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Hyperkinetic movement disorders in children

Hyperkinetic movement disorders in children
Author:
Joseph Jankovic, MD
Section Editors:
Marc C Patterson, MD, FRACP
Helen V Firth, DM, FRCP, FMedSci
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Dec 2022. | This topic last updated: Oct 06, 2022.

INTRODUCTION — Movement disorders are characterized by either excessive (hyperkinetic) or reduced (bradykinetic) activity. Hyperkinetic disorders are reviewed here. Bradykinetic disorders are discussed separately. (See "Bradykinetic movement disorders in children".)

Hyperkinetic disorders are characterized by abnormal involuntary movement. These excess movements can be regular and rhythmic, as in tremor; more sustained and patterned, as in dystonia; brief and random, as in chorea; or jerk-like and temporarily suppressible, as in tics. Diagnosis of the specific condition depends primarily upon careful observation of the clinical features [1]. Tics are the most common hyperkinetic disorder in children. Dystonia, stereotypies, choreoathetosis, tremors, and myoclonus also occur but are less common. Many hyperkinetic movement disorders manifest with multiple types of movements, which may include a combination of the various hyperkinesias.

ANATOMY OF THE BASAL GANGLIA — A brief review of the anatomy of the basal ganglia is appropriate since this site is involved in many of the bradykinetic disorders. The basal ganglia regulate the initiation, scaling, and control of the amplitude and direction of movement. Movement disorders can result from biochemical or structural abnormalities in these structures.

The basal ganglia are a complex of deep nuclei that consist of the corpus striatum, globus pallidus, and substantia nigra. The corpus striatum, which includes the caudate nucleus and the putamen, receives input from the cerebral cortex and the thalamus and, in turn, projects to the globus pallidus.

The substantia nigra is divided into the dopamine-rich pars compacta and the less dense pars reticularis. The pars reticularis is similar histologically and chemically to the medial segment of the globus pallidus, and both project via the thalamus to the premotor and motor cortex. The substantia nigra pars compacta gives rise to the nigral-striatal pathway, which is the main dopaminergic tract.

The output of the basal ganglia projects by way of the thalamus to the cerebral cortex and then to the pyramidal system. Basal ganglia output is sometimes referred to as the extrapyramidal system because it was formerly thought to be in parallel with the pyramidal system. Integration of the basal ganglia with the cortex facilitates motor control.

TIC DISORDERS — As defined by the Taskforce on Childhood Movement Disorders, "tics are repeated, individually recognizable, intermittent movements or movement fragments that are almost always briefly suppressible and are usually associated with awareness of an urge to perform the movement" [2,3]. Tics manifest as sudden, brief intermittent movements (motor tics) or utterances (vocal or phonic tics). Although tics can be voluntarily controlled for short periods of time, it is difficult to suppress tics for sustained periods of time. In some cases, tics can be so intense that they result in self-injury [3].

Transient tics last less than one year, whereas most with childhood-onset tics continue to have tics or have recurrence of the tics several years later. Persistent motor and phonic tics are features of Tourette syndrome, as described below (table 1).

Secondary causes should be considered in individuals in whom tics begin abruptly, are persistent, or are particularly problematic. Secondary causes of tics include the use of stimulant medications (dopaminergic agonists). Another potential but controversial cause is pediatric autoimmune neuropsychiatric disorder associated with group A streptococci (PANDAS). (See "Complications of streptococcal tonsillopharyngitis", section on 'PANDAS syndrome'.)

Provisional tic disorder — Provisional tic disorder, which has replaced the term "transient tic disorder" in the DSM-5 classification, specifies that tics have been present for less than one year (table 1) [4]. Transient tics occur in up to 10 percent of otherwise healthy children and may spontaneously remit in a few weeks or months [5,6]. Most children with simple motor tics do not require treatment.

There is growing evidence that once tics begin, they usually persist, certainly beyond one year and in many cases for a lifetime. One study identified several clinical features present at the first examination that predict persistence of tics after one year, including higher baseline tic severity, mild autism spectrum symptoms, and the presence of anxiety disorder [7].

Of note, an increase in functional tics has been seen during the coronavirus disease 2019 (COVID-19) pandemic, primarily affecting adolescent females and associated with complex, large-amplitude motor tics and a wide range of vocal utterances [8]. (See "Functional movement disorders", section on 'Functional tics'.)

Tourette syndrome — Tourette syndrome is reviewed here briefly and discussed in detail separately. (See "Tourette syndrome: Pathogenesis, clinical features, and diagnosis".)

Tourette syndrome is a common movement and neurobehavioral disorder in children. The hallmark of Tourette syndrome is the occurrence of multiple motor and vocal (phonic) tics. Tics in Tourette syndrome may be simple, involving a single muscle or muscle group, or complex, involving sequential, coordinated movements. Simple tics include blinking, facial grimacing, shoulder shrugging, and head jerking. Complex tics include bizarre gait, kicking, jumping, body gyrations, and seductive or obscene gestures. Involuntary vocalizations may include simple noises to more complex utterances such as coprolalia (shouting of obscenities or profanities), echolalia (repeating what others say), and palilalia (repeating the patient's own words or phrases).

There is growing evidence that transient tic and persistent motor and phonic tics represent a continuum rather than separate disorders [9].

DYSTONIA — The definition of dystonia, as updated in 2013 by an international consensus committee of movement disorder experts, is as follows [10]:

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both

Dystonic movements are typically patterned, twisting, and may be tremulous

Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation

The consensus committee also updated the classification system for dystonia (table 2), basing it upon clinical characteristics and etiology [10]. The clinical characteristics include age at onset, body distribution, temporal pattern, coexistence of other movement disorders, and other neurologic manifestations. The etiologic characteristics are the presence or absence of nervous system pathology and the pattern of inheritance.

Historically, dystonia was classified as primary, secondary, or psychogenic depending upon the cause. By definition, primary dystonia (formerly known as dystonia musculorum deformans or idiopathic torsion dystonia) was associated with no other neurologic impairment, such as intellectual, pyramidal, cerebellar, or sensory deficits. However, tremor that appears identical to essential tremor occurs in approximately 20 percent of patients with this condition. In some families, dystonia and essential tremor coexist. (See 'Essential tremor' below.)

Cerebral palsy is probably the most common cause of acquired dystonia (table 3) seen in children [11]. Other causes of childhood dystonia (table 4) include a variety of heredodegenerative disorders such as Wilson disease and neurodegeneration with brain iron accumulation [12]. (See 'Neurodegeneration with brain iron accumulation' below.)

Clinical features — The onset of involuntary movements occurs before age 20 in approximately 30 percent of patients with dystonia. The distribution of the affected muscle groups appears to depend upon age. The disorder typically begins distally in children, whereas a cranial-cervical distribution is more common in adults. Childhood dystonia usually progresses to a generalized disorder, whereas adult dystonia usually remains focal or segmental [13].

The range of severity of dystonia is variable and may depend upon the situation. As an example, some patients have task-specific dystonias that occur only when they participate in certain activities, such as writing, typing, or playing the piano ("musician's hands") [14]. As the dystonia worsens, it typically extends to adjacent muscles and eventually occurs even at rest. In rare cases, the spasms become severe and may cause cervical disc, nerve, or root problems [15]. Muscle breakdown with myoglobinuria ("dystonic storm") also can occur [16].

No specific morphologic changes have been noted in neuropathologic examinations of patients with isolated dystonia [17]. Rather, functional imaging studies provide evidence that dystonia is a network disease involving connections between the basal ganglia, cerebellum, and brainstem [18,19].

Hemidystonia — Hemidystonia (also known as unilateral dystonia) involves one-half of the body and occurs frequently in children and young adults. In a retrospective series of 33 patients with hemidystonia, approximately 60 percent of patients had a structural lesion in the contralateral basal ganglia, often the putamen, that resulted from an insult to the brain [20]. The most common etiologies were infarction or hemorrhage (30 percent), perinatal injury (27 percent), and trauma (24 percent). Hemidystonia often presented several years after the precipitating factor; this delay occurred more often in children.

Genetics — Early-onset generalized isolated dystonia (previously called primary dystonia) may be sporadic or inherited. Cases with onset in childhood usually are inherited in an autosomal dominant pattern (table 4). Many hereditary cases are caused by a defect in torsinA, a protein with uncertain function that is expressed in the brain. A rare cause of hereditary dystonia is dopa-responsive dystonia. The number of gene variants associated with dystonia has been expanding at an exponential pace, and genetic classification and nomenclature are continuously evolving [21]. (See "Etiology, clinical features, and diagnostic evaluation of dystonia".)

DYT1 dystonia — Many patients with inherited dystonia have a pathogenic variant in the TOR1A (DYT1) gene that encodes the protein torsinA, an adenosine triphosphate (ATP)-binding protein in the 9q34 locus. DYT1 dystonia is discussed in greater detail elsewhere. (See "Etiology, clinical features, and diagnostic evaluation of dystonia", section on 'DYT-TOR1A dystonia'.)

Dopa-responsive dystonia — Dopa-responsive dystonia (DRD) is an unusual form of inherited progressive dystonia that begins during the first decade after birth. The dystonia usually starts in the legs and becomes generalized. Some patients may also have hyperreflexia, rigidity, tremor, and other parkinsonian features, and less commonly, cerebellar signs. The most frequent form of DRD is autosomal dominant DYT5 dystonia. (See "Etiology, clinical features, and diagnostic evaluation of dystonia", section on 'Dopa-responsive dystonia'.)

The hallmark of DRD is a clinically significant, sustained response to levodopa. (See "Treatment of dystonia in children and adults".)

Paroxysmal dyskinesia with dystonia — Several rare genetic forms of dystonia are characterized by paroxysmal dyskinesia and discussed here briefly (table 5). They are reviewed in greater detail separately. (See "Etiology, clinical features, and diagnostic evaluation of dystonia", section on 'Paroxysmal dyskinesia with dystonia'.)

Paroxysmal nonkinesigenic dyskinesia (PNKD) is characterized by spontaneous episodes of dystonia and/or choreoathetosis not triggered by exercise or activity. Alcohol, coffee, tea, fatigue, stress, or excitement may be precipitating factors. Episodes last minutes to hours and recur two or three times a month.

Paroxysmal kinesigenic choreoathetosis, also known as paroxysmal kinesigenic dyskinesia, is characterized by episodic choreoathetosis and dystonia brought on by voluntary movement. The disorder is genetically heterogeneous.

Paroxysmal exertion-induced dyskinesia is an autosomal dominant disorder with reduced penetrance that begins in childhood with dyskinesia and dystonia induced by prolonged exertion (eg, ≥15 minutes), fasting and stress. Associated features include absence and/or partial complex seizures.

Neurodegeneration with brain iron accumulation — Neurodegeneration with brain iron accumulation (NBIA) represents a group of disorders that includes pantothenate kinase-associated neurodegeneration, infantile neuroaxonal dystrophy, fatty acid hydroxylase-associated neurodegeneration, aceruloplasminemia, neuroferritinopathy, and other conditions. Although dystonia is often a prominent feature, other hyperkinetic and bradykinetic movement disorders and neurologic deficits may also occur. (See "Bradykinetic movement disorders in children", section on 'Neurodegeneration with brain iron accumulation'.)

Other causes — Additional causes of paroxysmal or fluctuating dystonia in children (table 3) include multiple sclerosis, thyrotoxicosis, metabolic disorders (eg, Hartnup disease), paroxysmal dystonia in sleep (hypnogenic dystonia), "infectious torticollis," and the GLUT1 deficiency syndrome [22].

Pseudodystonias — Some conditions (table 6) may result in abnormal movements, postures, or spasms that mimic dystonia (ie, pseudodystonia), including gastroesophageal reflux (Sandifer syndrome). In addition, dystonia may be erroneously attributed to a postural deformity that results from common musculoskeletal or orthopedic problems such as congenital torticollis or scoliosis. (See "Acquired torticollis in children".)

Treatment of dystonia — Appropriate treatment of dystonia depends upon an accurate diagnosis [23]. Patients with atypical features, such as impaired intellect, seizures, neuro-ophthalmologic abnormalities, ataxia, corticospinal tract signs, sensory deficits, severe speech disturbance, and unilateral distribution of the dystonia, are more likely to have an underlying disorder that can be treated, such as Wilson disease.

The treatment of dystonia is reviewed here briefly and discussed in detail separately. (See "Treatment of dystonia in children and adults".)

For pediatric patients with focal or generalized dystonia of unknown etiology, we recommend a trial of levodopa to confirm or exclude the diagnosis of dopa-responsive dystonia. (See "Treatment of dystonia in children and adults".)

Patients with multifocal or generalized isolated dystonia who do not respond to levodopa can be treated with other oral medications, botulinum toxin injections, or deep brain stimulation in refractory cases.

For children with debilitating generalized isolated dystonia that does not respond to a trial of levodopa, treatment with trihexyphenidyl is suggested. (See "Treatment of dystonia in children and adults", section on 'Anticholinergic therapy'.)

For debilitating multifocal or generalized isolated dystonia that does not respond to pharmacologic treatment, we suggest botulinum toxin injection of selected muscles. (See "Treatment of dystonia in children and adults", section on 'Refractory disease'.)

For children with debilitating multifocal or generalized isolated dystonia who do not respond to pharmacologic therapy or botulinum toxin injections, we suggest bilateral deep brain stimulation of the internal globus pallidus. (See "Treatment of dystonia in children and adults", section on 'Deep brain stimulation'.)

Status dystonicus — Status dystonicus (also called dystonic storm) is a rare, life-threatening condition characterized by increasingly frequent or continuous severe generalized dystonic contractions that may be refractory to standard medical treatment [15]. Status dystonicus can occur in children and adults as a result of progressive worsening in various types of dystonia, often in the setting of an identifiable trigger such as intercurrent illness or infection [15,16,24,25]. Although data are limited by the small number of published cases (approximately 100) [24], commonly reported complications include bulbar weakness, progressive impairment of respiratory function leading to respiratory failure, exhaustion, pain, and metabolic derangements including rhabdomyolysis and acute kidney injury [15,24].

Status dystonicus constitutes a neurologic emergency and requires urgent intervention. Management includes the following measures [24,26]:

Supportive care:

Intensive care unit admission

Intravenous hydration

Antipyretics and cooling blankets

Pain control

Monitoring for the development of rhabdomyolysis (eg, creatine kinase, urinalysis, and renal function)

Sedation with intravenous midazolam or intravenous propofol

Airway support including mechanical ventilation when necessary

Specific measures to treat dystonia [24-26]:

Initial use of oral agents, often in combination:

-Trihexyphenidyl

-Benzodiazepines (unless midazolam already being used)

-Tetrabenazine, deutetrabenazine

-Baclofen

-Gabapentin

For chronic and/or refractory cases, consideration of invasive treatments:

-Botulinum toxin injection for focal and/or segmental dystonia

-Intrathecal baclofen [27]

-Deep brain stimulation of the globus pallidus interna [28-32]

-Pallidotomy [33]

Acute dystonic reaction — An acute dystonic reaction, usually transient, is a recognized complication of the dopamine receptor-blocking drugs, such as the antipsychotics (eg, haloperidol, chlorpromazine) and antiemetics (eg, phenothiazines, metoclopramide) [34-36]. Dystonic reactions also can occur with levodopa, anticonvulsants, antidepressants (eg, selective serotonin reuptake inhibitors), and ergots.

Treatment of acute dystonia with antihistamine or anticholinergic medications is usually rapidly effective [36,37]. Parenteral diphenhydramine at 1 to 2 mg/kg per dose (maximum dose 50 mg) is used most frequently and typically results in resolution of an acute dystonic reaction within minutes. Intravenous administration is preferred over oral administration for initiation of treatment because patients may have difficulty swallowing. Parenteral administration is required for life-threatening dystonia with associated laryngospasm or stridor [37]. Diphenhydramine may also be given intramuscularly but the onset of action is delayed compared with intravenous administration. Intravenous diazepam is also effective in the treatment of acute dystonic reaction [38].

Once the acute dystonic reaction is treated, diphenhydramine is given orally at 1.25 mg/kg per dose every six hours for one to two days to prevent recurrence. In some cases, however, a single dose of oral diphenhydramine or trihexyphenidyl suffices. The offending drug should be discontinued.

Patients treated with dopamine receptor-blocking agents occasionally develop persistent tardive dystonia after the offending drug is stopped. If no spontaneous improvement occurs, they may respond to trials of muscle relaxants, anticholinergic drugs, or dopamine depleting agents such as tetrabenazine, deutetrabenazine, and valbenazine [39,40].

STEREOTYPIES — As defined by the Taskforce on Childhood Movement Disorders, "stereotypies are repetitive, simple movements that can be voluntarily suppressed" [2]. Examples include repetitive chewing, rocking, twirling, or touching. These movements typically occur in children with infantile autism, intellectual disability, or other developmental disorders such as Rett syndrome (table 7). (See "Autism spectrum disorder: Clinical features", section on 'Stereotyped behaviors' and "Rett syndrome: Genetics, clinical features, and diagnosis", section on 'Classification and major features'.)

In addition, stereotypies can occur in otherwise normal children. The clinical features and course of complex stereotypies of the upper extremity were described in a case series of 40 children and adolescents from a tertiary specialty clinic [41]. The following features were noted:

The mean age was 7.9 years

90 percent had onset before 3 years of age

90 percent had occurrence at least daily, but were not reported to occur during sleep

The typical duration of episodes ranged from <10 seconds (30 percent) to >60 seconds (30 percent)

The movement involved flapping in 48 percent, shaking in 28 percent, clenching-stiffening-posturing in 38 percent, and ritual in 13 percent of patients

The movement stopped when cued in all but one patient

Triggers included excitement, boredom, being focused or engrossed, and anxiety/stress

25 percent had comorbid attention deficit hyperactivity disorder

20 percent had comorbid learning disability

25 percent had a positive family history of stereotypies

The clinical course involved resolution in 5 percent, improvement in 33 percent, no change in 50 percent, and worsening in 13 percent of patients

In addition to autistic disorders, there are many other causes of stereotypies, such as tardive dyskinesia, probably the most common cause of stereotypy in adults [42,43]. One of the most common stereotypies occurring in children and adults is leg stereotypy syndrome, which may occur in approximately 7 percent of otherwise normal individuals and in up to 17 percent of patients with other movement disorders [44]. This condition is typically manifested by repetitive, continuous movement present almost exclusively in the legs while the individual is seated. It may also occur while standing, during which time it involves not only the legs but may be also manifested by swaying of the trunk. While some individuals describe these movements as soothing, there is no evidence that they are associated with or driven by anxiety or an irresistible urge to move, as is typically seen with akathisia or restless legs syndrome. The affected individual may not be even aware of the repetitive movement, but it may be quite annoying to those in close proximity. This leg stereotypy syndrome is clearly separate from restless legs syndrome, which is often very troublesome to the patient and does not have diurnal variation.

Intellectual impairment is another condition frequently associated with stereotypies. In individuals with intellectual impairment, such as Lesch-Nyhan syndrome, stereotypies may be associated with self-injurious behavior. Supersensitivity of D1 receptors, possibly in response to abnormal arborization of dopamine neurons in the striatum, has been postulated as a possible mechanism of self-injurious behavior in Lesch-Nyhan syndrome. Dopamine receptor blockers or dopamine depleters, such as tetrabenazine, have been noted to ameliorate stereotypies and self-injurious behaviors [45].

Rett syndrome — Rett syndrome is an example of a disorder characterized by marked stereotypies [46]. This condition is one of the most common causes of intellectual disability in females. Most cases are caused by variants in the gene for methyl-CpG-binding protein 2 (MeCP2).

Rett syndrome typically presents at 6 to 18 months of age in girls with previously normal growth and development. Affected patients regress in their verbal and motor skills, lose purposeful use of their hands, and have jerky ataxia and typical stereotyped movements of the hands resembling hand washing and kneading. Other symptoms include breath-holding spells, hyperventilation, loss of facial expression, poor eye contact, bruxism, dystonia, occasional seizures, apparent insensitivity to pain, and a variety of self-injurious and aggressive behaviors.

The clinical features, diagnosis and management of Rett syndrome are discussed in detail separately. (See "Rett syndrome: Genetics, clinical features, and diagnosis".)

CHOREA, ATHETOSIS, AND BALLISMUS — Children can be affected by many acquired and hereditary types of chorea and related movement disorders (table 8). The following definitions from the Taskforce on Childhood Movement Disorders apply [2]:

Chorea is an ongoing random-appearing sequence of one or more discrete involuntary movements or movement fragments.

Athetosis is defined as "a slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture" and thus represents a form of slow chorea.

Ballism (ballismus) is defined "as chorea that affects proximal joints such as shoulder or hip," leading to "large amplitude movements of the limbs, sometimes with a flinging or flailing quality"; it is usually unilateral (hemiballismus) and often results from a lesion in the contralateral subthalamic nucleus and adjacent structures.

Physiologic chorea — Almost all normal infants make movements that resemble chorea, but this physiologic chorea resolves by eight months of age. Children with attention deficit disorder and hyperactivity may have distal chorea (chorea minima).

Cerebral palsy — Cerebral palsy is a common cause of chorea in children. Chorea or athetosis (choreoathetosis) is the predominant motor disturbance in approximately one-third of cases but occurs to a variable degree in almost all patients [47]. In one series, choreoathetosis was apparent in one-half of patients during the first year and developed in the remainder during the next four to five years, after which it remained static. Most patients with athetoid cerebral palsy were born prematurely (60 percent) or had a perinatal history of jaundice and/or asphyxia (82 percent). Dystonia also is common, occurring in up to 70 percent of cases.

Several patients have been reported with choreoathetosis and dystonia that is delayed in onset and progressive, in contrast to the nonprogressive neurologic impairment in cerebral palsy. The mechanism is attributed to sprouting and denervation supersensitivity of receptors in the basal ganglia.

Sydenham chorea — Sydenham chorea is one of the major clinical manifestations of acute rheumatic fever and the most common form of acquired chorea in childhood. The initial presentation typically occurs in patients between 5 and 13 years of age. This disorder is discussed in detail elsewhere and will be reviewed briefly here. (See "Sydenham chorea".)

Chorea usually develops one to eight months after the inciting infection, in contrast to carditis and arthritis which most often present within 21 days [48]. The onset is usually insidious but may be abrupt.

The chorea typically begins with distal movements of the hands, but generalized jerking of the face and feet emerges as the chorea becomes more active. The movements are rapid, irregular, and nonstereotyped jerks that are continuous while the patient is awake but improve with sleep. The chorea is usually generalized but may be more prominent on one side; approximately 20 percent of patients have hemichorea (ie, unilateral chorea). Emotional changes, such as easy crying or inappropriate laughing, may precede the development of chorea. In some cases, regression in school performance is the initial concern.

The diagnosis of Sydenham chorea is made clinically as no specific laboratory test exists. Although the neuropathology of Sydenham chorea is not well studied, vasculitis involving the basal ganglia, cortex, and cerebellum has been identified in the brains of some affected patients [49].

Sydenham chorea typically improves gradually, with a mean duration of 12 to 15 weeks. Treatment includes antibiotic therapy with penicillin for at least 10 days followed by antibiotic prophylaxis. Specific treatment for the chorea may be warranted when significant impairment of motor function and the possibility of self-injury are present. Treatments reported to be effective include valproic acid, phenobarbital, haloperidol, pimozide, diazepam, chlorpromazine, and carbamazepine. Corticosteroids may shorten the course of Sydenham chorea. (See "Sydenham chorea", section on 'Treatment'.)

Post-pump chorea — A dyskinetic movement disorder may complicate cardiac surgery in a small number of children with congenital heart disease. The estimated frequency of this complication is 10 percent (0.6 to 18 percent) per procedure, but the incidence appears to be decreasing over time, presumably as a result of changing operative techniques [50-52].

The complication has been described in children ages six weeks to 52 months [50,53]. Risk factors include more time on pump, deeper hypothermia (<36 degrees), and circulatory arrest [50].

Symptoms begin three to twelve days postoperatively [50,54]. The dyskinesia is usually in the form of choreoathetosis and mainly involves the mouth, tongue and face [54]. More severely affected children have involvement of extremities and trunk. Neuroimaging studies and electroencephalogram (EEG) are normal [50,54].

The underlying etiology is not understood. In two patients, neuropathologic findings included neuronal loss, reactive astrocytosis, and degeneration of myelinated fibers in the globus pallidus, primarily the outer segment [55]. Locations typically affected by hypoxic ischemic insult were spared. In some milder and transient cases, certain medications (eg, fentanyl, midazolam, captopril) have been implicated [56-58].

The movements remit in some children over several weeks; others, particularly those who are more severely affected, have persistent chorea [50]. Associated neurological deficits are common and range from mild learning deficits to hypotonia and obtundation [50]. Severely affected children may die. In one series, 1 of 8 died [50]; in another, 3 of 36 died [53]. Abnormal motor, cognitive, and behavioral development is the rule among children followed over several years [50,53]. Older children and those most severely affected at onset appear to be a higher risk for serious and more persistent deficits [53].

Other acquired causes — Kernicterus is a neurologic condition that may occur when serum total bilirubin concentrations in the perinatal period are excessive [59]. In the chronic phase, the disorder is characterized by choreoathetosis, tremor, dystonia, rigidity, dysarthria, sensorineural hearing loss, and limitation of upward gaze. Affected infants may have increased signal intensity in the basal ganglia in T2-weighted magnetic resonance images because of deposition of bilirubin [60]. (See "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia", section on 'Chronic bilirubin encephalopathy (kernicterus)'.)

Some infants with severe bronchopulmonary dysplasia develop a movement disorder similar to chorea. In one report describing 10 infants, the condition developed at approximately the third postnatal month and involved the limbs, neck, trunk, and oral-buccal-lingual structures [61]. The abnormalities completely or partially resolved in the seven surviving infants. A neuropathologic study of one infant showed neuronal loss with astrocytosis in the caudate, putamen, globus pallidus, and thalamus. (See "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features".)

Hereditary chorea — Huntington disease is one of the most frequent causes of hereditary chorea in children. (See "Bradykinetic movement disorders in children", section on 'Juvenile Huntington disease'.)

Childhood-onset hereditary chorea — There is a growing list of genetically defined childhood-onset choreas. NK2 homeobox 1 (NKX2-1)-related chorea is an autosomal dominant disorder that presents during infancy or childhood. Previously referred to as "benign hereditary chorea" (BHC), this term is no longer appropriate as this form of chorea can be quite troublesome and even disabling. Nearly all reported patients are heterozygous for pathogenic variants in the NKX2-1 gene (also known as the TITF1 gene) on chromosome 14q13 [62,63]. Variants in the ADCY5 gene have been identified in rare individuals with an NKX2-1 phenotype who were negative for NKX2-1 variants [64]; not all cases were "benign," as some patients exhibited dystonia, hypotonia, and other motor disorders that can significantly impair quality of life (see 'ADCY5-related dyskinesia' below). Patients thought to have BHC require thorough investigation and follow-up because some are diagnosed subsequently with other conditions [65].

As observed in one of the largest reports, which analyzed 28 patients and reviewed the literature, the typical features of NKX2-1 chorea include onset in infancy with marked hypotonia followed by generalized chorea [66]. Most children are delayed in motor and walking milestones. Associated neurologic features may include myoclonus, upper limb dystonia, and motor and vocal tics. The chorea is nonprogressive and often lessens over time or resolves by early adulthood. However, patients who have myoclonus and chorea early in the course of the disease sometimes develop worsening myoclonus, which becomes the major source of disability as the chorea improves [67]. Cognitive and behavioral disturbances, most often learning difficulties, and less often attention deficit hyperactivity disorder or intellectual disability, are common [66]. Other comorbid features reported in some affected individuals include growth hormone deficiency, pes cavus, kyphosis, duplex kidney anomaly, and obsessive-compulsive disorder [68].

Frequent systemic manifestations of NKX2-1 chorea are thyroid disease, with hypothyroidism or thyroid gland abnormalities on ultrasound, and pulmonary disease, manifesting as neonatal respiratory distress or recurrent pulmonary infections [66]. Thus, the phenotype of NKX2-1 chorea includes the syndrome of choreoathetosis, hypothyroidism, and neonatal respiratory distress (also known as brain-thyroid-lung syndrome), which is also caused by variants in the NKX2-1 gene [69,70].

The neurologic manifestations of NKX2-1 chorea may be related to impaired cerebral glucose metabolism in the caudate nucleus, as demonstrated by positron emission tomography (PET) with 18F-2-fluorodeoxyglucose [71]. However, this finding has not been observed in all cases [72].

Although there is no established therapy for NKX2-1 chorea, one study reported that treatment with tetrabenazine (using a dose of 0.5 mg/kg per day for children and 37.5 mg per day for adults) was associated with rapid and lasting improvement in chorea for five of eight patients [66]. In another report, treatment with levodopa (dose range 7 to 20 mg/kg per day) was associated with sustained improvement of gait and chorea for two patients [73].

ADCY5-related dyskinesia — ADCY5-related dyskinesia has a broad phenotypic spectrum with various manifestations including fluctuating dyskinesia, dystonia, chorea, myoclonus, axial hypotonia, painful spasms associated with falls, and sleep disturbances [74-77]. Onset is in childhood, often in infancy. The frequency and severity of abnormal movements can be highly variable. Cognitive impairment is mild or absent, and brain magnetic resonance imaging (MRI) is unrevealing. The disorder is often disabling [74,75].

There is one report of several patients who experienced dramatic, sustained improvement in ADCY5-related dyskinesia with caffeine administered by drinking coffee [78]. Very limited data suggest that some patients have mild improvement with clonazepam or clobazam [77]. In one report, three patients (two children and one adult) with ADCY5-related movement disorders who failed medication treatment trials had variable and partial improvement in hyperkinetic manifestations with deep brain stimulation [79].

Lesch-Nyhan syndrome — Lesch-Nyhan syndrome is a complex motor-behavioral condition that is inherited as an X-linked recessive trait. The disorder results from pathogenic variants in the gene coding for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), leading to deficient enzyme activity. This defect results in an often marked increase in production of uric acid and hyperuricemia.

More than 2000 variants of the HPRT gene have been reported, and the wide spectrum of neurologic symptoms (with some patients being asymptomatic) and severity of the disease have been associated with the degree of enzyme deficiency [80-82].

Affected boys have delayed developmental milestones, intellectual disability, and extrapyramidal and pyramidal motor symptoms; they also develop self-mutilating behavior.

While earlier literature emphasized choreoathetosis and spasticity as typical features of the motor disorder associated with Lesch-Nyhan syndrome, dystonia may be more common. This observation comes from a prospective observational study of a series of 44 patients with complete HPRT deficiency [83]. The study found a characteristic evolution of motor involvement, which began at three to six months of age with hypotonia, with or without delayed acquisition of motor skills. Involuntary movements, predominantly dystonia, developed between six and 24 months. Thereafter, the clinical course is relatively static and characterized by severe action dystonia with baseline hypotonia. Extrapyramidal symptoms such as choreoathetosis or ballismus may occur, but are less prominent than dystonia.

ESSENTIAL TREMOR — As defined by the Taskforce on Childhood Movement Disorders, "tremor is a rhythmic back-and-forth or oscillating involuntary movement about a joint axis" [2]. Back-and-forth is further stipulated to mean "a relatively symmetric velocity in both directions about a midpoint of the movement, and the velocity or oscillation may appear sinusoidal." Although of relatively constant frequency, the amplitude may be variable. Tremor is caused by either alternating or synchronous contractions of antagonistic muscles [84].

By definition, tremor should be the only neurologic manifestation of essential tremor (ET). ET usually is a benign condition. However, it may progress to a disabling movement disorder that interferes with feeding, speaking, writing, and other activities of daily living.

The cause of ET is uncertain. One form is inherited in an autosomal dominant manner. At least two loci have been identified: one on chromosome 3q13 and one on chromosome 2p22 [85,86]. Although no neurotransmitter abnormalities have been demonstrated in ET, physiologic studies have demonstrated dysfunction of the cerebellar system.

ET is the most common cause of an oscillatory involuntary movement disorder in childhood (table 9). ET may start at any age, including infancy. The clinical features of childhood-onset ET were described in a case series of 39 patients who were evaluated in a movement disorders clinic [87]:

The mean age of onset was 8.8 years (range 1 to 16 years), with a mean age of evaluation of 20.3 years

The majority of patients were boys (74 percent)

46 percent of patients had some neurologic comorbidity, including dystonia, which was present in 28 percent

80 percent of patients reported at least one relative with tremor

Exacerbating factors included stress, anxiety, physical activity, and caffeine

Two forms of hereditary ET that may begin in infancy are hereditary chin tremor and shuddering attacks.

Hereditary chin tremor — Hereditary chin tremor (also called hereditary geniospasm) consists of rhythmic contractions of the chin that occur at a frequency of 3/sec. This condition is inherited in an autosomal dominant pattern, with one locus on chromosome 9q13, and often is associated with deafness [88].

Shuddering attacks — Shuddering attacks begin during infancy or early childhood. Affected children have bursts of rapid trembling of the entire body, occasionally associated with head turning, involuntary sniffing, and throat clearing [89,90]. They usually fall to the floor if they have been standing. Attacks may occur during sleep. More than 100 attacks per day may occur; on the other hand, patients may be free of symptoms for as long as two weeks. The episodes tend to decrease in frequency or disappear over time [90]. (See "Nonepileptic paroxysmal disorders in infancy".)

Other variants — Another form of ET seen in children is an action-postural tremor that consists of slower and faster components. The slower tremor (approximately 6.5 Hz) typically involves the head and neck, whereas the more rapid tremor (8 to 12 Hz) usually involves the hands.

Other oscillatory involuntary movements occasionally are seen in infants and children. They include "head nodding," which is often associated with congenital nystagmus, including spasmus nutans, and the "bobble-head doll syndrome," which occurs with diencephalic lesions, including third-ventricle cysts or tumors, craniopharyngioma, hydrocephalus, and hypothalamic lesions.

Treatment — Therapy for ET is discussed separately. (See "Essential tremor: Treatment and prognosis" and "Surgical treatment of essential tremor".)

MYOCLONUS — As defined by the Taskforce on Childhood Movement Disorders, "Myoclonus is a sequence of repeated, often nonrhythmic, brief shock-like jerks due to sudden involuntary contraction or relaxation of one or more muscles" [2]. Myoclonus is not coordinated or suppressible and is often activated by volitional movement. Myoclonus can be physiologic or pathologic and can occur as an isolated disorder or associated with seizures or other conditions (table 10). One of the main considerations in the differential diagnosis of myoclonus is myoclonus-dystonia (DYT11) caused by variants of the SGCE gene, but there are a growing number of novel gene variants associated with the myoclonus-dystonia syndrome [91]. (See "Classification and evaluation of myoclonus", section on 'Myoclonus-dystonia'.)

Benign neonatal sleep myoclonus — Benign neonatal sleep myoclonus occurs in the first month after birth. It usually occurs in the early stages of sleep and is stimulus-sensitive. It should be differentiated from neonatal seizures and infantile spasms. (See "Clinical features, evaluation, and diagnosis of neonatal seizures" and "Infantile spasms: Clinical features and diagnosis".)

Essential myoclonus — Essential myoclonus has no associated neurologic deficit, although it may be associated with ET. The disorder is inherited in an autosomal dominant pattern or may occur sporadically. It typically begins before the patient reaches age 20 years [92].

Cortical myoclonus — Cortical myoclonus consists of continuous, repetitive, focal jerking that sometimes is associated with characteristic EEG changes. The myoclonus may be triggered by external stimuli or evoked by muscle stretch reflex.

The underlying mechanism of cortical myoclonus is thought to be a hyperexcitable sensorimotor cortex. In cortical reflex myoclonus, quick, passive movement of a distal phalanx elicits the myoclonic movement. This movement is preceded by a specific EEG event and enhanced amplitude of the somatosensory evoked potential. In cortical action myoclonus, myoclonus is elicited by active movement which may have an EEG correlate.

Epilepsia partialis continua — Epilepsia partialis continua (partial status epilepticus) may be associated with myoclonus. Common causes include cortical stroke and Rasmussen encephalitis, which results from a focal cortical lesion or inflammation possibly induced by viral infection.

Reticular reflex myoclonus is thought to result from a hyperexcitable brainstem reticular formation, particularly the nucleus reticularis gigantocellularis.

Unverricht-Lundborg disease — Unverricht-Lundborg disease (ULD or EPM1; MIM #254800), also known as "Mediterranean" or "Baltic" myoclonus, is one form of progressive myoclonus epilepsy (PME), a condition that consists of myoclonus, seizures, and a progressive clinical course [93].

In the EPM1 form, stimulus-sensitive myoclonus usually begins between ages 6 and 15 years [93]. Affected patients develop dysarthria, ataxia, intention tremor, and mild intellectual decline; many become bedridden within five years after onset of symptoms. In approximately 10 percent of cases, the disease follows a milder course, and some patients may remain mildly symptomatic and independent for decades [94]. Epileptiform EEG findings may precede symptoms by up to three years. The diagnosis of EPM1 can be confirmed by genetic studies [93]. An earlier age of onset and longer disease duration are associated with more severe disease manifestations, including disabling myoclonus [94,95].

Valproate is often effective for EPM1, reducing myoclonus and seizure-frequency [93,96]. By contrast, phenytoin has been associated with exacerbations. A French case series suggests that, with improved treatment, the course is not necessarily dire and stabilizes after five to ten years [96]. Among 20 patients with ULD who were followed over 25 years, only three were severely handicapped, and six led fully independent lives. In a Finnish population-based study that included 135 patients with EPM1, the median age at death was 54 years [94]. Comprehensive rehabilitative management is also helpful and can extend life [93].

EPM1 is inherited in an autosomal recessive pattern. The responsible cystatin B (CSTB) gene is localized to 21q22 and encodes cystatin B, a cysteine protease inhibitor [97-100]. Several different variants have been identified in the CSTB gene in patients with EPM1, but the most common is an unstable expansion of a dodecamer minisatellite repeat unit in the promoter region [100].

A novel form of ULD that maps to chromosome 12 has been described in an Arab family [101]. The locus on chromosome 12 (designated EPM1B) does not have genes known to be related to cystatin B or other forms of PME. The clinical phenotype of EPM1B is similar to EPM1, but appears to be distinguished by an earlier age of onset.

Lafora body disease — Lafora body disease (MIM #254780) is another form of progressive myoclonus epilepsy (PME) that is characterized by progressive and intractable myoclonic and photoconvulsive seizures, dementia, apraxia, and cortical blindness. Age of onset is usually between ages 11 and 18 years. Total disability typically occurs within 10 years, though some patients have a milder, more slowly progressive form of the disease [102]. Biopsy of the skin (especially in the axillary region) [103], liver, muscle, or brain reveals pathognomonic polyglucosan inclusions (Lafora bodies) that appear positive on periodic acid-Schiff staining.

The mode of inheritance is autosomal recessive. Lafora body disease is caused by variants in the EPM2A gene and the NHLRC1 gene (previously known as the EPM2B gene) [104-107], and an early-onset form of Lafora body disease may be caused by a variant in the PRDM8 gene [108,109]. The EPM2A gene codes for the protein laforin [104,105], and the NHLRC1 gene codes for the protein malin [106]. Laforin has a starch binding domain [105], while malin binds laforin [108], suggesting that both proteins interact in a cellular pathway that protects against polyglucosan accumulation and epilepsy [106,108]. The PRDM8 gene codes for a protein that interacts with and translocates laforin and malin to the nucleus; the mutated form may result in a deficiency of laforin and malin in the cytoplasm.

Hyperekplexia — Hyperekplexia, or "human startle disease," is a rare neurologic disorder characterized by generalized stiffness beginning in infancy [110,111]. Affected patients develop exaggerated myoclonic startle reactions and a short period of generalized stiffness following the startle that may result in falling.

Both hereditary and sporadic hyperekplexia are genetically heterogeneous. The most common hereditary form (MIM 149400) is caused by variants in the glycine receptor alpha 1 (GLRA1) gene on chromosome 5, which lead to decreased inhibitory glycine signaling and hyperexcitability in motor nerves [112,113]. Both autosomal dominant and recessive forms have been described, and the phenotypic spectrum includes milder as well as later-onset cases [113].

Other hyperekplexia genes include glycine receptor beta (GLRB) [114], ATPase family AAA domain containing 1 (ATAD1) [115], and solute carrier family 6 member 5 (SLC6A5), which encodes a presynaptic glycine transporter [116]. The SLC6A5 variants are predominately associated with recessive hyperekplexia; symptoms include life-threatening neonatal apnea and breath-holding spells [116].

Hyperekplexia with an excessive startle response may also be a feature of a number of severe neurometabolic and neurodevelopmental disorders such as Tay-Sachs disease and some early infantile epileptic encephalopathies.

The clinical features and management of hyperekplexia in infants are discussed separately. (See "Nonepileptic paroxysmal disorders in infancy", section on 'Hyperekplexia'.)

Other — A number of other types of symptomatic (secondary) myoclonus include the following (table 10):

Ramsay Hunt syndrome is a group of heterogeneous disorders characterized by a combination of progressive myoclonus and cerebellar ataxia. (See "Symptomatic (secondary) myoclonus", section on 'Progressive myoclonic epilepsy and progressive myoclonic ataxia'.)

Subacute sclerosing panencephalitis after viral encephalitis (eg, measles) may present with progressive dementia and slow myoclonus that occurs at a rate of approximately one per second and is associated with periodic complexes on EEG.

Opsoclonus-myoclonus syndrome or "dancing eyes-dancing feet" syndrome may occur in young children after a febrile viral illness or as a paraneoplastic syndrome associated with neuroblastoma. This disorder often improves with steroid therapy. The pathogenesis is thought to be immune mediated, but the precise mechanism remains unclear. One study found that B and T cell markers correlated with neurologic severity [117], and another found evidence of autoantibody reactivity to a neuronal surface antigen [118], but no single antibody has been consistently identified in children with this disorder [119]. (See "Epidemiology, pathogenesis, and pathology of neuroblastoma".)

Small myoclonic jerks (minipolymyoclonus) may occur in children with chronic spinal muscular atrophy.

Treatment — The treatment of myoclonus is discussed in detail elsewhere. (See "Treatment of myoclonus".)

MOVEMENT DISORDERS WITH ANTI-NMDAR ENCEPHALITIS — Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a neuropsychiatric disorder characterized by behavioral and psychiatric manifestations, followed by a subacute onset of a variety of movement disorders, including chorea, stereotypies particularly affecting the orofacial area, dystonia, slow tremor (myorhythmia), blepharospasm, opisthotonus, athetosis, and ataxia [119-122]. Atypical presentations have also been described. In one report, three children with positive anti-NMDAR antibodies presented with different movement disorders (hemichorea, chorea and myoclonus) in the absence of encephalopathy [121].

Anti-NMDAR encephalitis is often associated with ovarian teratoma and other benign tumors. Brain MRI is abnormal in approximately one-half of the patients, but cerebrospinal fluid pleocytosis is found in most cases. (See "Paraneoplastic and autoimmune encephalitis", section on 'Anti-NMDA receptor encephalitis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Tourette syndrome" and "Society guideline links: Huntington disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Dystonia (The Basics)")

SUMMARY AND RECOMMENDATIONS

Tics – Tics are repeated, individually recognizable, intermittent movements or movement fragments that are almost always briefly suppressible and are usually associated with awareness of an urge to perform the movement (table 1). (See 'Tic disorders' above.)

Multiple motor and vocal (phonic) tics are the hallmark of Tourette syndrome, a common movement and neurobehavioral disorder in children. (See "Tourette syndrome: Pathogenesis, clinical features, and diagnosis".)

Dystonia – Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both; dystonic movements are typically patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation.

Dystonia is classified based upon clinical characteristics and etiology (table 2). Cerebral palsy is probably the most common cause of acquired dystonia seen in children (table 3). (See 'Dystonia' above.)

Stereotypies – Stereotypies are repetitive, simple movements that can be voluntarily suppressed. Examples include repetitive chewing, rocking, twirling, or touching movements. These typically occur in children with infantile autism, intellectual disability, or other developmental disorders such as Rett syndrome (table 7). Stereotypies can also occur in otherwise healthy children. (See 'Stereotypies' above and "Rett syndrome: Genetics, clinical features, and diagnosis".)

Chorea and related movements – Children can be affected by many acquired and hereditary types of chorea and related movement disorders (table 8). Common causes of acquired chorea in children include cerebral palsy, Sydenham chorea, and post-pump chorea. A variety of rare hereditary disorders cause chorea, including but not limited to juvenile Huntington disease. (See 'Chorea, athetosis, and ballismus' above.)

Tremor – Tremor is a rhythmic back-and-forth or oscillating involuntary movement about a joint axis and occurs at a relatively symmetric velocity in both directions about a midpoint of the movement (table 9). Essential tremor (ET) is the most common movement disorder causing involuntary tremor in children. Two forms of hereditary ET that can begin in infancy are hereditary chin tremor and shuddering attacks. (See 'Essential tremor' above.)

Myoclonus – Myoclonus is a sequence of repeated, often nonrhythmic, brief shock-like jerks due to sudden involuntary contraction or relaxation of one or more muscles. Myoclonus is not coordinated or suppressible and is often activated by volitional movement. Myoclonus can be physiologic or pathologic and can occur as an isolated disorder or associated with seizures or other conditions (table 10). (See 'Myoclonus' above.)

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