"Chorea" is a borrowed Latin word that derives from the Greek khoreia, a choral dance. The basic Greek word for dance (written with the Roman alphabet) is khoros.[1, 2]
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."
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.
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).
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." 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]
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.
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]
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]
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.
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.
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.
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. 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. However, no systematic studies have been conducted on the use of GABAergic agents to treat HD.
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.
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]
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]
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.
Chorea can commence at any age. In children, postpump chorea and infectious, inflammatory, and striatal lesions may account for many cases.
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.
Because Huntington disease (HD) is the most clearly defined choreatic disease, its physical findings are described here.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Clinical Context: Useful in treatment of irregular spasmodic movements of limbs or facial muscles.
Clinical Context: Blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in brain. Exhibits strong alpha-adrenergic and anticholinergic effects. May depress reticular activating system.
Clinical Context: New 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.
Clinical Context: May inhibit serotonin, muscarinic, and dopamine effects.
Clinical Context: 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.
Clinical Context: May act by antagonizing dopamine and serotonin effects.
Block dopamine receptors and appear to have antispasmodic effects.
Clinical Context: Depletes norepinephrine and epinephrine, which, in turn, depress sympathetic nerve functions.
Clinical Context: 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.
Deplete CNS of dopamine, thereby reducing chorea.
Clinical Context: 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.
Demonstrated to reduce GABA concentrations in the caudate, putamen, substantia nigra, and globus pallidus. By analogy, increased GABA activity might ameliorate chorea.
Clinical Context: 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 mechanism of action not 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 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 concern that seizures are likely to occur with reduction. Monitor patients closely for increased seizure frequency during this period.
As adjunctive therapy, divalproex sodium may be added to patient's regimen at 10-15 mg/kg/d. Dosage may be increased by 5-10 mg/kg/d qwk 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.
Clinical Context: 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 thalamus, resulting in reduction of polysynaptic responses and blocking posttetanic potentiation. Reduces sustained high-frequency repetitive neural firing. Potent enzyme inducer that can induce own metabolism. Due to potentially serious blood dyscrasias, undertake benefit-to-risk evaluation before drug 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 liver to active metabolite (ie, epoxide derivative) with half-life of 5-8 h. Metabolites excreted through feces and urine.
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.
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.