Initial evaluation should determine whether ataxia appears sensory or cerebellar. Profoundly decreased sensation and hyporeflexia in the absence of dysarthria or oculomotor findings make sensory ataxia more likely. Nystagmus, ocular dysmetria, and dysarthria suggest a cerebellar etiology.
In some conditions (like Friedrich ataxia), sensory and cerebellar ataxia may coexist.
Patients with cerebellar ataxia should undergo brain imaging to exclude causative structural lesions. Certain ataxias have specific magnetic resonance imaging (MRI) changes that facilitate recognition; examples include restricted diffusion in patients with Creutzfeldt-Jakob disease (CJD), pontine hypomyelination in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), and middle cerebellar peduncle (MCP) signs in multiple systems atrophy (MSA) or fragile-X tremor ataxia syndrome (FXTAS).
Common causes of acute ataxia include toxic ingestions and Wernicke encephalopathy. Immune-mediated causes are an important consideration in patients with ataxia for less than 2 years. Antibodies recognized to cause autoimmune cerebellar degeneration include anti-Yo, anti-Hu, anti-Ri, and anti-TR. The opsoclonus-myoclonus-ataxia syndrome is associated with neuroblastoma in children and most often small cell lung cancer in adults. Other autoimmune causes include Hashimoto encephalopathy (associated with anti-TPO and anti-TG antibodies), anti-GAD65 cerebellar degeneration (which is also associated with stiff person syndrome), and gluten ataxia in celiac disease.
While a detailed family history is critical in the evaluation of patients with chronic ataxia, absence of a family history does not exclude a genetic cause. Nonpaternity, de novo mutations, and anticipation in triplet repeat disorders are common reasons a family history may be absent. Genetic testing should be performed in conjunction with genetic counseling to ensure patients understand the ramifications of positive, negative, unclear, or unexpected results. Knowledge of a patient’s genetic status can allow them to make decisions regarding family planning, avoid unnecessary diagnostic testing, and inform eligibility for clinical trials.
Identifying specific associated neurologic signs in autosomal dominant cerebellar ataxias narrows the differential diagnosis. Neuropathy and spasticity are seen in many spinocerebellar ataxias (SCAs). Spasticity is also a feature of Alexander disease and adult-onset leukodystrophy. Parkinsonism is seen in SCA2, SCA3, SCA9, SCA12, and SCA17, and in neuroferritonopathy. Epilepsy is often a component of SCA10 and dentatorubral-pallidoluysian atrophy (DRPLA). Myoclonus may be seen in SCA2, SCA14, DRPLA, and Gerstmann-Straussler-Scheinker syndrome, a rare familial prion disease caused by mutations in the PRNP gene. Chorea is a feature noted in SCA3, SCA17, and DRPLA. In cases with isolated ataxia, SCA5 and SCA6 are the most common entities. Of note, there can be considerable phenotypic heterogeneity between cases and even within families.
Episodic ataxias are characterized by attacks of ataxic symptoms. The two most common forms of episodic ataxia are EA1 and EA2. In EA1, episodes are brief, lasting seconds to minutes and classically provoked by startle or sudden movements. Interictal myokymia may be present. The attacks in EA2 are more prolonged, lasting from hours to days, and are often provoked by stress or exercise. Interictal extraocular movement abnormalities including downbeat nystagmus may be seen in EA2.
Associated neurologic signs can also help narrow the differential for autosomal recessive inherited cerebellar ataxias. Neuropathy is a prominent feature in Friedrich ataxia, ataxia with vitamin E deficiency (AVED), abetalipoproteinemia, ataxia telangiectasia, ARSACS, and ataxia with oculomotor apraxia types 1 and 2 (AOA1/2). Prominent spasticity is also seen in ARSACS, as well as in hereditary spastic paraplegia type 7 and cerebrotendinous xanthomatosis. Chorea can be a feature seen in ataxia telangiectasia and AOA1 or 2. Parkinsonism, psychiatric symptoms, and prominent dysarthria can be seen in Wilson disease. Dystonia is a feature of AOA2, ataxia telangiectasia, and Niemann Pick type C (NPC). Epilepsy may also be a feature of NPC, as well as autosomal recessive cerebellar ataxia 2 (ARCA2) and infantile onset spinocerebellar ataxia (IOSCA).
Ataxia is often present in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), and POLG -related ataxia neuropathy spectrum diseases, which include sensory ataxia with neuropathy dysarthria and ophthalmoplegia (SANDO) and mitochondrial recessive ataxia syndrome (MIRAS). Given heteroplasmy and the relatively low number of mitochondria found in peripheral blood cells, muscle biopsy may be necessary to make a diagnosis.
FXTAS is the most common form of X-linked ataxia. A family history should include asking about children or grandchildren with intellectual disability and if women in subsequent generations suffered premature ovarian failure. FXTAS may present with a combination of action, postural, and rest tremor. Mild Parkinsonism and cognitive impairment may be present as well. Characteristic magnetic resonance imaging features are T2 hyperintensities in the middle cerebral peduncles and the splenium of the corpus callosum, but these features are neither sensitive nor specific for FXTAS.
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