Movement Disorders

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.

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).