Chorea

Etiology

Primary Chorea

Primary chorea refers to chorea that is the main symptom or presentation of a medical condition. Primary chorea is classically described in Huntington disease. Most disorders giving rise to primary chorea have a genetic etiology. Other primary chorea disorders include Wilson disease, spinocerebellar ataxia subtypes, neurodegeneration with brain iron accumulation disorders (NBIA), X-linked dystonia-parkinsonism, and paroxysmal kinesigenic and nonkinesigenic dyskinesia.

The most common chorea disorder is Huntington disease, which is hereditary and comprises one of the trinucleotide repeat disorders. Huntington disease is caused by a cytosine-adenine-guanine (CAG) repeat on chromosome 4 in the Huntington or HTT gene.[11][12][13]

Secondary Chorea

Secondary chorea generally arises from a basal ganglia pathology, often noted on neuroimaging as lesions in the striatum, typically in the caudate nucleus or putamen. Systemic conditions that may cause secondary chorea include the following:

• Endocrine and metabolic disorders: Hypoglycemia, nonketotic hyperglycemia, hyperthyroidism, kernicterus, hypomagnesemia, complicated hemodialysis, oral contraceptive use, and pregnancy [14][15] 
• Infectious diseases: Rheumatic fever (Sydenham chorea), syphilis, subacute sclerosing panencephalitis, Lyme disease, toxoplasmosis, HIV, and endocarditis
• Adverse pharmacologic effects: Levodopa, oral contraceptive, neuroleptics, antihistamines, cocaine, amphetamine, tricyclics
• Toxic exposures: Carbon monoxide, mercury, excessive alcohol consumption
• Vascular conditions: Ischemic or hemorrhagic stroke
• Vasculitis and autoimmune disorders: Polycythemia, Churg-Strauss syndrome, systemic lupus erythematosus (SLE), Behcet disease, multiple sclerosis
• Malignant and paraneoplastic diseases: Primary brain tumors, metastatic lesions, anti-Hu and anti-CRMP5 antibody formation [16]

Note that Sydenham chorea, chorea gravidarum, and chorea associated with oral contraceptive use represent a continuum of conditions related to a prior group A β-hemolytic streptococcal infection. Sydenham chorea is a major criterion in the Jones criteria for diagnosing rheumatic fever. In cases where a child with a history of rheumatic fever or streptococcal infection develops chorea in adulthood, it is frequently triggered by pregnancy (chorea gravidarum) or the use of oral contraceptives.[17] Additionally, chorea gravidarum may be associated with systemic lupus erythematosus and antiphospholipid antibody syndrome.[18]

Epidemiology

Information on the global incidence of chorea is lacking, but the incidence of the conditions presenting with this symptom is known. For example, Huntington disease is a neurodegenerative autosomal dominant disorder with a prevalence of about 5 to 10 cases per 100,000 individuals in the U.S. The condition more commonly affects Whites and is now seen in expats settling in South and Central America. Wilson disease is an autosomal recessive, multisystem disorder with a prevalence of about 30 cases per million people. Benign hereditary chorea is a rare, autosomal dominant illness with a prevalence of 1 case per half a million people.

Chorea can occur at any age. In young people, the most common causes of chorea are infections, trauma, and inflammatory diseases. Sydenham chorea occurs in 25% of patients diagnosed with acute rheumatic fever, which is the most common cause of acute-onset chorea in pediatric patients and second only to cerebral palsy among all chorea etiologies in children. The symptom occurs in children between the ages of 5 and 15, most commonly around the ages of 8 or 9. Chorea's incidence has steadily declined over the past few decades due to a decrease in the incidence of rheumatic fever and the widespread use of antibiotics.[19]

Huntington chorea is progressive and usually presents in the 4th to 5th decade of life and is rarely seen before the 3rd decade of life. Early onset of this condition is often associated with paternal inheritance, while late-onset cases are more likely linked to maternal inheritance.

Pathophysiology

The basal ganglia, the primary deep gray matter structures of the brain, are responsible for controlling and fine-tuning movements. This control is modulated within the striatum, primarily through impulses mediated by dopamine and γ-aminobutyric acid (GABA) via 2 parallel pathways, with additional input from cholinergic and serotonergic mechanisms. The striatum serves as the main afferent nucleus, receiving input from the cerebral cortex and the substantia nigra. Striatal modulation occurs through the medial pallidum in the direct pathway and the lateral pallidum and subthalamic nuclei in the indirect pathway.

Striatal modulation is mainly inhibitory through GABAergic innervation. Consequently, any striatal lesion can disrupt this inhibitory mechanism, resulting in hyperkinetic movement disorders such as chorea or choreoathetosis.[20] Notably, the most consistent biochemical finding in patients with Huntington disease is the loss of GABAergic neurons in the basal ganglia.[21]

Huntington disease is an autosomal dominant inherited CAG triplet repeat disorder. The CAG repeats result in a mutated huntingtin protein containing numerous glutamate residues. These mutated huntingtin proteins are believed to aggregate rather than fold into functional proteins, leading to cellular dysfunction. Neurotransmitters involved in chorea include dopamine, acetylcholine, serotonin, GABA, substance P, and cannabinoids.

History and Physical

The most important aspects of the history of patients with chorea are age, mode of onset, and temporal progression. Huntington disease is the most common cause of chronic chorea in adults. Genetic testing is used to confirm the diagnosis. Besides cerebral palsy, various genetic causes must be considered in children with chronic chorea. Other phenotypic features, such as ataxia and hypotonia, may provide clues to the diagnosis. A detailed medical history and medication review are always important to rule out pharmacological and toxic-metabolic causes.

A sudden or acute onset of chorea may indicate a vascular or toxic-metabolic cause. An acute or subacute onset may suggest an autoimmune or structural neoplastic disorder. Autoimmune causes must be considered in the appropriate clinical context.

The universal feature of chorea is uncontrolled motor persistence, which prevents patients from maintaining a steady posture, position, or movement. For example, when asked to grip an object, patients will alternately release and squeeze, a sign often referred to as a "milkmaid grip." Another characteristic is the frequent dropping of objects.

Chorea can affect both distal and proximal muscles. Most patients have normal muscle tone, but some may exhibit hypotonia.

Excessive, unintentional movements of body parts are the most common reason for seeking medical consultation. These choreiform movements are clearly visible upon observation. Another frequent finding is motor persistence of the tongue, where patients cannot maintain tongue protrusion when asked to stick it out, causing it to dart in and out of the mouth. Magnetic resonance imaging (MRI) often shows caudate atrophy, characterized by the widening of the lateral ventricles. Cognitive and behavioral symptoms become prominent in later stages.

Evaluation

A detailed history and thorough physical examination are essential for diagnosis. Thyroid function testing and a complete metabolic panel are also vital, as these diagnostic modalities help identify toxic-metabolic causes. Serum glucose testing can easily rule out hypoglycemia or nonketotic hyperglycemia as the underlying cause.

Evaluation of patients with Huntington disease may include genetic testing, neuroimaging through computed tomography (CT) or MRI, and performing a psychiatric evaluation to assess deficits in cognitive, behavioral, and functional areas. Inquiry about suicidality is crucial. The classical MRI finding in Huntington disease is caudate atrophy, which results in a boxcar appearance.[22][23][24][25]

MRI is the preferred neuroimaging study for patients presenting with acute-onset chorea, as it helps identify underlying pathological lesions in the basal ganglia. Positron emission tomography (PET) is sometimes used to evaluate Huntington chorea and neuroacanthocytosis. Bilateral reductions in metabolism in the putamen and caudate nucleus are frequently observed. However, this metabolic reduction may not be seen in patients with benign hereditary chorea.[26]

Treatment / Management

Chorea is a symptom or sign, and treatment should focus on addressing the underlying etiology, particularly for secondary causes. Chorea arising from pharmacological, toxic, or metabolic factors often resolves with correction of the underlying cause.

For example, correcting glucose and electrolyte disturbances is typically sufficient in cases of hypoglycemia and nonketotic hyperglycemia. Discontinuing offending medications, such as neuroleptics, or lowering the dose of drugs like levodopa can alleviate drug-induced chorea. Oral contraceptive-induced chorea resolves with discontinuation of the hormonal agent. For autoimmune and paraneoplastic causes, treatment of the underlying malignancy or the use of immune modulators like intravenous immunoglobulin may be beneficial. When chorea is secondary to infection, medication, metabolic abnormalities, autoimmune processes, or paraneoplastic illness, the movements usually resolve once the underlying condition is treated.

Generally, no cure exists for primary chorea, such as that associated with Huntington disease, though symptoms can be managed. Evaluating and establishing a patient's support system are highly important. Patients often require specialized caregiving as the disease progresses. Nutrition management becomes crucial due to swallowing difficulties. Paroxysmal kinesigenic dyskinesia responds dramatically to treatment with sodium channel-blocking agents, including carbamazepine, oxcarbazepine, lamotrigine, and phenytoin.

Vesicular Monoamine Transporter Inhibitors for Symptomatic Treatment of Chorea

Monoamine neurotransmitters, including norepinephrine, dopamine, serotonin, and histamine, are packaged by vesicular monoamine transporter 2 (VMAT2) into synaptic vesicles for storage and subsequent release in neurons. Hyperkinetic movement disorders like Huntington disease and tardive dyskinesia are believed to result from increased phasic dopaminergic signaling in the striatum.

VMAT2 inhibitors work symptomatically by reducing dopaminergic hyperactivity. Tetrabenazine, the first VMAT2 inhibitor, was approved for Huntington disease in 2008. In 2017, deutetrabenazine was approved for tardive dyskinesia and Huntington disease-associated chorea. Valbenazine and deutetrabenazine have recently been made available in the market as treatment options for hyperkinetic movement disorders. This class of medications has partly revolutionized the symptomatic treatment of primary chorea, leading to improved patient satisfaction.[27][28][29](A1)

Other pharmacologic options for chorea target more specific neurotransmitter pathways. These medications include neuroleptics, which block dopamine receptors, and GABAergic agents like valproate, clonazepam, and gabapentin.

Surgical Treatment by Deep Brain Stimulation

Deep brain stimulation (DBS) has advanced in the past decade. This therapeutic modality may benefit some patients with chorea. Anecdotal reports indicate that the procedure can reduce chorea in selected patients. DBS is performed by placing electrodes in the globus pallidus internus (GPi-DBS). This intervention is effective for controlling medically refractory chorea associated with Huntington disease.[30]

Differential Diagnosis

The differential diagnosis of chorea includes all hyperkinetic disorders and their causes. The most important conditions to consider are the following:

• Huntington disease
• Lesch-Nyhan disease
• Lyme disease
• Multiple system atrophy
• Neuroacanthocytosis
• Pediatric torticollis surgery
• Ramsay Hunt syndrome
• Striatonigral degeneration
• Tourette syndrome
• Viral encephalitis

Accurately identifying the cause of chorea requires careful consideration of these potential diagnoses. Proper identification ensures targeted treatment and better patient outcomes.

Prognosis

The prognosis of chorea depends on the underlying cause. The majority of patients with Huntington disease and neuroacanthocytosis have a poor prognosis and die prematurely. Localized trauma or rhabdomyolysis may result from severe involuntary movements. Swallowing may be impaired in patients who have neuroacanthocytosis or develop tongue dystonia, resulting in body weight loss, recurrent aspiration pneumonia episodes, and even death. Patients with the best prognosis are those with secondary chorea disorders due to reversible causes, including medications, oral contraceptives, toxins, and metabolic etiologies.

Complications

Complications of chorea extend beyond physical impairments, often impacting patients' quality of life in multiple ways. Difficulty with motor control can affect basic functions such as speaking, eating, and walking, leading to weight loss, aspiration pneumonia, an increased risk of falls, and possibly death. Socially, patients may experience isolation due to embarrassment, inability to engage in social activities, or challenges with communication. Psychosocial complications, such as depression and anxiety, are also common, particularly in patients with chronic conditions like Huntington disease.