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Overview of chorea

Overview of chorea
Literature review current through: Jan 2024.
This topic last updated: Sep 27, 2022.

INTRODUCTION — The word "chorea" is derived from the Latin "choreus," meaning "dance." Chorea is a hyperkinetic movement disorder characterized by involuntary brief, random, and irregular contractions conveying a feeling of restlessness to the observer [1]. Chorea may be caused by hereditary neurodegenerative diseases, follow structural damage to deep brain structures, or be associated with autoimmune disorders, metabolic derangement, or certain drugs and hormones. Investigation is oriented at searching for a secondary or reversible cause of chorea or confirming a hereditary condition with genetic testing. Although the chorea arriving from acquired conditions may be reversed, there is usually no specific therapy for hereditary neurodegenerative disorders. Symptomatic treatment can reduce abnormal movements regardless of the cause.

This topic will provide an overview of the various types of chorea.

DEFINITIONS — Chorea, athetosis, and ballism frequently coexist in the same patient and are felt to be part of the same choreiform spectrum [2,3].

Chorea is a hyperkinetic movement disorder characterized by rapid and unpredictable contractions affecting mostly distal limbs, but also the face and trunk. The movements are involuntary and nonpatterned with variable speed, timing, and direction, flowing from one body part to another and giving, in less severe cases, an appearance of fidgetiness. The randomness and flowing quality of chorea is a feature that distinguishes it from tremor and dystonia [1].

Athetosis refers to slower, writhing movements with a sinuous quality, usually affecting distal extremities or the face. The term "choreoathetosis" is used when typical choreic movements coexist with athetosis. It has been suggested that athetosis could be a manifestation of associated dystonia rather than a simple variant of chorea, such as seen in cerebral palsy [4].

Ballism refers to involuntary movements that are proximal and large amplitude (in contrast to distal, low-amplitude contractions typical of chorea) with a flinging or kicking character. Ballism is most often unilateral (hemiballism) and although present at rest, it becomes more prominent with action [5].

ETIOLOGY — The structures involved in the production of chorea are the caudate nucleus, putamen, subthalamic nucleus, thalamus, and their interconnecting pathways [1,6]. Chorea results from damage or dysfunction of these structures that causes an imbalance between indirect and direct pathways in the basal ganglia circuitry, leading to excessive dopaminergic activity. Disruption of the indirect pathway with loss of inhibition to the pallidum allows hyperkinetic movements to occur [1]. The disruption of basal ganglia circuitry may be due to structural damage, selective neuronal degeneration, neurotransmitter receptor blockade, metabolic derangements, or autoimmune conditions.

EPIDEMIOLOGY — The prevalence of choreas as a whole is unknown since there are no community-based studies available. Huntington disease (HD) is the most frequent cause of hereditary chorea, with a worldwide prevalence rate of approximately 3 per 100,000 (see "Huntington disease: Clinical features and diagnosis", section on 'Epidemiology'). Although much rarer, this is followed by C9ORF72 gene mutations and HDL4/SCA17.

The most common cause of acquired chorea in adults is likely levodopa-induced dyskinesia. In an Italian series of 51 consecutive cases of chorea admitted to several neurology departments over a five-year period, the most frequent etiologies of chorea were vascular (40 percent), drug induced (14 percent), HD (10 percent), and acquired immune deficiency syndrome (10 percent) [7]. Other causes were found in less than 5 percent of patients, and the diagnosis remained unknown in 6 percent.

In children, Sydenham chorea (SC) accounts for up to 96 percent of acute chorea cases [8]. (See "Sydenham chorea".)

CLASSIFICATION — Chorea is usually classified as being primary (idiopathic, hereditary) or secondary (acquired).

Hereditary choreas (table 1) tend to develop insidiously (over more than one year) and are generally symmetrical, whereas acquired choreas (table 2 and table 3) are more likely to be acute or subacute and can be asymmetrical or unilateral. Therefore, choreas could also be divided according to their mode of onset (acute or insidious) or their distribution (unilateral or bilateral). In any case of unilateral chorea, a focal lesion should be sought, although the etiology is often linked to a systemic disorder. Age of onset can also be used to classify choreas. In children, most cases of chorea are acquired and develop acutely or subacutely, the most common etiology being Sydenham chorea (SC).

CLINICAL FEATURES — Chorea usually affects the distal limbs and face, but may also interfere with respiration and phonation, resulting in slurred speech or involuntary vocalizations [5]. The continuous flow of movements may appear semi-purposeful and difficult to distinguish from restless or fidgety behavior. Moreover, patients may mask the chorea by incorporating choreic movements into voluntary movements (parakinesia) [3,5]. Patients are often unaware of their abnormal movements, which are noted by family members.

Chorea is usually present at rest and may increase with distracting maneuvers, but disappears in sleep [5]. Patients with chorea often demonstrate motor impersistence, an inability to maintain an ongoing motor activity, such as holding the tongue out or maintaining a constant grip [5].

Chorea has the same phenomenology regardless of its etiology. Hence, the differential diagnosis relies on accompanying features, age, and mode of onset [1].

HEREDITARY CAUSES OF CHOREA — There are many different causes of hereditary chorea (table 1). Patterns of inheritance include autosomal dominant, autosomal recessive, and X-linked, as reviewed in the sections that follow.

Autosomal dominant — Important autosomal-dominant causes of hereditary chorea include Huntington disease (HD), C9ORF72 repeat expansions, Huntington disease-like (HDL) syndromes, benign hereditary chorea, dentatorubral pallidoluysian atrophy (DRPLA), several types of spinocerebellar ataxia (SCA), and neuroferritinopathy.

Huntington disease — HD is by far the most common cause of hereditary chorea. HD is caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat expansion of the huntingtin (HTT) gene on chromosome 4p leading to an enlarged polyglutamine tract in the huntingtin protein. This protein is widely expressed in the human brain, but its exact function is unknown. In HD, neuronal loss occurs predominantly in the caudate and putamen. (See "Huntington disease: Genetics and pathogenesis".)

Clinically, adult-onset HD is characterized by insidious development of chorea, cognitive decline, and behavioral changes leading to relentlessly increasing disability and ultimately death (table 4). The first symptoms typically occur at ages 30 to 50 years, but age of onset varies from childhood to the 80s. Chorea is a key feature of HD in adults, and the defining sign at the time of diagnosis. (See "Huntington disease: Clinical features and diagnosis".)

Onset of symptoms before 20 years of age is considered juvenile HD. The clinical presentation of juvenile HD is different from adults, and is marked by a combination of parkinsonism, dystonia, and myoclonus without prominent chorea (table 5). Seizures are also common. Most have the akinetic-rigid syndrome termed the "Westphal variant." Juvenile HD has a more rapid course with early dementia. (See "Bradykinetic movement disorders in children", section on 'Juvenile Huntington disease'.)

No treatment for HD has yet been shown to slow the progression or delay the onset of the disease. Innovative genetic therapies are under active investigation. Symptomatic treatment is offered for chorea and behavioral or cognitive symptoms as needed. (See "Huntington disease: Management".)

C9ORF72 repeat expansions — Neurodegenerative disease caused by hexanucleotide repeat expansions in the C9ORF72 gene can present as an HD phenocopy. In a cohort of 514 patients with suspected HD in whom genetic testing for HTT was negative, repeat expansions in the C9ORF72 gene were identified in 10 patients (2 percent), making it the most common genetic cause of HD phenocopy syndromes [9]. In addition to chorea, patients can present with dystonia, ataxia, parkinsonism, myoclonus, and pyramidal signs [9].

Limited available data suggest autosomal dominant transmission with incomplete penetrance. Mutations in the C9ORF gene involving the repeat expansion are the most common cause of familial frontotemporal dementia (FTD) and familial amyotrophic lateral sclerosis (ALS), and have been identified in some sporadic cases of FTD, ALS, and parkinsonism. (See "Familial amyotrophic lateral sclerosis", section on 'C9ORF72 gene' and "Epidemiology and pathogenesis of amyotrophic lateral sclerosis", section on 'Genetic susceptibility in sporadic ALS' and "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis", section on 'C9orf72 expansion'.)

Huntington disease-like syndromes — The HDL syndromes, numbered 1 through 4, are rare causes of chorea and can present as HD mimics with a combination of chorea, personality changes, and dementia [10,11]. Except for HDL3, they are autosomal dominant and the onset is usually between 20 and 45 years of age.

HDL1 typically presents like HD, but seizures have also been described [12]. It is caused by octapeptide repeat insertions in the PRNP gene on chromosome 20, encoding the prion protein [12].

HDL2 is usually found in families of African ancestry and is more common than HD in Black South Africans [11,13]. However, it has also been described in patients of European and Middle Eastern ancestry [14,15]. HDL2 is caused by a CAG/cytosine-thymine-guanine (CTG) triplet expansion in the JPH3 gene encoding junctophilin-3, a protein of unknown function [10,13]. Acanthocytes can sometimes be found in the peripheral blood smear [16,17]. (See "Neuroacanthocytosis", section on 'Huntington disease-like 2'.)

HDL3 is autosomal recessive and has only been described in two families from Saudi Arabia [11]. The disease appears in early childhood and is characterized by a combination of chorea, dystonia, ataxia, gait instability, spasticity, seizures, mutism, and intellectual impairment [18].

HDL4, better known as SCA17, has a markedly heterogeneous phenotype. The typical presentation includes cerebellar ataxia (the most common feature), intellectual decline, and epilepsy, but some patients can present with chorea [10,19]. Affected individuals can also exhibit dystonia, parkinsonism, pyramidal signs, epilepsy, dementia, and behavioral disturbances [10,20]. HDL4/SCA17 is caused by a CAG/cytosine-adenine-adenine (CAA) expansion in the TBP gene encoding TATA-box binding protein. (See "Autosomal dominant spinocerebellar ataxias", section on 'SCA types 9 to 20'.)

Benign hereditary chorea — Benign hereditary chorea is classically associated with autosomal dominant mutations in the NKX2-1 gene (also known as the TITF1 gene) on chromosome 14q. Patients usually present in infancy with mild, nonprogressive chorea and hypotonia. Chorea can even improve with age. Despite its name, this disorder is not always benign. Many patients also exhibit educational or behavioral difficulties, delayed motor milestones, dysarthria, axial dystonia, gait disturbance, tics, tremor, or myoclonic jerks [4,21]. (See "Hyperkinetic movement disorders in children", section on 'Childhood-onset hereditary chorea'.)

Since the NKX2-1 gene is also responsible for lung and thyroid development, involvement of these organs often coexists and can be a diagnostic clue, hence the term "brain-lung-thyroid syndrome." Mutations in the MBIP gene, which is located upstream from the NKX2-1 gene, have also been reported in association with the same symptoms. Both NKX2-1 and MBIP can be associated with an increased risk of malignancy [22].

Phenotypes similar to NKX2-1 gene-related benign hereditary chorea have been described with mutations in other genes, including ADCY5, PDE10A, GNAO1, and SLC16A2, although all have additional features to chorea [4,23]. (See 'ADCY5 and PDE10A mutations' below.)

Dentatorubral pallidoluysian atrophy — DRPLA is a rare disorder caused by CAG triplet expansions in the ATN1 gene encoding atrophin-1. The expansion can result in anticipation with paternal transmission. DRPLA is particularly prevalent in Japan, but has been reported in other ethnic groups as well. The age of onset varies widely. In adults, DRPLA causes ataxia, choreoathetosis, and cognitive decline and can mimic HD. A distinctive feature is myoclonic epilepsy, which is common in juvenile-onset cases. (See "Autosomal dominant spinocerebellar ataxias", section on 'Dentatorubral pallidoluysian atrophy'.)

Spinocerebellar ataxias — The SCAs are a group of heterogeneous disorders (table 6) characterized by progressive cerebellar ataxia often associated with other neurologic signs such as ophthalmoplegia, pyramidal or extrapyramidal signs, deep sensory loss, and dementia. Onset can be in childhood or old age, but is generally between 20 to 40 years. SCA types 1, 2, 3, and 17 are more likely than other SCA types to cause chorea [1,19]. (See "Autosomal dominant spinocerebellar ataxias".)

Neuroferritinopathy — Neuroferritinopathy is a form of neurodegeneration with brain iron accumulation (NBIA), a rare progressive syndrome that causes parkinsonism, dystonia, cognitive decline, and other neurologic deficits. NBIA is made up of several phenotypically overlapping disorders, with subtypes defined by differences at the molecular genetic level. (See "Bradykinetic movement disorders in children", section on 'Neurodegeneration with brain iron accumulation'.)

Neuroferritinopathy results in accumulation of iron in basal ganglia due to a mutation in the FTL gene encoding the ferritin light chain. It is characterized by adult onset of extrapyramidal features like chorea, dystonia, or parkinsonism that are commonly asymmetrical and associated with cognitive impairment [10,19,24]. Action-specific facial dystonia is particularly typical [25]. Dysarthria, spasticity, and cerebellar signs can also be seen [26,27]. Blood work shows low serum ferritin and brain magnetic resonance imaging (MRI) invariably reveals abnormal deposition of iron in the basal ganglia with gradient echo (T2*) signal loss, as well as cystic changes and necrosis in basal ganglia [24,27,28]. A distinct imaging pattern of iron deposition, termed "pencil lining," has been observed on susceptibility-weighted MRI with linear areas of low signal that outline the cerebral and cerebellar cortices and other gray matter structures as if traced by a black pencil [29].

ADCY5 and PDE10A mutations — Autosomal dominant mutations in the ADCY5 gene have been reported to cause a broad range of childhood-onset hyperkinetic movement disorders, sometimes referred to as familial dyskinesia with facial myokymia. Although chorea is often the main feature, patients can exhibit facial myokymias, dystonia, and myoclonus [24]. Clinical features that should raise suspicion for an ADCY5 mutation are onset of symptoms in the first years of life, absence of cognitive involvement, prominent facial twitches, and marked fluctuations of symptoms, either as paroxysmal attacks or exacerbations at night or upon awakening [30]. Some patients may experience episodic attacks before the movement disorder becomes persistent [31].

Childhood-onset chorea has also been associated with dominant or recessive mutations in the PDE10A gene [32]. Patients have hyperintense bilateral striatal lesions on brain MRI [30,32].

Autosomal recessive — Important autosomal recessive causes of hereditary chorea include chorea-acanthocytosis, Wilson disease, pantothenate kinase-associated neurodegeneration (PKAN), ataxia-telangiectasia, and ataxia with oculomotor apraxia (AOA).

Chorea-acanthocytosis — The clinical manifestations of chorea-acanthocytosis (also called choreoacanthocytosis) include chorea, dystonia, tics, parkinsonism, eye movement abnormalities, behavioral changes, and cognitive decline. The phenotype can be similar to HD, although orofacial and lingual dyskinesia are typically prominent and troublesome, resulting in self-mutilating lip and tongue biting and difficulty swallowing. Seizures, peripheral neuropathy with distal amyotrophy, and elevated serum creatine kinase are common. The mean age of onset is 30 years, and the disease is relentlessly progressive, with death occurring within 15 years of onset. Acanthocytes are usually present on peripheral blood films, but their absence does not exclude the diagnosis. Chorea-acanthocytosis is caused by a mutation in the VPS13A gene on chromosome 9, which encodes for the protein chorein. (See "Neuroacanthocytosis", section on 'Chorea-acanthocytosis'.)

Wilson disease — Chorea is a rare symptom of Wilson disease, but this condition should not be missed, because it is a treatable disorder. Wilson disease should be considered in all patients with a movement disorder who are under 40 years of age. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history".)

Wilson disease is a disorder of copper excretion caused by a mutation in the ATP7B gene resulting in relentless multisystemic copper accumulation. (See "Wilson disease: Epidemiology and pathogenesis".)

The clinical phenotype of Wilson disease is broad. The majority of patients with Wilson disease are diagnosed between the ages of 5 and 35 years, though it has been diagnosed in younger patients and in patients in their 70s. Unlike children, who are more likely to present with hepatic manifestations, older patients (mid-teens and older) are more likely to present with neurologic manifestations. Common neurologic manifestations of Wilson disease include tremor, dysarthria, ataxia, dystonia, parkinsonism, and drooling. Other symptoms can include risus sardonicus, tics, myoclonus, chorea, whispering dysphonia, seizures, and behavioral and cognitive changes. Nearly all patients with neurologic symptoms will exhibit Kayser-Fleisher rings (picture 1) on careful slit lamp examination. These rings are gold, brown, or greenish and first become visible in the upper pole of peripheral cornea. Investigation demonstrates low ceruloplasmin levels in most patients (normal in 5 to 15 percent of cases), low serum copper levels, increased 24-hour urine copper excretion, and abnormal liver function tests. Liver biopsy or genetic testing can confirm the diagnosis. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history".)

Brain MRI is nearly always abnormal in neurologic Wilson disease, showing hyperintensities in basal ganglia or claustrum on T2-weighted images or signal abnormalities in the midbrain ("face of the giant panda").

Pantothenate kinase-associated neurodegeneration — PKAN, formerly known as Hallervorden-Spatz disease, is another subtype of NBIA. (See "Bradykinetic movement disorders in children", section on 'Neurodegeneration with brain iron accumulation'.)

PKAN is caused by mutations in the gene encoding pantothenate kinase 2 (PANK2) and results in accumulation of iron in the basal ganglia, most abundant in globus pallidus interna. Onset is in the first decade, typically with gait dystonia evolving into generalized dystonia, dysarthria, parkinsonism, spasticity, pigmentary retinal degeneration, dementia, and behavioral changes. Brain MRI is invariably abnormal, typically showing the characteristic radiologic sign known as "eye of the tiger" with a central focus of increased T2 signal intensity in the medial globus pallidus surrounded by a zone of decreased signal. (See "Bradykinetic movement disorders in children", section on 'Neurodegeneration with brain iron accumulation'.)

Ataxia-telangiectasia — Ataxia-telangiectasia is the next most common autosomal recessive ataxia after Friedreich ataxia, with an estimated incidence of 1 in 20,000 to 100,000 live births. It is caused by mutations in the ataxia telangiectasia mutated (ATM) gene on chromosome 11; the ATM gene product is involved in the detection of DNA damage. The disease onset is usually between one to four years of age with progressive cerebellar ataxia. Over time, associated features become evident: conjunctival or facial telangiectasias, oculomotor apraxia, chorea, dystonia, myoclonus, and peripheral neuropathy. Associated features include immunodeficiency with recurrent sinus or pulmonary infections, an increased incidence of malignancy, radiation sensitivity, and diabetes mellitus caused by insulin resistance. The diagnosis is established by the presence of characteristic clinical findings (particularly progressive cerebellar ataxia) and identification of pathogenic variants on both alleles for the ATM gene. It is supported by serum immunoglobulin A at least two standard deviations below normal for age and by increased spontaneous and radiation-induced chromosome fragility in cultured cells. In the appropriate clinical setting, the finding of a serum alpha-fetoprotein at least two standard deviations above normal for age is diagnostic of the disorder. (See "Ataxia-telangiectasia".)

Ataxia with oculomotor apraxia — AOA types 1 (AOA1) and 2 (AOA2; also called ataxia-ocular apraxia types 1 and 2) are disorders that present as autosomal recessive or sporadic cerebellar ataxias with oculomotor apraxia, chorea, facial and limb dystonias, sensorimotor polyneuropathy, and cognitive impairment.

AOA1, also known as early-onset AOA, usually presents in the first decade of life, although onset has been reported as late as age 25 years. It is associated with hypercholesterolemia and hypoalbuminemia. The disease is caused by mutations of the APTX gene coding for aprataxin, a protein involved in single-strand DNA repair. Most reported cases are of Portuguese, Italian, and Japanese descent. (See "Ataxia-telangiectasia", section on 'Differential diagnosis'.)

AOA2 is similar to AOA1 but is more common and has a later age of onset (from 20 to 60 years) and slower progression. It is less frequently associated with cognitive impairment, and oculomotor apraxia is a feature in only approximately 50 percent of cases. Patients usually have elevated alpha-fetoprotein and creatine kinase. The disease results from mutations in the SETX gene that encodes senataxin, a protein also involved in single-strand DNA repair.

X-linked — The main X-linked causes of chorea include McLeod syndrome and Lesch-Nyhan syndrome.

McLeod syndrome — The phenotype of McLeod syndrome is similar to chorea-acanthocytosis, with a combination of chorea, subcortical cognitive deficits, behavioral changes, peripheral axonal polyneuropathy, myopathy (usually mild or subclinical) with elevated creatine kinase, and possible seizures (in approximately one-half of patients). However, this disease begins later, between 20 and 50 years, and lacks the self-mutilation or eating difficulties typical of chorea-acanthocytosis. Associated features include cardiac involvement with cardiomyopathy and arrhythmias in approximately two-thirds. Acanthocytes are seen on peripheral blood smear. McLeod syndrome is due to a mutation on the XK gene causing reduction of all Kell antigens and absence of Kx antigen on red blood cells. (See "Neuroacanthocytosis", section on 'Mcleod syndrome'.)

Lesch-Nyhan syndrome — Lesch-Nyhan syndrome is a complex motor-behavioral condition that is inherited as an X-linked recessive trait. The disorder results from mutations in the gene coding for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), leading to deficient enzyme activity. This defect results in an often marked increase in production of uric acid and hyperuricemia. The wide spectrum of neurologic symptoms (with some patients being asymptomatic) and severity of the disease have been associated with the degree of enzyme deficiency. Affected boys have delayed developmental milestones, intellectual disability, and extrapyramidal and pyramidal motor symptoms; they also develop self-mutilating behavior. While earlier literature emphasized choreoathetosis and spasticity as typical features of the motor disorder associated with Lesch-Nyhan syndrome, dystonia is more common. (See "Hyperkinetic movement disorders in children", section on 'Lesch-Nyhan syndrome'.)

ACQUIRED CAUSES OF CHOREA — A variety of acquired conditions can cause chorea (table 2). These include central nervous system vascular lesions; autoimmune/inflammatory disorders, particularly Sydenham chorea (SC); metabolic and endocrine disorders; infectious diseases; toxins; drugs (table 3); structural lesions of the basal ganglia; and so-called senile chorea.

Vascular — Chorea can occur as a consequence of acute ischemic or hemorrhagic stroke or in the context of low-grade ischemic changes in the basal ganglia without obvious infarction. Ischemic and hemorrhagic stroke are the most common causes of nongenetic chorea in the hospital population. Stroke results in early or delayed contralateral hemichorea or hemiballism in less than 1 percent of patients [33-35].

In contrast to traditional textbook concepts, a lesion of the subthalamic nucleus is found in only a minority of cases of vascular hemichorea/hemiballism. Other reported localizations include the caudate nucleus, putamen, thalamus, globus pallidus, corona radiata, subcortical white matter, and cortex [35-37]. Despite this anatomic heterogeneity, there is evidence that most stroke lesions causing hemichorea/hemiballism involve a common functional network connected to the posterolateral putamen [38]. The majority of patients improve within one or two years, but chorea will persist in some individuals [35,37].

Moyamoya disease can rarely present with movement disorders such as unilateral or bilateral acute or subacute chorea and paroxysmal dyskinesia, especially in children. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Clinical presentations'.)

Post-pump chorea, also known as postoperative encephalopathy with choreoathetosis, is a rare form of chorea following extracorporeal circulation. It is typically seen in children, but it can also occur in adult patients [39]. It is possibly caused by hypoxia, hypothermia, or a combination of both. Some patients are left with persistent abnormal movements and cognitive and behavioral changes. (See "Hyperkinetic movement disorders in children", section on 'Post-pump chorea'.)

Chorea rarely occurs in polycythemia vera (0.5 to 5 percent of patients), especially in older women, and can precede hematologic changes [40]. The choreic syndrome is usually acute and generalized with predominant involvement of the orofaciolingual muscles, but it may be unilateral. (See "Clinical manifestations and diagnosis of polycythemia vera".)

Autoimmune or inflammatory disorders — SC is a common cause of chorea in children. Rare autoimmune or inflammatory causes of chorea include paraneoplastic chorea, systemic lupus erythematosus (SLE), and several other immune-mediated conditions [41].

Sydenham chorea — SC is the most common cause of chorea in childhood. It is one of the clinical manifestations of acute rheumatic fever, a nonsuppurative sequela of group A streptococcus infection. SC is an autoimmune disorder, thought to result from cross-reactivity between antibodies to group A streptococcal bacteria and striatal antigens. (See "Sydenham chorea", section on 'Pathophysiology'.)

SC typically occurs in children between 5 and 15 years, although it has also been described in adults. Females are affected more frequently than males by a ratio of 2:1. As opposed to the other major manifestations (ie, arthritis, carditis, erythema marginatum, subcutaneous nodules) of acute rheumatic fever, which emerge one to three weeks after the inciting infection, SC is a later manifestation occurring commonly four to eight weeks after the infection, although it can be delayed up to eight months. Chorea develops subacutely and is generally bilateral, but 20 to 30 percent of cases will experience hemichorea. Affected patients can also exhibit tics, dysarthria, hypotonia, muscular weakness, gait disorder, and vocalizations. SC is often associated with psychologic and psychiatric manifestations that may precede the onset of chorea, including emotional lability with irritability, inattention, hyperactivity, obsessive compulsiveness, anxiety, psychotic symptoms, and depression. The bouts of chorea typically last two to nine months followed by complete spontaneous resolution. However, a substantial proportion of patients has persistence of chorea after two years or has recurrences. Individuals who have developed SC are at increased risk of developing chorea associated with subsequent group A beta-hemolytic streptococcus (GABHS) pharyngitis, pregnancy, oral contraceptives, or other drugs. (See "Sydenham chorea", section on 'Clinical manifestations'.)

The diagnosis of SC is made clinically, based on characteristic neurologic findings. Some patients with SC have no other manifestations of acute rheumatic fever but should have an evaluation for carditis with echocardiography. Since SC is a late manifestation of the streptococcal infection, throat culture at the moment of the chorea is usually negative, and other signs of systemic inflammation have often abated. The antistreptolysin O titer is of limited use in patients with SC because titers generally peak before the onset of SC symptoms and children without rheumatic fever or SC often have low positive titers of ASLO. The antideoxyribonuclease B titer is more useful for supporting the diagnosis of SC because it tends to remain elevated longer. (See "Sydenham chorea", section on 'Diagnostic evaluation'.)

Although most patients with SC recover fully without treatment, those with significant impairment of motor function and the possibility of self-injury may benefit from treatment as discussed separately. (See "Sydenham chorea", section on 'Treatment'.)

All patients with SC should be given treatment for acute pharyngitis followed by prophylactic antibiotic therapy to prevent rheumatic recurrences, which can manifest as chorea, carditis, or psychiatric symptoms. The prophylaxis should be continued at least until early adulthood. (See "Acute rheumatic fever: Treatment and prevention".)

Paraneoplastic chorea — Chorea is a rare paraneoplastic manifestation of cancer, usually associated with CV2/collapsin-responsive mediator protein 5 (CRMP5) antibodies in the context of small cell lung carcinoma [42,43]. The majority of these patients also have other neurologic signs and symptoms, such as vision loss, neuropathy, ataxia, or limbic encephalitis [44]. Chorea has also been reported in other cancers (breast cancer, thymoma, lymphoma, renal cell carcinoma, and testicular cancer) and with other types of antibodies (anti-Hu, anti-Ri, anti-Yo) [41,42,45-47]. The majority of patients with paraneoplastic chorea show abnormal signal in basal ganglia on MRI. Chorea improves with treatment of the underlying malignancy. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'High-risk antibodies (>70 percent cancer association)'.)

Paraneoplastic encephalitis associated with N-methyl-D-aspartate (NMDA) receptor antibodies often presents with abnormal movements including chorea, stereotypies, dystonia, and myoclonus, and is usually associated with other neurologic signs such as behavioral or psychiatric manifestations, ataxia, and seizures [48]. NMDA encephalitis can be associated with ovarian teratoma or can be autoimmune, without an underlying tumor. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Anti-NMDA receptor encephalitis'.)

Encephalitis caused by antibodies against leucine-rich glioma inactivated 1 (LGI1), contactin-associated protein-like 2 (Caspr2), Hu, or gamma-aminobutyric acid type B (GABA-B) receptors can also feature bilateral or unilateral chorea, with either paraneoplastic or autoimmune origin [48-50]. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Anti-LGI1 encephalitis' and "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Anti-Caspr2-associated encephalitis'.)

Other immune-mediated choreas — Although central nervous system involvement is common (up to 80 percent) in SLE, chorea is an uncommon manifestation [51]. Chorea is also seen in approximately 1 percent of patients with primary antiphospholipid syndrome [51]. In childhood, chorea can appear long before the other manifestations of SLE or the antiphospholipid syndrome. (See "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus", section on 'Chorea' and "Hyperkinetic movement disorders in children", section on 'Other acquired causes' and "Clinical manifestations of antiphospholipid syndrome", section on 'Neurologic involvement'.)

Chorea is an uncommon or rare manifestation of other immune diseases such as Behçet syndrome, Sjögren's disease, immunoglobulin A vasculitis (IgAV; Henoch-Schönlein purpura [HSP]), polyarteritis nodosa, primary angiitis of the central nervous system, celiac disease, and sarcoidosis [3,52-56]. (See "Clinical manifestations and diagnosis of Behçet syndrome" and "Clinical manifestations of Sjögren’s disease: Extraglandular disease" and "Neurologic manifestations of rheumatoid arthritis" and "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of polyarteritis nodosa in adults" and "Primary angiitis of the central nervous system in adults" and "Childhood primary angiitis of the central nervous system: Angiography-positive subtype" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children" and "Neurologic sarcoidosis".)

Anti-IgLON5 disease is a slowly progressive disorder with a unique combination of autoimmune-mediated inflammation associated with neuropathological tau protein accumulation. Most patients experience sleep abnormalities (severe insomnia, non-rapid eye movement [REM] sleep parasomnias, REM sleep behavior disorder, obstructive sleep apnea) along with other neurologic manifestations such as chorea or other movement disorders, dementia, ataxia, dysautonomia, peripheral signs, and vertical supranuclear gaze palsy [57]. Antibodies to IgLON5 are present in both serum and cerebrospinal fluid (CSF), and most patients have partial response to immunotherapy. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Anti-IgLON5 disease'.)

Metabolic and endocrine disorders — Chorea gravidarum, hyperglycemia, and other metabolic or endocrine disorders may be associated with chorea.

Chorea gravidarum — Pregnancy-induced chorea is typically unilateral and begins after the first trimester of pregnancy, to improve later in the pregnancy or after delivery [58]. Women with a previous history of chorea associated with oral contraceptive use, SC, SLE, or antiphospholipid antibody syndrome are more prone to developing chorea gravidarum. The abnormal movements may recur in subsequent pregnancies. (See "Neurologic disorders complicating pregnancy", section on 'Chorea gravidarum'.)

Hyperglycemia — Nonketotic hyperglycemic hemichorea-hemiballism (also referred to as "diabetic striatopathy") is a well-described cause of acute acquired hemichorea in adults [33,59-61]. Most cases occur in the setting of poorly controlled, longstanding type 2 diabetes (mean blood glucose 414 mg/dL, mean glycated hemoglobin 13.1 percent) [61], although this condition is also seen in newly diagnosed diabetes or acute hyperglycemia. Aside from poor glucose control, risk factors include older age and female sex [36,62].

Most patients present with acute hemichorea involving both arm and leg; facial involvement and bilateral chorea have also been described. The characteristic finding on MRI is hyperintense signal abnormality on T1-weighted images in the contralateral striatum, with normal diffusion-weighted and susceptibility images (figure 1) [63]. These characteristics distinguish striatopathy from hemorrhage, which may be initially suspected based on computed tomography (CT) showing an area of hyperdense signal in the striatum. Thus, MRI is critical to making the correct diagnosis.

Most patients show remission of chorea over a period of days to several weeks once glycemic control is achieved, but abnormal movements can persist for more than a year or recur after previous remission. Short-term use of symptomatic therapies for chorea (eg, antipsychotic drugs) may be needed for severe cases. (See 'Management of chorea' below.)

Other metabolic or endocrine disturbances — Hypoglycemia, hypernatremia, hyponatremia, hypomagnesemia, and hypocalcemia have also been implicated in the development of acute or subacute chorea [2,33]. In addition, a few case reports have linked chorea to vitamin B12 deficiency [64-66]. Correction of the metabolic abnormality leads to resolution of abnormal movements.

Chorea is rarely associated with hyperthyroidism (less than 2 percent of patients) and is usually abolished after successful treatment of thyrotoxicosis [67-69]. Hypoparathyroidism often leads to hypocalcemia, which can produce generalized or focal chorea that is often paroxysmal and triggered by action (called paroxysmal kinesigenic dyskinesias) [2,70-72].

Chronic acquired hepatocerebral degeneration can occur in any form of acquired liver disease and may produce chorea, as well as other movement disorders such as tremor, parkinsonism, myoclonus, or dystonia [73]. MRI shows hyperintense T1 signal in basal ganglia, thought to result from deposition of manganese [73].

Patients with renal failure rarely present with chorea that is reversible with dialysis [74].

Celiac disease has been described to present with rapidly progressive generalized chorea, which resolved after gluten-free dietary treatment [75].

Infectious diseases — Many infectious diseases of the central nervous system may produce acute or insidious chorea (table 2). Human immunodeficiency virus (HIV) infection has been reported as the most frequent cause of infectious chorea [33]. Fifty percent of patients with acquired immune deficiency syndrome (AIDS) develop movement disorders, with hemiballism-hemichorea and tremor being the most common, although it is rarely clinically disabling (3 percent) [76]. Abnormal movements can result either from direct action of the virus in the setting of HIV encephalitis, opportunistic infections (toxoplasmosis, syphilis, tuberculosis, etc), or drugs [33,76,77].

Acute bacterial meningitis, aseptic meningitis, tuberculous meningitis, encephalitis, Lyme disease, parasitic or fungal infections, as well as prion diseases have all been reported to cause chorea in some patients. Chorea has rarely been reported with viral encephalitis, including in cases of coronavirus disease 2019 (COVID-19) and herpes simplex virus infection [78,79].

Toxin exposure — Although uncommon, exposure or intoxication with carbon monoxide, manganese, thallium, toluene, methanol, cyanide, or mercury can result in transient or permanent movement disorders, including chorea [80]. Recreative use of alcohol, amphetamines, cocaine, or heroin as well as glue-sniffing can also produce chorea.

Drug-induced chorea — Many different drugs have been reported to cause chorea (table 3), either as an acute phenomenon or as the consequence of long-term therapy. Certain drugs (eg, oral contraceptives and levodopa) seem to require preexisting basal ganglia dysfunction, such as a remote history of SC or Parkinson disease, in order to cause chorea; others seem to be more universally choreogenic [1]. Withdrawal of the offending agent is the treatment of choice but does not always lead to remission of abnormal movements.

Chronic exposure to a dopamine antagonist (eg, antipsychotics and antiemetics such as metoclopramide and prochlorperazine) that crosses the blood-brain barrier can lead to abnormal movements of the oro-bucco-lingual region called tardive dyskinesia; domperidone does not result in tardive dyskinesia because it does not cross the blood-brain barrier. Although tardive dyskinesia has been referred to as "chorea," the term "stereotypies" appears to be more appropriate to describe the stereotyped oro-bucco-lingual movements, as opposed to typical random and flowy choreiform movements [4]. (See "Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis".)

Tardive dyskinesia is rare in children. Chorea related to dopamine receptor blocker use in children tends to occur with rapid discontinuation of the drug (rather than chronic use) and is called withdrawal emergent syndrome. In this setting, chorea is not restricted to the orofacial muscles and is often associated with other types of abnormal movements. (See "Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis", section on 'Children'.)

Once the offending medication has been withdrawn, the resolution of tardive movements can be a slow process (months to years) and is not assured. The prevention and management of tardive dyskinesia are discussed in detail elsewhere. (See "Tardive dyskinesia: Prevention, treatment, and prognosis".)

Levodopa-induced motor fluctuations and dyskinesia eventually develop in more than 50 percent of patients with Parkinson disease depending on current age, age at disease onset, and duration of levodopa treatment. Levodopa-induced dyskinesias consist of abnormal involuntary movements that are usually choreic or dystonic but may be ballistic or myoclonic when more severe. (See "Medical management of motor fluctuations and dyskinesia in Parkinson disease".)

Oral contraceptive use can result in unilateral or generalized insidious chorea, especially in individuals with previous SC, chorea gravidarum, SLE, or antiphospholipid syndrome [81]. Time between initiation of treatment and appearance of abnormal movements can vary from days to years [81]. Hormone replacement therapy inducing chorea in postmenopausal women has also been described [3].

Structural lesion in basal ganglia — Any appropriately placed deep brain lesion (space occupying lesion, vascular lesion, infection, trauma, etc) can cause typical distal chorea or more proximal ballistic movements.

Senile chorea — Senile chorea is a controversial entity previously referring to development of chorea in old age. However, investigation of these patients often reveals alternative diagnoses, the most common being Huntington disease (HD) [33,82,83].

Edentulous dyskinesia — Older adult patients can exhibit choreic-like movements of the lips, tongue, and jaw associated with ill-fitting dentures or lack of dentures, referred to as "edentulous dyskinesia" [84,85]. This condition has been reported in up to 16 percent of edentulous patients [85]. It is thought that malocclusion or lack of sensory contact may play a role in the production of such orodyskinesia [85]. Insertion of well-fitting dentures can abate abnormal movements [85].

EVALUATION FOR THE CAUSE OF CHOREA — To identify the cause of chorea in a particular patient, a careful history should include age of onset, time course (acute or insidious), past medical history, history of recent infection with group A beta-hemolytic streptococcus (GABHS), family history, and drug exposure (table 3). Chronic and progressive chorea is typical of neurodegenerative diseases, whereas static chorea can be seen in structural or toxic injuries to basal ganglia or in benign hereditary chorea. Subacute or acute chorea can occur with autoimmune, metabolic, vascular, infectious, or toxic causes. Neurologic examination is also crucial and must include distribution of chorea and associated features.

Hemichorea can occur due to a structural lesion. However, unilateral or asymmetric symptoms may also occur with autoimmune and metabolic choreas as well as chorea gravidarum.

Chorea associated with ataxia raises the suspicion for spinocerebellar ataxia (SCA) types 1, 2, 3, 8, or 17, dentatorubral pallidoluysian atrophy (DRPLA), ataxia-telangiectasia, ataxia with oculomotor apraxia types 1 (AOA1) or 2 (AOA2), and even rarely Friedreich ataxia.

Chorea associated with dementia suggests Huntington disease (HD), C9ORF72 gene mutations, Huntington disease-like (HDL) syndromes, SCA17, DRPLA, or chorea-acanthocytosis.

Chorea associated with signs of peripheral neuropathy can occur in chorea-acanthocytosis, McLeod syndrome, SCA, ataxia-telangiectasia, or AOA1 or AOA2.

To rule out a secondary cause, a basic workup includes the following:

Complete blood count

Serum glucose and electrolytes

Serum calcium, magnesium, vitamin B12, and parathyroid levels

Renal, liver, and thyroid function tests

Pregnancy test

Blood smear may reveal the presence of acanthocytes in chorea-acanthocytosis, McLeod syndrome, HDL2, and pantothenate kinase-associated neurodegeneration (PKAN). In suspected Sydenham chorea (SC), other major or minor symptoms and signs of rheumatic fever should be sought, including evaluation for carditis; antideoxyribonuclease B and antistreptolysin O titers can be helpful. Screening for possible autoimmune chorea includes antinuclear antibodies and antiphospholipid antibodies, while a paraneoplastic evaluation would add anti-CRMP5/CV2, anti-Hu, anti-Yo, anti-Ri, anti-NMDA, anti-LGI1, and anti-Caspr2 antibodies.

Screening for Wilson disease with serum ceruloplasmin and 24-hour urine copper is recommended in any case of movement disorder under the age of 40 years, especially if there is a positive family history of neuropsychiatric disorders or a history of liver disease. Workup for infectious causes of chorea should be directed by the clinical setting and degree of suspicion for particular infections. Specific considerations in appropriate settings include HIV testing, lumbar puncture for cerebrospinal fluid (CSF) examination (including Venereal Disease Research Laboratory [VDRL]), Lyme serologies, and toxoplasmosis titers (in immunosuppressed patients).

Neuroimaging with brain MRI (preferred) or CT will help to rule out a structural lesion in patients with focal or unilateral choreas, but may also reveal evidence of hereditary, immunologic, or metabolic choreas, such as caudate and frontal atrophy in HD, cerebellar atrophy in SCA, or basal ganglia anomalies in neuroferritinopathy, chorea-acanthocytosis, Wilson disease, PKAN, liver dysfunction, or hyperglycemia.

Genetic testing is available for many hereditary choreas, which allows confirmation of the diagnosis and genetic counseling to family members.

MANAGEMENT OF CHOREA — Secondary chorea often improves or resolves with appropriate treatment of the underlying cause or withdrawal of the offending agent. Unfortunately, no agent has been proven to slow or halt progression of hereditary choreas, with the exception of copper-reducing therapies in Wilson disease. Clinical trials are underway to reduce expression of mutated huntingtin in HD, hoping to slow progression or delay onset of disease.

The mainstay of management in genetic choreas includes careful genetic counseling of affected patients and their relatives and symptomatic treatment of chorea and other symptoms if they cause functional disability or social embarrassment. The same agents used to reduce choreic movements in primary chorea can also be used for secondary chorea, although treatment is often unnecessary because many patients are unaware of or untroubled by the movements.

The management of specific causes of chorea is reviewed in detail elsewhere:

Huntington disease (HD) (see "Huntington disease: Management")

Levodopa-induced dyskinesia in Parkinson disease (see "Medical management of motor fluctuations and dyskinesia in Parkinson disease")

Sydenham chorea (SC) (see "Sydenham chorea", section on 'Treatment')

Wilson disease (see "Wilson disease: Management")

Symptomatically, dopamine receptor blockers have been generally considered the most effective agents to reduce the severity of choreic movements, regardless of the cause. First-generation antipsychotic agents (typical neuroleptics) have a long history of use to reduce chorea, although there is little evidence to support their efficacy, and they are increasingly avoided due to higher risk of side effects.

Second-generation antipsychotic drugs (atypical neuroleptics) including olanzapine, risperidone, and aripiprazole can help reduce chorea and may have a better side effect profile. Common side effects and risks of second-generation agents, including weight gain and related metabolic effects, should be reviewed with the patient when considering long-term therapy. In the authors' experience, quetiapine is not helpful for control of chorea, except in very high doses (eg, 300 mg daily). (See "Second-generation antipsychotic medications: Pharmacology, administration, and side effects", section on 'Adverse effects'.)

Dopamine depleting agents also have the potential to treat chorea. In particular, inhibitors of presynaptic vesicular monoamine transporter type 2 (VMAT2) such as tetrabenazine, valbenazine, and deutetrabenazine are now a first-line option for chorea associated with HD and are also becoming a treatment of choice for chorea of any cause [86-88]. Clinicians should be aware of the risk of depression with VMAT inhibitors as well as the potential for a variety of important drug interactions. (See "Huntington disease: Management", section on 'Management of chorea'.)

Although evidence is limited, valproic acid, carbamazepine, oxcarbazepine, topiramate, levetiracetam, gabapentin, and levodopa may be useful to suppress chorea in some patients [89-104].

Autoimmune choreas including autoimmune or paraneoplastic encephalitis, systemic lupus erythematosus (SLE), and antiphospholipid antibody syndrome may be responsive to treatment with glucocorticoids, plasma exchange, or intravenous immunoglobulin (IVIG) [102,105-109].

Clinical experience suggests that benzodiazepines have a mild antichorea effect, but the use of such agents is poorly documented [110].

Although surgical therapy (eg, pallidotomy, thalamotomy, deep brain stimulation) has been reported to reduce chorea in case reports and small series, it is not generally recommended in HD, vascular chorea, cerebral palsy, senile chorea, or dentatorubral pallidoluysian atrophy (DRPLA) due to lack of proven efficacy and risk of side effects [111-115]. If used, surgical therapies should be considered carefully and only in patients with no cognitive abnormalities.

SUMMARY AND RECOMMENDATIONS

Clinical features – Chorea is a hyperkinetic movement disorder characterized by rapid and unpredictable contractions affecting mostly distal limbs, but also the face and trunk. The movements are involuntary and nonpatterned, with variable speed, timing, and direction. (See 'Definitions' above.)

The continuous flow of choreiform movements may appear semipurposeful and difficult to distinguish from restless or fidgety behavior. Chorea disappears in sleep. (See 'Clinical features' above.)

Localization – The structures involved in the production of chorea are the caudate nucleus, putamen, subthalamic nucleus, thalamus, and their interconnecting pathways. (See 'Etiology' above.)

Classification – Chorea is usually classified as being primary (idiopathic, hereditary) or secondary (acquired). Hereditary choreas tend to develop insidiously and are generally symmetrical, whereas acquired choreas are more likely to be acute or subacute and can be asymmetrical or unilateral. (See 'Classification' above.)

Hereditary causes – There are many different causes of hereditary chorea (table 1). Patterns of inheritance include autosomal dominant, autosomal recessive, and X-linked.

Autosomal dominant – Important autosomal-dominant causes include Huntington disease (HD), C9ORF72 repeat expansions, Huntington disease-like (HDL) syndromes, benign hereditary chorea, dentatorubral pallidoluysian atrophy (DRPLA), several types of spinocerebellar ataxia (SCA), and neuroferritinopathy.

Autosomal recessive Important autosomal-recessive causes of hereditary chorea include chorea-acanthocytosis, Wilson disease, pantothenate kinase-associated neurodegeneration (PKAN), ataxia-telangiectasia, and ataxia with oculomotor apraxia (AOA).

X-linked The main X-linked causes of chorea include McLeod syndrome and Lesch-Nyhan syndrome. (See 'Hereditary causes of chorea' above.)

Acquired causes – A variety of acquired conditions can cause chorea (table 2). These include central nervous system vascular lesions; autoimmune/inflammatory disorders, particularly Sydenham chorea; metabolic and endocrine disorders; infectious diseases; toxins; drugs (table 3); structural lesions of the basal ganglia; and so-called senile chorea. (See 'Acquired causes of chorea' above.)

In children, most cases of chorea are acquired and develop acutely or subacutely, the most common etiology being Sydenham chorea. (See 'Sydenham chorea' above.)

Evaluation – A careful history should include age of onset, time course (acute or insidious), past medical history, history of recent infection with group A beta-hemolytic streptococcus (GABHS), family history, and drug exposure (table 3). Neuroimaging should be performed for new-onset cases, especially when asymmetric. A variety of laboratory tests may be useful depending on the clinical context. (See 'Evaluation for the cause of chorea' above.)

Management – Treatment of chorea is symptomatic. Secondary chorea often improves or resolves with appropriate treatment of the underlying cause or withdrawal of the offending agent. Dopamine receptor blockers can reduce the severity of choreic movements, regardless of the cause. (See 'Management of chorea' above.)

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Topic 14133 Version 27.0

References

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