chorea, athetosis, and ballism lie on a single phenomenologic spectrum differentiated by speed, amplitude, and distribution rather than distinct pathology:

• Athetosis: A slow form of chorea with writhing movements, predominantly distal.
• Chorea: The intermediate, flowing form.
• Ballism: A severe, high-amplitude, flinging form, usually proximal and most often unilateral (hemiballism). It classically results from a lesion in the contralateral subthalamic nucleus; hemiballism frequently evolves into hemichorea as it improves.

Distinguishing Chorea from Mimics

Differentiation relies on phenomenology plus accompanying findings:

• Dystonia: Sustained contractions producing abnormal postures or torsion (chorea is not sustained).
• Tics: Stereotyped, preceded by a premonitory urge, and voluntarily suppressible.
• Stereotypies: Repetitive, patterned movements mimicking normal motor behaviors.
• Myoclonus: Brief (<200 ms) shock-like jerks lacking continuous flow.
• Tremor: Rhythmic and oscillatory.
• Pseudoathetosis: Writhing caused by severe proprioceptive loss (thalamic, cord, or neuropathic), not a basal-ganglia phenomenon.

Etiologic Classification

The differential diagnosis is organized first by tempo and inheritance, then by category. Acquired and sporadic causes tend to present acutely or subacutely, while hereditary causes typically present insidiously.

Etiologic Classification of Chorea

Category	Representative Causes	References
Hereditary	Huntington disease; HD phenocopies (HDL2/JPH3, C9orf72, SCA17/TBP, SCA1/2/3, DRPLA); neuroacanthocytosis syndromes; benign hereditary chorea (NKX2-1, ADCY5, PDE10A); Wilson disease; NBIA/neuroferritinopathy; ataxia-telangiectasia
Autoimmune / Parainfectious	Sydenham chorea; SLE; primary antiphospholipid syndrome; anti-NMDA receptor encephalitis and other neuronal-antibody encephalitis; anti-IgLON5 disease
Paraneoplastic	CRMP-5/CV2 (small-cell lung cancer), ANNA-1/Hu
Vascular / Structural	Striatal or subthalamic stroke/hemorrhage, tumor, demyelination, Moyamoya disease
Metabolic / Toxic	Nonketotic hyperglycemia, hypo-/hyperglycemia, hyperthyroidism, hypoparathyroidism, uremia, hepatic disease, polycythemia vera, carbon monoxide poisoning
Drug-induced	Dopaminergic therapy (levodopa), stimulants, anticonvulsants, dopamine-receptor blockers (tardive dyskinesia), oral contraceptives, lithium
Physiologic / Other	Chorea gravidarum (frequently associated with antiphospholipid antibodies or prior Sydenham chorea), post-pump chorea, physiologic chorea of infancy, functional (psychogenic)

Causes in Alphabetical Order

Note: This list is retained from legacy content for completeness and internal linking. Many entries are historical, rare, or not verified against modern high-quality sources; the classification table above reflects current evidence-based practice.

3-Methylglutaconic aciduria type 3 ADCY5-related dyskinesia Alternating hemiplegia of childhood Amphetamines Anti-NMDA receptor encephalitis Antiphospholipid syndrome Arteriovenous malformations Ataxia-telangiectasia Benedikt syndrome Benign hereditary chorea Carbon monoxide poisoning Cerebral palsy Cerebral birth injury Cerebral trauma Ceroid lipofuscinosis Ceruloplasmin deficiency (aceruloplasminemia) Chorea gravidarum Creutzfeldt-Jakob disease Cross-McKusick-Breen syndrome De Barsy syndrome Dentatorubral-pallidoluysian atrophy Dopamine agonists Ethotoin Fahr disease (idiopathic basal ganglia calcification) Familial benign chorea Gilles de la Tourette syndrome Glutaric aciduria type 1 Hallervorden-Spatz disease Haw River syndrome Henoch-Schönlein purpura HIV infection Huntington disease Hypoglycemia Thyrotoxicosis Hypoparathyroidism

Nonketotic hyperglycemia Idiopathic basal ganglia calcification Kernicterus Lacunar infarction Lamotrigine Lesch-Nyhan syndrome Levodopa Levomepromazine Lithium McLeod phenotype Methadone Moyamoya disease Neuroacanthocytosis Neuroferritinopathy Olivopontocerebellar atrophy Oral contraceptives Paroxysmal kinesigenic choreoathetosis Paroxysmal nonkinesigenic choreoathetosis Phenothiazines Phenytoin Polycythemia vera Porphyria Pramipexole Pregnancy Pyruvate dehydrogenase deficiency Rheumatic fever / Sydenham chorea Senile chorea Systemic lupus erythematosus Spinocerebellar ataxia type 17 Spinocerebellar ataxia (recessive) Tolcapone Toluene toxicity Tricyclic antidepressants Troyer syndrome Wilson disease Wolfram syndrome

Diagnostic Approach

The workup is directed by the patient's age, symptom tempo, family history, and accompanying signs. A phenotype-driven strategy is critical to avoid indiscriminate testing.

• First-tier laboratories: CBC with peripheral smear for acanthocytes (must use isotonically diluted wet-prep; abnormal if >6.3% of erythrocytes), electrolytes, glucose/HbA1c, renal and liver function, and TSH. When Wilson disease is possible, obtain serum ceruloplasmin, 24-hour urine copper, and a slit-lamp examination for Kayser-Fleischer rings.
• Autoimmune and infectious: ANA, antiphospholipid antibodies, and—in suspected Sydenham chorea—ASO and anti-DNase B titers (note that ASO wanes after ~2 months, whereas anti-DNase B remains elevated for up to ~1 year). A Doppler echocardiogram is mandatory to evaluate for rheumatic carditis. Consider neuronal or paraneoplastic antibody panels (NMDAR, CRMP-5, ANNA-1) when the syndrome or specific cancer risks warrant.
• Imaging: MRI is the preferred modality for evaluating structural causes, including striatal atrophy (HD), the suggestive finding of T1 basal-ganglia hyperintensity (nonketotic hyperglycemic hemichorea), iron deposition, and inflammatory lesions. CT is appropriate for rapid evaluation of acute hemichorea or hemiballism to rule out hemorrhage.
• Genetic testing: HD CAG-repeat analysis is the first-line test for chronic, progressive chorea. Genetic testing is high-yield even when family history is negative; in recent sporadic-chorea cohorts, up to 83% of patients received a confirmed genetic diagnosis (most commonly HD). If HD testing is negative, phenocopy gene panels should be pursued guided by phenotype and ancestry.
• CSF analysis: CSF is normal in most choreas and is not part of the routine workup. It should be reserved for suspected autoimmune, infectious, or paraneoplastic encephalitis.

Treatment Principles

Management focuses on two overarching goals: treating the underlying cause and suppressing disabling chorea symptomatically. Core cause-directed treatments include removing offending drugs, correcting metabolic derangements, treating specific autoimmune conditions, and pursuing underlying malignancies in paraneoplastic disease.

• Huntington disease chorea: VMAT2 inhibitors are first-line. Tetrabenazine improves UHDRS Total Maximal Chorea scores (2012 AAN guideline: Class I evidence, Level B recommendation). Starting dose is 12.5 mg/day, titrated weekly by 12.5 mg; the maximum is 50 mg/day (single dose ≤25 mg) in CYP2D6 poor metabolizers or with strong CYP2D6 inhibitors, and 100 mg/day (single dose ≤37.5 mg) in extensive/intermediate metabolizers. CYP2D6 genotyping is required before exceeding 50 mg/day. Tetrabenazine carries a boxed warning for depression and suicidality and is contraindicated in actively suicidal patients, untreated/inadequately treated depression, hepatic impairment, and with MAOIs or reserpine (≥20-day washout). Valbenazine (KINECT-HD): start 40 mg once daily, increase by 20 mg every 2 weeks to a target of 80 mg once daily; reduce to 40 mg in moderate-to-severe hepatic impairment and in CYP2D6 poor metabolizers; avoid with prior hypersensitivity. Deutetrabenazine is dosed twice daily with weekly titration and is contraindicated in hepatic impairment. All VMAT2 inhibitors can prolong the QT interval and require monitoring for depression/suicidality; additionally, there is a risk of neuroleptic malignant syndrome (NMS). Monotherapy is generally preferred, with dual therapy (VMAT2 inhibitor plus antipsychotic) reserved for intractable chorea or concurrent neuropsychiatric symptoms.
• Sydenham chorea: International consensus guidelines (2025 Delphi, expert opinion) recommend corticosteroids for moderate-to-severe disease, with IVIG or plasma exchange for inadequate responders. Supporting efficacy data are observational: an individual-patient-data meta-analysis found ≥1 month of corticosteroids shortened median chorea duration (1.2 vs 2.8 months; P = .004) and reduced relapsing course (OR 0.10; 95% CI 0.04-0.25), with antibiotics, corticosteroids, and sodium valproate each independently reducing relapse. Randomized trials are ongoing (e.g., NCT06259006).
• Hemiballism / Hemichorea: These presentations are usually self-limited when occurring post-stroke. They can be managed with dopamine antagonists or VMAT2 inhibitors when highly disabling.

High-Yield Clinical Pearls

• Chorea is a clinical sign, not a final diagnosis. Physicians must always search for a treatable or reversible underlying cause first.
• The tempo of symptom onset triages the differential diagnosis: acute/subacute onset points toward acquired etiologies, while insidious onset suggests a hereditary disorder.
• The "milkmaid grip" and the inability to sustain tongue protrusion are rapid, high-yield bedside confirmations of motor impersistence (a hallmark of chorea).
• Genetic testing for HD should be ordered even in the absence of a family history, as the diagnostic yield in apparent "sporadic" chorea is substantial.
• Doppler echocardiography is mandatory in all suspected cases of Sydenham chorea, regardless of whether the patient has overt cardiac symptoms.
• The chorea-suppressing benefit of VMAT2 inhibitors is quickly reversible upon drug withdrawal, confirming their mechanism is purely symptomatic, not disease-modifying.

Common Pitfalls

• Anchoring prematurely on Huntington disease in adults and overlooking autoimmune or paraneoplastic choreas, which may be entirely treatable or signal an occult malignancy.
• Misclassifying chorea as tics or akathisia. The absence of a premonitory urge and the patient's inability to voluntarily suppress the movements strongly favor chorea.
• Relying solely on an ECG instead of obtaining a comprehensive echocardiogram to evaluate for rheumatic carditis.
• Withholding immunotherapy in moderate-to-severe Sydenham chorea, thereby missing a critical opportunity to shorten the disease course and significantly reduce the likelihood of relapse.
• Overlooking nonketotic hyperglycemic hemichorea, a rapidly reversible metabolic etiology characterized by the suggestive finding of T1 basal-ganglia hyperintensity on MRI.
• Ignoring the neuropsychiatric risks (depression, suicidality) associated with VMAT2 inhibitors and failing to adjust tetrabenazine dosing based on the patient's CYP2D6 metabolizer status.

See also

• Movement disorder
• Choreoathetosis
• Huntington disease
• Sydenham chorea