Movement Disorders II: Chorea, Dystonia, Myoclonus, and Tremor

After completing this article, readers should be able to: In a previous article, (1) we considered the two most common movement disorders in children: tics and stereotypies. Although less common, chorea, dystonia, myoclonus, and tremor are not rare in children. Therefore, it is important for the pediatric clinician to be able to recognize and distinguish these movement disorders. The first step in diagnosis and treatment is to identify and classify the disorders. In this article, we review these and drug-induced movement disorders. Drug-induced movement disorders fall into the same phenomenologic categories (chorea, dystonia, myoclonus, and tremor) but often are considered as a separate entity because of their specific causes and treatments.Chorea is characterized by frequent, brief, unpredictable, purposeless movements that tend to flow from body part to body part chaotically and unpredictably. The movements are less sustained than those of dystonia but are more sustained and less “shocklike” than myoclonus. Low-amplitude chorea may cause an individual to appear fidgety. Large-amplitude chorea, sometimes termed “ballismus,” can occur as dramatic flinging limb movements. Choreic movements (ie, characterized by chorea) can be sudden and jerky or can be more continuous and flowing. In the latter case, the term choreoathetosis is used. The term “choreiform” often is used to describe the minimal twitching or “piano playing” movements seen in many otherwise healthy young children when their arms are extended during the neurologic examination. The difference between “choreic” and “choreiform” in clinical usage is based on amplitude differences only and not on other characteristics of the movements. We prefer not to use the term “choreiform” but rather the more inclusive term “minimal chorea.” (For examples of chorea, view the first three video segments in the data supplement.)Chorea can be classified by cause into primary and secondary disorders. Primary chorea is uncommon in childhood. Primary causes include benign familial (hereditary) chorea and Huntington disease. However, Huntington disease rarely presents in childhood with chorea; juvenile-onset Huntington disease usually is characterized by parkinsonism and dystonia. Most chorea in childhood is due to other disorders. More than 100 causes of secondary chorea have been identified, but in most of those disorders, chorea is not the only sign or symptom. The most common cause of secondary chorea in childhood is acute rheumatic fever (ARF). Other important causes include systemic lupus erythematosus (SLE), cardiac surgery (“post-pump chorea”), and perinatal hypoxia-ischemia. A more extensive list of causes is shown in Table 1. A diagnostic strategy based on the more likely causes, with an emphasis on treatable causes, is shown in Table 2.Chorea is one of the major Jones criteria for the diagnosis of ARF. The presence of chorea without any other criteria is sufficient to make the diagnosis of ARF. Although it is widely accepted that chorea can follow group A beta-hemolytic Streptococcus (GABHS) infection, it often is hard to demonstrate the antecedent infection. Depending on the series, 10% to 40% of children who have ARF have chorea. Sydenham chorea (SC) is most common in children 5 to 15 years old. There is a 2:1 female predominance after age 10 years. SC begins several weeks to several months after a GABHS infection. The onset of symptoms usually is insidious, with gradually progressive clumsiness and behavior change, usually including emotional lability. After a week or more, choreic movements become more obvious and typically become generalized. The chorea usually is asymmetric and, in rare cases, can be unilateral. The chorea commonly is accompanied by hypotonia and dysarthria. Classically described findings also include the “spooning sign” caused by hyperextension at the metacarpophalangeal joints; the “milkmaid's grasp,” a sign of chorea that is detected by having the patient squeeze the examiner's fingers in a sustained manner, due to choreic intrusions and motor impersistence (ie, inability to maintain a posture), which are felt by the examiner as continuous fluctuation of the grasp; and the “darting tongue,” due to choreic movements of the tongue and motor impersistence. Some children also display “hung-up” tendon jerk reflexes (ie, brisk reflex followed by a slowed return to the neutral position).Behavioral changes may be striking and include impulsivity, aggression, and obsessive-compulsive behaviors. The natural history of SC is weeks to months of a waxing and waning course, with ultimate resolution of the chorea. Some individuals have behavioral changes that persist for months. Chorea relapse can occur with or without subsequent GABHS infection, and increased risk of relapse is associated with pregnancy (chorea gravidarum) and oral contraceptives.The diagnosis of SC is based on clinical history and physical examination findings but can be supported by laboratory data. However, laboratory data should not be viewed as confirmatory. Most children who have SC have positive serology (antistreptolysin O [ASO] and anti-DNase B antibodies) for GABHS, but more than 25% are serologically negative. Conversely, ASO titers can be elevated in children who do not have ARF. There is no correlation between titers and the severity of the chorea. Most children who develop SC have negative throat cultures for GABHS, but a positive culture result requires acute treatment. Magnetic resonance imaging scans may show signal abnormalities in the basal ganglia, but no sensitive or specific diagnostic tests for SC exist. The presence of carditis or other manifestations of ARF supports the diagnosis of SC. Every child believed to have SC should have an evaluation for rheumatic heart disease. Depending on the series, 40% to 75% of children who develop SC have carditis. Arthritis is less common.Treatment of SC consists of secondary prevention, symptomatic treatment of chorea, and immune modulation. All children diagnosed as having SC, even in cases of isolated chorea, should be treated with penicillin, according to American Academy of Pediatrics guidelines. (2) An appropriate alternative may be selected for children who have penicillin allergies. Penicillin or an acceptable alternative is effective as secondary prevention of recurrent chorea but more importantly, reduces the likelihood that future GABHS infections will cause carditis and permanent valvular damage. Current recommendations in the United States are for treatment until age 21 years, regardless of the age of onset of the chorea.Symptomatic treatment of SC depends on the impairment or disability associated with the chorea. In many cases, the chorea causes only mild disability, and symptomatic treatment is not required because SC usually is self-limited. When symptomatic treatment is desired, referral to a neurologist is recommended. Antiepileptic medications such as carbamazepine or valproate can be effective and usually are associated with fewer adverse effects than phenothiazines or butyrophenones. Benzodiazepines also may be beneficial. Symptomatic treatment for 2 to 4 months generally is sufficient. There have been no controlled studies of long-term outcomes of these treatments compared with placebo.Based on the pathophysiology of SC, it is reasonable to consider using immune-modulating therapies to shorten the course of illness. According to one randomized, blinded, placebo-controlled study, (3) a 4-week course of oral prednisone (2 mg/kg daily) followed by a taper reduced the duration of chorea and accelerated the reduction in symptoms. Weight gain was substantial by the end of 2 months, and long-term outcome, including recurrence rates, was not different between groups. Other studies have been less conclusive. Because long-term outcome appears to be no different whether or not patients are treated with steroid medications, this treatment should be reserved for those who have severe chorea unresponsive to symptomatic treatment.Chorea is an uncommon manifestation of SLE but can be the presenting symptom. When chorea is the sole manifestation of SLE, it can remain so for years. Although fewer than 10% of children who have SLE have chorea, about 50% of individuals who have chorea due to SLE are younger than 16 years of age. The presence of neurologic manifestations such as chorea in SLE conveys a less favorable prognosis. The diagnosis and treatment of SLE is beyond the scope of this review. When chorea is due to SLE, treatment of the underlying SLE is indicated. Additional symptomatic treatment of the chorea may be indicated if it is bothersome. Haloperidol has been reported to be effective for SLE chorea, but the other previously described treatments described for SC also may be effective.Dystonia is a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. There are several classification schemes for dystonia, based on age of onset, cause, or body part affected (Table 3). Primary dystonias are those disorders in which dystonia is either the only feature or the primary feature, and the cause either is a specific genetic mutation or is unknown. Secondary dystonias are those disorders in which the dystonia is due to another identifiable cause.Focal dystonia occurs when only a single body part is affected. Almost any part of the body can be affected. Examples of focal dystonia include torticollis and writer's cramp. Segmental dystonia refers to involvement of two or more adjacent body parts; multifocal dystonia describes involvement of multiple nonadjacent body parts. Hemidystonia affects only one side of the body, and generalized dystonia involves the entire body. Note that these classification schemes overlap. Childhood onset of primary generalized dystonia typically starts in an extremity and commonly progresses to generalized involvement with involuntary twisting of nearly all parts of the body.Dystonia has several characteristic clinical features. Dystonia commonly is triggered or exacerbated by attempted voluntary movement and may fluctuate in occurrence and severity over time. Dystonic contractions resolve during sleep. The dystonic posturing may occur only with selected movements and paradoxically not with others that may use the same muscles. For example, walking forward may elicit severe lower extremity and truncal twisting, yet walking backward, running, or swimming may be completely normal. Individuals who have dystonia often find that touching one part of the body may relieve the dystonic spasms; this phenomenon is called a sensory trick or geste antagoniste. For example, rubbing the back of the hand may diminish hand dystonia. (For an example of a patient who demonstrates dystonia, view the fourth segment of the video in the data supplement.)Historically, dystonia has been divided into primary (idiopathic) and secondary causes. A full discussion of the many causes of dystonia is beyond the scope of this review. The two most important types of primary dystonia in children are dopa-responsive dystonia (DRD) and idiopathic torsion dystonia associated with the DYT1 mutation. Other important causes of secondary dystonia in children are listed in Table 4.DRD is a syndrome characterized by childhood onset and progressive dystonia that has a sustained dramatic response to low doses of levodopa. DRD also is known as hereditary progressive dystonia with diurnal fluctuations or Segawa syndrome. DRD typically presents with a gait disturbance due to foot dystonia starting between 1 and 12 years of age. In untreated older children, diurnal fluctuation develops, with worsening of symptoms toward the end of the day and marked improvement in the morning. Such diurnal fluctuation usually is not apparent in younger children. In late adolescence or early adulthood, features of parkinsonism can develop.There are two major forms of DRD: a more common autosomal dominant form due to deficiency of guanosine 5′-triphosphate (GTP) cyclohydrolase (GTPCH) and a relatively uncommon autosomal recessive form caused by a deficiency in tyrosine hydroxylase (TH). Both forms produce dopamine deficiency without loss of nigrostriatal dopamine neurons. A few clinical differences may help distinguish TH deficiency from GTPCH deficiency, but these are neither sensitive nor specific. DRD due to TH deficiency can be distinguished from DRD due to GTPCH deficiency by measuring cerebrospinal fluid (CSF) catecholamines, their metabolites, and pterins. In practice, diagnosing DRD by its exquisite response to levodopa typically is sufficient. In some cases, a specific diagnosis is required, either for the purpose of genetic counseling or, in atypical cases, warranting CSF investigations or genetic testing.It is important to recognize the entity of DRD because it responds dramatically to low doses of levodopa. DRD has been misdiagnosed as cerebral palsy, particularly spastic diplegia. Therefore, it is important to develop suspicion for DRD in children who have motor impairment, prominent dystonia, and a slowly progressive rather than static course. With appropriate diagnosis and treatment, affected children can lead normal lives.Childhood-onset idiopathic torsion dystonia, formerly known as dystonia musculorum deformans, is an autosomal dominant condition with incomplete (30%) penetrance. Genetic studies have found that a GAG deletion at the DYT1 locus on chromosome 9 causes most cases of autosomal dominant, early-onset, primary generalized dystonia affecting Ashkenazi Jewish families (90%) and non-Jews (50% to 60%). In childhood-onset idiopathic torsion dystonia, symptoms usually begin in a limb at a mean age of 12.5 years. Onset typically is before 28 years of age but seldom before age 6 years. The legs generally are affected before the arms, and symptoms usually become generalized within 5 years. Diagnosis is based on identifying a GAG deletion in the DYT1 gene; genetic testing is available commercially.Treatment of most types of dystonia can be difficult, and often the response is incomplete. The clear exception is DRD, which responds dramatically to low doses of levodopa. For this reason, a trial of levodopa with carbidopa is recommended for all children who have primary dystonia. Because some secondary dystonias also may respond to levodopa, a trial of levodopa is recommended for any child in whom dystonia is a prominent component of his or her neurologic syndrome. The anticholinergic medication trihexyphenidyl has been used with success in some patients who have dystonia. Some patients who were believed to have idiopathic torsion dystonia and had a dramatic response to anticholinergic medication have been shown to have DRD due to GTPCH deficiency. Thus, dramatic response to trihexyphenidyl should suggest the possibility of DRD.If benefit is inadequate from levodopa or trihexyphenidyl, baclofen alone or in combination with trihexyphenidyl may be beneficial. Intrathecal baclofen has been found to be effective in treating dystonia due to cerebral palsy, but adverse effects are frequent and can be serious. For that reason, we recommend an adequate trial of oral baclofen before considering intrathecal baclofen. Benzodiazepines also may be beneficial, but often the benefit is limited by adverse effects or tolerance.If oral medications are ineffective, botulinum toxin injections may be highly effective, especially if impairment or disability is attributable to a few muscle groups. Deep brain stimulation of the medial globus pallidus has been used with increasing success for a select group of patients who have dystonia and may be the most effective treatment for dystonia due to the DYT1 mutation. Because of the broad differential diagnosis of dystonia and the complexities of treatment, we recommend that any patient who has dystonia be evaluated by a neurologist.Myoclonus is characterized by brief, abrupt, involuntary, nonsuppressible, jerky contractions involving a single muscle or muscle group. The rapidity of the movements warrants the descriptor “shocklike” or “lightning-fast,” as if an electrical shock had just been applied to the peripheral nerve innervating the muscle. Myoclonus can be rhythmic, in which case it often appears tremor-like. However, in true tremor, the movement oscillates with near-equal amplitude around a midpoint; in myoclonus, the movement has a more “sawtooth” character. In some cases, myoclonus can be elicited by a sensory stimulus (reflex myoclonus, with the most famous example being the acoustic startle response in infancy) or volitional movement (action myoclonus). Myoclonus can be focal, multifocal, segmental, or generalized. Occasional myoclonus is seen as a sudden muscle relaxation rather than active contraction. In the case of sudden relaxation causing a visible jerk, the term “negative myoclonus” has been used. (For an example of a baby who demonstrates myoclonus, view the fifth segment of the video in the data supplement.)The causes of myoclonus are numerous. A first step in classifying myoclonic disorders is to determine if the myoclonus is epileptic. Electroencephalography is the most useful tool in making this distinction. Myoclonus can be the manifestation of epileptic neurodegenerative diseases such as progressive myoclonic epilepsy, Lafora body disease, and neuronal ceroid lipofuscinosis, as well as mitochondrial diseases such as myoclonic epilepsy and ragged-red fiber disease (MERRF). A full discussion of epileptic myoclonus is beyond the scope of this review.Important causes of nonepileptic myoclonus are listed in Table 5. The location and quality of myoclonic movements can be helpful in determining cause. For example, segmental myoclonus of thoracic muscles suggests spinal cord pathology, whereas segmental myoclonus of palatal muscles suggests a brainstem lesion or Whipple disease. Asterixis, a form of negative myoclonus, suggests metabolic encephalopathy. Myoclonus in the setting of opsoclonus or ataxia suggests paraneoplastic syndrome (eg, neuroblastoma) or a peri-infectious autoimmune process. Alternatively, myoclonus can be a manifestation of neurodegenerative processes such as lysosomal storage diseases, Wilson disease, or Huntington disease. Diffuse central nervous system injury from virtually any cause (toxic, infectious, metabolic, hypoxic) can result in myoclonus. Essential myoclonus (ie, myoclonus of undetermined cause) typically is a diagnosis of exclusion. Myoclonus, even nonepileptic forms, may respond to anticonvulsant medications such as valproate, levetiracetam, or clonazepam. Given the complex differential diagnosis associated with myoclonus, we recommend that any affected pediatric patient be evaluated by a pediatric neurologist.Tremor is a rhythmic oscillation about a central point or position involving one or more body parts. Tremor in childhood is not rare, but few epidemiologic data are available to indicate the incidence or prevalence. Tremor is classified by when it occurs: with rest, intention, or action. Rest tremor is defined as tremor involving a body part that is inactive and supported against gravity. Rest tremor is associated most commonly with other signs of parkinsonism but may occur in isolation. In children, the most common cause of rest tremor is antipsychotic (neuroleptic) medications. Intention tremor occurs as a moving body part approaches a target. Intention tremor usually is associated with other signs of cerebellar dysfunction. Action tremor occurs during maintained posture, voluntary movement, or both. In evaluating the child who has tremor, attention should be paid to possible other neurologic signs or symptoms. When present, such features usually direct the diagnostic evaluation. When tremor is the only abnormality, it is important to identify potential tremor-enhancing medications. The primary laboratory tests to be considered are thyroid function tests.The most important childhood tremors are action tremors and include physiologic tremor and essential (familial) tremor. Physiologic tremor is a normal phenomenon, consisting of a 6 to 12-Hz oscillation that usually is noticed by the individual or other observers only under certain conditions. A few individuals have a more easily noticed physiologic tremor that is termed “enhanced physiologic tremor.” Such individuals otherwise are indistinguishable from those who have no enhanced physiologic tremor. Physiologic tremor may increase with anxiety, excitement, fear, or certain medications. These medications include sodium valproate, theophylline, beta-agonists, corticosteroids, and stimulants. The tremor of hyperthyroidism is an enhanced physiologic tremor.Essential tremor often is considered a disorder of adults but can begin in infancy or childhood. Essential tremor is the most common movement disorder in adults, but it appears to be less common in children. Essential tremor is present with posture and with action but usually is greatest with maintained posture. The tremor typically involves the upper extremities but may involve the head and neck, voice, and legs. By definition, essential tremor is unaccompanied by other neurologic abnormalities, although individuals may have slight clumsiness. Essential tremor is “familial” (autosomal dominant) in about 60% of cases. There have been no studies of treating essential tremor in children, but experience has shown that children respond to the same medications that are effective in adults. The most effective medications are propranolol (or other beta blockers) and primidone. Clonazepam may be effective in some cases. Children should be referred to a neurologist for diagnosis and treatment of essential tremor.The phenomenologic classification of drug-induced movement disorders is the same as for nondrug-induced disorders. However, because medications are a relatively common cause of movement disorders in children, they deserve special consideration. Perhaps the best known drug-induced movement disorders are those associated with antipsychotic (neuroleptic) treatment. These medications are dopamine receptor antagonists and cause both acute and tardive (ie, “late”) syndromes. The acute adverse effects of dopamine antagonists include parkinsonism and acute dystonic reactions. Acute dystonic reactions can occur even after a single dose of a dopamine antagonist. The typical acute dystonic reaction involves involuntary gaze deviation (oculogyric crisis), torticollis, and appendicular twisting postures associated with more than appendicular muscles. The reaction can for but is treated with anticholinergic medications such as mg/kg dose 6 or to 2 or a most severe reaction to dopamine antagonists is the syndrome which is characterized by dystonic tremor, and can be Children of having should be evaluated by a is and consists of fever and metabolic should be to diminish muscle contraction. such as may be medications should be is uncommon in childhood. The can as any of the movement disorders. typically as an but it can involve other body parts. The risk of with dose and treatment duration of antipsychotic medication and with age of the There is some that children who have previous brain are more likely to develop effects such as acute dystonic and are more likely to occur with the medications such as and and other such as and medications, such as and have a lower incidence of such but such adverse effects can of can be and requires referral to a neurologist or in its treatment. of requires in use of antipsychotic medications, duration of treatment, and other medications have been associated with movement disorders. The more common are in Table The treatment of drug-induced movement disorders is to the In most cases, it not make to another medication to adverse effects from the causing a movement

Topic: Neurological and metabolic disorders
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences