Clinical manifestations

Presentation and course

Primary chorea

Huntington disease. Huntington disease (HD) 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 (105). 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 (133). 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 (129). 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 (91). 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.

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 (19; 24). 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 (106). 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 (15).

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 (109). There is also a description of a homozygous loss-of-function mutation in PDE2A associated with an early onset hereditary chorea (134).

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 (102).

Chorea acanthocytosis. Chorea acanthocytosis (ChAc) is a rare neurodegenerative disease that can be transmitted by autosomal recessive, dominant, or X-linked inheritance. It is a part of the group of neuroacanthocytosis syndrome consisting of McLeod syndrome, Huntington disease-like syndrome 2, and pantothenate kinase-associated neurodegeneration. 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 (151). 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. According to a multicenter retrospective analysis, GPi-DBS provides long-lasting improvement in patients with chorea acanthocytosis. A study reported the efficacy of the use of STN-DBS in two siblings with severe oromandibular dystonia and gait abnormalities (156). Further research is needed to improve the understanding of the mechanisms and the treatment modalities for chorea acanthocytosis.

Dentatorubralpallidoluysian atrophy. Dentatorubralpallidoluysian atrophy (DRPLA) is an autosomal dominant disorder caused by a CAG trineucleotide repeat expansion in chromosome 12 (73). 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 (14). Neuronal loss and gliosis in the dentate nucleus, red nucleus, globus pallidus, and subthalamic nucleus is often seen pathologically (14).

Benign hereditary chorea. Patients with benign hereditary chorea, an autosomal dominant illness, have a mutation in the TITF1/NKX2-1 gene, which codes for a transcription factor essential for the organogenesis of the lung, thyroid, and basal ganglia (84; 71). In fact, the clinical picture of these patients is characterized by a variable combination of chorea, mental retardation, congenital hypothyroidism, and chronic lung disease; hence, the term brain-thyroid-lung syndrome has been proposed for this disease (154; 45). Studies with clinical-genetic correlation have helped to demonstrate that the clinical spectrum of benign hereditary chorea is wider than previously thought, including dystonia, myoclonus, restless legs syndrome, psychosis, hypotonia, seizures, joint laxity, neonatal respiratory failure, pituitary involvement, and short stature (03; 83; 57; 67; 119; 68). It has also been demonstrated that the phenotype of benign hereditary chorea and hypothyroidism can be caused by distinct NKX2-1 mutations (51; 123; 71). A description of 28 patients from France harboring TITF1/NKX2-1 gene mutations confirms that a gamut of movement disorders and nonmotor features are associated with benign hereditary chorea: hypotonia and chorea were present in early infancy, with delayed walking ability (25 out of 28); dystonia, myoclonus, and tics were often associated; and attention deficit hyperactivity disorder was present in seven (58). In summary, the clinical presentation of NKX2-1 mutations is heterogeneous, often including severely disabling features. Few patients with this condition who underwent PET imaging to study postsynaptic nigro-striatal dopamine receptors were found to have decreased density of receptors (85).

Secondary chorea

Immune-mediated chorea. Sydenham chorea 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 (159). The typical age of onset is 5 to 15 years with a female gender predominance (43). The first episode of Sydenham chorea typically occurs 6 to 8 weeks poststreptococcal infection (11). 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 (115). 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.

Multiple neuronal antibodies, including anti-glutamic acid decarboxylase 65 (anti-GAD 65), contactin-associated protein-like 2 (CASPR2), leucine-rich glioma-inactivated 1 protein (LGI1), and voltage-gated calcium channel antibody (VGCC) are associated with nonparaneoplastic antibody-positive chorea. High-titer 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 (39). Progressive encephalomyelitis with rigidity and myoclonus (PERM) is an atypical form of stiff person spectrum disorder (07). LGI1 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 sec), frequent, stereotypical, and focal movements of the arm and ipsilateral face or arm (55). 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 (136). All of these can lead to muscle twitching and muscle cramps.

N-methyl-D-aspartate receptor (NMDA-R) encephalitis is the most common sporadic autoimmune encephalitis in children and younger adults. There is a female predominance (48; 89). 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 (89). 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 (48). Some patients are diagnosed with NMDA-R encephalitis after HSV encephalitis, typically 1 to 4 weeks after initial infection (48; 89).

Anti-IgLON5 disease is a recently discovered neurodegenerative disorder associated with antibodies against the neuronal cell adhesion protein, IgLON5, of unknown function (54). 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 (53). 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.

Systemic lupus erythematosus and primary antiphospholipid syndrome are rare causes of chorea and occur in 1% to 2% of all cases (05). 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.

Vascular chorea. Hemichorea can occur contralateral to the lesion in the basal ganglia, thalamus, or lentiform nucleus after stroke (30). When a lesion involves the subthalamic nucleus, hemichorea occurs ipsilateral to the lesion.

Polycythemia vera (PV) is a myeloproliferative neoplasm associated with erythrocytosis. A diagnosis of polycythemia vera is made when an individual has hemoglobin greater than 16.5 g/dL (greater than 16.0 g/dL in women) or hematocrit greater than 49% (greater than 48% in women), or increased red cell mass, hypercellularity in bone marrow biopsy, and presence of the JAK2 mutation (13). In addition, chorea can occur after a stroke, especially when the subthalamic nucleus is involved.

Infectious chorea. Chorea can occur as an acute manifestation of bacterial, viral, aseptic, or tuberculous encephalitis and meningitis. Various movement orders have been observed in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). Ataxia and myoclonus are the most common manifestations; however, chorea, parkinsonism, and dystonia have also been reported (137).

Drug-induced chorea. Acute chorea can be caused multiple drugs including dopamine agonists, stimulants (eg, cocaine and amphetamines), levodopa therapy, oral contraceptives, and anticonvulsants (eg, carbamazepine, valproate, phenytoin, and gabapentin) (70). Tardive dyskinesia is a movement disorder characterized by irregular bucco-oral movements after prolonged use of antipsychotics, especially the first-generation antipsychotic medications.

Metabolic causes for chorea. Chorea and hemichorea have been reported as the initial presenting symptoms in the setting of hypoglycemia and nonketotic hyperglycemia (128; 59; 96).

Prognosis and complications

Prognosis depends on etiology. Drug-induced chorea is usually reversible after the medication is discontinued, but 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). Classically, Sydenham chorea resolves in 1 to 6 months. There is evidence that patients who had Sydenham chorea in the past are often left with frontal lobe dysfunction, such as dysexecutive syndrome, as well as attention deficit disorder (10; 26). Harsanyi and colleagues not only replicated the findings of patients with Sydenham chorea who performed worse than healthy controls in tasks of phonemic and semantic verbal fluency but also showed that they had a poorer performance on the Token test, which assesses verbal comprehension (61). Interestingly, individuals with rheumatic fever without chorea also had a significantly worse verbal fluency (61). Huntington disease, neuroacanthocytosis, and other degenerative illnesses have poor prognoses, dependent more on the underlying condition than on the choreic movements, 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 (150).

Biological basis

Etiology and pathogenesis

The causes of chorea, as listed in the section under differential diagnosis and summarized in Table 1, are many. In addition to the classical presentation, chorea is also found in less widely recognized settings. For instance, in a review of the phenomenology of 100 patients with focal motor seizures, a group of experts identified chorea in 4% of these individuals (49). The etiology also depends on the age at onset. For instance, in adults, vascular chorea is the most common etiology (127). In contrast, in children, Sydenham chorea account for more than 90% of the acute cases of chorea (159).

In all cases of chorea, it is assumed that there is disruption of basal ganglia modulation of thalamocortical motor pathways. This disruption may be due to structural damage, selective neuronal degeneration, neurotransmitter receptor blockade, or other metabolic factors within the basal ganglia. Structural lesions of the subthalamic nucleus or subthalamic region, caused by infarcts, hemorrhage, or tumors, produce chorea (94). Alterations in striatal neurotransmitters may occur endogenously, as in Huntington disease; or exogenously, as seen with drug use or withdrawal (122; 99; 08).

In Huntington disease, mutant Huntingtin (mHTT) protein, an intracellular protein, was found to be transiently increased in the cerebrospinal fluid after acute neurotoxic injury, suggesting the mutant protein was released from dying neurons into the extracellular space and then cerebrospinal fluid (25). mHTT protein in the cerebrospinal fluid correlates with disease burden as well as motor and cognitive performance (25). However, the cell type and brain region source of mHTT remains unclear, but striatum and cortex likely contribute to the pool mHTT in the cerebrospinal fluid given that these brain regions are most affected in Huntington disease.

The role of autoimmune processes in chorea is of growing interest. Antibasal ganglia antibodies have been detected in subjects with Sydenham chorea using ELISA and Western immunoblotting methods. The antibasal ganglia antibodies play a role in the development of chorea by disrupting corticostriate circuitry (31). It was demonstrated that these autoantibodies target neuronal tubulin (82). Interestingly, there are data suggesting that persistence of Sydenham chorea for 2 years or more is related to structural dysfunction rather than to an ongoing autoimmune process (144). A study, however, failed to induce behavioral changes in rodents infused with antibodies from patients with Sydenham chorea although they bound to neural cells (12). Nevertheless, studies provide compelling evidence that Streptococcus-induced antibodies cross-react with central dopamine receptors inducing movement disorders and behavioral abnormalities (41; 17; 46; 38). Autoimmune-mediated damage may be the result of small vessel occlusive disease in the basal ganglia or by direct antibody attack on neuronal antigens in the basal ganglia (79; 146).

In systemic lupus erythematosus, 90% of patients with chorea test positive for antiphospholipid antibodies (131). These patients also have circulating antibodies that bind to neuronal surface (41). Immunologic studies show that antiphospholipid antibodies associated with chorea target beta2-glycoprotein I cause thrombotic phenomena (124). Chorea may also be a component of paraneoplastic syndromes. Although rare, paraneoplastic chorea associated with small cell lung cancer, lymphoma, renal cell cancer, and cardiac fibroelastoma has been reported (35; 148; 16). Previous investigations suggested that paraneoplastic chorea was almost exclusively associated with CV2/CRMP5 related to small cell lung cancer or, less commonly, malignant thymoma or breast cancer (63; 56). Similar results were provided by a report of 13 subjects with paraneoplastic chorea who corresponded to 1.2% of a large, multinational European cohort of individuals with paraneoplastic syndromes and, after small cell lung cancer, the most common neoplasms were lymphoma, bowel, or kidney cancers (149). A series of 14 patients from the U.S., however, indicates that ANNA is an antibody also commonly associated with paraneoplastic chorea and most patients were found to have small cell carcinoma or adenocarcinoma (117).

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 (88). In mice with quinolinic acid striatal lesions, inhibition of JAK2 led to reduced apoptosis and astrogliosis, suggesting that JAK2 inhibition is neuroprotective (66). 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.

Table 1 contains a list of a number of licit and illicit drugs that can cause chorea. Of note, in the context of patients with movement disorders, levodopa and other dopaminergic agents are a common cause of chorea in subjects with Parkinson disease. Antiepileptic agents have long been recognized as a cause of chorea, particularly in patients with structural brain lesions. There are reports relating valproate use to onset of chorea, which is surprising considering the established antichoreic action of this agent in Sydenham chorea (142; 147).

There are reports of causes of chorea in the adults or the elderly that, although rare, should be kept in mind by the clinician: acute bilateral basal ganglia lesions in patients with brainstem cavernous malformation, brainstem glioma, diabetic uremia, moyamoya disease, post-pump, valproic acid use, pontine hemorrhage and putaminal cavernous angioma (81; 95; 132; 147; 92; 90; 120; 158). There are reports describing that the damage of post-pump chorea may result in a clinical picture similar to progressive supranuclear palsy (118). It is interesting that although not often recognized as a cause of chorea, uremia can cause this movement disorder and lead to neuroimaging findings rather similar to what one sees in chorea associated with hyperglycemia. A study showed that there are differences between the two conditions on magnetic resonance imaging of the brain: the diabetic patients demonstrated T1-hyperintense and inhomogeneous lesions in the basal ganglia, whereas the others had T2-hyperintense and homogeneous lesions in this area (80).

Another rare cause of the combination of ataxia and chorea is mutation in the mitochondrial DNA polymerase gamma. In a report of a series of patients, the authors found a myriad of clinical features: chronic external ophthalmoplegia (100%), areflexia to the lower extremity (100%), impaired vibration sense (100%), bilateral ptosis (69%), epilepsy (38%), and hyperkinetic movement disorders, including chorea (31%), dystonia (31%), and myoclonus (23%) (143). There are also reports of unusual causes of chorea: extrapontine myelinolysis (110) and associated with intratumoral chemotherapy catheter (160), as well as induced by cerebrospinal fluid shunt (42).

The presence of chorea reflects striatal dysfunction, as seen in the classic chorea of Huntington disease or subthalamic dysfunction (34). Although many biological factors are associated with chorea, neuroanatomic data implicate the putamen, globus pallidus, and subthalamic nuclei as key structures in all choreic disorders (125). 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 (02). Multiple neurotransmitters seem to play a role in the pathophysiology of chorea, most importantly dopamine (74). Once manifested clinically, no specific electrophysiologic features reliably discriminate chorea from normal movements or other involuntary movements (145). Electrophysiologic studies indicate that cortical modulation is normal in some forms of chorea, thus, confirming the subcortical origins of the involuntary movements (60). 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. However, there are also inconsistencies between the model and clinical evidence, including the abolition of drug-induced chorea in Parkinson disease through pallidotomy, which, according to the model, should lead to increased excitatory thalamocortical drive and, thus, worsening of chorea. 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 (112; 104; 107). 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 (77).

Epidemiology

Although there are no community-based studies available regarding the prevalence and incidence of chorea as a whole, there is information regarding the situation in tertiary care centers. According to a study from Pennsylvania, Sydenham chorea accounts for almost 100% of acute cases of chorea seen in children (159). Studies from Australia confirm the remaining importance of rheumatic fever as a cause of chorea in children (40; 141; 111). In fact, an epidemiological study in Ireland showed that the incidence is 0.23 out of 100,000 (33). In contrast, the situation is distinct in adult patients. Although no data are available, it is likely that levodopa-induced chorea in Parkinson disease patients is the most common cause of chorea seen by neurologists. Huntington disease is the most frequent cause of genetic chorea with reported prevalence rates in North America and Europe ranging from 3 to 7 per 100,000 (23). The other genetic conditions causing chorea (see Table 1) are rare. One study of consecutive patients seen at a tertiary hospital found that stroke accounted for 50% of all cases, drug abuse was identified in one third of the patients, and the remaining patients had chorea related to AIDS and other infections as well as metabolic problems (127).

Prevention

As might be expected, a discussion regarding prevention of chorea from such diverse etiologies is not practical. Prevention in the context of specific conditions is worthwhile. For example, prenatal and preimplantation genetic diagnosis in families at-risk for Huntington disease is available. The following reproductive choices are discussed with the at-risk individuals during genetic counseling: (1) the wish to have a pregnancy free of Huntington disease and without the risk of a mutation carrier offspring, (2) the option to test an ongoing pregnancy by chorionic villous sampling and termination of the pregnancy if the fetus is a carrier of the Huntington disease mutation, (3) the decision to perform the predictive testing to the at-risk couple prior to requesting the prenatal diagnosis (if the fetus is positive for Huntington disease before the at-risk parent undergoing the presymptomatic test, the genetic status of the at-risk parent would be indirectly revealed), (4) the request of pre-implantation genetic diagnosis that is performed as part of an in vitro fertilization procedure (138). Genetic counselor should communicate with the at-risk couple in a compassionate and unambiguous manner so that they can make the most informed reproductive decision before pregnancy.

Differential diagnosis

Confusing conditions

The approach to diagnosis is guided by several factors, including the onset of symptoms, age, family history, and associated neurologic symptoms. In the setting of acute presentation, vascular etiology should be suspected. Sydenham chorea should be considered in children presenting with acute to subacute onset of chorea. Other etiologies with subacute onset of chorea include autoimmune diseases, metabolic derangement, and drugs. Chronic presentation should raise suspicion of genetic diseases, such as Huntington disease in adults and Wilson disease in children.

Table 1 lists both common and uncommon conditions associated with chorea. As mentioned in the Etiology section, the reader should consider age at onset when developing a plan for diagnostic evaluation. A review discusses the etiology of chorea in children (06).

Table 1. Conditions Associated with Chorea

Autoimmune causes
		• Paraneoplastic
				- CRMP-5 (CV2) - ANNA-1 (Hu) - NMDAR - ANNA-2 (Ri) - CASPR2 - PDE-10A
		• Systemic disease
				- SLE - PAPS
		• Idiopathic
				- NMDAR - GAD-65 - CASPR2 - LGI1 - IgLON5
Genetic causes
	• Ataxia-telangiectasia • Ataxia associated with oculomotor apraxia • Benign hereditary chorea • C9orf72 expansions • Dentatorubropallidoluysian degeneration • Friedreich ataxia • Glucose transporter deficiency • Huntington disease • Huntington disease-like illnesses • Leigh disease and other mitochondriopathies • Lesch-Nyhan disease • McLeod syndrome • Neuroacanthocytosis • Neuroferritinopathy • Pantothenate kinase associated degeneration • POLG mutation • Prion disease • PRRT2 gene mutation • Spinocerebellar atrophy type 2 • Spinocerebellar atrophy type 3 • Spinocerebellar atrophy type 17 • Tuberous sclerosis • Xeroderma pigmentosum • Wilson disease
Drug-related
	• Amantadine • Amphetamine • Anticonvulsants • Antihistamine agents • Carbon monoxide • CNS stimulants (methylphenidate, pemoline, cyproheptadine) • Cocaine • Dopamine agonists • Dopamine-receptor blockers • Ethanol • Levodopa • Levofloxacin • Lithium • Sympathomimetics • Theophylline • Tricyclic antidepressants • Valproic acid • Withdrawal emergent syndrome
Infections
	• AIDS related (toxoplasmosis, progressive multifocal leukoencephalopathy, HIV encephalitis) • Bacteria
			- Diphtheria - Scarlet fever - Whooping cough
	• Virus
			- B19 parvovirus - Herpes-6 virus encephalitis - Influenza encephalitis - Japanese encephalitis - Measles - Mumps - HIV - West Nile River encephalitis - SARS-CoV-2
	• Parasites
			- Neurocysticercosis
	• Protozoan
			- Malaria - Syphilis
Endocrine-metabolic dysfunction
	• Adrenal insufficiency • Hyper/hypocalcemia • Hyper/hypoglycemia • Hypomagnesemia • Hypernatremia • Liver failure • Uremia
Vascular
	• Polycythemia vera • Postpump chorea (cardiac surgery) • Posterior reversible encephalopathy syndrome • Stroke • Subdural hematoma
Miscellaneous
	• Anoxic encephalopathy • Brainstem cavernous malformation • Brainstem glioma • Cerebral palsy • Cerebrospinal fluid shunt-induced • Extrapontine myelinolysis • Intratumoral chemotherapy catheter • Kernicterus • Multiple sclerosis • Normal maturation (less than 12 months old) • Nutritional (eg, B12 deficiency) • Pontine hemorrhage • Posttraumatic (brain injury) • Putaminal cavernous malformation

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 is preferable to CT due to the superior delineation of the subcortical tissue usually involved. Table 2 outlines the basic testing recommended. Further studies should be undertaken when clinical factors warrant. These might include genetic testing for Huntington disease or Huntington disease phenocopies, benign hereditary chorea, and other less common causes of genetic chorea and HIV antibody testing (126), muscle biopsy for mitochondrial disease, cerebrospinal fluid analysis for inflammation, drug or toxin assays, and peripheral blood smear with 1:1 saline dilution for acanthocytes and amino acid measurements. The genetic test 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 (140). Because diabetes mellitus can cause chorea in adults, appropriate studies should always be ordered (28). Paraneoplastic antibody studies should also be considered in patients with new-onset unexplained chorea (148). Functional neuroimaging studies show that patients with chorea associated with diabetes have evidence of presynaptic nigrostriatal dysfunction on SPECT (135), and there is hypometabolism of the basal ganglia in chorea-acanthocytosis (37).

Table 2. Initial Laboratory Investigation of Chorea

• Antinuclear antibody • Antineuronal antibodies • Antiphospholipid antibodies • Antistreptolysin O titers • Brain MRI • Complete blood count • Ceruloplasmin • Comprehensive metabolic panel, including tests for diabetes mellitus type II • Thyroid hormone assay (TSH, T4) • Urine toxicologic screen for drugs of abuse

Management

The most important principle of management of chorea is to remove the cause. This is possible in drug-induced chorea, metabolic or endocrine chorea, and to some extent even in immunologic chorea, such as Sydenham chorea, with penicillin prophylaxis. Unfortunately, in most choreic syndromes encountered in clinical practice causal therapies are not available and symptomatic treatment is required.

Dopamine depletors or 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 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 (44). Similarly, in hemiballism-hemichorea, chorea suppression on one side of the body may be accompanied by simultaneous development of parkinsonism on the opposite hemibody. Risperidone and olanzapine are atypical antipsychotics with definite antichoreic activity but lesser potential to induce parkinsonism than typical neuroleptics.

There are numerous reports of use of tetrabenazine, which inhibits vesicular monoamine transporter 2 inhibitor (VMAT2) and, thus, acts as a presynaptic dopamine depletor to treat chorea associated with cerebral palsy and other causes (114; Chatterjee and Frucht 2003; 76; 71; 106). Controlled data have confirmed that this agent is indeed efficacious in controlling chorea in Huntington disease (64; 76; 52; 72). 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 (139; 71). Another VMAT2 inhibitor, deutetrabenazine, has been found to be efficacious in the treatment of chorea associated with Huntington disease, tardive dyskinesia, and tics associated with Tourette syndrome (65; 71). Also, valbenazine, another VMAT2 inhibitor, was evaluated for the treatment of chorea, tardive dyskinesia, and tics (71; 09). Approved by the U.S. Food and Drug Administration for the treatment of chorea associated with Huntington disease (tetrabenazine, deutetrabenazine) and tardive dyskinesia (valbenazine, deutetrabenazine), these VMAT2 inhibitors are considered the treatment of choice for other choreas (09; 50). An open-label study suggests that aripiprazole has efficacy comparable to tetrabenazine in the control of chorea in Huntington disease, but further studies are required to confirm this observation (18). Even if confirmed, aripiprazole, in contrast to tetrabenazine, carries the risk of tardive dyskinesia. Levodopa may be required in patients with juvenile Huntington disease or in adults with advanced disease and severe rigidity. This drug has also been reported as useful to the management of patients with NKX2-1 mutation (04), but this requires further confirmation.

Nondopaminergic agents may also be effective in the management of chorea. Amantadine is believed to act primarily via a NMDA blocking mechanism. There are a few small, controlled studies of this agent in Huntington disease (97; 116). Although the results are contradictory, the weight of evidence is in favor of a weak antichoreic action in this condition. 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 (62). First-line immunotherapy consists of intravenous methylprednisolone, IVIg or plasmapheresis, or a combination of these modalities (108; 27; 22; 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 (78). 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 a few 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 (21; 29). There are also a few reports describing effectiveness of surgery to treat chorea related to cerebral palsy (87), “senile chorea” (157), and dentatorubral-pallidoluysian atrophy (153). Finally, pallidotomy and pallidal-stimulation have also been used in Huntington disease (36; 107). Although chorea is effectively controlled by these procedures, the relentless progression of Huntington disease leads to a loss of functional improvement (75). 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 (76; 32). With the advent of deep brain stimulation (DBS), there is growing awareness of the beneficial role of this procedure to treat chorea (47). Reports describe its usefulness in the management of selected patients with chorea-acanthocytosis (93). A large series of patients with refractory tardive dyskinesia that included chorea underwent GPi deep brain stimulation with sustained benefit (130). In the past few years, several groups have reported effective use of deep brain stimulation to treat chorea in chorea-acanthocytosis (152; 156).

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 (100; 25). There are mainly 3 Huntingtin level lowering strategies. First one is genome editing by interrupting the CAG repeat expansion, which can potentially delay the onset of disease. 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.

Special considerations

Pregnancy

Chorea gravidarum and endocrine or metabolic-related chorea should be considered in any pregnant woman with hyperkinetic movements (113; 20; 86). Treatment is not usually needed as chorea resolves postpartum (or following correction of the underlying endocrine or metabolic derangement). Human chorionic gonadotropin may be the reason for reduced chorea during pregnancy in a woman with paroxysmal kinesigenic choreoathetosis (98). Neuroleptics should be avoided, particularly during the limb-genesis period of the first trimester (101). Low-dose benzodiazepines may be considered in the second and third trimesters if the potential benefit outweighs the risks of fetal respiratory depression and possible teratogenicity.

Anesthesia

Choreic movements may occur with a variety of general anesthetics during induction or the postoperative recovery period. Differential diagnosis should include medication-related myoclonus and postanoxic myoclonus. Choreoathetosis may occur after cardiac surgery, particularly if cooling and bypass are utilized (155; 103). A report of hemiballism and hemichorea serves to point out that hypotension may result in ischemia of the subthalamic nucleus even following spinal anesthesia (69). There are no specific anesthetic agents to avoid in someone with chorea, although drugs with anticholinergic properties may exacerbate symptoms.