Chapter 7. Ataxia

Ataxia is a term derived from Greek referring to impairment and lack of ability to coordinate or perform voluntary movements.1 Ataxia can present and be noted in children of all age groups ranging from young infants to adolescents. Both genders, plus all racial and ethnic groups, may be affected. However, since there are many conditions and disorders that may cause ataxia in children, there is great variability in its underlying pathogenesis, risk factors, and presentation.

The cerebellum is the structure that, its dysfunction, is commonly attributed to the presentation of ataxia. On the other hand, disturbance to the structures or function of other sites such as the peripheral nerves, dorsal columns of the spinal cord, brainstem, or frontal cerebral cortex, which provide connections or pathways into and out of the cerebellum, may also play contributing roles in ataxia.2,3

Most children presenting with ataxia typically present with abnormal gait.2 Some parents usually describe their children as clumsy, with poor coordination and balance, and unable to perform motor tasks smoothly4,5; whereas some are reported to walk as if under the influence of alcohol.6 The gait is usually wide-based and staggering, with elevation of the feet and then slapping the soles on the ground.2 The impaired balance and coordination may be worsened by closing both eyes (Romberg sign). Dysfunctions in the sensory and proprioceptive cerebellar inputs from the peripheral nerves and the posterior spinal columns may result in children looking at their feet during ambulation.2,3 Frequent falls and fears of injury may urge parents to seek advice from health care professionals. Lesions affecting the cerebellar vermis may lead into ataxia affecting the trunk with difficulties in maintaining axial posture and balance in an upright position. In addition, titubation (bobbing of the head forward and backward)4 may be noted with vermal lesions. The lesions affecting the cerebellar hemispheres may lead into hypotonia and ataxia affecting the limbs ipsilaterally.4

Associated findings in children presenting with ataxia may also include impaired speech, ocular movements, fine motor skills, and intentional tremors.4 The speech may be described as slow, scanning, with uneven volume and separation of syllables.2,4 Nystagmus and ocular dysmetria, overshooting and an inability to keep the moving eyes towards a targeted point, may be noted.1,6 The smooth and accurate performance of rapid alternating movements (diadochokinesia) and complex motor activities may be impaired.4Tables 7-1 summarizes some of the common and rare presentations of signs and symptoms of ataxia in children.

Obtaining an adequate history is the most essential part of evaluating children who present with ataxia. Some of the key elements in the history that can help with identifying the underlying causes include the child's age plus the course and pattern of onset at the time of presentation (acute versus chronic, intermittent, or progressive). Presence of fever, cough, congestion, rhinorrhea, rash, vomiting, or diarrhea at the time of or within few weeks prior to presentation may identify an infectious or postinfectious source. Other features such as confusion, stiff neck, and seizures may be worrisome for more serious etiologies including meningitis, meningoencephalitis, or acute disseminating encephalomyelitis (ADEM). Experiencing head and neck trauma plus exposure to drugs and toxins should be determined. Headaches, emesis, and focal neurological findings are of concern for acute complications of mass lesions (tumors, abscess, arteriovenous malformations), strokes, or hemorrhage in the regions of the brainstem, cerebellum, or the posterior fossa. Intermittent and recurrent ataxia may be suggestive of migraines, epileptic seizures, postictal period, or disorders of inborn error of metabolism. Chronic or progressive ataxia may be caused by slowly developing tumors or congenital structural malformations, genetic, inherited disorders.

Additional information that may be beneficial in evaluating and diagnosing a child with ataxia include the presence of other medical or systemic illnesses, adequate assessment of the developmental milestones, plus the detailed family and social histories.

After gathering and obtaining a detailed history, a comprehensive general and neurological examination should be performed. The neurological examination should start with the evaluation of the child's mental status. The examiner should assess the alertness, social interaction, eye contact, and response to verbal and tactile stimuli. In older children, the speech, spelling, naming of objects, calculation, attention, recent or remote memory, and general fund of knowledge should be determined.

A detailed examination of the cranial nerve function and integrity with assessment of the vision, pupillary response to light and accommodation, extraocular movements, nystagmus, facial muscles strength and sensation, hearing, chewing, swallowing, gag reflex, neck and tongue sensation, plus movement should be emphasized. A fundoscopic examination of the eyes should be performed to evaluate for papilledema.

The strength, sensation for light touch, pin prick, temperature, vibration, proprioception, muscle tone, and deep tendon reflexes can also be helpful in localizing other lesions within the nervous system that may be attributed to ataxia.

The cerebellar exam may reveal intentional tremor, dysmetria, abnormal diadochokinesia, and heel to shin or a positive Romberg sign. The gait exam focusing on heel, toe, and tandem walking are also essential in evaluating children with ataxia.

Acute presentation of ataxia may be caused by a variety of conditions including infections, postinfections, trauma, toxins, inflammatory, tumors, strokes, hemorrhage, and seizures (Table 7-2).2,3,5 Among the infectious agents, viruses including varicella, Epstein–Barr virus, echovirus, coxsackievirus, measles, mumps, HIV, rubella, and polio are commonly associated with ataxia.2,3,5 Bacterial agents such as Streptococcus pneumoniae, Haemophilus influenzae, Listeria monocytogenes, and Escherichia coli are common pathogens.2,3,5 Syphilis, Lyme disease, tuberculosis, and mycoplasma pneumoniae have also been associated with ataxia in children. Toxoplasmosis and cysticercosis are two parasitic agents commonly attributed to ataxia,3 especially among individuals exposed to cat feces and the immigrant population from Latin America and Asia, respectively. Postinfectious conditions such as ADEM and inflammatory disorders such as multiple sclerosis can also lead to acute ataxia.

Head injuries sustained from falls or motor vehicle accidents to nonaccidental injuries due to child abuse can lead to acute ataxia. Exposure to toxins such as drugs (antiepileptics, benzodiazepines), alcohol, lead, mercury, and carbon monoxide must be excluded. Mass lesions such as tumors or vascular insults to the cerebellum or brainstem as the result of thrombosis, embolism, or hemorrhage may occur, along with cranial nerve deficits plus signs and symptoms worrisome for increased intracranial pressure.

Chronic, intermittent, and progressive ataxias may be caused by genetic, structural, or degenerative disorders. The hereditary causes are usually categorized into autosomal dominant and autosomal recessive disorders.7 Some of the autosomal dominant conditions include the spinocerebellar ataxias (SCA types 1–28) and episodic ataxias (EA type 1 and 2). The autosomal recessive disorders include Friedreich ataxia (FRDA), ataxia-telangiectasia (A-T), and ataxia with vitamin E deficiency (AVED).7 The urea cycle enzyme deficiencies, aminoacidurias, and impaired lactate and pyruvate metabolism are examples of inborn errors of metabolism that can lead to progressive ataxia in children.2 Congenital structural malformations such as aplasia or dysplasia of the cerebellar hemisphere or vermis, plus Dandy-Walker and Chiari malformations, may also present with chronic ataxia.2 Brain tumors such as ependymomas, meduloblastomas, and cerebellar astrocytomas should be excluded (Table 7-3).

There are several genetic disorders such as Friedreich and non-Friedreich ataxias that can present with ataxia among children.

Friedreich Ataxia

Epidemiology

Friedreich ataxia is an autosomal recessive triple repeat disease with a number of components. Symptoms are present by age 10 years in about half of those affected, and almost all have symptoms by the early 20s.

Etiology/Pathogenesis

Friedreich ataxia occurs secondary to a mutation of the mitochondrial protein, frataxin, located on chromosome 9. Spinal cord degeneration occurs in three distinct regions: (1) posterior columns and dorsal root ganglia, (2) corticospinal tracts, and (3) spinocerebellar tracts. The sensory neuropathy associated with Friedreich ataxia occurs because of progressive degeneration of the dorsal ganglion and axon. There is some associated secondary demyelination.

Clinical Features

The primary feature of Friedreich ataxia is gait ataxia. This ataxia is progressive and typically leads to the need for a wheelchair. There is associated peripheral neuropathy, dysarthria, and cardiomyopathy (in 50% of cases). Hearing loss and optic atrophy occur only rarely. Most patients are unable to walk by age 30 years.

Treatment

There is no specific treatment for Friedreich ataxia. The patient is at risk of falling, and appropriate safety measures should be taken. Furthermore, the patient's feet should be checked on a daily basis for cuts or blisters that might otherwise go unnoticed because of the sensory loss.

Non-Friedreich Ataxia

There are a number of distinct and unrelated diseases that have phenotypes similar to Friedreich ataxia.

Ataxia with Vitamin E Deficiency (Aved)

Ataxia with vitamin E deficiency arises secondary to abnormalities in vitamin E absorption or metabolism. AVED can result in a syndrome clinically indistinguishable from Friedreich ataxia. AVED is an autosomal recessive disease with a mutation in the gene encoding for alpha-tocopherol transfer protein (alpha-TTP), and results in low or undetectable levels of vitamin E without associated fat malabsorption.

Abetalipoproteinemia (Bassen-Kornzweig Syndrome)

Abetalipoproteinemia is a rare autosomal recessive disorder of lipoprotein metabolism. There is malabsorption of vitamin E. There is an absence of apolipoprotein B-containing proteins (chylomicrons, LDL, VLDL), and diagnostic studies can help in distinguishing this disorder from Friedreich ataxia, including a low serum cholesterol level, acanthocytosis on peripheral blood smear, and an abnormal serum protein electrophoresis. Furthermore the presence of retinopathy distinguishes the disorder from Friedreich ataxia.

Acquired Vitamin E Deficiency

Acquired vitamin E deficiency can be associated with severe fat malabsorption in diseases such as cystic fibrosis, cholestatic liver disease, celiac disease, and short bowel syndrome. While there may be an ataxia clinically similar to Friedreich ataxia, there are typically symptoms associated with the primary disease that guide diagnosis.

Early-Onset Cerebellar Ataxia with Retained Reflexes (Eoca)

The early-onset cerebellar ataxias are a heterogeneous group of disorders, most of which are autosomal recessive. The EOCA disorders have a childhood onset resembling Friedreich ataxia but with retained reflexes. There may be spasticity, but the diabetes, cardiac disease, and skeletal deformities are absent. The Friedreich ataxia triplet repeat test is negative and the prognosis is better than with Friedreich ataxia.

Progressive Ataxia Associated with Biochemical Abnormalities

Multiple inherited diseases can cause progressive ataxia, including ceroid lipofuscinosis, cholestanolosis, ataxia-telangiectasia, xeroderma pigmentosum, Cockayne syndrome, GM-2 gangliosidosis, adrenoleukodystrophy, metachromatic leukodystrophy, mitochondrial diseases (MERRF, KSS, NARP), sialidosis, and Niemann-Pick and sphingomyelin storage disorders.

Ataxia Telangiectasia (Louis-Bar Syndrome)

Ataxia telangiectasia is an autosomal recessive disease with a mutation in the ATM gene (leads to defect in DNA repair) on chromosome 11. Symptoms of ataxia telangiectasia typically begin during infancy. There is progressive truncal ataxia, usually resulting in the patient being wheelchair-bound by age 12 years. The hallmark oculocutaneous telangiectasias usually appear between ages 3 and 5 years, well after the onset of ataxia. Other symptoms include dysarthria, nystagmus, oculomotor dyspraxia, dystonia, athetosis, myoclonic jerks, polyneuropathy, and cognitive dysfunction.

Diagnostic studies reveal elevated AFP and CEA levels (alpha-fetoprotein and carcinoembryonic antigen), and decreased or absent IgA levels. Fibroblasts can be screened for increased x-ray sensitivity and radioresistant DNA synthesis. The associated immunodeficiency leads to recurrent respiratory infections. Ataxia telangiectasia is also associated with cancer, typically leukemias and lymphomas. The average age of death is 20 years and is usually from infection or neoplasm.

Progressive Myoclonic Ataxias

The progressive myoclonic ataxias are a heterogenous group of childhood disorders associated with progressive cerebellar ataxia and action myoclonus. Most of these disorders are due to mitochondrial disorders (MERRF, KSS, NARP). Rare cases of polyQ disease and dentatorubral-pallidoluysian atrophy (DRPLA) have juvenile onset.

The information obtained from an adequate history and detailed exam can help the clinician select the appropriate diagnostic tests that can help identify the underlying causes of ataxia. Table 7-4 provides a list of some diagnostic tests commonly used in evaluating children who present with ataxia. Imaging techniques such as MRI and CT scans should be performed in children presenting with ataxia who are suspected of harboring mass lesions, stroke, or hemorrhage in the cerebellum and brainstem. In the case of suspected infectious etiologies, appropriate microbiological cultures and cerebrospinal fluid specimens should be obtained. A urine drug screen can be helpful in identifying any potential exposure to medications, drugs, or toxins. For those children with family histories of ataxia, specific genetic testing for either the autosomal dominant or recessive disorders is encouraged. Electroencephalograms (EEG) should be considered if the child presents with encephalopathy or suspected seizures. Testing the blood, urine, and CSF for metabolic disorders is emphasized in the progressive circumstances. Table 7-5 recommends appropriate specialists who may be helpful in evaluating and managing children presenting with ataxia.

Antibiotics and antiviral agents may be used in the case of infectious sources of ataxia. Anti-inflammatory drugs such as corticosteroids and immunomodulating drugs can be helpful in postinfectious and autoimmune disorders such as ADEM and multiple sclerosis, respectively. Eliminating and discontinuing the use of toxins or substances leading to ataxia should be emphasized. Surgical resection and radiation therapy of mass lesions may be appropriate. Providing the appropriate hormones such as thyroid and nutritional supplements such as vitamins E, B12 and thiamine may be helpful in preventing the progression of their corresponding disorders. Dietary restriction of proteins and glucose may be beneficial in children suffering from the inborn errors of metabolism. The anti-epileptic drugs can prevent ataxia related to epileptic seizures but in some cases can cause ataxia as a side effect. Acetazolamide may be beneficial in reducing the increased intracranial pressure in children with episodic ataxia. Referral of individuals with strong family histories of ataxia to a geneticist is highly recommended. Children presenting with conversion disorders (a rare cause) should be treated and managed by counselors and psychiatrists.