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." [1]
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. [2]
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). [2]
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). [2, 3] 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." [3] 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. [2, 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. [2]
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. [2, 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. [2, 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 [2] , while the worldwide prevalence is between 0.4 and 5.7 per 100,000. [27]
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. [2, 28, 29]
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. [2, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42]
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. [43] 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. [2, 44] 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. [45]
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. [2, 28, 46, 47]
Sydenham chorea most commonly affects the pediatric population between the ages of 5 and 13 years. [48]
Senile chorea manifests gradually in middle-to-late life.
Benign hereditary chorea presents as onset of chorea before the age of 5 years. [49]
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. [31, 50]
