Ataxias of Childhood

Home , Ataxic cerebral palsy, Dyssynergia, Sensory ataxia

ATAXIAS OF CHILDHOOD

Jayaprakash A. Gosalakkal, MD, FAAP

BACKGROUND– This review examines the causes of ataxias in children. It is a relatively common manifestation of neurological diseases in children. The etiology of ataxia covers a broad range, from infections to rare hereditary metabolic diseases. A systematic approach is required to make the correct diagnosis. REVIEW SUMMARY– The more common causes of ataxias in children are discussed in detail. The importance of recognizing potentially reversible conditions such as vitamin E deﬁciency and Refsum’s disease is stressed. Recent advances in molecular genetics of some of the chronic ataxias are discussed. The importance of categorizing diseases based on the duration of symptoms and associated signs is discussed. Treatment options are mentioned. CONCLUSION– Ataxia is a common mode of presentation of cerebellar, posterior column, and vestibular disease in children. Awareness of the spectrum of disease entities that cause ataxia in childhood may lead to better diagnosis. KEY WORDS ataxia, cerebellar, childhood (THE NEUROLOGIST 7:300–306, 2001)

The term ataxia refers to a special disorder of movement tected early in life in conditions such as Dejerine-Sottas resulting from lesions of the cerebellum or spinocerebellar disease by the ability to correct posture with eyes open but tracts. The disorders, which result in ataxia in children, are not with eyes closed. somewhat different from those in adults. Signs of ataxia in children may be detected as early as the first year of life. This ACUTE AND ACUTE EPISODIC ATAXIA is especially apparent when the child sits down and reaches for objects. Ataxias of childhood can be categorized initially Infectious and Postinfectious by ascertaining the following: 1) whether this is an acute, Acute cerebellar ataxia in children most often follows an acute recurrent, or chronic disorder; 2) if chronic, whether it infectious process. Varicella-zoster virus infection is most a progressive or static disorder; and 3) whether this is a often implicated. Other viruses can produce a similar picture symptom of cerebellar, posterior column, or vestibular dys- [Epstein-Barr virus (1), Coxsackievirus, and other enterovi- function. ruses, etc.]. The onset is sudden and can occur immediately In adolescents, the manifestations of cerebellar ataxia are or as late as 6 weeks after the viral illness. Cerebrospinal fluid similar to those in adults and are associated with other signs examination may show mild pleocytosis. The course is usu- of cerebellar dysfunction (dysdiadochokinesis, dyssynergia, ally benign (2). Complications can sometimes rise because of etc.). The diagnosis may be more difficult in younger chil- cerebellar swelling, with development of obstructive hydro- dren, and care must be taken before ascribing minor prob- cephalus (3–6). If there are other neurological signs, imaging lems of gait and stance to cerebellar disorders. Sensory ataxia should be obtained to evaluate for strokes and mass lesions. in older children can be detected as in adults when Romberg sign is present. Severe sensory ataxia can sometimes be de- Drugs

From the Department of Pediatric Neurology, New York University A number of drugs can cause acute ataxia, often associ- Medical Center, New York, New York. ated with nystagmus, drowsiness, and vomiting. Intoxication Send reprint requests to Jayaprakash A Gosalakkal, 545 First Avenue, with benzodiazepines, barbiturates, phenytoin, phenothia- Apartment 2-O, New York, NY 10016. E-mail [email protected] zines, and carbamazepines are well known to cause ataxia.

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Vascular Causes provoked by movement and startle, missense mutations in a potassium channel gene KCNA1 have been found. Patients Basilar migraine, vascular occlusions, malformations aris- with EA2, another form of paroxysmal ataxia, carry muta- ing from vertebral or basilar arteries, and cerebellar hemato- tions of the gene encoding for the ␣1A voltage-dependent mas can cause ataxia. Asymmetrical ataxia is present on the calcium channel subunit CACNA1A that are predicted to side of unilateral cerebellar involvement. result in truncated channel proteins (12). Episodic ataxia responds to acetazolamide. Miller-Fisher Syndrome The Gullain-Barre´ syndrome and its variants can manifest CONDITIONS THAT MAY BE ASSOCIATED WITH as acute ataxia in children. On closer examination, other ACUTE ATAXIA manifestations such as muscle weakness, hypotonia, and areflexia are usually present. Cerebrospinal fluid examination Opsoclonus-Myoclonus syndrome will show elevated protein with normal cell count. The GQ1 This syndrome of dancing eyes, acute incordination, and antibody test is positive in the Miller-Fisher variant. muscle jerks may be associated with acute ataxia. It is important to recognize this syndrome, as it may be associated with Posterior Fossa Tumors and Abscess neuroblastoma (13). Opsoclonus-myoclonus may sometimes be associated with varicella and other viral infections and More than 50% of the brain tumors in childhood occur sometimes may be idiopathic. The prognosis ranges from in the posterior fossa (7). Posterior fossa tumors, including complete recovery to persistence for several years and seems cerebellar astrocytoma, brain stem glioma, and medulloblas- independent of etiology. This syndrome may persist after toma, can present with acute ataxia (8). There may be evi- removal of the neuroblastoma. Patients may respond to ad- renocorticotropic hormone or prednisone therapy. Acute cerebellar ataxia in children Chronic Progressive Ataxias of Childhood most often follows an infectious Chronic progressive ataxias may be hereditary or ac- quired. Ataxia is rarely an isolated manifestation of hereditary process. metabolic disease. The prototype of hereditary ataxia is Frie- dreich ataxia. Other conditions include ataxia-telengectasia, dence of increased intracranial pressure. The prognosis for vitamin E deficiency, abetalipoproteinemia, Refsum’s dis- these childhood tumors has improved greatly in recent times ease, and late infantile and juvenile sphingolipidosis with early diagnosis and treatment (9). Thus, it is imperative to get imaging studies in suspicious cases. Friedreich Ataxia Friedrich ataxia is a trinucleotide repeat disorder that is Episodic Ataxias inherited in an autosomal-recessive manner. The trinucle- Recurrent episodic ataxia in childhood may be a mani- otide repeat is GAA, and most patients have a range of 600 to festation of a number of hereditary metabolic disorders (10). 900 repeats. The gene is localized to chromosome 9q (14) The ataxia may be precipitated by an acute infection or and regulates the synthesis of a protein called fraxitin. When during recovery. There may be associated lethargy and vom- direct molecular testing became available for Friedreich iting. Some of the better known examples are maple syrup ataxia, up to 10% of patients who did not fulfill the criteria for urine disease, Hartnup disease, and Leigh disease. Several Friedreich ataxia tested positive (15). Friedreich ataxia is the other lesser known aminoacidopathies and organic acidemias most frequently inherited ataxia in Caucasians. also may present with acute ataxia. Most commonly, the onset of Friedreich ataxia occurs at the beginning of puberty (16), but earlier as well as later onset has been reported. Progressive unrelenting ataxia with mixed Hereditary Episodic Ataxia cerebellar and sensory features is the cardinal feature of this This disease is inherited in an autosomal-dominant man- disease. Truncal ataxia is usually the first symptom, followed ner and is characterized by paroxysmal bouts of ataxia, dys- by incordination, dysmetria, and intention tremor. A pro- arthria, and nystagmus. Ataxia is often severe. Between epi- gressive dysarthria appears soon after onset (17). Muscular sodes, electroencephalograms, caloric testing of vestibular weakness is common and progressive. There is an axonal function, and serum chemistry are normal (11). Cerebellar sensory neuropathy resulting in sensory loss and loss of deep vermian atrophy has been reported in long-standing cases. tendon reflexes. Loss of tendon reflexes was considered es- Hereditary episodic ataxia is now classified into two groups sential for the diagnosis in the past; however, it recently has and is the result of mutations of genes that code for ion been noticed that a minority of patients may have preserved channels. In EA1, a disease characterized by episodes of ataxia and even exaggerated tendon reflexes (18). The plantar re- 302 T HE N EUROLOGIST A TAXIAS OF C HILDHOOD

flexes are extensor because of involvement of the pyramidal of the large myelinated fibers of the posterior columns and tract. Extensor plantar responses were in the past considered spinocerebellar tracts. Fat-soluble vitamins should be supple- essential to make the diagnosis (19). It now is known that mented. exceptions to these rules can occur. Position and vibration sensations are reduced. Optic atrophy occurs in 30% of Vitamin E Deficiency patients (20). Sensorineural hearing loss occurs in 20% of patients. Friedreich considered degeneration of the posterior Vitamin E deficiency is an important cause of ataxia, column as the cardinal pathological feature. Other patholog- peripheral neuropathy, or both. In most cases, it is caused by ical changes in the nervous system include degeneration of malabsorption. An isolated ataxia with vitamin E deficiency the dorsal root ganglion and corticospinal and spinocerebellar in the absence of malabsorption also has been described (31). tracts. This is one of the few reversible metabolic ataxias in child- Other features include kyphoscoliosis, pes cavus, and pes hood, and, hence, there is the need to measure vitamin E equinovarus (21). Cardiomyopathy is present in 50% of cases. levels in all cases of unexplained ataxia. Ataxia with isolated In most patients, heart disease remains asymptomatic, but it vitamin E deficiency is an autosomal-recessive disease with a can contribute to disability and premature death (22). About defect in the liver of ␣-tocopheral transfer protein. The ataxia 10% of patients develop diabetes mellitus. Neuroimaging with isolated vitamin E deficiency locus has been mapped to reveals thinning of the cervical spinal cord with abnormal chromosome 8q13 (32–34). Onset of disease is in the first or signals in the posterior and lateral columns on sagittal and second decade, and it is indistinguishable from Friedreich axial magnetic resonance imaging in almost all patients with ataxia. Areflexia, dysarthria, and propioceptive loss are com- Friedreich ataxia (23, 24). mon. Low fasting vitamin E levels in the presence of normal

Ataxia-Telengeictasia Ataxia-telengeictasia is an autosomal-recessive disorder Vitamin E deficiency is an important first described by Syllaba and Henner (25) and Louis Barr cause of ataxia, peripheral (26). The onset is in childhood with ataxia, choreoathetosis, oculocutaneous telengectasia, immunological deficiency, in- neuropathy, or both. creased frequency of malignancies, and endocrine abnormalities. Recurrent infections are common, with reduced im- munoglobulins (Ig) A, IgE, and IgG2. The gene has been localized to chromosome 11q22–23 (27). Neurological vitamin E absorption suggest diagnosis. This can be demon- symptoms can appear at as early as 12 to 18 months of age. strated by vitamin E tolerance tests. Treatment with 800 to Ataxia is usually the fist symptom, followed by dysarthria. 900 IU of oral DL-␣-tocopheral stabilizes or improves neu- The disease progresses slowly. The incidence of malignancies rological status. has been estimated to be 38% (28). Elevated carcinoembry- onic antigen is present. Cytogenetic abnormalities indicating chromosomal instability are frequent. In cell cultures, there is Refsum’s Disease an increased sensitivity of the patient’s chromosomes to x- Refsum’s disease is an autosomal-recessive disorder with radiation. a genetic defect in the ␣-oxidation of phytanic acid (35) The tetrad of symptoms includes cerebellar ataxia, retinitis pigmentosa, chronic progressive demyelinating sensory-motor Abetalipoproteinemia (Bassen-Kornzweig Syndrome) polyneuropathy, and elevated cerebrospinal fluid protein Bassen and Kornzweig (29) first described abetalipopro- concentration. Age of onset is variable, and symptoms may be teinemia in 1950. It is a recessively inherited disease charac- present in early infancy. There is a high incidence of deafness. terized by the virtual absence of apolipoprotein B and apo- Phytanic acid levels are elevated in serum and urine. A lipoprotein B-containing lipoproteins in plasma. Microsomal Refsum’s disease gene, phytanoyl-CoA hydroxylase triglyceride transfer protein, a resident lipid transfer protein (PAHX), has been localized to chromosome 10p13 between within the endoplasmic reticulum of hepatocytes and entero- the markers D10S226 and D10S223 (36). The clinical course cytes, is absent in affected individuals (30). The first symptom can be improved by restricting phytanic acid in the diet. is fat malabsorption. Ataxia develops at about 5 to 10 years of Therapeutic plasma exchange has been shown to be partic- age. Areflexia, propioceptive disturbance, and cerebellar signs ularly useful for rapidly lowering plasma phytanic acid levels constitute the usual syndrome. Acanthocytosis is a constant during acute attacks and may play a significant role as a and early finding. Cardiac abnormalities such as cardiomegaly maintenance therapy as well (37). It must be remembered and arrhythmias are common and may be the cause of death that infantile Refsum’s disease is a completely different entity in some patients. Retinitis pigmentosa is present. There are characterized by loss of multiple peroxisomal metabolic func- low levels of vitamins A, D, E, and K. There is degeneration tions. Phytanic acid can accumulate in peroxisomal disorders, V OL.7/NO .5/SEPTEMBER 2001 THE N EUROLOGIST 303 probably because peroxisomes play a role in phytanic acid THE CHRONIC NONPROGRESSIVE ATAXIAS metabolism (38). Ataxic Cerebral Palsy A form of cerebral palsy with predominant ataxia is well Sensory Ataxia known. These patients are hypotonic docile infants with delayed speech and motor skills. Ataxic cerebral palsy ac- Subacute degeneration of the spinal cord may be taken counts for 5% to 10% of all forms of cerebral palsy, and it is as a prototype of sensory ataxia. In children, this may result from familial malabsorption of cobalamin or from inborn errors of folate or cobalamin metabolism (39). Although rare, childhood pernicious anemia is a treatable disease that should be included in the differential diagnosis of the Carbohydrate-deficient glycoprotein sensory ataxias in children (40). Loss of proprioception and syndrome is a newly delineated vibration sensation leads to sensory ataxia and a positive Romberg sign. Motor signs include loss of strength, spas- group of inherited multisystemic ticity, and extensor plantar responses. Visual impairment may occur. Serum vitamin B12 levels are normal in chil- disorders associated with abnormal dren with inborn errors of folate or cobalamin synthesis. Early diagnosis and treatment may prevent permanent glycosylation of a number of serum neurological damage. It is important to remember that glycoproteins. megaloblastic anemia may be absent in genetic errors of folate and cobalamin synthesis. Homocystinuria is present. Mental changes and developmental delay may be present. Sensory ataxia may occasionally be present in hereditary estimated that approximately 50% of ataxic cerebral palsy is polyneuropathies. inherited as an autosomal-recessive trait. Recently, the genetic locus has been mapped in a family to chromosome 9p12-q12. (42). The identification of genes involved in the Carbohydrate-Deficient Glycoprotein Syndrome etiology of cerebral palsy will offer the possibility of prenatal/ premarital testing to some families with children affected Carbohydrate-deficient glycoprotein syndrome is a with the disorder and will greatly increase our understanding newly delineated group of inherited multisystemic disorders of the development of the control of motor function. Mental associated with abnormal glycosylation of a number of serum retardation often is associated, leading to questions about the glycoproteins. Several types have been described on the basis role of the cerebellum in cognitive functions (43). Patients of clinical presentation and biochemical changes (41). Pa- may present with the disequilibrium syndrome described by tients with carbohydrate-deficient glycoprotein syndrome Hagberg and colleagues (44). Before making this diagnosis, type la usually present with neurological (hypotonia, strabis- genetic diseases must be ruled out. mus, and cerebellar hypoplasia) and cutaneous (inverted nip- ples and abnormal distribution of adipose tissue) abnormalities, together with multivisceral involvement (digestive, Other Nonprogressive Cerebellar Ataxias in hepatic, cardiac, and renal). In childhood, the prominent Childhood features include cerebellar ataxia, mental retardation, retinitis pigmentosa, and peripheral neuropathy. Computed tomog- A form of olivopontocerebellar atrophy has been de- raphy and magnetic resonance imaging show cerebellar atro- scribed in adolescents. Congenital pontocerebellar aplasia is phy and pathological changes include olivopontocerebellar probably a different disorder. The vermis is preserved in this atrophy, hepatic micronodular cirrhosis, and renal micro- condition. An inherited form of idiopathic cerebellar ataxia cysts. also has been described. It is not clear if these are definite A number of other hereditary and metabolic diseases may entities or phenotypical variants of other more common cerebellar disorders. have ataxia as a primary or associated manifestation. This group includes autosomal-dominant spinocerebellar ataxia and cerebellar ataxia (predominantly adult), Lafora disease, Leigh disease, and a number of late infantile and juvenile APPROACH TO DIAGNOSIS sphingolipidoses. Other conditions to be considered in There is a diverse group of conditions that can give rise chronic progressive ataxia include tumors of the cerebellum to ataxia in childhood, but with a systematic approach the and subacute encephalitis. Long-standing hydrocephalus also possibilities can be significantly narrowed down, and inves- may present with unsteady gait. tigations can be directed toward the most likely diagnosis. 304 T HE N EUROLOGIST A TAXIAS OF C HILDHOOD

Table 1. Approach to Diagnosis of Acute Ataxias Disease Diagnostic Features/Tests Acute cerebellar ataxia History of varicella-zoster/other viral infection CSF pleocytosis Drugs History of drug ingestion Blood drug levels Guillain-Barre´ syndrome Hyptonia, areﬂexia Elevated protein in cerebrospinal ﬂuid with normal cell count Cerebellar tumors Headache, vomiting, pappiledema Magnetic resonance imaging/computed tomography posterior fossa tumor

Acute Ataxias suspicion of a metabolic disease. Benign paroxsymal vertigo of childhood may present with a symptom complex charac- A history of viral illness, especially varicella-zoster virus terized by attacks of vertigo in young children combined infection or drug ingestion, may point toward the etiology. with nystagmus, ataxia, and transiently decreased vestibular The highest diagnostic yield is from a drug screen and cere- function but without impaired consciousness. Diagnostic and brospinal fluid examination. In one study, 80% of children follow-up studies reveal a close relationship to migraine who presented with ataxia had a discharge diagnosis of drug- (Table 2). induced or postviral ataxia or Gullain-Barre´ syndrome (45). However, the presence of other neurological signs would indicate the need for imaging and other studies. The presence Chronic Ataxia of headache, vomiting, and other signs of raised intracranial pressure would make imaging mandatory. Vertebrobasilar The most important considerations here are the progres- disease, strokes, and basilar migraine are other important sion of the disease process and associated signs. A static ataxia considerations (Table 1). represents either an inherited condition or a cerebral palsy. The inherited form is a heterogeneous group including such conditions as olivopontocerebellar atrophy (a predominantly Intermittent or Episodic Ataxia adult condition) to cerebellar atrophy with Werdnig- There are two important considerations here. Hereditary Hoffmann disease seen in children (46). Before making a episodic ataxia is a channelopathy and may respond to acet- diagnosis, pure ataxic cerebral palsy and hereditary metabolic azolamide. The other important consideration is metabolic conditions must be ruled out in the young child (Table 3). diseases presenting with intermittent ataxia. A variant form of Chronic progressive ataxias are important to recognize. maple syrup urine disease leading to intermittent branch Some of them are potentially treatable, such as ataxia with chain ketoaciduria, ataxia, and lethargy is known. Other vitamin E deficiency and Refsum’s disease. Most can be well-known metabolic diseases associated with ataxia are diagnosed by genetic or biochemical studies. It is important Hartnup disease, Leigh disease, pyruvate carboxylase defi- to remember that ataxia is almost never an isolated symptom ciency, and biotidinase deficiency. The presence of lethargy in metabolic or hereditary disease. Progressive ataxias also and vomiting and raised intracranial pressure should raise the may be a manifestation of slow-growing brain tumors and

Table 2. Approach to Diagnosis of Episodic/Intermitted Ataxia Disease Diagnostic Features/Tests Hereditary episodic ataxia Family history Response to acetazolamide Patients normal in between attacks Mutations in genes encoding for channels Metabolic diseases Vomiting and lethargy precipitated by infection Urine, blood for metabolic screen Benign paroxysmal vertigo Nystagmus, vestibular dysfunction No loss of consciousness Migraine variant V OL.7/NO .5/SEPTEMBER 2001 THE N EUROLOGIST 305

Table 3. Approach to Diagnosis of Chronic Ataxia Friedreich ataxia Progressive ataxia with mixed cerebellar and sensory features, sensory loss, loss of deep tendon reflexes Pes cavus, upward plantar, cardiomegaly, diabetes Variable phenotype with ataxia most constant feature Hyperexpansion of GAA trinucleotide repeat Ataxia-telangectasia Ataxia, oculocutaneous telangiectasia, immunological deficiencies, increased risk of malignancies Reduced IgG2, IgA, IgE Elevated AFP, CEA, chromosomal instability Abetalipoproteinemia (Bassen-Kornzweig syndrome) Fat malabsorption, areflexia, proprioceptive disturbances, acanthocytosis, cardiomegaly Absent apolipoprotein B Vitamin E deficiency Hereditary or with fat malabsorption Low fasting Vitamin E levels Reversible Refsum’s disease Retinitis pigmentosa, deafness, peripheral neuropathy Elevated cerebrospinal fluid protein and blood phytanic acid Subacute combined degeneration of the spinal cord Familial/genetic types more common in children Loss of proprioception, vibration Sensory ataxia, spasticity Homocystinuria present Vitamin B12 levels may be normal Reversible IG ϭ immunoglobulin; AFP ϭ alpha-feto protein; CEO ϭ careinoembyonic antigen.

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