Chorea in Adults 

Updated: Jul 01, 2019
Author: Pradeep C Bollu, MD; Chief Editor: Selim R Benbadis, MD 

Overview

Background

The ad hoc Committee on Classification of the World Federation of Neurology has defined chorea as "a state of excessive, spontaneous movements, irregularly timed, non-repetitive, randomly distributed and abrupt in character. These movements may vary in severity from restlessness with mild intermittent exaggeration of gesture and expression, fidgeting movements of the hands, unstable dance-like gait to a continuous flow of disabling, violent movements."[3]

Patients with chorea exhibit motor impersistence (ie, they cannot maintain a sustained posture). When attempting to grip an object, they alternately squeeze and release ("milkmaid's grip"). When they attempt to protrude the tongue, the tongue often pops in and out ("harlequin's tongue"). Patients often drop objects involuntarily. Also common are attempts by patients to mask the chorea by voluntarily augmenting the choreiform movements with semipurposeful movements.[1]

Chorea involves both proximal and distal muscles. In most patients, normal tone is noted, but, in some instances, hypotonia is present. In a busy movement disorder center, levodopa-induced chorea is the most common movement disorder, followed by Huntington disease (HD).[1]

Any discussion of chorea must also address the related terms athetosis, choreoathetosis, and ballism (also known as ballismus).

The term athetosis comes from the Greek word athetos (not fixed).[1, 2] It is a slow form of chorea. Because of the slowness, the movements have a writhing (ie, squirming, twisting, or snakelike) appearance. Choreoathetosis is essentially an intermediate form (ie, a bit more rapid than the usual athetosis, slower than the usual chorea, or a mingling of chorea and athetosis within the same patient at different times or in different limbs). Given that the only difference between chorea, choreoathetosis, and athetosis is the speed of movement, some neurologists argue that the term athetosis is unnecessary and even confusing. They argue a simpler nomenclature would delineate fast, intermediate, and slow chorea. While the authors of this article understand the basis of that argument, they also believe that in some cases, the writhing movements are extremely prominent, even apart from the speed of the movement. Thus, the authors of this article advocate retaining this descriptive term.

Ballism or ballismus is considered a very severe form of chorea in which the movements have a violent, flinging quality. In Greek, ballismos means "a jumping about or dancing."[2] Ballism has been defined as "continuous, violent, coordinated involuntary activity involving the axial and proximal appendicular musculature such that the limbs are flung about." This movement disorder most often involves only one side of the body (ie, hemiballism or hemiballismus). Occasionally, bilateral movements occur (ie, biballism or paraballism). Many patients with hemiballism have choreiform movements and vice versa, and hemiballism often evolves into hemichorea. Currently, ballism should be viewed as a severe form of chorea.[1, 4, 5, 6, 7, 8]

Pathophysiology

A simple model of basal ganglia function states that dopaminergic and GABAergic impulses from the substantia nigra and motor cortex, respectively, are funneled through the pallidum into the motor thalamus and motor cortex. These impulses are modulated in the striatum via two segregated, parallel, direct and indirect loops through the medial pallidum and lateral pallidum/subthalamic nucleus. Subthalamic nucleus activity drives the medial pallidum to inhibit cortex-mediated impulses, thereby inducing parkinsonism. Absent subthalamic nucleus inhibition enhances motor activity through the motor thalamus, resulting in abnormal involuntary movements such as dystonia, chorea, and tics. A classic example of loss of subthalamic inhibitory drive is ballism.[1]

The most well-studied choreatic syndrome is Huntington chorea; therefore, the pathophysiology of HD as it applies to chorea is the focus of the discussion that follows.

Huntington disease is caused by an expanded CAG trinucleotide repeat in the gene that encodes the protein huntingtin. Mutant huntingtin is thought to cause neuronal degeneration through transcription dysregulation as well as mitochondrial impairment.[9, 10, 11, 12]

Dopaminergic mechanism

In Huntington chorea, the content of striatal dopamine is normal, indicating that the major pathological alterations lay in the surviving — but diseased — medium-sized, spiny, striatal dopaminergic neurons. Pharmacologic agents that either deplete dopamine (eg, reserpine and tetrabenazine) or block dopamine receptors (eg, neuroleptic medications) improve chorea, which gives further support to this observation. Given that drugs that decrease the striatal content of dopamine improve chorea, increasing the amount of dopamine worsens chorea, such as in the levodopa-induced chorea seen in persons with Parkinson disease (PD).[13, 14]

Cholinergic mechanism

The concept that a critical striatal balance between acetylcholine (Ach) and dopamine is essential for normal striatal function received its greatest acceptance in the understanding of PD. In the early days of PD therapy, anticholinergic medications were used frequently, especially when tremor was the predominant symptom. Other PD symptoms, such as bradykinesia and rigidity, often improved as well.[15]

The development of chorea in patients treated with anticholinergic medications, such as trihexyphenidyl, is a common clinical observation. Furthermore, the intravenous administration of physostigmine (a centrally acting anticholinesterase) can temporarily reduce chorea. The same treatment can also promptly overcome anticholinergic-induced chorea.

Patients with HD have a patchy reduction of choline acetyltransferase in the basal ganglia. This enzyme catalyzes the synthesis of ACh. A marked reduction of muscarinic cholinergic receptor sites has also been reported. These two observations could explain the variability of patients' response to physostigmine and the limited efficacy of Ach precursors such as choline and lecithin.

Serotonergic mechanism

Fluctuations in striatal serotonin may play a role in the genesis of many abnormal movements. Selective serotonin reuptake inhibitors, such as fluoxetine, may induce or aggravate parkinsonism, akinesia, myoclonus, or tremor. The role of serotonin (5-hydroxytryptamine [5-HT]) in choreiform movements is less clear since the striatum has a relatively high concentration of serotonin. Pharmacologic attempts to either stimulate or inhibit serotonin receptors in persons with Huntington chorea have shown no effect, indicating that serotonin's contribution to the pathogenesis of chorea is limited.

GABAergic mechanism

The most consistent biochemical lesion in patients with Huntington chorea appears to be a loss of neurons in the basal ganglia that synthesize and contain GABA.[16] The significance of this remains unknown. A variety of pharmacologic techniques have been attempted to increase CNS GABA levels. Valproic acid, which acts in part via a GABAergic mechanism, has, in a limited number of uncontrolled cases, ameliorated not only the agitation sometimes seen in persons with HD but also the movement problem.[17] However, no systematic studies have been conducted on the use of GABAergic agents to treat HD.

Substance P and somatostatin

Substance P levels have been shown to be markedly lower in persons with Huntington disease (HD), while somatostatin levels are higher. The significance of this remains unknown as well.

Cannabinoids

Endocannabinoids are thought to play a role in HD. Loss of the cannabinoid CB1 receptor from the medium spiny neurons is one of the earliest neurochemical changes seen in HD. Reuptake inhibition of anandamine, an endogenous cannabinoid, has been shown to alleviate motor symptoms in animal models of HD and other neurodegenerative disorders such as PD and MS.[18, 19, 16]

Ballism

This movement disorder usually involves only one side of the body (ie, hemiballism). Hemiballism is usually attributed to lesions of the contralateral subthalamic nucleus, although infarction in the caudate, striatum, lenticular nucleus, or thalamus has also been associated with hemiballism.[1, 4]

Lesions of the subthalamic nucleus can cause contralateral hemiballism-hemichorea by reducing the normal excitatory drive from the subthalamic nucleus to the internal segment of the globus pallidus. This reduces the inhibitory output of the globus pallidus on the thalamus, and this disinhibition gives rise to excessive excitatory drive to the cortex, which is expressed as contralateral hyperkinetic movements. Confusingly, however, this disorder often appears in the absence of a lesion in the subthalamic nucleus.[1, 20]

Klawans[21, 22] suggested that increased dopaminergic transmission might play a role in the pathophysiology of this disorder. This hypothesis is supported by the observation that dopamine-receptor blockers and catecholamine-depleting agents often improve hemiballism. While hemiballism and hemichorea are distinguishable on the basis of the type and distribution of movements, they represent two different symptoms on a spectrum of the same disease process. Why one patient with basal ganglia dysfunction develops hemiballism and another with similar pathologic changes develops hemichorea is not understood. On the cellular and molecular level, ballism can be caused by multiple pathologies including ischemia, infection, demyelination, and tumor.[5, 6, 23, 24, 25, 26, 7, 8]

Epidemiology

Frequency

Although no data are available regarding the incidence of chorea, the incidences of several disorders in which chorea is the main clinical feature are well known.

Huntington disease (HD) is an autosomal dominant, neurodegenerative disorder in which the defective gene is located on the short arm of chromosome 4. The estimated prevalence of HD in the United States is 5–10 cases per 100,000 people[1] , while the worldwide prevalence is between 0.4 and 5.7 per 100,000.[98]

Wilson disease is an autosomal recessive, multisystem disease caused by a mutation in the ATP7B gene, which resides on the long arm (q) of chromosome 13 (13q14.3). This gene codes for an ATPase, which is involved with the transport of copper. Although the gene prevalence (heterozygous carriers who inherited only 1 abnormal gene) has been estimated to be as high as 1%, the disease prevalence is only 30 cases per 1 million people.[1, 27, 28]

Benign hereditary chorea, a fairly rare disorder in which most of the pedigrees have clearly demonstrated dominant inheritance, has a prevalence of approximately 1 case per 500,000 people.[1, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41]

Race

In 1872, George Huntington first described HD inheritance in successive generations of natives of Long Island, New York. All of the affected individuals descended from ancestors who had emigrated from East Anglia, England, to the New World in 1649. This disorder is now dispersed widely around the globe.

HD is best known in white populations. All cases of the disorder are probably part of the line originating in East Anglia.

In addition, informative genotypes were obtained from a vast family lineage carrying the gene; they are located in and around Lake Maracaibo, Venezuela.

Age

Chorea can commence at any age. In children, postpump chorea and infectious, inflammatory, and striatal lesions may account for many cases.

For Huntington disease (HD), the typical age at onset is in the 40s or 50s.[99]  Cases have been recognized in patients younger than 5 years, but generally no more than 10% of the cases show onset prior to age 20. Patients with early onset usually inherited the disease from their father, while patients with later onset are more likely to have inherited the gene from their mother. The relatively low rate of expression in childhood is succeeded by a virtually exponential upsweep in the rate of appearance through the 20s and 30s to reach a plateau that is sustained from the 40s to the 70s. Although 27% of cases are first recognized in patients older than 50 years, most of the cases are documented in patients younger than 60 years. Onset has been recorded as late as the eighth decade.[1, 42] The age at onset is inversely correlated to the size of CAG repeat expansion, which allows us to predict the onset of motor symptoms in patients.[100]  

Neuroacanthocytosis, perhaps the most common form of hereditary chorea, usually manifests clinically in the 30s or 40s (age range is 8–62 years). It should be differentiated from late-onset HD through careful pedigree analysis and genetic testing.[1, 27, 43, 101]

Sydenham chorea most commonly affects the pediatric population between the ages of 5 and 13 years.[102]

Senile chorea manifests gradually in middle-to-late life.

Benign hereditary chorea presents as onset of chorea before the age of 5 years.[103]

In general, on the basis of age at onset, benign hereditary chorea may be divided into 3 types: (1) early infancy, (2) approximately 1 year of age, and (3) late childhood or adolescence. The most common type is the second; children are usually around 1 year old when they begin to walk. Benign hereditary chorea is now known to be caused by a mutation in the TITF1 gene. Interestingly, this gene contains the code for a transcription factor essential for the organogenesis of the basal ganglia, lungs, and thyroid.[30, 44]

 

Presentation

History

Patients with chorea may not initially be aware of the abnormal movements because they may be subtle. Patients can suppress the chorea temporarily and frequently camouflage some of the movements by incorporating them into semipurposeful activities (ie, parakinesia). The inability to maintain voluntary contraction (ie, motor impersistence), as is seen during manual grip (milkmaid grip) tests or tongue protrusion, is a characteristic feature of chorea and results in the dropping of objects and clumsiness. Muscle stretch reflexes are often hung-up and pendular. In severely affected patients, a peculiar dancelike gait may be noted. Depending on the underlying cause of the chorea, other motor symptoms include dysarthria, dysphagia, postural instability, ataxia, dystonia, and myoclonus. A brief discussion of the clinical manifestations of the most common choreatic diseases is presented.

Huntington disease

Penetrance of HD is 100%. Expression is highly variable, both with respect to clinical manifestations and age of onset. When the disorder emerges early, particularly in patients younger than 20 years, it is most likely to run a rapid course with grave disability due to cognitive decline.[45, 1, 42]

The Westphal variant, a rigid dystonic disorder, may be accompanied by seizures and even myoclonus. It is encountered principally among those with childhood onset. In contrast, when the disorder appears late in life, the cardinal manifestation is chorea.

The insidious onset of clumsiness and adventitious movements may be wrongly attributed to simple nervousness. Although chorea and other motor disabilities are the most readily recognized manifestations of HD, they may be neither the earliest to appear nor the most disabling manifestations of the disease.

Psychological disturbances and personality change are the initial manifestations in greater than 50% of affected persons. Symptoms consistent with a depressive state are the most frequent psychological disturbances.

Despite the challenge in defining the onset of the disease due to the subjective nature of initial symptoms, the inverse correlation between age at motor onset and CAG repeat expansion accounts for approximately 50–70% of the variance in the onset. The remaining difference in age of onset is likely to be genetically encoded.[104]

The duration of illness from onset to death is approximately 15 years in the case of adult HD and 8-10 years for the juvenile variant.

Wilson disease

The clinical features are age-dependent. In children, the disease is manifested initially by progressive dystonia, rigidity and dysarthria, and hepatic dysfunction, whereas in adults, psychiatric symptoms, tremor, and dysarthria usually predominate.[27, 28, 46]

Because Kayser-Fleischer rings are almost always present when neurological symptoms are present, slit-lamp examination of the cornea must be performed to be certain that Wilson disease is excluded in a patient with chorea beginning in childhood or young adulthood. In patients with chorea and negative findings from a slit-lamp examination, serum copper and ceruloplasmin analysis along with a 24-hour copper urine excretion test need to be performed.

Neuroacanthocytosis

Symptoms usually begin in young adulthood with lip and tongue biting (often causing self-injury), orolingual dystonia, motor and phonic tics, generalized chorea, parkinsonism, and seizures. Patients with neuroacanthocytosis may report an inability to feed themselves because of dystonic tongue protrusion every time they try to eat. Although chorea is the typical manifestation, some patients may also present with a parkinsonian picture with rigidity and bradykinesia.[105, 1, 43, 47]

Other features include cognitive and personality changes, dysphagia, dysarthria, amyotrophy, areflexia, evidence of axonal neuropathy with absent deep ankle tendon stretch reflexes, and elevated serum creatine kinase levels without evidence of myopathy.

Senile chorea

This clinical entity is characterized by a gradual onset of generalized and symmetric chorea with slow progression and specifically excluding mental deterioration, emotional disturbances, or family history.[48, 49, 50]

To rule out the possibility of HD, genetic testing is recommended because family history can be inaccurate and distinguishing age-related mental changes from early features of HD in an elderly person may be difficult.

Sydenham chorea

Sydenham chorea is a major manifestation of acute rheumatic fever. With the 1992 modifications of the Jones criteria (see the Jones Criteria for Diagnosis of Rheumatic Fever calculator), it alone is sufficient to enable the physician to make the diagnosis of the first attack of acute rheumatic fever. Sydenham chorea is considered a disease of childhood; however, it also may be seen in adults. Rheumatic chorea is characterized by muscle weakness and the presence of chorea. The patients have the milkmaid grip sign, clumsy gait, and explosive bursts of dysarthric speech. Often, harlequin tongue, which pops in and out when the patient tries to hold it out, can be prominently demonstrated.[51, 52, 53]

Psychological symptoms are equally prominent and typically precede the appearance of even the most subtle choreiform movements. Emotional lability is the most common symptom; decreased attention span, obsessive-compulsive symptoms, and separation anxiety disorder also are seen. Symptoms can lag behind the etiologic streptococcal infection by 1-6 months. In adults, generalized poststreptococcal chorea may complicate birth control or pregnancy (chorea gravidarum).

Benign hereditary chorea

This is a rare autosomal dominant genetic disorder characterized by nonprogressive choreiform movements that appear in childhood, without intellectual impairment. It is further distinguished clinically from juvenile HD by the absence of seizures, rigidity, or cerebellar features.[1, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41]

Benign hereditary chorea is caused by a mutation in the TITF1 gene. Interestingly, this gene contains the code for a transcription factor essential for the organogenesis of the basal ganglia, the lungs, and the thyroid.

It does not shorten the life span of affected patients, but severely affected patients can be markedly disabled by the chorea.

Physical

Because Huntington disease (HD) is the most clearly defined choreatic disease, its physical findings are described here.

HD is caused by an expansion repeat (CAG) mutation in the IT15 ("interesting transcript 15") gene (which codes for the protein called huntingtin) on chromosome 4. Initial signs of chorea generally are flickers in the fingers and ticlike grimaces of the face. Over time, higher-amplitude dancelike movements disrupt voluntary actions of the extremities and interfere with gait. Speech becomes dysrhythmic. In later stages, chorea involves the pharynx, diaphragm, and larynx presenting as dysarthria and dysphagia. This progressive loss of voluntary motor control leads to a picture of a Parkinson-like rigid and akinetic state.[1, 54, 42]

Characteristically, the patient is hypotonic, although reflexes may be augmented and clonus may be noted.

Voluntary gaze is disturbed early. In particular, saccades may be irregular or of prolonged latency and may require an initial blink for their initiation with preserved pursuit movements. Advanced stages of the disease may have impairment of smooth pursuit, saccades, and refixation.

Loss of optokinetic nystagmus is common after a decade of progressive disease but sometimes can be seen as an early manifestation of the disease too.[114]

Cognitive changes are manifested early as loss of recent memory and impaired judgment. Apraxia is also present. Ultimately, the patient becomes severely demented.

Neurobehavioral changes typically consist of personality changes, apathy, social withdrawal, agitation, impulsiveness, depression, mania, paranoia, delusions, hostility, hallucinations, or psychosis.

The Westphal variant is dominated by rigidity, bradykinesia, and dystonic postures. Generalized seizures and myoclonus may be seen. Ataxia and dementia are also present.

Causes

See the list below:

  • Idiopathic - Physiological chorea of infancy, buccal-oral-lingual dyskinesia, senile chorea[48, 49, 50]

  • Hereditary - HD, hereditary nonprogressive chorea (benign hereditary chorea)[1, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41] , benign recessively inherited choreoathetosis of early onset[55] , familial inverted chorea[56] , neuroacanthocytosis[43] , familial remitting chorea nystagmus and cataracts[57] , ataxia-telangiectasia, tuberous sclerosis[58] , familial calcification of basal ganglia, pantothenate kinase associated neurodegeneration (PKAN) or pantothenate kinase 2 (PANK2) deficiency (previously termed Hallervorden-Spatz disease), Friedreich ataxia, dentatorubro-pallidoluysian atrophy[59] . ADCY5 mutation, PDE10A mutations, C9ORF72 mutations can also cause chorea.

  • Hereditary (metabolic) - Wilson disease[27, 28] , glutaric aciduria, Lesch-Nyhan disease, phenylketonuria, acute intermittent porphyria, propionic acidemia[60] , abetalipoproteinemia, hypobetalipoproteinemia, lipid storage diseases

  • Other metabolic and endocrine disorders -Kernicterus, hyperthyroidism, hypoparathyroidism, hypoglycemia[61] , nonketotic hyperglycemia[62] , chorea gravidarum, hypomagnesemia, chronic nonfamilial hepatic encephalopathy[63] , anoxic encephalopathy (including postcardiac transplantation)[64] , cardiac surgery[65] , postportocaval anastomosis for portal hypertension

  • Paroxysmal - Paroxysmal kinesogenic choreoathetosis, paroxysmal dystonic choreoathetosis

  • Infectious - Sydenham chorea, encephalitides[66] , subacute sclerosing panencephalitis, syphilis, enteric cytopathogenic human orphan (ECHO) virus infection[66] , Lyme disease, HIV infection[7, 67] , cerebral toxoplasmosis, Creutzfeldt-Jakob disease, subacute bacterial endocarditis

  • Drug induced - Neuroleptics, levodopa, anticholinergics, oral contraceptives, antihistamines, amphetamines, cocaine, phenytoin, tricyclics

  • Toxins - Alcohol intoxication and withdrawal, carbon monoxide[68, 69] , manganese, mercury

  • Vascular - Cerebrovascular disease (ischemic or hemorrhagic)[70, 5, 24, 71, 72, 73] , chronic subdural hematoma[74] , Moyamoya disease[75] , migraine/hemicrania choreatica[76] , Churg-Strauss syndrome[77] , polycythemia vera

  • Immunologic -Systemic lupus erythematosus, Behçet disease[78] , primary antiphospholipid antibody syndrome[79, 80] , multiple sclerosis, postcardiac transplantation[64] , postvaccination and other autoimmune causes[110]

  • Tumors - Primary, metastatic

  • Paraneoplastic[113] - CRMP-5 autoantibodies in testicular cancer can be associated with limbic encephalitis[111] and choreiform dyskinesias. Morvan's fibrillary chorea can be a manifestation of thymoma.[112]

  • Miscellaneous - Mitochondrial cytopathies, ventriculoperitoneal shunts[81] , cardiac sugery[65]

 

Workup

Laboratory Studies

Diagnosis of the primary choreatic conditions is based on history and clinical findings; however, several laboratory studies are useful, especially in distinguishing the secondary forms of chorea from the primary forms. Some of them are mentioned here.

  • Huntington disease: The only laboratory study presently available to confirm HD is genetic testing. It identifies a gene abnormality in the short arm of chromosome 4, characterized by abnormal repetition of the trinucleotide CAG, the length of which determines the age of onset (anticipation).[54, 82, 42]  Genetic testing has a sensitivity of 98.8% and a specificity of 100%, making it a valuable test to confirm the diagnosis of HD.[109]

  • Wilson disease[27, 28] : A low serum ceruloplasmin level and serum copper values showing increased urinary copper excretion corroborate the diagnosis in most cases. Persistent aminoaciduria, reflecting a renal tubular abnormality, is present in most but not all patients. Liver function test results are usually abnormal. Serum ammonia levels may be elevated. If the diagnosis is still uncertain, liver biopsy can help confirm the diagnosis.

  • Sydenham chorea[51, 52] : The chorea can lag behind the etiologic streptococcal infection by 1-6 months, sometimes as long as 30 years; therefore, antistreptococcal antibody titers may no longer be elevated at presentation. Without documentation of an antecedent streptococcal infection, the diagnosis of Sydenham chorea must be made by excluding other causes.

  • Neuroacanthocytosis: The diagnosis is confirmed by the presence of spiky erythrocytes (acanthocytes) in peripheral blood smears. The serum creatine kinase level may be elevated.[43]

Other laboratory studies useful in the differential diagnosis of chorea include complement levels, antinuclear antibody titers, antiphospholipid antibody titers, amino acid levels in serum and urine, enzymatic studies from skin fibroblasts, thyrotropin levels, thyroxine values, and parathormone levels.

Imaging Studies

MRI

Patients with Huntington disease (HD) and chorea-acanthocytosis show decreased signal in the neostriatum, caudate, and putamen. No significant difference has been observed between these diseases. The decreased neostriatal signal corresponds to increased iron deposition.[83, 84] Generalized atrophy, as well as focal atrophy of the neostriatum, predominantly of the caudate, with resulting enlargement of the frontal horns, follows the initial findings of decreased neostriatal signal.[85] Along with the changes in subcortical basal ganglia structures, progressive regional thinning of the cerebral cortex may also be seen in HD.[108]

Most patients with Sydenham chorea show no abnormalities. However, a study reported volumetric differences in the caudate, putamen, and globus pallidus; they were significantly larger in patients with Sydenham chorea than in controls. Patients with hemiballismus demonstrate signal changes in the contralateral subthalamic nucleus or, less often, the striatum or thalamic nuclei.[20]

MRI of the brain of patients with senile chorea shows a decrease in signal intensity throughout the striatum (suggesting iron deposition)[83, 84] and narrowing of the space separating the caudate head and putamen, but no overt atrophy of these structures.[55]

Positron emission tomography

Fluorodopa (F-dopa) uptake is normal or mildly reduced in patients with chorea. HD and chorea-acanthocytosis show bilateral hypometabolism in the caudate nucleus and putamen.[86, 87, 88]

Patients with chorea and dementia show decreased glucose metabolism in the frontal, temporal, and parietal cortices.

Patients with benign hereditary chorea may or may not show decreased metabolism in the caudate.[29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 67, 41]

The finding of normal cerebral glucose metabolism in the striatal region practically excludes HD, this being a useful tool for differential diagnosis. The definite diagnosis of HD is made easily by neurogenetic studies.[54]

Hypometabolism in the caudate nucleus and putamen on the contralateral side is seen in patients with hemichorea.

 

Treatment

Medical Care

Only symptomatic treatment is available for patients with chorea. Chorea may be a disabling symptom, leading to bruises, fractures, and falls, and may impair the ability of patients to feed themselves. In addition, patients sometimes express a desire for antichorea treatment for cosmetic reasons.

The most widely used agents in the treatment of chorea are the neuroleptics. The basis of their mechanism of action is thought to be related to blocking of dopamine receptors. Neuroleptics can be classified as typical and atypical. Typical neuroleptics include haloperidol and fluphenazine. Atypical neuroleptics include risperidone, olanzapine, clozapine, and quetiapine.

Dopamine-depleting agents (eg, reserpine, tetrabenazine, deutetrabenazine), represent another option in the treatment of chorea.[13, 14, 97]

GABAergic drugs, such as clonazepam, gabapentin, and valproate,[89]  can be used as adjunctive therapy.

Coenzyme Q10 alone and in combination with minocycline have been proposed as potential therapies and have shown promise in HD rodent models. Coenzyme Q10 is thought to target mitochondrial dysfunction, which has been implicated as one of the pathologic mechanisms of mutant huntingtin. Minocycline, one of the tetracyclines, is known to have anti-apoptosis effects.[10, 11]

Intravenous immunoglobulin and plasmapheresis may shorten the course of the illness and decrease symptom severity in patients with Sydenham chorea.

Chorea following cardiac transplantation has been reported to be responsive to steroid treatment.[64]

Reports of drug treatment for hemiballism must take into account the high spontaneous remission rate for the disorder. Anecdotal reports must be viewed with caution, unless they can demonstrate that the response is due to the agent (by recurrence of the movements with drug withdrawal). The rarity of this disorder and the severity of its manifestations have precluded placebo-controlled drug trials. Pharmacologic treatment is the same as that prescribed for other choreatic disorders.[22, 24, 90, 8]

Surgical Care

Deep brain stimulation

Deep brain stimulation r(DBS) is an emerging technique that may benefit patients, at least in certain cases.

In 2000, Thompson et al reported a reduction in choreiform movements in 2 pediatric cases of chorea. One patient had cerebral palsy from birth secondary to brain hemorrhage. The other, an 11-year-old child, developed chorea subsequent to a thalamic hemorrhage 4 years before. Both children improved after the procedure.[91]

Reported in 2003, Krauss et al tested globus pallidus stimulation on 2 patients with dystonia (one adult and one child) and 4 adult patients with essentially static (ie, nonchanging) chorea secondary to cerebral palsy. The dystonia patients markedly improved. Two of the 4 chorea patients showed no improvement, but 2 showed mild improvement.[92]

In 2004, Moro et al reported on bilateral globus pallidus internus stimulation on a patient with Huntington disease (HD). Stimulation at 130 and 40 Hz improved the chorea, but the stimulation at 130 Hz worsened the bradykinesia. Stimulation of 40 Hz had little effect on the bradykinesia and appeared to increase blood flow (assessed by positron emission tomography scanning) in areas associated with executive functions and judgment.[93]

Although DBS is not yet used routinely for chorea, as it is for PD, exciting progress has been made with this modality. Prior to DBS, surgeries like thalamotomy and pallidotomy were found to be effective in some cases.[106, 107]  However, due to the invasive nature of the surgeries and the complications due to lesional surgery, they are not used in routine clinical practice.

Cell transplantation

Cell transplantation is controversial and in early stages of research. It has shown variable results for HD patient participants.

In 2006, Bachoud-L é vi et al reported that fetal neural cell transplantation into host striatum resulted in stabilization or improvement in chorea, oculomotor dysfunction, gait, tapping, and cognition, but dystonia progressed at the same rate as nongrafted patients. However, these results persisted for up to 6 years only, and then patients' disease continued to progress at pretransplantation rates.[94]

In 2008, Keene et al demonstrated on autopsy that fetal neural cell grafts in 2 patients had shown neuronal differentiation and survival, but they had poor integration with host striatum, likely explaining the lack of clinical improvement in these patients.[95]

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Antipsychotic agents

Class Summary

Block dopamine receptors and appear to have antispasmodic effects.

Haloperidol (Haldol)

Useful in treatment of irregular spasmodic movements of limbs or facial muscles.

Fluphenazine

Blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in brain. Exhibits strong alpha-adrenergic and anticholinergic effects. May depress reticular activating system.

Clozapine (Clozaril, FazaClo, Versacloz)

Atypical neuroleptic medication available in 25- and 100-mg tab. Blocks norepinephrine, serotonergic, cholinergic, histamine, and dopaminergic receptors. Mechanism of action still unclear. Affinity for mesolimbic D4 dopamine receptor accounts for striking effects in control of behavioral and psychiatric symptoms with low incidence of extrapyramidal symptoms. Histamine receptor blockade accounts for increased incidence of sleep disturbances.

Olanzapine (Zyprexa, Zyprexa Relprevv, Zyprexa Zydis )

A thienobenzodiazepine antipsychotic known to cause serotonergic, dopaminergic and adrenergic blockade

Risperidone (Risperdal)

Binds to dopamine D2-receptor with 20 times lower affinity than for 5-HT2 receptor. Improves negative symptoms of psychoses and reduces incidence of extrapyramidal adverse effects.

Quetiapine (Seroquel)

May act by antagonizing dopamine and serotonin effects.

Monoamine depleting agents

Class Summary

Antichorea effect of central monamine-depleting agents is believed to be related to its effect on reversible depletion of monoamines (eg, dopamine, serotonin, norepinephrine) from nerve terminals.

Reserpine

First isolated from the root of Rauwolfia Serpentina (Indian Snakeroot), reserpine was FDA approved in 1955. Reserpine irreversibly blocks the Vesicular Monoamine Transporters- VMAT 1 and 2 reducing the stores of the monoamines (norepinephrine, dopamine, serotonin). It was primarily used as an antihypertensive agent and generally no longer used in the treatment of chorea due to its side effects. 

Tetrabenazine (Xenazine)

Depletes neurotransmitter stores of dopamine, serotonin, and noradrenaline within nerve cells in the brain, thereby altering transmission of electric signals from the brain that control movement by reversibly inhibiting vesicular monoamine transporter 2 (VMAT2).

Efficacy and safety established in a randomized, double-blind, placebo-controlled, multicenter study. Patients treated with tetrabenazine had significant improvement in chorea compared with those treated with placebo. Additional studies support this effect. Indicated for chorea associated with Huntington disease.

Deutetrabenazine (Austedo)

Orally administered VMAT-2 inhibitor. It is indicated for chorea associated Huntington disease.

Benzodiazepines

Class Summary

Demonstrated to reduce GABA concentrations in the caudate, putamen, substantia nigra, and globus pallidus. By analogy, increased GABA activity might ameliorate chorea.

Clonazepam (Klonopin)

Developed as antiepileptic, hypnotic, and anxiolytic used as adjunct for treatment of chorea. Belongs to benzodiazepine group, increasing GABAergic transmission in CNS. Reaches peak plasma concentration at 2-4 h after oral or rectal administration.

Anticonvulsants

Class Summary

May help by various neuropharmacological mechanisms. Valproate is a GABAergic agent and thus it may help in the same way as benzodiazepines. Main mechanism of action of carbamazepine appears to be stabilization of inactivated state of voltage-gated sodium channels. This may reduce neuronal firing in many systems and therefore may nonspecifically reduce abnormal movements in some patients.

Valproic acid (Depacon, Depakote, Depakote ER, Depakene)

Off-label therapy sometimes helpful in reducing choreiform movements and ameliorating disruptive behavior (eg, behavior induced by anger) in patients with HD. Dosages and other information mentioned is taken from dosages used for epilepsy because dosages for HD are not clearly established. Chemically unrelated to other drugs used to treat seizure disorders. Although the mechanism of action is not clearly established, its activity may be related to increased brain levels of GABA or enhanced GABA action. Also, may potentiate postsynaptic GABA responses, affect potassium channel, or have a direct membrane-stabilizing effect.

For conversion to monotherapy, concomitant AED dosage ordinarily can be reduced by approximately 25% q2wk. This reduction may be started at initiation of therapy or delayed by 1–2 wk if there is a concern that seizures are likely to occur with this reduction. Monitor patients closely for increased seizure frequency during this period.

As adjunctive therapy, divalproex sodium may be added to the patient's regimen at 10–15 mg/kg/d. Dosage may be increased by 5–10 mg/kg/d every week to achieve optimal clinical response. Ordinarily, optimal clinical response achieved at daily doses of < 60 mg/kg/d.

Depakote Sprinkle Capsules (daily doses > 250 mg should be divided bid/tid) and Depakote ER (once-daily formulation) are convenient dosage forms used in adults and children > 10 y.

Carbamazepine (Carbatrol, Tegretol, Epitol, Equetro)

Has been of symptomatic help in chorea, particularly in Sydenham chorea and chorea gravidarum, but also in other types. Dosage recommendations and cautions are essentially the same in this off-label use as for the more common indication of seizures.

When used as an anticonvulsant, mechanism of action may involve depressing activity in nucleus ventralis anterior of the thalamus, resulting in a reduction of polysynaptic responses and blocking post-tetanic potentiation. Reduces sustained high-frequency repetitive neuronal firing. Potent enzyme inducer that can induce own metabolism. Due to potentially serious blood dyscrasias, undertake benefit-to-risk evaluation before the drug is instituted. Therapeutic plasma levels are 4-12 mcg/mL for analgesic and antiseizure response. Peak serum levels in 4-5 h. Half-life (serum) in 12-17 h with repeated doses. Metabolized in the liver to an active metabolite (ie, epoxide derivative) with a half-life of 5-8 h. Metabolites are excreted through feces and urine.

 

Follow-up

Complications

See the list below:

  • The severity of the abnormal involuntary movements may cause rhabdomyolysis or local trauma in some patients.

  • The swallowing difficulties and tongue dystonia usually present in neuroacanthocytosis patients may cause aspiration pneumonia and early death in some patients.

Prognosis

Prognosis depends on the cause of the chorea. Huntington disease (HD) has a poor prognosis, because all patients will die of complications of the disease. Similarly, patients with neuroacanthocytosis may develop aspiration pneumonia, which can cause early death.

Patient Education

Genetic counseling

See the list below:

  • Both Huntington disease and benign hereditary chorea are inherited in an autosomal dominant pattern. Therefore, if there is a couple planning to conceive and one of the pair has Huntington disease, they should be educated that there is a 1-in-2 chance that each child they have could be affected.

  • Wilson disease and neuroacanthocytosis both have an autosomal recessive inheritance pattern. Therefore, if both parents are carriers, there is a 1-in-4 chance that each child could be affected, and a 1-in-2 chance that each child could be a carrier.

  • Genetic testing is available for each of these conditions. Testing should be offered to potentially affected patients and their family members, and they should be informed about the potential risk of inheriting the disease, clinical manifestations of the disease, treatment options, and prognosis. However, patients refuse to have testing for a number of reasons, and this should be respected.