HYPERKYNETIC MOVEMENT DISORDERS

INTRODUCTION — Movement disorders are characterized by either excessive (hyperkinetic) or reduced (bradykinetic) activity. 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. Tics are the most common hyperkinetic disorder in children. Dystonia, stereotypies, choreoathetosis, tremors, and myoclonus also occur but are less common.

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 known 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.

TOURETTE SYNDROME — Tourette syndrome (TS) is a common movement and neurobehavioral disorder in children. The hallmark of TS is the occurrence of multiple motor and vocal (phonic) tics. Tics in TS 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). TS must be differentiated from transient tics, which occur in otherwise normal children and spontaneously remit in a few weeks or months. 

Dystonia consists of repetitive, patterned, twisting, and sustained movements that may be either slow or rapid. Dystonic states are classified as primary, secondary, or psychogenic depending upon the cause. By definition, primary dystonia (formerly known as dystonia musculorum deformans or idiopathic torsion dystonia) is 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. Cerebral palsy probably is the most common cause of secondary dystonia seen in children.

STEREOTYPIES — Stereotypies are repetitive, purposeless, and apparently voluntary movements such as chewing, rocking, twirling, or touching. These movements typically occur in children with infantile autism or mental retardation. In addition, stereotypies also 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. 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

Rett syndrome — Rett syndrome is an example of a disorder characterized by marked stereotypy. This condition is one of the most common causes of mental retardation in females. Most cases are caused by mutations in the gene for methyl-CpG-binding protein 2 (MeCP2).

Rett syndrome typically presents at six 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").

CHOREA, ATHETOSIS, AND BALLISMUS — Children can be affected by many acquired and hereditary types of chorea and related movement disorders. The following definitions apply: Chorea refers to continuous, unsustained, rapid, abrupt, and random contractions. Athetosis consists of nonpatterned, writhing movements that represent a form of "slow chorea".  Ballismus is a form of severe, coarse chorea; 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. 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 (SC) 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. The onset usually is 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 usually is generalized but may be more prominent on one side; approximately 20 percent of patients have hemichorea (i.e, unilateral chorea). Emotional changes, such as easy crying or inappropriate laughing, may precede the development of chorea and, in some cases, regression in school performance is the initial concern.

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

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, pemozide, diazepam, chlorpromazine, and carbamazepine. Corticosteroids may shorten the course of SC.

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. The complication has been described in children ages six weeks to 52 months. Risk factors include more time on pump, deeper hypothermia (<36 degrees), and circulatory arrest. Symptoms begin three to twelve days postoperatively. The dyskinesia is usually in the form of choreoathetosis and mainly involves the mouth, tongue and face. More severely affected children have involvement of extremities and trunk. Neuroimaging studies and EEG are normal.

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. Locations typically affected by hypoxic ischemic insult were spared. In some milder and transient cases, certain medications (eg, fentanyl, midazolam, captopril) have been implicated.

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

Other acquired causes — Kernicterus is a neurologic condition that may occur when serum total bilirubin concentrations in the perinatal period are excessive. 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.

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. 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.

Hereditary chorea — Huntington disease is the most frequent cause of hereditary chorea in children. Other causes include benign hereditary chorea and Lesch-Nyhan syndrome. Huntington’s disease (HD) is an autosomal-dominant inherited neurodegenerative disorder caused by a CAG polyglutamine repeat expansion in exon 1 of the HD gene. Patients affected by this devastating disease suffer early cognitive impairment, motor deficits, and psychiatric disturbances. Symptoms are attributed to cell death in the striatum and disruption of cortico–striatal circuitry. The mechanisms that underlie selective neuronal cell death and dysfunction remain poorly understood, but processes involving mitochondrial abnormalities, excitotoxicity, and abnormal protein degradation have been implicated. The diagnosis may be made by genetic testing. Therapy that slows the progressive neuronal dysfunction or degeneration is unavailable and pharmaceutical therapies are commonly used, with limited benefit, to treat disease symptoms.
Several neuroprotective therapies as well as cell replacement strategies such as fetal transplantation have been used with minimal success. In this context, newer neuroimaging technologies may provide surrogate markers of both disease onset and disease progression.
Most of the HD studies using either qualitative or volumetric MRI have focused on the basal ganglia. Several studies have shown evidence of basal ganglia atrophy, even before the onset of motor symptoms. Caudate volumes were found to correlate with performance on neuropsychological tests, suggesting that caudate atrophy may play a role in cognitive symptoms. A measurable rate of change in caudate volume over time was reported, which correlated with age at onset and length of trinucleotide repeat, suggesting that striatal volume loss is a potentially important surrogate marker of HD that may be useful in clinical therapeutic trials. Studies showed that, as suggested by the clinical picture, extrastriatal degeneration also plays an important role in HD with regionally specific degeneration of the cortex. Patients at earlier or even at preclinical disease stages may demonstrate prominent cortical thinning, suggesting that cortical degeneration may play a role in the clinical symptoms.
1H-MRSpectroscopy in Huntington disease.
1H-MRS has been essentially used to assess disease mechanisms and, in rare cases, to monitor the effect of treatment in patients with HD. These studies mainly found reduced NAA and increased Lac in the striatum, occipital cortex, and frontal cortex. Lac levels were increased in the occipital cortex and basal ganglia of symptomatic HD patients and the Lac level correlated with duration of illness. Subsequently, an elevation of Lac signal was found in the striatum and not in the cortex in a few presymptomatic carriers of the HD gene. However, other studies have failed to observe elevated lactate with 1H-MRS in HD patients. Increased glutamine–glutamate level in the striatum also have been reported, supporting the theory of glutamate excitotoxicity in HD.
Overall, the 1H-MRS studies support the notion of the altered energy metabolism in HD. Future studies are needed to determine whether these alterations are causative or secondary measures. The use of 1H-MRS in HD for diagnostic purposes is not recommended.
Nevertheless, 1H-MRS can definitely provide surrogate markers, especially with respect to the use of potential therapeutic intervention. In this context, 1H-MRS should be performed in the basal ganglia at either relatively long TE (135 ms) or short TE (30–35 ms) to allow quantification of Lac or glutamine–glutamate, respectively.

Benign hereditary chorea — Benign hereditary chorea (BHC) is an autosomal dominant disorder that may present during infancy, childhood, or adolescence and persists throughout life. The mechanism of benign hereditary chorea may be related to impaired cerebral glucose metabolism in the caudate nucleus, as demonstrated by positron emission tomography with 18F-2-fluorodeoxyglucose. However, this finding has not been found in all cases. Patients thought to have this disorder require thorough investigation and follow-up because some and perhaps many are diagnosed subsequently with other conditions.

Some patients with BHC are heterozygous for mutations in the thyroid transcription factor-1 (TITF1) gene on chromosome 14q13. A rare syndrome of chorea combined with mental retardation, congenital hypothyroidism, and chronic lung disease has also been linked to a TITF1 gene mutation. This constellation of features is the basis for the term Brain-Thyroid-Lung syndrome proposed for this disease. Suspicion should be raised for a TITF1 gene mutation in children and adults who have these combined features.

Although there is no established therapy for BHC, one study reported that two patients with BHC and typical choreoathetosis responded to levodopa, 7 to 20 mg/kg per day, with sustained improvement of gait and chorea.

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 mutations 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 mutations 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. Affected boys have delayed developmental milestones, mental retardation, 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. 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 — Tremor is defined as a rhythmic and oscillatory movement of a body part with a relatively constant frequency and variable amplitude. It is caused by either alternating or synchronous contractions of antagonistic muscles. 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. 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. 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: 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.

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. 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.

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 mutans, and the "bobble-headed doll's 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 "Pharmacologic treatment of essential tremor" and see "Surgical treatment of essential tremor").

MYOCLONUS — Myoclonus is a simple, jerk-like movement that is not coordinated or suppressible and often is activated by volitional movement. Myoclonus can be physiologic or pathologic and can occur as an isolated disorder or associated with seizures or other conditions.

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.

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.

Cortical myoclonus — Cortical myoclonus consists of continuous, repetitive, focal jerking that sometimes is associated with characteristic electroencephalographic (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; also known as "Mediterranean" or "Baltic" myoclonus or EPM1) is one form of progressive myoclonus epilepsy (PME), a condition that consists of myoclonus, seizures, and a progressive clinical course.

In the EPM1 form, stimulus-sensitive myoclonus usually begins between ages 6 and 15 years. Affected patients develop dysarthria, ataxia, intention tremor, and mild intellectual decline; many become bedridden within five years after onset of symptoms. Epileptiform EEG findings may precede symptoms by up to three years. Valproate and carbamazepine are often very effective treatments for EPM1, however, phenytoin and possibly lamotrigine have 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. Among 20 patients with ULD who were followed over 25 years, only three were severely handicapped, and six led fully independent lives.

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

A novel form of ULD that maps to chromosome 12 has been described in an Arab family. 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 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 five to eight years. Biopsy of the skin (especially in the axillary region), 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 has been associated with mutations in the EPM2A and EPM2B genes, and a third locus may exist as well. The EPM2A gene codes for the protein laforin, and the EPM2B gene codes for the protein malin. Laforin has a starch binding domain, while malin binds laforin, suggesting that both proteins interact in a cellular pathway that protects against polyglucosan accumulation and epilepsy.

Hyperekplexia — Hyperekplexia, or 'human startle disease', is a rare disorder characterized by generalized stiffness beginning in infancy. Affected patients develop exaggerated myoclonic startle reactions that may result in falling.

Both hereditary and sporadic hyperekplexia are genetically heterogeneous. The hereditary form (OMIM 149400) is typically caused by mutations in the gene coding for the alpha-1 subunit of the inhibitory glycine receptor (GLRA1) on chromosome 5. The disorder is also caused by mutations in the beta subunit of the inhibitory glycine receptor (GLRB), by mutations in the gephyrin gene (GPHN), and by mutations in SLC6A5, which encodes the presynaptic glycine transporter-2 (GlyT2).

The SLC6A5 mutations are predominately associated with recessive hyperekplexia; symptoms include life-threatening neonatal apnea and breath-holding spells.

Other — A number of other types of symptomatic myoclonus include: Ramsay Hunt syndrome is a group of heterogeneous disorders characterized by a combination of progressive myoclonus and cerebellar 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, and another found evidence of autoantibody reactivity to a neuronal surface antigen, but no single antibody has been consistently identified in children with this disorder. Small myoclonic jerks (minipolymyoclonus) may occur in children with chronic spinal muscular atrophy.

Treatment — The idiopathic, generalized, or segmental forms of myoclonus may improve with drug therapy. Therapeutic trials are attempted using (in order) clonazepam, piracetam, levetiracetam, sodium valproate, 5-hydroxytryptophan, tetrabenazine, reserpine, levodopa, trihexyphenidyl, and lisuride.