Chorea in Children

Numerous factors, both inherited and acquired, can contribute to the development of chorea. ^[1]

This table outlines various categories and specific causes of chorea.

Causes of chorea (Open Table in a new window)

Movement disorders (particularly chorea, athetosis, and dystonia) are thought to result from basal ganglia pathology.

Connections of the basal ganglia can be categorized as follows:

• Input from the cerebral cortex and the thalamus

• Interconnections among the basal ganglia

• Output from the basal ganglia to other nuclear masses

The main neurotransmitters associated with the basal ganglia include gamma aminobutyric acid (GABA), dopamine, acetylcholine, and glutamate. Other potentially important neurotransmitters include enkephalin, substance P, dynorphin, cholecystokinin, and somatostatin.

Dopamine is highly concentrated in the substantia nigra. It is released in the postsynaptic area in the striatum from axons originating in the substantia nigra. It is inactivated by reuptake in the presynaptic terminal and degraded by monoamine oxidase and catechol-O-methyltransferase.

GABA is concentrated mainly in the globus pallidus, the substantia nigra, and to a lesser extent in the caudate and the putamen. It functions mainly in the interneurons of the striatum and the striatonigral pathways. It is synthesized from glutamic acid by glutamic acid decarboxylase and is inactivated by GABA transaminase through the formation of a succinic semialdehyde.

Glutamic acid is an excitatory neurotransmitter that is involved primarily in the pathways leading from the cerebral cortex to the striatum.

Acetylcholine is active in both the central and peripheral nervous systems. It exerts its greatest activity as a neurotransmitter in the striatum, hippocampus, and ascending reticular activating system. It is synthesized from choline through choline acetyltransferase, which exerts its greatest activity in the caudate nucleus. It is degraded by cholinesterase with the formation of choline, which may be used once again for synthesis by the presynaptic neuron.

Dopaminergic neurons within the substantia nigra project rostrally to the neostriatum (caudate and putamen). The feedback loop from the neostriatum appears to be segregated into two parallel pathways.

• The so-called indirect pathway consists of GABAergic/encephalinergic neurons that project to the external segment of the globus pallidus. Inhibitory neurons from the external globus pallidus synapse on neurons of the subthalamic nucleus, which then provide excitatory input (presumably glutamatergic) to the final output structures of the basal ganglia (the internal globus pallidus and the substantia nigra pars reticulata), which then inhibit the ventral thalamus.

• The so-called direct pathway consists of GABAergic neurons that project directly to the internal globus pallidus and substantia nigra pars reticulata, inhibiting these nuclei.

The two output pathways are modulated differentially by dopamine. The GABA-containing neostriatal neurons that form the indirect pathway preferentially express dopamine type 2 receptors and are inhibited by dopamine, while the GABAergic neostriatal neurons that form the direct pathway tend to express dopamine type 1 receptors and are excited by dopamine.

Chorea may be viewed as resulting from increased dopaminergic activity in the projections from the substantia nigra to the striatum, resulting in decreased GABAergic projection from the striatum to the globus pallidus.

Most of the drugs used in symptomatic treatment of chorea act through attenuation of dopaminergic transmission or enhancement of GABA transmission.

Anticonvulsant drugs may suppress chorea but also may induce chorea, especially in patients with basal ganglia dysfunction.

Sydenham chorea (SC), or rheumatic chorea, is one of the major clinical manifestations of acute rheumatic fever and the most common cause of acquired chorea in the young. It has been linked to numerous neuropsychiatric disorders, including obsessive compulsive disorder, attention deficit-hyperactivity disorder, depression, and anxiety. ^[3]

Epidemiology

In the United States, there are fewer than 2 cases of acute rheumatic fever per 100,000 school-aged children annually, compared to rates as high as 150 cases per 100,000 globally. ^[4]

The incidence of rheumatic fever is clearly higher in developing countries, where the absence of consistent and early antibiotic treatment makes it a more endemic problem.

Chorea is a major manifestation of acute rheumatic fever and is the only evidence of rheumatic fever in approximately 20% of cases. In some outbreaks, chorea has been present in more than 30% of patients with acute rheumatic fever.

The female-to-male ratio is approximately 2:1, and most patients present between 5 and 15 years of age.

Studies have demonstrated a high frequency of a positive family history in patients with SC and rheumatic fever. One study found that 3.5% of parents and 2.1% of siblings of children with SC had also been affected. ^[5]

Clinical features and course

According to the Jones criteria, to diagnose rheumatic fever a patient must present with two major criteria (including chorea) or one major and two minor criteria, along with evidence of a recent group A streptococcal infection. ^[6]

SC typically presents with other manifestations of rheumatic fever, but in 20% of cases chorea may be the presenting or sole manifestation of rheumatic fever.

The main features of SC are involuntary movements, hypotonia, and mild muscular weakness. Chorea can be generalized or unilateral, predominantly involving the face, hands, and arms. Movements are present at rest, aggravated by stress, and usually cease during sleep. Children may attempt to hide the movements with quasi-purposeful actions (such as flinging hair back), or they may sit on their hands is an attempt to prevent these movements. In about 20% of patients, only one side of the body may seem to be affected (hemichorea); however, careful examination usually reveals some involvement of the opposite side.

The choreic movements interfere with volitional movements and result in a clumsy gait, dropping and spilling, and explosive bursts of dysarthric speech. Muscular weakness leads to inability to sustain a contraction (milkmaid's grip). The pronator sign consists of hyperpronation of the hands, causing the palms to face outward when the arms are held over the head. Another sign of weakness and hypotonia is the so-called choreic hand—with the arms extended, the wrist will flex and the metacarpophalangeal joints overextend.

Some children may have such profound weakness that they appear paralyzed. Not uncommonly, children are restricted to bed or are unable to attend school for the duration of the illness. Fortunately, paralytic chorea is uncommon.

Patients with SC may also have psychiatric symptoms such as depression, anxiety, personality changes, emotional lability, OCD, and attention deficit disorder (ADD). ^[7]  Whether the psychological manifestations are secondary to the movement disorder or an integral part of the disease is not clear. Occasionally, these symptoms precede the onset of chorea.

On average, the disease resolves spontaneously in 3–6 months and rarely lasts longer than 1 year.

Mild chorea without functional disability may be found in a small proportion of patients up to 10 years after the initial attack of SC.

About 20% of patients experience 2–10 recurrences, usually within 2 years after the initial attack.

Pathophysiology

Immunology

Evidence suggests that SC may result from the production of immunoglobin G antibodies that crossreact with antigens in the membrane of group A streptococci and antigens in the neuronal cytoplasm of the caudate and subthalamic nuclei, namely intracellular tubulin and extracellular lysoganglioside. ^[8] Antineuronal antibodies have also been found in the cerebrospinal fluid (CSF) of patients with acute rheumatic chorea. Immunofluorescent staining has shown that sera from approximately half of the children with SC have antibodies that react with neuronal cytoplasmic antigens in the caudate and subthalamic nuclei. Serum antineuronal antibody titers have been found to decrease as the chorea improves. In children who suffer a relapse, the increase in symptom severity correlates with a rise in these neuronal antibodies.

Neurochemistry

The main symptoms of SC are believed to arise from an imbalance among the dopaminergic system, intrastriatal cholinergic system, and inhibitory gamma-aminobutyric acid (GABA) system. Evidence of this imbalance has been suggested by the successful control of chorea by dopaminergic antagonists and valproic acid, a drug known to enhance GABA levels in the striatum and substantia nigra.

Neuroimaging

MRI findings in SC are not consistent and may be normal. Published abnormalities include areas of increased signal intensity on T2-weighted images that usually involve the basal ganglia or cerebral white matter. One study reported an increase in basal ganglia volume consistent with localized swelling. Follow-up studies may show improvement but some residual abnormality is common. ^[9]

Functional neuroimaging using fluorodeoxyglucose (FDG) positron emission tomography (PET) has demonstrated reversible striatal hypermetabolism.

Diagnosis

Diagnosis of SC may be difficult, because no single, established diagnostic test is available.

SC usually develops in those aged 3–13 years and is believed to result from a preceding streptococcal infection. The patient may have no history of rheumatic fever, and a preceding streptococcal infection cannot always be documented. Infections can be subclinical and often precede the development of neurologic symptoms by age 1–6 months. At least 25% of patients with SC fail to have serologic evidence of prior infection.

Chorea may be the first and only manifestation of rheumatic fever. However, some patients may have subtle evidence of carditis by echocardiography despite a normal clinical examination and ECG. Chorea alone is sufficient for diagnosis providing other causes of the condition have been excluded.

Treatment

SC is usually self-limited, and treatment should be limited to patients with chorea severe enough to interfere with function.

Anticonvulsants (valproic acid and carbamazepine) have been shown to be effective in diminishing choreic movements at doses normally used for seizure control. In particular, valproate may be quite helpful in children with SC.

One meta-analysis found that corticosteroids and immunotherapy (especially corticosteroids) were associated with faster resolution of chorea and fewer relapses in SC. While antibiotics, corticosteroids, and sodium valproate improved the disease course by reducing relapses, no treatment factor was linked to better functional outcomes. ^[10]

Dopaminergic blockers (pimozide and haloperidol) are effective and, when used in small doses, are usually well tolerated.

Neuroleptics such as haloperidol and pimozide remain an important treatment option, especially in older children.

Prednisone, plasma exchange, and intravenous immunoglobulin (IVIG) have been shown to be effective. One study showed sustained improvement in three children treated with plasma exchange. ^[11]  Three other children treated with IVIG showed initial improvement but had recurrences after subsequent streptococcal infection. Case reports have shown IVIG to be a safe, effective option in disabling SC. ^[12] Because this treatment modality is quite expensive, it should be reserved for protracted or debilitating cases. ^{[12, 8]}  

Children with SC require prophylaxis against streptococcal infections until 18 years of age.

Parents and school officials should be informed that emotional lability is characteristic of this organic condition.

Introduction

Huntington chorea is an autosomal-dominant, neurodegenerative disorder in which chorea is a primary clinical manifestation. Other prominent clinical features include progressive cognitive decline and an array of psychiatric disturbances. ^{[13, 14]}

The average age of onset is at 35–40 years; however, the disease has been reported in children as young as 4 years. The age of onset varies among families, with some showing consistently older age of onset than others. Age of onset among individuals of the same family also can vary widely; children of an affected father may have a younger age of onset than children of an affected mother.

The term juvenile Huntington disease designates patients whose clinical manifestations begin before the age of 20 years. This group also may be classified further into those with onset before the age of 10 years and those with onset in adolescence.

Genetics

Huntington disease (HD) is an autosomal-dominantly inherited disease with complete penetrance. The responsible gene, IT-15, is located on the p16.3 subband of chromosome 4. The genetic mutation is an unstable, expanded DNA trinucleotide (cytosine-adenosine-guanosine or CAG) repeat within the coding region for a 348-kD protein named huntingtin.

All individuals possess this repeat sequence; it is the number of triplet repeats that is significant. Patients with HD have 38 or more repeats. The earlier the age of onset, the greater the number of repeats for a given individual.

The correlation between repeat length and rate of disease progression is unclear. Approximately 10% of HD gene carriers develop signs of illness before age 20 years.

Between 70% and 80% of patients with childhood-onset HD have inherited the gene from an affected father. ^[14]

Note that as many as 1% of individuals with HD may have a negative test result.

Clinical features

HD in the young presents differently than in adults. Initial stages in children include one or more of the following: cognitive and behavioral problems, rigidity with gait disturbance, cerebellar dysfunction, and occasionally seizures. ^[14] Impaired ocular motility may also be an early sign of HD in the pediatric patient and resembles oculomotor apraxia.

• The patient may appear to be primarily clumsy, rather than either rigid or choreiform.

• Reflexes are usually brisk, and pyramidal signs with extensor plantar responses are common.

• Seizures occur in about 30–50% of patients and are difficult to control.

Diagnosis

The availability of a DNA-based testing (to reliably identify the HD mutation) greatly facilitates diagnosis. The ability to determine the size of the trinucleotide repeat enables one to have accurate preclinical and prenatal diagnosis. Allele sizes of 40 or more CAG repeats are universally associated with the HD phenotype.

Brain MRI and CT in juvenile HD may show caudate atrophy. ^[15] MRI findings also include nonspecific increased T2 signal in the putamen. PET scanning in symptomatic patients using radiolabeled FDG uniformly shows a marked reduction in caudate glucose metabolism.

Presymptomatic testing should be executed only under rigid guidelines. ^[16]

• It should be performed only at the request of the patient.

• Test results should be released only to the patient; if the result is to be released to another party, written consent is required from the patient. ^[17]

• Testing minors is considered inappropriate at this time because results may have significant negative repercussions in raising the child.

Treatment

Presently, no specific therapy is available for HD. Management consists of symptomatic therapy and counseling.

• Some patients benefit from antidepressants; carbamazepine may be useful for mood swings. Choline, reserpine, and dopamine antagonists may decrease choreiform movements.

• Agents such as L-dopa or dopamine agonists can be helpful in the rigid form of the disease but may exacerbate chorea and provoke hallucinations and psychosis.

Experimental therapies (eg, agents that improve mitochondrial energy metabolism, agents that attenuate glutamate neurotransmission and free radical scavengers) have been ineffective.

Childhood-onset hereditary chorea

Introduction

Formerly known as benign hereditary chorea, childhood-onset hereditary chorea is a rare familial disorder that presents during infancy or childhood. Transmission is autosomal dominant with the gene locus on chromosome 14q. ^[18] However, rare cases of autosomal-recessive and X-linked inheritance have been reported.

The suggestion has been made that childhood-onset hereditary chorea could be allelic to Huntington disease (HD). One family was reported to have expanded CAG repeats, suggesting that some families with childhood-onset hereditary chorea may in fact have a phenotypic variant of HD. More recently, mutations in the thyroid transcription factor-1 gene on chromosome 14q have been proposed as a potential causative factor. ^{[19, 18]}

Clinical features

Chorea usually begins around the time the child is learning to walk but may occur throughout childhood. Most children only have chorea, which is nonprogressive and tends to diminish during adolescence. Associated features may include delayed motor development, dysarthria, intention tremor, athetosis, and hypotonia. ^[20] Severity is highly variable but choreic movements are typically continuous and not episodic. Intellectual function is typically normal.

• Intellectual impairment has been reported in one family in which affected individuals had intelligence quotient scores averaging 10 points lower than unaffected relatives.

• Functional neuroimaging showed decreased striatal FDG metabolism in one study. Routine imaging and EEG results are normal.

Treatment

Various drugs have been used with mixed results. ^{[20, 21]} Commonly used drugs include anticonvulsants (phenytoin and carbamazepine), haloperidol, and prednisone. Dopamine antagonists appear to have the most benefit but should be reserved for significant cases as the chorea frequently does not require treatment.

Neuroacanthocytosis

Neuroacanthocytosis is a progressive multisystem disease with a wide range of symptoms. Characteristic features include acanthocytosis, normal beta-lipoprotein levels, and multiple movement disorders.

Genetics

Neuroacanthocytosis is most likely an autosomal-recessive disorder, although autosomal-dominant and X-linked inheritances have been proposed. In one genetic study, neuroacanthocytosis was linked to a 6-cM region of chromosome band 9q21. ^[22]

Clinical features

Onset usually occurs in adults aged 20–40 years but may occur before age 10. In a large British survey of neuroacanthocytosis, the mean age for disease onset was 32 years. ^[23] Death occurs approximately 10–20 years after onset.

Chorea is the most prominent finding, but dystonia, motor and vocal tics, and Parkinson features can also occur.

• Oromandibular dystonia and orolingual dyskinesia commonly lead to dysarthria. Most patients have difficulty eating and swallowing early in the course of the disease. Lingual-labial dyskinesia may be so severe as to cause self-mutilation of the lips.

• Axonal sensorimotor polyneuropathy with amyotrophy, elevated creatine phosphokinase (CK), and decreased or absent deep tendon reflexes also occurs.

• Seizures occur in about one third of patients.

• MRI may demonstrate atrophy of the caudate nucleus or T2-weighted hyperintensities in the striatum.

Diagnosis

Identify characteristic clinical features, a positive family history, the presence of acanthocytes on peripheral blood smear, and a normal plasma lipid profile.

Treatment

Treatment is symptomatic.

Antidopaminergic agents may suppress the chorea, but they may worsen concomitant parkinsonism.

Seizures should be treated with appropriate anticonvulsants.

Wilson disease

Wilson disease is an inborn error of copper metabolism that may present with neurologic, hepatic, or psychiatric symptoms. It is inherited in an autosomal-recessive fashion.

In 1993, Bull et al suggested that Wilson disease is the result of a defect in the Wc1 gene (chromosome 13q14.3-q21.1) which encodes a copper transporting P-type adenosine triphosphatase that is expressed in the liver and kidney. ^[24] Excess copper accumulates in the liver, brain, cornea, kidneys, and other tissues of untreated patients. Serum ceruloplasmin is low and excessive copper occurs in the plasma and urine.

Clinical features

Hepatic dysfunction is the initial feature in more than 50% of cases. Patients typically develop acute hepatitis that either resolves spontaneously or progresses to fulminant hepatic failure. Less common presentations are asymptomatic hepatomegaly, chronic active hepatitis, or cirrhosis.

• Age at onset ranges from 3 to older than 50 years. ^{[25, 26]} Children younger than age 10 years usually present with hepatic failure unassociated with neurologic manifestations. ^[27]

• Untreated most individuals eventually develop neurologic dysfunction.

• In 40% of individuals, neurologic symptoms are the presenting feature. These children typically present during the second decade of life.

• Neurologic manifestations vary widely and may include chorea as well as dystonia, tremor, dysarthria, dysphagia, bradykinesia, and gait disorder. Most patients have gradual decline in school performance and intellectual abilities. Seizures are uncommon.

• The average age of onset in those who present with neurologic symptoms is 18.9 years.

Almost all patients with neurologic involvement also have Kaiser-Fleischer rings, which result from deposition of copper in the Descemet membrane of the peripheral cornea. ^[26]

Psychiatric manifestations include depression, personality changes, and emotional lability. Hemolytic anemia and renal tubular acidosis also may occur.

Diagnosis

Determining hepatic copper content via liver biopsy is the single most sensitive and accurate test for Wilson disease. Assay of serum ceruloplasmin is simple and practical, but values are normal in 5–15% of affected patients. Other tests include the following:

• Slit-lamp examination to check for the presence of corneal Kaiser-Fleischer rings is a vital part in the diagnostic evaluation.

• Twenty-four-hour urinary copper excretion rises dramatically in symptomatic patients and is a useful test to monitor therapy.

Because of its protean manifestations, Wilson disease should be excluded in any patient who presents with unexplained neurological dysfunction, especially if the basal ganglia or cerebellum is involved.

Treatment

The four primary strategies for managing Wilson disease are as follows: ^[26]

• Limiting copper intake

• Therapy to reduce copper absorption

• Copper chelation therapy

• Liver transplantation

Demirkiran and Jankovic divided paroxysmal dyskinesias into 4 groups according to the precipitating circumstances. ^[28]

• Paroxysmal kinesiogenic dyskinesia

• Paroxysmal nonkinesiogenic dyskinesia

• Paroxysmal exertion-induced dyskinesia

• Paroxysmal hypnogenic dyskinesia

Paroxysmal kinesiogenic dyskinesia

These choreas consist of any combination of these paroxysmal attacks: dystonia, chorea, athetosis, and ballismus. One study noted choreoathetosis in 64% of patients. ^[29] The age of onset ranges from 6 to 15 years. The attacks typically last less than 1 minute but occur frequently (more than 100 times per day).

• The extremities are affected primarily, but facial, neck, and trunk muscles also can be affected.

• The attacks may be disabling and interfere with walking, working, and daily activities.

• Neurologic examination findings between the attacks are normal.

About half of the reported cases are familial, with both autosomal-dominant and -recessive patterns of inheritance. Multiple sclerosis, head trauma, thalamic infarcts, hypoparathyroidism, hypernatremia, and hyperglycemia represent common causes of secondary paroxysmal kinesiogenic dyskinesia.

The response to anticonvulsant medications is often striking.

• Phenytoin has been considered the drug of choice and generally is used in dosages similar to those used in epilepsy; however, it also has been shown to be effective in smaller doses.

• Satisfactory response has been obtained with other anticonvulsants, particularly carbamazepine; acetazolamide also may be used.

• In one case, haloperidol worsened paroxysmal kinesiogenic dyskinesia.

Paroxysmal nonkinesiogenic dyskinesia

The attacks occur spontaneously without any specific precipitant. The duration ranges from 2–3 minutes to 4 hours, a major feature that differentiates it from paroxysmal kinesiogenic dyskinesia.

In one series, 81% of cases were familial. Multiple sclerosis is the leading cause of secondary paroxysmal nonkinesiogenic dyskinesia. Other causes include encephalitis, hypoparathyroidism, thyrotoxicosis, head injury, basal ganglia calcification, AIDS, and Leigh syndrome.

Attacks of paroxysmal nonkinesiogenic dyskinesia may diminish with age in frequency and severity.

It is more difficult to treat than paroxysmal kinesiogenic dyskinesia, since the nonkinesiogenic form does not respond to anticonvulsant drugs. Clonazepam (1–2 mg/d) appears to be the drug of choice; phenobarbital and valproic acid also may be effective.

Paroxysmal hypnogenic dyskinesia

This condition consists of brief, occasionally painful dystonic or choreoathetoid movements occurring during non–rapid eye movement sleep. In some cases, daytime kinesigenic or nonkinesiogenic attacks also have been described along with hypnogenic attacks. Short-lasting paroxysmal hypnogenic dyskinesia generally is regarded as a form of mesiofrontal epilepsy.

Paroxysmal exertion-induced dyskinesia

This disorder consists of attacks of dystonia, sometimes combined with chorea and athetosis, that are triggered by exertion such as walking or running. The attacks usually involve the lower limbs and are often bilateral. They may last from a few minutes to 30 minutes. Most of the described cases suggest an autosomal-dominant mode of inheritance. Treatment with anticonvulsants and levodopa has proven unsatisfactory.

Antidopaminergic agents

The hyperdopaminergic hypothesis supports the use of dopamine antagonists for chorea treatment.

In children, particularly those who will need treatment for long periods of time, neuroleptics present a potentially serious problem (ie, the risk of tardive dyskinesia). Thus, neuroleptics should only be used as a last resort.

Dopaminergic blockers. (Open Table in a new window)

Dopaminergic depletors. (Open Table in a new window)

Drugs acting through GABA

Benzodiazepines such as clonazepam and diazepam may be used to treat chorea, particularly in the early stages. Sedation is a major concern. They may be useful in the first few days until a satisfactory response to other drugs is achieved.

Benzodiazepines. (Open Table in a new window)

Anticonvulsants are commonly used to manage chorea in children, particularly when the movements are severe, cause significant distress, or are refractory to other treatments. Their primary mechanism of action involves stabilizing neuronal excitability, which can help reduce involuntary movements associated with chorea.

In one study, 15 children with Sydenham chorea were treated with sodium valproate (15–20 mg/kg/d) for a mean duration of 19.2 months. In 13 of the children, the choreiform movements disappeared within 1 week of beginning therapy. ^[30]

Anticonvulsants. (Open Table in a new window)