Chorea …

Movement Disorders

Updated 12.29.2024
Released 08.05.1994
Expires For CME 12.29.2027

Chorea

Authors: Serena Wong MD, Robert Fekete MD

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Chorea

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Introduction

Overview

Chorea, derived from the Latin choreus meaning "dance," describes a syndrome characterized by irregular, hyperkinetic, involuntary movements of the limbs, face, neck, and trunk. Choreiform movements can occur both at rest and during voluntary movements. Athetosis refers to the writhing, slow, and irregular movements involving the hand and fingers. Proximal flinging movements are referred to as ballism. Chorea can be classified by hereditary and nonheredity etiology. Nonheredity chorea is associated with autoimmune, vascular, infectious, pharmacologic, and metabolic disorders. The author aims to provide an up-to-date discussion of the clinical presentations, etiology, pathogenesis, differential diagnosis, and management of this disorder.

Key points

	• Chorea can be distinguished by hereditary and nonheredity etiology.
	• The diagnosis of chorea is made by careful medical history taking. Drug exposure, family history, age of onset, course of the disease, and other associated symptoms should be considered. Imaging studies and comprehensive laboratory testing help refine the differentials. Lastly, molecular genetic testing is warranted even if family history is unrevealing.
	• Treatment for chorea is based on reversing the underlying cause of chorea, if feasible.
	• Dopamine receptor antagonists achieved by inhibition of vesicular monoamine transporter-2 (VMAT2) are the mainstream treatments for patients with Huntington disease, tardive dyskinesia, and other movement disorders.

Clinical manifestations

Presentation and course

Table 1. Hereditary Chorea Etiology

• Adenylate cyclase 5 mutation
• Ataxia-telangiectasia
• Ataxia associated with oculomotor apraxia
• Benign hereditary chorea/NKX2-1-related disorder (NKX2-1-RD)
• C9orf72 expansion in frontotemporal dementia, motor neuron disease
• Chorea-acanthocytosis
• Dentato-rubro-pallido-luysian degeneration (mainly in Japan)
• Friedreich ataxia
• Fragile X-associated tremor/ataxia syndrome
• Glucose transporter deficiency
• Huntington disease
• Huntington disease-like 2
• Laurence-Moon-Biedl-Bardet syndrome
• Leigh disease
• Lesch-Nyhan disease
• Lipidoses, aminoacidosis, and carbohydrate metabolism disorders
• McLeod syndrome
• Neuroferritinopathy
• Niemann-Pick type C
• Pantothenate kinase-associated neurodegeneration (PKAN)
• Paroxysmal kinesiogenic dyskinesia
• Paroxysmal non-kinesiogenic dyskinesia; dystonia type 8
• Phosphodiesterase 10A mutation
• Primary familial brain calcification
• POLG mutation
• PRRT2 gene mutation
• Spinocerebellar atrophy types 1, 2, 3, and 7
• Spinocerebellar atrophy type 8
• Spinocerebellar atrophy type 12 (mainly in India)
• Spinocerebellar atrophy type 17
• Tuberous sclerosis
• Wilson disease
• Xeroderma pigmentosum
• X-linked dystonia-parkinsonism

Adopted from the Guidelines of the German Neurological Society 2023

Adenylate cyclase 5 mutation. Mutations of adenylate cyclase 5 (ADCY5) have emerged as an important causal gene for early-onset autosomal dominant chorea and dystonia (15; 20). Although ADCY5 mutations have been initially mentioned as a phenocopy of Huntington disease, this is certainly not the case. The two conditions are easily distinguishable because juvenile Huntington disease is characterized by rigid-akinetic syndrome, cognitive decline, and occasional seizure disorder, but almost never chorea. In contrast, ADCY5 syndrome is characterized by delayed motor and speech milestones, episodic axial hypotonia, ataxia, generalized chorea and dystonia, myoclonus, and myopathy-like facial appearance. The disorder is frequently misdiagnosed as dyskinetic cerebral palsy (94). Nevertheless, as often happens with newly described genetic conditions, there is growing evidence pointing towards the great genetic and phenotypic variability of ADCY5 mutations: autosomal recessive mutations and a wide range of hyperkinetic movement disorders including chorea, dystonia, myoclonus, and tics (12).

Benign hereditary chorea. Also referred to as NKX2-1-related disorder (NKX2-1-RD), benign hereditary chorea is a rare condition resulting from variations or deletions in the NKX2-1 gene, leading to early onset of choreiform movements, respiratory symptoms, and endocrine dysfunction (71; 107). Patients with this condition present with hypotonia and associated movement disorders, including chorea, ataxia, dystonia, and myoclonus, which impede motor development, gait, and normal daily activities (37; 70; 47; 05; 57; 105; 58). It has also been demonstrated that the phenotype of benign hereditary chorea and hypothyroidism can be caused by distinct NKX2-1 mutations (42; 109; 107). Chorea is the most common manifestation of this disorder, and the onset is typically at 2 years of age (99). Common treatments include levodopa, tetrabenazine, and methylphenidate; carbamazepine and topiramate are used in some cases (48). The optimal age for treatment initiation, duration of treatment, and dosage may vary case by case, and further studies would be warranted to evaluate the use of deep brain stimulation in these patients (99).

Chorea acanthocytosis. Chorea acanthocytosis (ChAc) is a rare disease that is associated with mutations of VPS13A, which encodes for chorein, a protein implicated in lipid transport at intracellular membrane contact sites. A study on patients with ChAc showed evidence of increased sphingolipid and phospholipid levels in the caudate nucleus and putamen, congruent with the findings in cellular and animal models (91). The defects of lipid processing in VPS13A help elucidate the pathophysiology of ChAc and related disorders.

The clinical manifestation includes orofacial dyskinesia, chorea, and peripheral neuropathy. Epilepsy and parkinsonism can sometimes be seen in patients with chorea acanthocytosis. Behavioral problems such as depression, obsessions, compulsions, self-mutilation, and psychotic disorders are commonly seen in chorea acanthocytosis (132). In clinical practice, obsessions and compulsions are often more disabling herein than in Huntington disease. In both Huntington disease and chorea acanthocytosis, the muscle tone is increased, and with progression of the illness, there is a tendency for worsening of the rigidity and a decrease of the severity of the chorea. Currently, there is no cure for VPS13A disease. Supportive care involving neurology, psychiatry, physical therapy, occupational therapy, speech therapy, and medical genetics help improve the quality of life of these patients. According to a multicenter retrospective analysis, GPi-DBS provides long-lasting improvement in patients with chorea acanthocytosis. A study reported some benefit of the use of STN-DBS in two siblings with severe oromandibular dystonia and gait abnormalities (136).

Dentatorubralpallidoluysian atrophy. Dentatorubralpallidoluysian atrophy (DRPLA) is an autosomal dominant disorder caused by a CAG trinucleotide repeat expansion in chromosome 12 (63). The function of the mutant protein, Atrophin-1, is unknown. Individuals with 53 or more CAG repeats develop the symptoms. Clinical manifestation of this disease includes chorea, myoclonus, ataxia, epilepsy, and cognitive decline. Neuroimaging studies demonstrated atrophy of the cerebellum, tegmentum, and cerebral hemispheres with ventricular dilatation (11). Neuronal loss and gliosis in the dentate nucleus, red nucleus, globus pallidus, and subthalamic nucleus is often seen pathologically (11).

Huntington disease. Huntington disease is a progressive neurodegenerative disease. It is an autosomal dominant disorder caused by a CAG trinucleotide repeat expansion in a gene on chromosome 4p16.3. A repeat of 36 CAG or more can lead to the disease. The age of onset decreases with longer CAG repeats. The mutated Huntingtin protein in Huntington disease impaired neural progenitor cell division and neuronal migration and maturation, leading to underdevelopment of the cortex in Huntington disease mice (93). The expanded repeat is unstable and tends to increase in the subsequent generation, a phenomenon called anticipation. A systematic review was conducted to estimate the prevalence of Huntington disease in the postdiagnostic testing era (1993 to 2015); the prevalence of Huntington disease is significantly lower in Asian populations compared to western Europe, North America, and Australia (121). Huntington disease is characterized by a triad of choleric movements (facial grimacing and writhing limb movements), dementia, and behavioral disturbances including personality changes, depression, as well as psychosis (114). In general, the age of onset is approximately 40 years. Approximately 5% of the affected individuals have a juvenile onset under the age of 20, and about 30% are diagnosed with Huntington disease at the age of 50 or above. In juvenile onset cases, rigidity, hypokinesia and dystonia are common. Other common motor manifestations in Huntington disease include slowing of saccades, myoclonus, rigidity, and ataxia (78). Dystonia is usually observed in the advanced stage of Huntington disease or is associated with the use of dopaminergic medications. Dysphagia and aspiration tend to occur in the terminal stage of the disease; however, cortical language is usually spared.

Neuroferritinopathy. Neuroferritinopathy is an autosomal dominant condition causing chorea (50%), dystonia (42.5%) and, less often, parkinsonism (7%). It is caused by mutations in the ferritin light chain gene, resulting in iron deposition and cavitation in the basal ganglia on brain MRI (89).

Phosphodiesterase 10A mutation. Phosphodiesterase 10A (PDE10A) mutation is another genetic disorder that causes an early-onset chorea. The phenotype can be similar to the one seen in the ADCY5 disease. Interestingly, both mutations are associated with same changes in the basal ganglia, including decreased PDE10A expression in the striatum and globus pallidus (97). There is also a description of a homozygous loss-of-function mutation in PDE2A associated with an early onset hereditary chorea (122).

Table 2. Nonhereditary Chorea Etiology

Autoimmune choreiform syndromes
	• Antiphospholipid syndrome • Autoimmune encephalitis (GAD-65 Ab, VGCC Ab, CASPR2 Ab, NMDA-R Ab, LGI-1 Ab, and IgLON5 Ab) • Chorea gravidarum • Sydenham chorea • Systemic lupus erythematosus
Paraneoplastic choreiform syndromes
	• Anti-Hu, anti-Yo, anti-Ma, Anti-CV2/CRMP-5
Infectious causes
	• Viral: mumps, measles, varicella zoster, herpes simplex virus, influenza A, SAR-CoV-2, West Nile, HIV • Bacterial: diphtheria, syphilis, borreliosis, toxoplasmosis, cryptococcosis • Parasitic: neurocysticercosis, Whipple disease
Lesions of the basal ganglia
	• Ischemic or hemorrhagic infarcts • Neoplasms • Abscess • Demyelinating lesions
Pontine lesions
	• Central pontine myelinolysis • Pontine hemorrhage
Hematological cause
	• Polycythemia vera
Metabolic/endocrine dysfunction
	• Hyper/hypocalcemia • Hyper/hypoglycemia • Hyper/hyponatremia • Hypomagnesemia • Hyperthyroidism • Acute intermittent porphyria • Liver failure • Kidney failure with uremia • Carbon monoxide, manganese, mercury, thallium, organophosphate toxicity • Vitamin B12 deficiency • Wernicke encephalopathy
Drug-related causes
	• Dopamine receptor antagonists (eg, phenothiazine, butyrophenone, metoclopramide) • Dopamine receptor agonist (eg, levodopa) • Antiepileptic medications (eg, phenytoin, carbamazepine, valproic acid, gabapentin, lamotrigine, levetiracetam) • Antihistamine medications • Calcium channel blockers (eg, verapamil) • Stimulants (eg, methylphenidate, amphetamines, cocaine, pemoline) • Lithium • Tricyclic antidepressants and SSRIs Adopted from the Guidelines of the German Neurological Society 2023

Autoimmune choreiform syndromes

Antiphospholipid syndrome. Chorea is a rare manifestation of antiphospholipid syndrome and has been associated with isolated presence of antiphospholipid antibodies. The pathophysiological mechanism is not entirely clear. One postulated mechanism is immune-mediated attack against basal ganglia, and the other postulated mechanism is endothelial dysfunction from autoantibody binding to the endothelium, resulting in a proinflammatory cascade. Contralateral striatal hypermetabolism on PET scan can assist in diagnosis (02; 53).

GAD-65 antibody. GAD-65 antibody is associated with stiff person spectrum disorder, which is characterized by truncal and proximal limb stiffness, hyperlordosis, and painful episodic spasm triggered by tactile or auditory stimuli (33). Progressive encephalomyelitis with rigidity and myoclonus (PERM) is an atypical form of stiff person spectrum disorder (08).

Anti-LGI1 and CASPR2 encephalitis. Both LGI-1 and CASPR2 are associated proteins of voltage-gated potassium channels. The clinical features of LGI1 antibody encephalitis include memory impairment, faciobrachial dystonic seizure, and hyponatremia. Faciobrachial dystonic seizure is characterized by brief (1 to 3 seconds), frequent, stereotypical, and focal movements of the arm and ipsilateral face or arm (46). Rarely, isolated chorea is the initial manifestation of LGI-1 autoimmune encephalitis with associated mild hyponatremia (118). In contrast, the clinical manifestation of CASPR2 antibody is much more diverse and can affect both central and peripheral nervous systems. CASPR2 antibody is associated with peripheral nerve hyperexcitability syndromes, including cramp fasciculation syndrome, Isaacs syndrome, and Morvan syndrome (123). All of these can lead to muscle twitching and muscle cramps.

N-methyl-D-aspartate receptor (NMDA-R) encephalitis. It is the most common sporadic autoimmune encephalitis in children and younger adults. There is a female predominance (40; 76). Interestingly, it can be paraneoplastic, postinfectious, or idiopathic in etiology. Ovarian teratomas are found in half of the cases of adult women, whereas one third of the cases are identified in teenage females (76). Patients with this disease can experience neuropsychiatric symptoms characterized by psychosis, catatonia, and disinhibition as well as various motor disorders, including limb dyskinesia/chorea, orofacial dyskinesia, ataxia, and dystonia (40). Some patients are diagnosed with NMDA-R encephalitis after HSV encephalitis, typically 1 to 4 weeks after initial infection (40; 76).

Anti-IgLON5 disease. Anti-IgLON5 disease is a neurodegenerative disorder associated with antibodies against the neuronal cell adhesion protein, IgLON5, of unknown function (45). The four main symptoms in patients with this disorder include REM and non-REM parasomnias, bulbar syndromes, cognitive decline, and movement disorders. A retrospective, observational study demonstrated that the first signs and symptoms of this disease were abnormal movements (44). Gait and balance disturbance is the most frequent complaint, followed by chorea, bradykinesia, abnormal body postures or rigidity, and tremors. About one-third of the participants in the study also reported other hyperkinetic movements including myoclonus, akathisia, myorhythmia, myokymia, or abdominal dyskinesias. The craniofacial dyskinesias were frequently associated with concurrent abnormal movements. The constellation of multiple movement disorders, sleep alternations, bulbar symptoms, and cognitive impairment should alert clinicians to consider this disease.

Sydenham chorea. This is a hyperkinetic disorder characterized by involuntary, irregular, jerky movements involving more than one region of the body. It is a common form of acquired childhood chorea (140). The typical age of onset is 5 to 15 years with a female gender predominance (35). The first episode of Sydenham chorea typically occurs 6 to 8 weeks poststreptococcal infection (10). Sydenham chorea is one of the major diagnostic criteria of rheumatic fever and is caused by a group A beta-hemolytic Streptococcus infection. The diagnosis of Sydenham chorea is clinical and can be confirmed by elevated erythrocyte sedimentation rate or the anti-streptolysin-O (ASLO) and anti-DNAse B titers (103). Neuropsychiatric symptoms are highly prevalent in Sydenham chorea, including major depression, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder, and may persist even after the improvement of motor symptoms. In addition, other neurologic manifestations associated with Sydenham chorea are dysarthria, dysgraphia, lingual dystonia, muscle weakness, and dysphagia.

Systemic lupus erythematosus. Systemic lupus erythematosus is a rare cause of chorea and occurs in 1% to 2% of all cases (07). Neuropsychiatric symptoms are more common than movement disorders in systemic lupus erythematosus, but chorea is the most common movement disorder. The typical age of onset is between 15 and 26 years, with a female predominance.

Structural lesions. Hemichorea can occur contralateral to the lesion in the basal ganglia, thalamus, or lentiform nucleus after stroke (24). When a lesion involves the subthalamic nucleus, hemichorea occurs ipsilateral to the lesion. Chorea is reported in patients with brainstem cavernous malformation, brainstem glioma, pontine hemorrhage, and putaminal cavernous angioma (82; 120; 130; 69; 79; 77; 106; 138).

Metabolic dysfunction. Chorea and hemichorea have been reported as the initial presenting symptoms in the setting of hypoglycemia and nonketotic hyperglycemia in adults (51; 83; 113; 49; 75). Striatal anomalies, such as hyperdensity on CT head or hyperintensity on T1-weighted MRI brain, can be seen (04).

Drug-induced chorea. Acute chorea can be caused by multiple drugs including dopamine agonists, stimulants (eg, cocaine and amphetamines), levodopa therapy, oral contraceptives, and anticonvulsants (eg, carbamazepine, valproate, phenytoin, and gabapentin) (60). Tardive dyskinesia is a movement disorder characterized by irregular bucco-oral movements after prolonged use of antipsychotics, especially the first-generation antipsychotic medications.

Prognosis and complications

Prognosis depends on etiology. Drug-induced chorea is usually reversible after the medication is discontinued but can be persistent as a tardive syndrome following prolonged use of antipsychotic medications. Vascular chorea-hemiballism following lacunar stroke is dramatic at the onset, but its severity spontaneously declines with time in most patients. Most choreas may be treated with medication to reduce symptom intensity, although some, such as powerful persistent chorea-hemiballism, may be refractory to all but aggressive intervention (eg, thalamotomy, pallidotomy).

There is no disease-modifying agent or cure for Huntington disease, neuroacanthocytosis, and other degenerative illnesses. These diseases have poor prognoses, with inexorable progression leading to death. A review of 52 individuals with chorea-acanthocytosis found that the mean disease duration from diagnosis was 11 years, whereas patients with McLeod syndrome, another cause of neuroacanthocytosis, had a much longer survival of 21 years. The most common causes of death were pneumonia, cardiac disease, seizure, suicide, and sepsis. Of note, suicide accounted for 10% of deaths in subjects with chorea-acanthocytosis (131).

Biological basis

Etiology and pathogenesis

In all cases of chorea, it is assumed that there is disruption of basal ganglia modulation of thalamocortical motor pathways, as seen in the classic chorea of Huntington disease or subthalamic dysfunction (28). This disruption may be due to structural damage, selective neuronal degeneration, neurotransmitter receptor blockade, or other metabolic factors within the basal ganglia.

Neuroanatomic data implicate the putamen, globus pallidus, and subthalamic nuclei as key structures in all choreic disorders (110). The brief involuntary movements are initiated via the motor outflow pathway from thalamocortical to corticospinal. Modulation of the thalamocortical output occurs via inhibition of the thalamic nuclei by the globus pallidus and subthalamic nuclei and the inhibitory neurotransmitter gamma-aminobutyric acid (03). Multiple neurotransmitters seem to play a role in the pathophysiology of chorea, most importantly dopamine (64). Etiologically diverse types of chorea are thought to reflect deficient globus pallidum internal inhibitory input to the motor thalamus resulting in excessive thalamocortical motor facilitation. Current views maintain that more complex changes in the temporal and spatial firing pattern of the globus pallidum internal underlie hyperkinetic movement disorders such as chorea (100; 92; 95). This has been challenged by studies suggesting that in both Sydenham chorea and chorea associated with Huntington disease there is an increase of inhibition in the motor cortex (67).

Structural lesions of the subthalamic nucleus or subthalamic region, caused by infarcts, hemorrhage, or tumors, produce chorea (81). Alterations in striatal neurotransmitters may occur endogenously, as in Huntington disease; or exogenously, as seen with drug use or withdrawal (108; 86; 09).

The role of autoimmune processes in chorea is of growing interest. Anti-basal ganglia antibodies have been detected in subjects with Sydenham chorea using ELISA and Western immunoblotting methods. The anti-basal ganglia antibodies play a role in the development of chorea by disrupting corticostriate circuitry (25). There is compelling evidence that Streptococcus-induced antibodies cross-react with central dopamine receptors inducing movement disorders and behavioral abnormalities (34; 14; 38; 31). However, persistence of Sydenham chorea for 2 years or more is related to structural dysfunction rather than to an ongoing autoimmune process (129).

The association between chorea and polycythemia vera was thought to be due to hyperviscosity in the basal ganglia, thereby causing chorea. However, some patients develop chorea without a particularly high hematocrit (74). In mice with quinolinic acid striatal lesions, inhibition of JAK2 led to reduced apoptosis and astrogliosis, suggesting that JAK2 inhibition is neuroprotective (56). It was postulated that the expression of JAK2 in the stratum may promote astrogliosis and inflammation in the basal ganglia, leading to chorea in the setting of JAK2 mutation without polycythemia vera.

Diagnostic workup

Children and adults with chorea should undergo diagnostic evaluation, which includes neuroimaging and laboratory study. A thorough medical history including current and past medications and family and social history will help refine the differential diagnosis. MRI can evaluate the subcortical brain structures and pathognomonic signs for certain diseases, eg, “eye of the tiger” sign for pantothenate kinase-associated neurodegeneration, hypointensities in the basal ganglia and substantia nigra for neurodegeneration with brain iron accumulation (NBIA), and cerebellar atrophy for hereditary ataxia.

Comprehensive laboratory testing, heavy metal panel, cerebrospinal fluid analysis, and drug tests are obtained as the initial workup for chorea. In children and young adults with chorea, anti-streptolysin O titers can be obtained to rule out Sydenham chorea. If paraneoplastic etiology is suspected, PDG-PET-CT or FDG-PET-MRI can be performed for tumor screening. PDG-PET scan can detect decreased glucose utilization/hypometabolism in basal ganglia seen in neurodegenerative disorders and chorea-acanthocytosis (30), or increased glucose utilization/hypermetabolism in Sydenham chorea. Additional tests include genetic testing for Huntington disease or Huntington disease phenocopies, benign hereditary chorea, and other less common causes of genetic chorea (111); muscle biopsy for mitochondrial disease; and peripheral blood smear with 1:1 saline dilution for acanthocytes and amino acid measurements. Molecular genetic testing for Huntington disease should be considered even for patients without a suggestive family history. A de novo expansion of the unstable triplet CAG repeat occurs in approximately 3% of affected patients (126).

Management

Dopamine receptor blockers are the mainstay of pharmacological treatment of chorea regardless of the etiology. As a rule, the more D2 receptor blocking action, the greater the antichoreic efficacy. Although there are no controlled studies, open label reports and clinical experience indicate that atypical agents such as quetiapine and clozapine have a limited role in the treatment of chorea. On the other hand, if typical neuroleptics are effective in the reduction of chorea, they are often associated with unacceptable side effects such as sedation, acute dystonic reaction, tardive dyskinesia, and parkinsonism. The latter can be a problem in Huntington disease because with progression of the illness there is a tendency for development of rigidity and dystonia (36). Similarly, in hemiballism-hemichorea, chorea suppression on one side of the body may be accompanied by simultaneous development of parkinsonism on the contralateral side of the body. Risperidone and olanzapine are atypical antipsychotics with definite antichoreic activity but lesser potential to induce parkinsonism than typical neuroleptics.

Tetrabenazine is a vesicular monoamine transporter 2 inhibitor (VMAT2), which acts as a presynaptic dopamine depletor to treat chorea associated with cerebral palsy (102; Chatterjee and Frucht 2003; 66; Jankovic 2016; 94). It was found to be efficacious in controlling chorea in Huntington disease (54; 66; 43; 62). Tetrabenazine is now an FDA-approved agent for symptomatic control of chorea in Huntington disease. A review of a large number of patients with chorea of different causes confirms the efficacy and safety of treatment with tetrabenazine (125; Jankovic 2016).

Deutetrabenazine was approved by the FDA in 2017 as the treatment for Huntington disease (55). Its structure is similar to tetrabenazine, but has a longer half-life, less plasma fluctuations, and less frequent dosing. Real-world retrospective data collected from 58 patients from 2017 to 2019 at the University of Alabama supported that deutetrabenazine is an effective treatment for Huntington-related chorea with low rates of side effects (32).

Valbenazine, a highly selective VMAT2 inhibitor, was initially approved for the treatment of tardive dyskinesia. A phase 3, randomized, double-blind clinical trial demonstrated that it is efficacious for chorea in individuals with Huntington disease. Ongoing research is needed to evaluate the long-term safety and effectiveness of this medication (128).

Levodopa may be required in patients with juvenile Huntington disease or in adults with advanced disease and severe rigidity. In infancy-onset benign hereditary chorea resulting from a novel nonsense mutation of the TITF-1 gene, treatment with levodopa improved gait and reduced chorea (06). Given the small sample size, further studies are needed to investigate the effectiveness of levodopa for this choreiform disorder.

Amantadine has been predominantly used as a treatment for levodopa-related dyskinesia in Parkinson disease. Its mechanism of action is thought to be a noncompetitive antagonist of NMDA receptors; however, it also facilities dopamine transmission between neurons, antimuscarinic activity, nicotine receptor inhibition, and interaction with the serotoninergic-noradrenergic pathway (116). One case report showed that amantadine improved motor functioning and nonmotor symptoms, such as sialorrhea, impulsivity, and restlessness in a patient with chorea-acanthocytosis (139). The effectiveness of amantadine as a treatment for chorea is not well-established, although it was shown to be beneficial in a few small studies (84; 104). The use of amantadine to treat chorea is highly controversial among experts.

Valproic acid is widely used in the treatment of chorea in Sydenham chorea. Although a few open-label studies and clinical experience strongly support the efficacy of the drug in this indication, no controlled studies have addressed this issue. Carbamazepine is also rarely used to treat Sydenham chorea (52). First-line immunotherapy consists of intravenous methylprednisolone, IVIg or plasmapheresis, or a combination of these modalities (96; 22; 18; 01). Second-line agents include rituximab or cyclophosphamide. In refractory cases, tocilizumab (an interleukin-6 receptor inhibitor) or bortezomib (a proteasome inhibitor) have been utilized. Latrepirdine, an agent that possibly improves mitochondrial function, has been shown to cause mild improvement of cognition in patients with Huntington disease (68). Subsequent studies, however, were disappointing and the agent is no longer in development.

Surgery to treat chorea is rarely needed. However, this may be the case in patients with persistent vascular chorea (arbitrarily defined as duration longer than 1 year) in whom stereotactic surgery such as thalamotomy or posteroventral pallidotomy is effective (17; 23). There are also a few reports describing effectiveness of surgery to treat chorea related to cerebral palsy (73), “senile chorea” (137), and dentatorubral-pallidoluysian atrophy (134). Finally, pallidotomy and pallidal-stimulation have also been used in Huntington disease (29; 95). Although chorea is effectively controlled by these procedures, the relentless progression of Huntington disease leads to a loss of functional improvement (65). There have been several patients with Huntington disease treated with fetal cell implantation in the striatum. Despite a few positive reports, in the majority of cases no improvement has been observed. Autopsy studies have shown that the grafts survive but do not integrate with host striatum (66; 26).

With the advent of deep brain stimulation (DBS), there is growing awareness of the beneficial role of this procedure to treat chorea (39). Several studies have described its usefulness in the management of selected patients with chorea-acanthocytosis (80; 133; 136). A large series of patients with refractory tardive dyskinesia that included chorea underwent GPi deep brain stimulation with sustained benefit (115).

Ongoing clinical trials aim to use antisense oligonucleotide technology to lower Huntingtin levels in Huntington disease based on the preclinical findings that lowering Huntingtin in the brain is correlated with the reduction of Huntington disease-like symptoms in rodent models (87; 21). There are mainly three Huntingtin level-lowering strategies. The first one is genome editing by interrupting the CAG repeat expansion, which can potentially delay the onset of disease. The second strategy aims at the protein level by interrupting axonal transport of Huntingtin and induction of autophagy to inhibit the accumulation of mutant Huntingtin protein. Although the first two strategies are still in preclinical phase, phase III clinical trials are ongoing to investigate gene expression modification strategies, which aim to inhibit the generation of Huntingtin protein.

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All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Serena Wong MD

Dr. Wong of Cedars-Sinai Medical Center has no relevant financial relationships to disclose.
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Robert Fekete MD

Dr. Fekete of New York Medical College received consultation fees from Acadia Pharmaceutical, Acorda, Adamas/Supernus Pharmaceuticals, Amneal/Impax, Kyowa Kirin, Lundbeck Inc., Neurocrine Inc., and Teva Pharmaceutical, Inc.
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Former Authors

Christopher F O'Brien MD
Sharin Y Sakurai MD PhD
Francisco Cardoso MD PhD

ICD & OMIM codes

ICD-10: Chorea, NOS: G25.5
OMIM: Familial benign chorea: 215450

Hereditary benign chorea: #118700

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Chorea

Differential Diagnosis

focal motor seizure
tic disorders
SGCE myoclonus-dystonia
rheumatic fever
vascular chorea
- lupus

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Chorea in childhood
Hemiballism
Huntington disease
Motor control of movement disorders
Movement disorders in childhood
- Neuroacanthocytosis
- Rating scales of movement disorders
- Sydenham chorea
- Valproic acid
- Wilson disease

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FDA approves Ingrezza (valbenazine) for chorea associated with Huntington disease

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Chorea …

Chorea

Cite this article

Introduction

Overview

Key points

Clinical manifestations

Presentation and course

Table 1. Hereditary Chorea Etiology

Table 2. Nonhereditary Chorea Etiology

Autoimmune choreiform syndromes

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Former Authors

ICD & OMIM codes

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Also in This Category

Motor control of movement disorders

Fragile X-associated tremor/ataxia syndrome

Acute drug-induced movement disorders

Movement disorder emergencies

Tardive dystonia

Ataxia

Sleep and parkinsonism

Movement disorders associated with autoimmune encephalitis

Chorea

Cite this article

Introduction

Overview

Key points

Clinical manifestations

Presentation and course

Table 1. Hereditary Chorea Etiology

Table 2. Nonhereditary Chorea Etiology

Autoimmune choreiform syndromes

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Former Authors

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Motor control of movement disorders

Fragile X-associated tremor/ataxia syndrome

Acute drug-induced movement disorders

Movement disorder emergencies

Tardive dystonia

Ataxia

Sleep and parkinsonism

Movement disorders associated with autoimmune encephalitis

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