590.1 Ataxias

Ataxia is the inability to make smooth, accurate, and coordinated movements, usually due to a dysfunction of the cerebellum, its inputs or outputs, sensory pathways in the posterior columns of the spinal cord, or a combination of these. Ataxias may be generalized or primarily affect gait or the hands and arms; they may be acute (Table 590-2) or chronic (Table 590-3). Congenital anomalies of the posterior fossa, including the Dandy-Walker syndrome, Chiari malformation, and encephalocele, are prominently associated with ataxia because of their destruction or replacement of the cerebellum (Chapters 585.9 and 585.11). Agenesis of the cerebellar vermis presents in infancy with generalized hypotonia and decreased deep tendon reflexes. Delayed motor milestones and truncal ataxia are typical. Joubert syndrome is an autosomal recessive disorder marked by agenesis of the cerebellar vermis, ataxia, hypotonia, oculomotor apraxia, neonatal breathing problems, and mental retardation. Mutations have been identified in the AHI1 gene on chromosome 6, encoding the Jouberin protein. This gene is strongly expressed in embryonic hindbrain, especially in neurons that give rise to the axons of the corticospinal tract and superior cerebellar peduncles, which fail to cross properly in Joubert syndrome. MRI is the method of choice for investigating congenital abnormalities of the cerebellum, vermis, and related structures. In Joubert syndrome, MRI reveals enlargement of the 4th ventricle at the junction between the midbrain and medulla, creating the “molar tooth sign.”

The major infectious causes of ataxia include cerebellar abscess, acute labyrinthitis, and acute cerebellar ataxia. Acute cerebellar ataxia occurs primarily in children 1-3 yr of age and is a diagnosis of exclusion. The condition often follows a viral illness, such as varicella, coxsackievirus, or echovirus infection by 2-3 wk and is thought to represent an autoimmune response to the viral agent affecting the cerebellum (Chapters 242, 245, and 595). The onset is sudden, and the truncal ataxia can be so severe that the child is unable to stand or sit. Vomiting may occur initially, but fever and nuchal rigidity are absent. Horizontal nystagmus is evident in approximately 50% of cases and, if the child is able to speak, dysarthria may be impressive. Examination of the cerebrospinal fluid (CSF) is typically normal at the onset of ataxia; a pleocytosis of lymphocytes (10-30/mm³) is not unusual. Later in the course, the CSF protein undergoes a moderate elevation. The ataxia begins to improve in a few weeks but may persist for as long as 2 mo. The incidence of acute cerebellar ataxia appears to have declined with increased rates of vaccination against varicella. The prognosis for complete recovery is excellent; a small number have long-term sequelae, including behavioral and speech disorders as well as ataxia and incoordination. Acute labyrinthitis may be difficult to differentiate from acute cerebellar ataxia in a toddler. The condition is associated with middle-ear infections and intense vertigo, vomiting, and abnormalities in labyrinthine function, particularly ice water caloric testing.

Toxic causes of ataxia include alcohol, thallium (which is used occasionally in homes as a pesticide), and the anticonvulsants, particularly phenytoin when serum levels reach or exceed 30 µg/mL (120 µmol/L).

Brain tumors, including tumors of the cerebellum and frontal lobe, as well as peripheral nervous system neuroblastoma, may present with ataxia. Frontal lobe tumors may cause ataxia due to destruction of the association fibers connecting the frontal lobe with the cerebellum or due to increased intracranial pressure. Neuroblastoma may be associated with a paraneoplastic encephalopathy characterized by progressive ataxia, myoclonic jerks, and opsoclonus (nonrhythmic, conjugate horizontal and vertical oscillations of the eyes).

Several metabolic disorders are characterized by ataxia, including abetalipoproteinemia, arginosuccinic aciduria, and Hartnup disease. Abetalipoproteinemia (Bassen-Kornzweig disease) begins in childhood with steatorrhea and failure to thrive (Chapter 592). A blood smear shows acanthocytosis and decreased serum levels of cholesterol and triglycerides, and the serum β-lipoproteins are absent. Neurologic signs become evident by late childhood and consist of ataxia, retinitis pigmentosa, peripheral neuritis, abnormalities in position and vibration sense, muscle weakness, and mental retardation. Vitamin E is undetectable in the serum of patients with neurologic symptoms.

Degenerative diseases of the central nervous system (CNS) represent an important group of ataxic disorders of childhood because of the genetic consequences and poor prognosis. Ataxia-telangiectasia, an autosomal recessive condition, is the most common of the degenerative ataxias and is heralded by ataxia beginning at about age 2 yr and progressing to loss of ambulation by adolescence (Chapter 589). Ataxia-telangiectasia is caused by mutations in the ATM gene located at 11q22-q23. ATM is a phosphytidylinositol-3 kinase that phosphorylates proteins involved in DNA repair and cell cycle control. Oculomotor apraxia of horizontal gaze, defined as having difficulty fixating smoothly on an object and therefore overshooting the target with lateral movement of the head, followed by refixating the eyes, is a frequent finding, as is strabismus, hypometric saccade pursuit abnormalities, and nystagmus. Ataxia-telangiectasia may present with chorea rather than ataxia. The telangiectasia becomes evident by mid-childhood and is found on the bulbar conjunctiva, over the bridge of the nose, and on the ears and exposed surfaces of the extremities. Examination of the skin shows a loss of elasticity. Abnormalities of immunologic function that lead to frequent sinopulmonary infections include decreased serum and secretory IgA as well as diminished IgG₂, IgG₄, and IgE levels in more than 50% of patients. Children with ataxia-telangiectasia have a 50- to 100-fold greater chance over the normal population of developing lymphoreticular tumors (lymphoma, leukemia, and Hodgkin disease) as well as brain tumors. Additional laboratory abnormalities include an increased incidence of chromosome breaks, particularly of chromosome 14, and elevated levels of α-fetoprotein. Death results from infection or tumor dissemination.

Friedreich ataxia is inherited as an autosomal recessive disorder involving the spinocerebellar tracts, dorsal columns in the spinal cord, the pyramidal tracts, and the cerebellum and medulla. The majority of patients are homozygous for a GAA repeat expansion in the noncoding region of the gene coding for the mitochondrial protein frataxin. Mutations cause oxidative injury associated with excessive iron deposits in mitochondria. The onset of ataxia is somewhat later than in ataxia-telangiectasia but usually occurs before age 10 yr. The ataxia is slowly progressive and involves the lower extremities to a greater degree than the upper extremities. The Romberg test result is positive; the deep tendon reflexes are absent (particularly the Achilles), and the plantar response is extensor. Patients develop a characteristic explosive, dysarthric speech, and nystagmus is present in most children. Although patients may appear apathetic, their intelligence is preserved. They may have significant weakness of the distal musculature of the hands and feet. Typically noted is a marked loss of vibration and position sense caused by degeneration of the posterior columns and indistinct sensory changes in the distal extremities. Friedreich ataxia is also characterized by skeletal abnormalities, including high-arched feet (pes cavus) and hammertoes, as well as progressive kyphoscoliosis. Results of electrophysiologic studies including visual, auditory brainstem, and somatosensory-evoked potentials are often abnormal. Hypertrophic cardiomyopathy with progression to intractable congestive heart failure is the cause of death for most patients. Antioxidant therapy with coenzyme Q10 and vitamin E has been reported to slow progression in some patients.

Several forms of spinocerebellar ataxia are similar to Friedreich ataxia. Roussy-Levy disease has, in addition, atrophy of the muscles of the lower extremity with a similar pattern of wasting observed in Charcot-Marie-Tooth disease; Ramsay Hunt syndrome has an associated myoclonic epilepsy. There are also more than 20 dominantly inherited spinocerebellar ataxias, some of which present in childhood. These include those associated with CAG (polyglutamine) repeats and noncoding microsatellite expansions. Dominantly inherited episodic ataxias caused by potassium or calcium channel dysfunction present as episodes of ataxia and muscle weakness. Some of these disorders may respond to acetazolamide. The dominantly inherited olivopontocerebellar atrophies (OPCA) include ataxia, cranial nerve palsies, and abnormal sensory findings in the 2nd or 3rd decade, but can present in children with rapidly progressive ataxia, nystagmus, dysarthria, and seizures.

Additional degenerative ataxias include Pelizaeus-Merzbacher disease, neuronal ceroid lipofuscinoses, and late-onset GM₂ gangliosidosis (Chapter 592). Rare forms of progressive cerebellar ataxia have been described in association with vitamin E deficiency. A number of autosomal dominant progressive spinocerebellar ataxias have been defined at the molecular level, including those caused by unstable trinucleotide repeat expansions.

590.2 Chorea, Athetosis, Tremor

Chorea, meaning “dance-like” in Greek, refers to rapid, chaotic movements that seem to flow from one body part to another. Affected individuals exhibit motor impersistence, with difficulty keeping the tongue protruded (“darting tongue”) or maintaining grip (“milkmaid grip”). Chorea tends to occur both at rest and with action. Patients often attempt to incorporate the involuntary movements into more purposeful movements, making them appear fidgety. Chorea increases with stress and disappears in sleep. Chorea can be divided into primary (i.e., disorders in which chorea is the dominant symptom and the etiology is presumed to be genetic) and secondary forms, with the vast majority of pediatric cases falling into the latter category (Tables 590-4 and 590-5).

Sydenham chorea (SC, St. Vitus dance) is the most common acquired chorea of childhood. It occurs in 10% to 20% of patients with acute rheumatic fever, typically weeks to months after a group A β-hemolytic streptococcal infection (Chapter 176.1). Peak incidence is at age 8 to 9 yr, with a female predominance of 2 : 1.

Pathophysiologically, there is good evidence that group A streptococci promote the generation of cross-reactive or polyreactive antibodies through molecular mimicry between streptococcal and host antigens. Specifically, antibodies against the N-acetyl-β-D-glucosamine epitope (GlcNAc) of streptococcal group A carbohydrate have been shown to target intracellular β-tubulin and extracellular lysoganglioside G_M1 in human caudate-putamen preparations. These antibodies are also capable of directing calcium/calmodulin–dependent protein kinase II activation, which may cause the neurologic manifestations of SC by increasing dopamine release into the synapse.

The clinical hallmarks of SC are chorea, hypotonia, and emotional lability. Onset of the chorea is usually insidious but may be abrupt. Most patients have generalized chorea. However, the majority has asymmetric chorea and up to 20% of patients have hemichorea. Hypotonia manifests with the “pronator sign” (arms and palms turn outward when held overhead) and the “choreic hand” (spooning of the extended hand by flexion of the wrist and extension of the fingers). When chorea and hypotonia are severe, the child may be incapable of feeding, dressing, or walking. Speech is often involved, sometimes to the point of being unintelligible. Periods of uncontrollable crying and extreme mood swings are characteristic and may precede the onset of the movement disorder.

Sydenham chorea is a clinical diagnosis; however, a combination of acute and convalescent serum antistreptolysin O titers may help to confirm an acute streptococcal infection. Negative titers do not exclude the diagnosis. All patients with SC should be evaluated for carditis and started on long-term antibiotic prophylaxis (e.g., penicillin G benzathine 1.2 million units IM every 2-3 weeks) to decrease the risk of rheumatic heart disease. For patients with chorea that is impairing, treatment options include valproate, carbamazepine, and/or dopamine receptor antagonists. Although phenothiazines, haloperidol, and pimozide are also effective, their side effects limit their utility. Historically, there have been conflicting data regarding the efficacy of prednisone, intravenous immunoglobulin, and other immunomodulatory agents in SC, making it difficult to recommend their routine use. Recently, a randomized, double-blinded study of 37 children with SC compared high-dose prednisone (2 mg/kg/day, max. 60 mg) for 4 wk versus a placebo and found that steroids significantly reduced time to remission (54.3 days versus 119.9 days in controls).

Sydenham chorea usually resolves spontaneously within 6 to 9 mo, though it can persist for up to 2 yr and, in rare cases, can remain a lifelong condition. Relapse in the 1st few years is relatively common, occurring in 37.9% of patients in 1 series. Remote recurrence of chorea is rare but may be provoked by streptococcal infections, pregnancy (chorea gravidarum), or oral contraceptive use.

Though much rarer than SC, systemic lupus erythematosus (SLE) is a well-known cause of chorea in children. In some cases, chorea may be the presenting sign of SLE. A recent retrospective study of a large pediatric lupus cohort examined the prevalence of antiphosolipid antibodies and evaluated their association with neuropsychiatric symptoms. There was a statistically significant association between a persistently positive lupus anticoagulant and chorea (p = .02); however, only 2 of the 137 patients in the cohort had chorea. Regardless, any child with chorea of unknown cause should be investigated for the presence of antiphospholipid antibodies.

Additional causes of secondary chorea include metabolic (hyperthyroidism, hypoparathyroidism), infectious (Lyme disease), immune-mediated (systemic lupus erythematosus), vascular (stroke, moyamoya disease), heredodegenerative disorders (Wilson disease), and drugs (Table 590-6). Although chorea is a hallmark of Huntington disease in adults, children who develop Huntington disease tend to present with rigidity and bradykinesia (Westphal variant) or dystonia rather than chorea.

Athetosis is characterized by slow, continuous, writhing movements that repeatedly involve the same body part(s), usually the distal extremities, face, neck, or trunk. Like chorea, athetosis may occur at rest and is often worsened by voluntary movement. Because athetosis tends to co-occur with other movement disorders, such as chorea (choreoathetosis) and dystonia, it is often difficult to distinguish as a discrete entity. Choreoathetosis is associated with cerebral palsy, kernicterus, and other forms of basal ganglia injury; therefore, it is often seen in conjunction with rigidity—increased muscle tone that is equal in the flexors and extensors in all directions of passive movement regardless of the velocity of the movement. This is to be differentiated from spasticity, a velocity-dependent (“clasp-knife”) form of hypertonia that is seen with upper motor neuron dysfunction. As with chorea, athetosis/choreoathetosis can also be seen with hypoxic-ischemic injury and dopamine-blocking drugs.

Tremor is a rhythmic, oscillatory movement around a central point or plane, which results from the action of antagonist muscles. Tremor can affect the extremities, head, trunk, or voice and can be classified by both its frequency (slow [4 Hz], intermediate [4-7 Hz], and fast [>7 Hz]) and by the context in which it is most pronounced. Rest tremor is maximal when the affected body part is inactive and supported against gravity, whereas postural tremor is most notable when the patient sustains a position against gravity. Action tremor occurs with performance of a voluntary activity and can be subclassified into simple kinetic tremor, which occurs with limb movement, and intention tremor, which occurs as the patient’s limb approaches a target and is a feature of cerebellar disease.

Essential tremor (ET) is the most common movement disorder in adults, and 50% of persons diagnosed with ET report an onset in childhood; thus ET may be more common in the pediatric population than the literature would suggest. ET is an autosomal dominant condition with variable expressivity but complete penetrance by the age of 60 yr. Although the genetics of ET are not fully understood, at least 3 different loci—EMT1 on chromosome 3q13, EMT2 on chromosome 2p22-25, and a locus on 6p23—have been linked to the condition. Based on functional imaging studies, the defect is thought to localize to cerebellar circuits.

Essential tremor is characterized by a slowly progressive, bilateral, 4-9 Hz postural tremor that involves the upper extremities and occurs in the absence of other known causes of tremor. Mild asymmetry is common, but ET is rarely unilateral. ET may be worsened by actions, such as trying to pour water from cup to cup, and affected adults may report a history of ethanol responsiveness. Most young children present to care because a parent, teacher, or physician has noticed the tremor, rather than because the tremor is causing impairment. That being the case, most children with ET do not require pharmacologic intervention. If they are having difficulty with their handwriting or self-feeding, an occupational therapy evaluation and/or assistive devices, such as wrist weights and weighted silverware, may be helpful. Teenagers tend to report more impairment from ET; however, it is unclear whether this is due to actual or subjective progression of the tremor. Teenagers who do require pharmacotherapy usually respond to the same medications that are used in adults—propranolol and primidone. Propranolol, which is generally considered the first-line treatment, can be started at 30 mg daily and then titrated to effect, with most patients responding to doses of 60-80 mg/day. Propranolol should not be used in patients with reactive airway disease. Primidone can be started at 12.5-25 mg at bedtime and increased gradually in a twice daily schedule. Most patients respond to doses of 50-200 mg/day. Other treatments options for ET reported in the adult literature include sotalol, atenolol, gabapentin, topiramate, and alprazolam. Botulinum toxin A may be effective for treating limb tremor, though it causes nonpermanent, dose-dependent limb weakness. Surgical treatments, which include deep brain stimulation of the thalamus and unilateral thalamotomy, are generally reserved for adults.

While ET is the most common primary etiology of tremor in children, there are numerous secondary etiologies (Table 590-7). Holmes tremor, previously referred to as midbrain or rubral tremor, is characterized by a slow frequency, high amplitude tremor that is present at rest and with intention. It is a symptomatic tremor, which usually results from lesions of the brainstem, cerebellum, or thalamus. Psychogenic tremor is distinguished by its variable appearance, abrupt onset and remission, nonprogressive course, and association with selective but not task-specific disabilities. In some cases, tremor may even occur as a manifestation of another movement disorder, as is seen with position- or task-specific tremor (e.g., writing tremor), dystonic tremor, and myoclonic tremor.

When evaluating a child with tremor, it is important to screen for common metabolic disturbances, including electrolyte abnormalities and thyroid disease, assess the child’s caffeine intake, and review the child’s medication list for known tremor-inducing agents. It is also critical to exclude Wilson disease, which has a characteristic “wing-beating” tremor, as this is a treatable condition.

590.3 Dystonia

Dystonia is a disorder of movement characterized by sustained muscle contraction, frequently causing twisting and repetitive movements or abnormal postures. Major causes of dystonia include primary generalized dystonia, medications, metabolic disorders, and perinatal asphyxia. In this section, we will provide an overview of major causes of dystonia, organized by etiologic category.

Aromatic amino acid decarboxylase deficiency (AADC) ARX gene mutation (X-linked) Benign paroxysmal torticollis of infancy Complex regional pain syndrome Dopa-responsive dystonia (DRD) Drug-induced dystonia   Dystonia-deafness optic neuropathy syndrome DYT1 dystonia Glutaric aciduria type 1 GM1 gangliosidosis type 3 Huntington disease (HD) Kernicterus Leigh syndrome Lesch-Nyhan syndrome (X-linked) Myoclonus dystonia Niemann-Pick type C Neuroacanthocytosis Neurodegeneration with brain iron accumulation Rapid onset dystonia parkinsonism (DYT12) Rett syndrome Spinocerebellar ataxia 17 (SCA17) Tics Tyrosine hydroxylase deficiency