Ataxia in children: early recognition and clinical evaluation

The most common causes of acute ataxia in children are excessive drug ingestion, drug intoxications and post-infectious cerebellitis. Antiepileptic drugs that may cause ataxia include benzodiazepines (diazepam, clobazam, nitrazepam), oxcarbamazepine, lamotrigine and phenytoin [7‐9] and antineoplastic/immunosuppressive agents such as cyclosporine, tacrolimus, cytosine arabinoside and similar drugs [1]. Ataxia may also be related to intoxications to various elements such as alcohol, ethylene glycol, lead, mercury, thallium, lithium and toluene [10, 11].

Low intake of the vitamins thiamine, cobalamin, vitamin E, zinc and folate in neglected children or in children affected by intestinal disorders may results in symptoms of ataxia [1‐3].

Varicella is one of the primary infectious agents that affects the cerebellum. The disorder may hit children of all ages, but it is most prevalent between the ages of 2 and 8 years. In this case, ataxia begins 2–6 days after the onset of rash, but it may also occur during the incubation period or after resolution of the rash [12]. Among the other involved infectious agents, cerebellar impairment may manifest itself after mumps or infectious mononucleosis. Syphilis and Whiplle’s disease, HIV, and Kawasaki disease may also be causes of ataxia [1‐3]. Labyrinthitis is often associated to ataxia and is difficult to differentiate from acute cerebellar ataxia.

The recent discoveries on immunomediated disorders have increased the number of the various affections that exhibit signs of ataxia. One of the most controversial is the association of ataxia with antigliadin antibodies, so-called “gluten ataxia.” Children presumed to be affected by this disorder present gait ataxia, nystagmus, peripheral neuropathy and brain involvement upon MRI as a consequence of a gluten trigger. A gluten-free diet has been reported to improve the clinical signs in the affected patients [13]. In a systematic review and metanalysis led by Lionetti et al. [14], the presence of cerebellar gluten-ataxia was documented in two large studies and reported in 2.7 and 5.4% of patients, respectively; no correlation was found between coeliac patients and ataxia in two other study-analyses. Patients with malignancies—mainly patients with Hodgkin’s lymphoma and other types of neoplasms—may present ataxia. Anti-Purkinje cells, anti-Yo (type 1), anti Hu, and anti Ri antibodies have been reported in affected patients [15]. Antibodies to glutamic acid decarboxylase associated with thyroid disorders and/or insulin-dependent diabetes mellitus may manifest ataxia as one of the presenting signs [16], but this disorder is rare among children. In the group of thyroid disorders, the autoimmune thyroiditis also called Hashimoto encephalopathy may manifest with ataxia. This severe condition presents a progressive course and behavioral changes such as aggressivity and psychotic crises, sensory dulling, headache, memory deficits, tremor, myoclonus, and, in the most severe cases, coma [17, 18]. Ataxia is one of the components of ophthalmoplegia and areflexia of the triad of Miller-Fisher syndrome, which belongs to the group of Guillain-Barrè syndrome and is linked to the presence of the antibody anti CQ1B. Diagnosis of this syndrome is obtained via an analysis of cerebral liquor, which displays a dissociation between high CSF protein levels and a low or absent leucocyte response [19].

Basilar migraine, “episodic ataxias” (EAs) including benign paroxysmal ataxia may manifest with ataxia. Basilar migraine is part of the subgroup of headaches, and intermittent ataxia is one of the signs of this condition, together with impaired vision, dysarthria, dizziness and occasional loss of consciousness. Familiarity, recurrence of headache episodes, and normality of the neurologic examination are elements that often lead to a diagnosis of basilar migraine [20]. EAs represent a clinically heterogeneous groups of conditions with recurrent bouts of abrupt-onset of ataxia lasting minutes to hours. Clinical manifestations may also include vomiting, vertigo, headache, dysarthria, diplopia and dystonic attacks. Eight subtypes have been recently distinguished according to clinical and genetic characteristics and 5 genes are recognized to be linked to EAs more common being KCNA1 and CACNA1A genes mutations [21]. Some of these disorders, mainly the types 2, 3, and 5 EAs have shown a good response to treatment with acetazolamide [22].

Some inborn errors of metabolism may present with intermittent ataxia. An example of this condition is Hartnup disease, an autosomal recessive (AR)-inherited disorder due to an abnormal renal and gastrointestinal transport of neutral amino acids. The primary sign of this disorder is cutaneous photosensitivity. Sun exposure in affected children causes cutaneous redness, and a pellagra-like rash that is severely pruritic. Some patients show an intermittent, unsteady, wide-based gait. Prognosis is usually benign [23‐25]. Maple syrup urine disease (MSUD) is an AR disorder that involves branched-chain amino acids. The diagnosis is based on the classical sweet smell of maple syrup of the urines. Several phenotypes of MSUD are recognized: in the intermittent MSUD type during stress or an infectious episode, children may present vomiting and ataxia. When not treated, the disorder can lead to lethargy until coma [26, 27]. Pyruvate dehydrogenase complex deficiency is typically a severe disorder with different clinical aspects and biochemical presentations. In older children, the enzyme activity may be partially present and result in mild-to-moderate hyperlactic acidemia and ketoacidosis following stress, infectious episodes and high carbohydrate ingestion. This disorder is clinically associated with frequent episodes of ataxia, vomiting and breathing difficulties [28, 29].

Mutations in genes coding for ion channels and transport proteins are associated with hereditary episodic ataxia and vertigo [30, 31].

This group includes the outcome of patients suffering from stroke and hypoxic-ischemic encephalopathy outcome. This condition is the most frequent cause of cerebral damage with an incidence rate of 1.5 individuals per 1000 newborns. The cerebral involvement is linked in about 90% of cases to perinatal asphyxia that acts through two linked pathogenetic mechanisms: hypoxia with reduced hematic O₂ concentration and ischemia with lowered cerebral perfusion [32]. The affected children show several manifestations with cognitive delay, epileptic seizures, spasticity, impairment of voluntary movements and coordination and neuro-behavioral anomalies such as aggressivity and restlessness [3].

Chronic ataxic manifestations that are typically not progressive may be found within two cerebral malformation syndromes: Dandy-Walker syndrome (DWS) and Arnold-Chiari malformation (ACM). The first syndrome is characterized by an enlargement of the fourth ventricle, the complete absence of cerebellar vermis and cystic formation near the internal base of the skull. In ACM, the affected children show a downwards displacement of the cerebellar tonsils through the foramen magnum with a presumed risk to complicate with a non-obstructive hydrocephalus.

Multiple sclerosis in young children may initially manifest as intermittent ataxia [1, 3, 6].

Ataxia is one of the signs indicative of cerebellar malformation in which the cerebellum can be totally or partially involved. The most well-known form is Joubert’s syndrome, an AR disorder due to a congenital ponto-cerebellar hypoplasia (PCH). Affected patients present neonatal hypotonia, ocular motor apraxia, breathing difficulties and multiple systemic involvement. More than 20 causative genes of Joubert’s syndrome have been recognized, most of which are related to proteins of the primary cilium, a subcellular organelle that carries out specific cellular functions. Diagnosis may be based on a typical sign of the molar tooth observed in the brain MRI of affected patients. The sign is related to the extension of the cerebellar superior peduncles in association with the depth interpeduncular furrow that resembles the shape of a molar tooth [33, 34].

Lack of development and/or early neurodegeneration of cerebellum and brainstem are the main characteristics of PCH. These conditions encompasses a constellation of genetic conditions with involvement of several genes and distinctive clinic-radiological phenotypes [35].

The pathologic anomalies of PCH consist of distinctive features including a reduced number of cellular folia and poor folial branching, degeneration and disappearance of pontine nuclei, fragmentation of dentate nuclei, variable degenerative changes and poor branching of the inferior olivar nuclei [36].

Inherited ataxias include a heterogenous group of clinically and genetically distinguished neurodegenerative disorders. The most well-known of the inherited ataxias include autosomal dominant cerebellar ataxia reported as spino-cerebellar ataxias (SCAs) and autosomal recessive cerebellar ataxias (ARCAs). X-linked inherited forms and ataxia associated with mithochondrial disorders are also included in this group (Figs. 4 and 5).

Presently, more than 35 types of SCAs are recognized. The forms of SCAs are categorized according to the number assigned to the gene loci from SCA1 to SCA37. Dentato-rubral-pallidoluysian atrophy (DRPLA) belongs to this group. Some of these forms are caused by the expansion of microsatellite repeats (SCA 1–3, 6–8, 10, 12, 17, 31, 36). Expansion of polyglutamine coding CAG repeats are related to the forms SCAs 1–3, 6, 7 and 17, and the expansion of non-coding repeats are related to SCAs 8, 10, 12, 31 and 36. Point mutations are linked to the other forms. Ataxia, with a variable age of onset, from congenital to adult, and a variable course ranging from non-progressive to slowly progressive, is related to a single type of SCA. Associations with ophthalmologic and auditory anomalies, hypotonia, cognitive delay and sensory anomalies may be a component of each of these forms [1, 37‐41]. SCA type 3 (Machado-Joseph disease) is a well-known disorder. Affected patients exhibit both ataxia and pyramidal signs and peripheral amyotrophy, nystagmus, ophthalmoparesis and bulging eyes. Fasciculations involve the face, tongue and limbs. Dystonia and movement disorders are also associated [4, 42].

X-linked SCAs include the Fragile X syndrome associated with tremor/ataxia syndrome with mutations in the FMR1 gene. Mutations in mitochondrial DNA may manifest themselves with ataxia, myopathy, external ophthalmoplegia, endocrine deficiencies, short stature and retinal pigmentary degeneration [43, 44].

ARCAs are distinctive disorders linked to cerebellar and spinal cord degeneration. The most well-known ARCAs include Friedreich’s ataxia (FA) and ataxia teleangectasia. Both of these disorders are inherited with autosomal recessive inheritance. FA involves the chromosome 9 GAA trinucleotide expansion. This disorder strongly affects the afferent/sensory circuits and the cerebellum. Its primary symptoms consist of ataxia, pes cavus, scoliosis and areflexia. Hypertrophic cardiomyopathy is a relevant sign present in affected children [45, 46]. Ataxia teleangectasia involves chromosome 11. Over 200 mutations involving the ATM gene have been reported. The primary symptoms consist of progressive truncal ataxia, oculo-cutaneous teleangectasias, polyneuropathy, hypotonia and oculomotor apraxia. Teleangectasia is more frequently localized on the conjunctivae but is also found in ear lobes and the popliteal fossa (Fig. 6). Low levels of circulating immunoglobulins (IgA, IgM, IgG and IgE), together with lymphocytopenia and increased alpha-fetoprotein, are reported. Recurring infections of the upper and lower respiratory tracts have been quoted [47, 48]. Ataxia with oculomotor apraxia (AOAs) is a group of recessive disorders associated to FA. Children with AOAs manifest ataxia, oculomotor apraxia, polyneuropathy and, in some cases, also dysarthria, choreoatetosis and dystonia. Cognitive delay may be present. In patients with AOA type 2 axonal neuropathy, cerebellar atrophy and increased levels of alpha-fetoprotein are found. Movement disorders are also present [49, 50]. Ataxias are signs reported in other AR disorders such as SeSAME syndrome (seizures, sensoneural deafness, ataxia, mental retardation and electrolyte unbalance) and in SYNC1 ataxia (spinocerebellar ataxia, spinocerebellar atrophy, and cerebellar ataxia and coenzyme Q10 deficiency (ARCA2) [51, 52].

Recently, cerebellar ataxia has been linked to mutations in the PEX10 gene related to peroxisomal biogenesis disorders in a young patient with marked cerebellar atrophy [53].

Autosomal recessive spastic ataxia of Charlevoix Seguenay is a complex disorder characterized by spasticity, ataxia, polyneuropathy and amyotrophy of distal muscles. Chromosome 13 is involved with over 70 mutations that have been reported in the SAC genes [54‐56]. Marinesco-Sjogren syndrome exhibit cerebellar ataxia, myopathy with progressive muscular hypotonia, cognitive delay and congenital cataracts, often associated with skeletal deformities, short stature and hypogonadotropic hypogonadism [57, 58].

Congenital errors of metabolism may show ataxia among the other progressive severe neurologic involvement. Examples of these disorders include some types of gangliosidoses, lipidoses and adrenoleukodystrophy. Abetalipoproteinemia (Bassen-Kornzeig disease) is an AR disorder linked to a mutation in microsomal triglyceride transfer protein (MTTP) genes. Steatorrhea and a failure to thrive are the initial signs later followed by ataxia, retinitis pigmentosa, peripheral neuritis, muscle weakness and cognitive delay. A blood smear is diagnostic with acanthocytosis together with low blood levels of cholesterol and triglycerides and the absence of beta-lipoproteins. The disorder is associated with malabsorption of lipids and lipid-soluble vitamins (i.e. A, D, E, and K) [59].

Cerebral tumors, particularly medulloblastoma, cerebellar astrocytoma, brain stem glioma and ependymomas, are among the most common causes of progressive ataxia in children [31]. The clinical onset of cerebral tumors is frequently preceded by episodes of headaches and vomiting followed rapidly by additional signs or symptoms. Warming signs beyond morning vomiting and headaches include specific neurologic symptoms such as seizures, vision difficulties and frontal and occipital pain. There is a progression of the symptoms both in frequency and intensity with exacerbation given a change of position or movement. Mood changes with irritability, aggressivity and nocturnal awakening are also relevant diagnostic signs. Ataxia associated with myoclonus and opsoclonus is a characteristic sign of medulloblastoma [60, 61]. In all the types of cerebral tumors, brain imaging represents the best way to obtain a correct diagnosis.