Ataxia

Introduction and Overview

This chapter encompasses diseases and disorders of the cerebellum and its connections that cause problems coordinating movements.

A vast number of conditions adversely affect cerebellar function in children, and thus, a systematic approach to diagnosis is helpful. These present to neurologists as referrals for clumsiness, balance problems, gait problems, tremor, poor coordination, and abnormal eye movements. The diagnoses can be classified broadly. A first category, which commonly generates visits to the emergency department, are acute or subacute onset, acquired ataxias. These generally result from intoxications, infections, autoimmune or inflammatory processes, vascular insults, or trauma. Of particular importance are neoplasms, although these are far less common, and symptoms usually develop more slowly. A second broad category is children with nonprogressive difficulties with coordination who may either have Developmental Coordination Disorder or, less commonly, a nonprogressive congenital ataxia. A third broad category is paroxysmal, or episodic ataxias. Finally, there are the chronic, degenerative ataxias. While far rarer individually, their combined prevalence makes it likely they will be seen by pediatric neurologists in practice. Increased scope and availability of genetic panels and exome sequencing has improved speed and precision of diagnosis. Symptomatic or rational treatments may be worth pursuing, but to date effective rational, symptom-reducing or disease-modifying treatments remain extremely limited. Nonetheless, arriving at the most precise diagnosis possible has value for families, and some diagnoses have clear implications for management.

Definition of Ataxia

Ataxia is defined as an inability to generate a normal or expected voluntary movement trajectory that cannot be attributed to weakness or involuntary muscle activity (chorea, dystonia, myoclonus, tremor) about the affected joints. Ataxia can result from impairment of spatial pattern of muscle activity or from the impairment of the timing of that activity, or both.

Clinical Characteristics—Phenomenology of Ataxia in Children

Recognition of ataxia in children entails understanding the typical developmental course and acceptable variations in acquisition of motor milestones. Healthy children undergo development of motor coordination, and thus immature, ataxic-appearing movements can be physiological as new skills emerge in the context of development of motor circuits and networks. Walking, reaching, manipulating objects, and speaking mature in trajectories with broad variability. Experts rating 156 healthy, typically developing children ages 4–16 years using the Scale for Assessment and Rating of Ataxia (SARA) have shown that there are broad limits of normal up to age 8 years, and that typically developing children have “elevated” ataxia scores up to age 11 years. Judging dysarthria can be challenging as articulation problems are commonly encountered in healthy children. Pediatric neurologists evaluating possible ataxia thus must interpret the child's examination within this context.

Recognition also requires distinguishing ataxia from conditions which can mimic it. As implied by the definition, problems with coordinating movements can also occur due to various other neurological, orthopedic, and medical conditions. Reaching toward a target with a weak limb may give an appearance of dysmetria, as can the intrusion of other movement disorders such as chorea. Walking affected by pain or musculoskeletal pathology may have a wide-based, ataxic appearance. Functional movement disorders may mimic ataxia. Ataxia may also be accompanied by problems in other neurological symptoms, requiring comprehensive neurological evaluation.

The ataxic child may have generalized or localized motor coordination problems resulting in function below age-expected norms. Abnormal eye movements of several kinds, notably difficulties with saccade initiation, smooth pursuit, or fixation stability, may be identifiable as red flags, problems are not part of normal development. Speech in a cerebellar disease may be excessively slow and/or slurred relative to age-norms. Reaching out of hands to a target or to perform a task may demonstrate tremor and excessive clumsiness. Stability of the head and trunk may be poor and there may be consistent bobbing movements. Walking or running skills may be delayed and gait irregular or excessively broad-based. Older children may demonstrate lurching or staggering. Finally, ataxia may occur in combination with other movement disorders and other neurological signs.

Cerebellar disorders and diseases can adversely affect motor control of eyes, speech, trunk, and limbs in characteristic ways. Complex, multijoint movements are more impaired than single joint movements, with compensatory responses contributing to some aspects of observed movement abnormalities. Hallmark findings in patients with ataxias are presented in Table 14.1 .

Localization and Pathophysiology

Understanding the anatomy of the cerebellum and its afferent and efferent connections is helpful in clinical-anatomic correlations. This is addressed in detail in Chapter 2 . Clinical examples with MRI images in Figs. 14.1–14.8 provide an overview of some types of genetic and acquired cerebellar pathology in children and link these to clinical symptoms and signs described in Table 14.1 .

Diseases and Disorders

This chapter reviews some of the more common or important conditions causing ataxia in children. Acute clinical presentations of ataxia are discussed first. These often present to the emergency department, where neurologists see them in consultation. Metabolic and other genetic and conditions that present with acute bouts and sometimes recurring episodes of ataxia are discussed next. Finally, chronic conditions are discussed. Children with delays in motor development are often referred to pediatric neurologists, and it can be challenging to determine when clinical observation without diagnostic testing is reasonable. The emphasis of the remainder of the chapter is on genetic diseases presenting in childhood. These include syndromes with cerebellar malformations. For other static as well as progressive, degenerative diseases, discussion is organized by mode of inheritance.

Acquired Ataxias

Overview of Clinical Features and Diagnostic Approach

Acute ataxia, developing over a period of minutes to hours in a previously well child, usually presents with gait and balance impairment. This is often accompanied by tremor, eye movement abnormalities, and a confusional state. A large number of acute processes (partial list in Table 14.2 ) can affect cerebellar function in an acute or subacute manner. These include intoxications and accidental ingestions, seizures with post-ictal ataxia, trauma, autoimmune conditions, and metabolic diseases. Acute recurrent ataxias are discussed in the next section. A thorough history and skilled neurological examination, focusing on mental status, meningeal signs, signs of elevated intracranial pressure, oculomotor function, and focal motor signs is essential to identify serious causes. Pathophysiology, treatment, and outcomes are discussed by disease or category.

Table 14.2

Differential Diagnosis of Acute Ataxia in Childhood

Category	Examples	Clinical features, diagnostic essentials	Diagnostic testing
Acute Onset
Toxic acute ingestion	Alcohol, anticonvulsants, antihistamines, benzodiazepines, toluene	Toddlers—accidental ingestion; adolescents—substance abuse. Mental status changes common.	Urine/serum toxicology screen.
Inflammatory	Acute cerebellar ataxia	Symmetric cerebellar findings, gait impairment, truncal ataxia, titubation, nystagmus. Mental status normal or irritable. Usually postinfectious. Consider opsoclonus myoclonus ataxia syndrome.	Brain MRI (should be normal). Consider lumbar puncture for CSF studies.
Trauma/Vascular	Stroke, vertebrobasilar dissection	Consider after neck trauma or if hypercoagulable.	MRI brain, stroke protocol; vascular imaging of head and neck.
Subacute Onset
Inflammatory	Acute disseminated encephalomyelitis (ADEM)	Mental status changes; and multifocal neurologic deficits. Obtain brain MRI.	Brain MRI (should show multiple discrete lesions involving both gray and white matter). Lumbar puncture for CSF studies.
	Guillain Barre syndrome, including Miller Fischer Variant	Oculomotor paresis, bulbar weakness, hyporeflexia, radicular pain. Risk for respiratory/autonomic failure. Note—weakness localizing peripherally may masquerade as ataxia due to problems with limb control and gait.	Brain MRI (should be normal). CSF for cells, protein, possibly infectious/inflammatory markers.
	Opsoclonus myoclonus ataxia syndrome	Truncal ataxia, multifocal myoclonus, opsoclonus (may be transient), behavioral irritability.	Image abdomen, pelvis, chest for occult neuroblastoma. Urine catecholamines.
	Chronic lymphocytic inflammation with pontine perivascular enhancement, responsive to steroid (CLIPPERS)	Oculomotor paresis, facial weakness or numbness, dysarthria, nystagmus, ataxia.	Brain MRI.
Infections/Inflammatory	Acute cerebellitis	Headaches, vomiting, papilledema, cranial nerve palsies, ataxia.	Brain MRI.
Mass lesions	Posterior fossa neoplasms	Headaches, vomiting, papilledema, cranial nerve palsies, ataxia.	Brain MRI.
Recurring/Episodic
Metabolic	Inborn errors of metabolism: Amino or organic aciduria, mitochondrial disorders, biotinidase deficiency, biotin-thiamine-responsive basal ganglia disease, glucose transporter type 1 deficiency.	Can result from metabolic decompensation during illness. Consider if child has preexisting intellectual disabilities, positive family history, consanguinity; or presents with encephalopathy and vomiting.	Obtain biochemical testing while ill. Follow-up with genetic testing.
Migrainous	Basilar migraine, benign paroxysmal vertigo	In the young child, headache may not be prominent.	Brain MRI for initial episode.
Episodic ataxias	Genetic episodic ataxias, often due to mutations in ion channel genes.	Bouts of dysarthria, gait ataxia, sometimes with characteristic provoking factors.	Review home video of episodes. Genetic testing.
Functional	Functional neurologic symptom disorders with abnormal movements	Gait disturbance or abnormal tremor-like movements which have fluctuating, on-off time course, variable direction, amplitude, and frequency, and otherwise do not conform to usual pattern of disease. Uneconomical gait, excessive sway without falling may be seen.	Neurological examination of gait, motor control (video). For tremor-like movement, include distraction, entrainment.

Intoxications

Accidental ingestions, often in toddlers and young children, may cause ataxia, sometimes in conjunction with an acute confusional state. Anticonvulsant medications, alcohol, stimulants, and other exposures can often be identified by history, and urine/serum drug screening. Pathophysiology relates to disruption of neural signaling in cerebellum or damage to cerebellar pathways. Intoxication through cannabis ingestion has increased in young children, with approximately 10% of these cases presenting with ataxia. Methadone poisoning can also present with ataxia. Treatment for intoxications is mainly supportive, and outcomes in children are usually excellent.

Acute Cerebellar Ataxia: Inflammatory and Infectious Etiologies

Acute Cerebellar Ataxia

Acute cerebellar ataxia may occur after a clinical or subclinical infection, particularly with varicella zoster virus, or after vaccination. ^, After vaccinations in adolescents, functional (psychogenic) illness may also occur, so caution must be taken in verifying the history, time course, and especially the phenomenology. A variety of other preceding infections, including enterovirus, parvovirus, rotavirus, and malaria have been described, but most often no single preceding infection is accurately identified. Symptoms of gait ataxia occur almost universally, with truncal ataxia less common and nystagmus in fewer than 25%. CSF abnormalities, if present, are nonspecific: elevated WBC in 30%–50%, elevated protein in 6%–27%. The pathophysiology is unclear but may be similar to paraneoplastic ataxia in adults. Antibodies to multiple glutamate receptors, expressed in Purkinje and other cells, have been described. Recovery is complete in approximately 90%, with mean time to normal gait of 2–3 months. Treatment is not currently recommended although steroids, IVIG, or plasmapheresis can be considered. ^,

Opsoclonus Myoclonus Ataxia Syndrome (OMS or OMAS)

OMAS should be considered in the differential diagnosis of the young child presenting with subacute ataxia because of phenomenological overlap. The clinical features are contained in the name of the syndrome, but it is noteworthy that the classic eye movement abnormality, opsoclonus (saccadomania), may be missed due to its transient nature, and by history may be difficult to distinguish from nystagmus. In addition, truncal myoclonus and multifocal myoclonus may be difficult to distinguish from truncal ataxia, titubation, and action tremor in a toddler. Opsoclonus myoclonus may be postviral or paraneoplastic, related to the solid tumor neuroblastoma. Additional details on the diagnostic testing process and management are found in Chapter 12 .

Acute Disseminated Encephalomyelitis (ADEM)

ADEM is a multifocal, clinical CNS event with presumed inflammatory demyelinating cause. In addition to encephalopathy, motor findings such as ataxia are common. Brain MRI during the acute phase shows multiple diffuse, poorly demarcated lesions in white matter and also sometimes in deep gray matter. Time course is usually monophasic, lasting for weeks, with recurrence rate estimates variable. The pathophysiology is presumed autoimmune, triggered by infections or in rare cases by vaccinations. The presence of antibodies to myelin oligodendrocyte glycoprotein (anti-MOG) has been linked to higher rates of ataxia. Presentation may overlap with other autoimmune ataxias. The diagnosis should be considered in a child with subacute decline in mental status and motor function and is generally confirmed through the characteristic MRI findings: multi-focal, multiple sclerosis-like lesions involving both white and gray matter. The most common treatment approach is steroids (intravenous [IV] methylprednisolone at 10–30 mg/kg/day up to a maximum of 1 g/day, followed by a 4–6 week oral taper). IV immunoglobulins (1–2 g/kg dose) and/or plasmapheresis are sometimes deployed. There are no randomized controlled treatment trials. Outcomes of ADEM vary. The majority have no recurrence at 2 years of follow-up, but up to 36% experience another demyelinating event.

Acute Cerebellitis

This term describes a rare acute/subacute encephalitis syndrome involving the cerebellum, typically caused by current or recent infection. Presenting symptoms and signs may include ataxia, headache, vomiting, altered mental status, dysarthria, nystagmus, mutism, and other cerebellar signs. In the acute period, brain MRI shows cerebellar involvement including edema with hyperintensity in T2 or fluid attenuated inversion recovery (FLAIR) imaging, diffusion restriction, or contrast enhancement. ^, Typically, this occurs in young children, usually aged 2–14 years. While the cause may not be identified, cases have been described with specific infections including varicella virus, rotavirus, ^, hemolytic streptococcal infection, and JC Virus. Tonsillar herniation, obstructive hydrocephalus, and death may occur. Lumbar puncture may be contraindicated due to posterior fossa swelling. If obtained, CSF findings may be noninformative in some cases. The most common treatment is steroids, for example, intravenous methylprednisolone. Intravenous immunoglobulin, antivirals, and/or antibiotics may also be used. Long-term clinical sequelae may include ataxia, tremor, learning or behavioral problems. Repeat imaging may demonstrate sequelae of cerebellar volume loss (See Fig. 14.1 ).

Guillain-Barre Syndrome, Miller Fisher Syndrome Variant

Guillain-Barre Syndrome designates an acquired, immune-mediated polyneuropathy presenting primarily with acute, ascending flaccid paralysis and hypo- or areflexia on neurological examination. This is a heterogeneous group of overlapping neuropathic conditions that may be generalized or localized. In most pediatric cases, there is an upper respiratory infection or, less commonly, acute gastroenteritis, preceding the neurological presentation by two to 4 weeks. The diagnosis is generally confirmed by lumbar puncture, with CSF showing elevated protein levels with no or only minimal elevation of white blood cells. The Miller Fisher variant is characterized by ophthalmoplegia and ataxia. ^, First-line recommended treatment is intravenous immunoglobulin primarily, second line is plasmapheresis if needed.

Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids (Clippers)

Clippers is a rare, pontine-predominant encephalomyelitis. Patients may present with diplopia, facial paresthesias or weakness, dysarthria, nystagmus, and ataxia. MRI shows enhancing, speckled or patchy areas of signal change in the pons and cerebellum. CSF may show lymphocyte-predominant pleocytosis. Biopsies have shown perivascular infiltration of T cells. Treatment with steroids improves symptoms, but relapses occur during tapering. Other treatments may then be added such as rituximab, an anti-CD20 monoclonal antibody, or natalizumab, a humanized monoclonal antibody against the cell adhesion molecule alpha4-integrin.

Tick Paralysis

Children with tick paralysis may present with ascending paralysis, bulbar weakness, and occasionally ataxia, due to a neurotoxin carried in tick saliva. Children may be misdiagnosed as having Guillain Barre Syndrome. The pathophysiology is believed to involve a failure of neuromuscular transmission. The diagnosis should be considered in the proper clinical context, and the scalp of the child carefully inspected for ticks. Treatment is removal of the tick, and supportive care until symptoms resolve, usually rapidly.

Malignancy-Related Ataxia

In addition to Opsoclonus Myoclonus Ataxia syndrome described above, children can present with ataxia or other movement disorders due to tumors in the cerebellum, due to paraneoplastic pathophysiology, or due to complications of treatment.

Tumors

In children with more rapidly progressive symptoms or when neoplasms are suspected, the neurological examination should be carefully documented and brain MRI with intravenous contrast should be ordered. Particularly when the subacute presentation of ataxia also involves headaches and acquired ocular malalignment, neuroimaging may identify a neoplasm or other space occupying lesion. A thorough discussion of neoplasms and surgical lesions lies outside the scope of this textbook, but helpful recent reviews may be consulted. In general, it should be borne in mind, however, that the most common pediatric brain tumors—pilocytic astrocytomas, primitive neuroectodermal tumors (PNETS, also known as medulloblastomas), ependymomas (see Fig. 14.2A ), and diffuse intrinsic pontine gliomas (DIPGs) (see Fig. 14.2B )—are more likely to present in the posterior fossa in children. Thus headache, ocular malalignment, and ataxia may develop. Of these tumors, the pilocytic astrocytomas are most amenable to surgery and have the best outcome. Surgical treatment of cerebellar tumors may be curative but may also induce new neurological problems such as cerebellar mutism. This is most common after resections of midline PNETs with brainstem invasion, and varying degrees of mutism and ataxia may persist for greater than 1 year. Cerebellar tumor survivors often have fine motor impairment, ataxia, and cognitive dysfunction.

Paraneoplastic, Histiocytosis-Related Cerebellar Leukoencephalopathy

Children with histiocytosis may present with progressive cerebellar symptoms affecting gait, coordination, and speech. Spasticity, tremor, dystonia, cognitive decline, and behavioral symptoms, and dystonia may also occur. MRI demonstrates symmetric T2 signal change in cerebellar white matter as well as the hilus of the dentate nucleus, pyramidal tracts, basal ganglia, and spinal cord in some cases and calcification of dentate nuclei. This is believed to be a neurodegenerative, paraneoplastic complication of histiocytosis, a disease characterized by abnormally increased numbers of histiocytes, either Langerhans cells (LCH), non-Langerhans cells (nLCH), or malignant cells. A cerebellar leukoencephalopathy may precede or follow the diagnoses of Langerhans or non-Langerhans cell histiocytosis. Characteristic or specific paraneoplastic antibodies have not been identified. The diagnosis should be suspected in children with progressive ataxia and symmetric white matter findings in the clinical context known or suspected histiocytic disease or in children with progressive ataxia with symmetric hyperintense T2 signal in cerebellar white matter and dentate nuclei. Endocrine abnormalities including diabetes insipidus and growth failure due to pituitary infiltration may also occur. Treatment focuses on the histiocytosis, the underlying hematological disorder.

Limbic Encephalitis and Subacute Cerebellar Degeneration

The typical presentation of limbic encephalitis includes encephalopathy, with cognitive and emotional symptoms, seizures, and continuously present movement disorders such as chorea, ataxia, or dystonia. Subacute cerebellar degeneration presents with ataxia, vestibular symptoms, parkinsonism, dystonia, tics, and psychiatric symptoms. Malignancies inducing these syndromes can include ovarian and testicular tumors, germ cell tumors, thymomas, and Hodgkin's lymphoma. Antibodies that can be identified include Purkinje cell cytoplasmic antibody 2 (PCA-2), ^, among others. Imaging (ultrasound, MRI, CT) of the abdomen and pelvis is indicated when paraneoplastic syndromes are suspected. Treatment includes removal of or other treatment of malignancy, immunomodulatory therapy, particularly for syndromes with antibodies to membrane (as opposed to intracellular) proteins, and rehabilitative therapy.

Ataxia due to Chemotheraphy Side Effects

Life-saving chemotherapies may have unwanted effects in the nervous system. These include seizures, posterior reversable encephalopathy syndrome, and neuropathy. Transient ataxia can occur with blinatumomab, fludarabine, and retinoids as well as after intrathecal cytarabine. Delayed onset ataxia and sensory neuropathy can occur with fludarabine, nitrosureas, platinum-based (e.g., cisplatin), and vinca alkyloids (e.g., vincristine). Ataxia can also occur transiently after cranial radiation therapy. Progressive ataxia and neurological dysfunction has also been described as a long-term complication of allogeneic bone marrow transplantation in patients with Chediak-Higashi syndrome.

Vitamin/Nutritional Deficiency Related Ataxia

Vitamin B12 Deficiency

Vitamin B12 deficiency causes megaloblastic anemia but can also cause neurological symptoms including a sensory ataxia, with demyelination of the posterior columns of the spinal cord or subacute combined degeneration, which also includes the lateral columns. While rare in children, it can result from nutritional deficiency, including severely restricted vegan diet, or from more generalized nutritional deficiencies, when it may present with other symptoms and signs including visual complaints, fatigue, poor concentration, paresthesia, and hypotonia. B12 treatment can reverse the neurological deficits and normalize MRI findings.

Celiac Disease

Celiac disease is a gastrointestinal disorder involving immunological responses to gluten, a protein found in wheat, rye, and barley. Its development is highly associated with presence of human leukocyte antigen HLA-DQ2 or HLA-DQ8. Clinical symptoms vary and include both intestinal and extraintestinal problems including neuropathy and, rarely, ataxia. While purported immune biomarkers of neurological disease related to gluten include transglutaminase (Tg)-6 immunoglobulin IgA/IgG and Tg-2/deamidated gliadin IgA/IgG, these are nonspecific and their etiological role is controversial. ^, Neurological symptoms in celiac disease may develop due to enteropathy and subsequent malabsorption of nutrients such as copper or vitamin E. Gluten ataxia results from damage to the cerebellum, posterior columns of the spinal cord, and peripheral nerves. As this a late complication, it appears to be quite rare in children. ^,