What are the common etiologies of cerebellar ataxia and how should it be investigated and managed?

Cerebellar Ataxia Etiology

Primary Etiologic Categories

Cerebellar ataxia results from a heterogeneous spectrum of inherited and acquired disorders affecting the cerebellum and its connections, with the most common causes varying by age and time course of presentation. 1, 2

Acute/Subacute Causes (Hours to Weeks)

Structural and Vascular:

• Posterior circulation stroke is the most critical acute cause requiring immediate recognition and represents a neurologic emergency 2, 3
• Cerebellar hemorrhage demands urgent evaluation for potential surgical intervention 2
• Acute cerebellitis presents with truncal ataxia, dysmetria, and headache, potentially progressing to altered consciousness and increased intracranial pressure 2, 3
• Posterior fossa masses including cerebellar tumors cause progressive symptoms with other posterior fossa signs 2

Infectious and Post-Infectious:

• Postinfectious cerebellar ataxia accounts for approximately 50% of acute pediatric ataxia presentations 3
• Bacterial cerebellitis may occur with meningitis and can result in late-stage cerebellar atrophy 2

Autoimmune:

• Miller Fisher syndrome presents with the classic triad of ataxia, areflexia, and ophthalmoplegia 2, 3
• Paraneoplastic cerebellar degeneration manifests with subacute onset of gait and limb ataxia, dysarthria, and ocular dysmetria 2, 4
• Anti-GAD antibody-associated cerebellar ataxia presents with subacute progressive ataxia and may have normal initial MRI 4

Toxic/Metabolic:

• Metronidazole-induced cerebellar toxicity shows increased T2 signal and reduced diffusivity in the dentate nuclei 2
• Thiamine deficiency (Wernicke's encephalopathy) can present acutely with ataxia 4

Chronic/Progressive Causes (Months to Years)

Genetic/Hereditary Ataxias:

Autosomal Dominant:

• Spinocerebellar ataxias (SCAs) represent genetically heterogeneous neurodegenerative disorders with variable phenotypic expression 1, 3
• SCA6 accounts for 14% of familial ataxias 5
• Episodic ataxia type 2 (EA2) is the most common genetic ataxia identified by next-generation sequencing, representing 13% of familial cases 5

Autosomal Recessive:

• Friedreich ataxia is the most common autosomal recessive cerebellar ataxia, accounting for 22% of familial ataxias 3, 5
• Ataxia-telangiectasia presents with cerebellar ataxia and characteristic telangiectasias 3
• SPG7 mutations account for 10% of familial ataxias 5

Acquired Sporadic Causes:

Immune-Mediated:

• Gluten ataxia is the most common cause of sporadic ataxia, accounting for 25% of cases in large prospective series 5
• Non-paraneoplastic autoimmune cerebellar syndromes associated with antibodies to neuronal surface antigens are generally responsive to immunotherapy 4

Toxic/Nutritional:

• Chronic ethanol abuse accounts for 12% of sporadic ataxias and is a common cause of cerebellar atrophy 2, 5
• Vitamin E deficiency results in cerebellar atrophy and ataxia with potential spinal cord involvement 2, 4
• Methanol toxicity and heroin use can cause cerebellar damage and atrophy 2

Degenerative:

• Cerebellar variant of multiple system atrophy accounts for 11% of sporadic ataxias 5

Diagnostic Approach Algorithm

Step 1: Categorize by Time Course

• Acute/subacute (hours to weeks): Prioritize exclusion of stroke, hemorrhage, infection, and toxic causes 3
• Chronic/progressive (months to years): Focus on inherited causes, degenerative disorders, and structural abnormalities 3

Step 2: Initial Imaging

• MRI brain without and with IV contrast is the preferred initial imaging modality for all presentations 1, 2, 3
• MRI provides superior visualization of the posterior fossa and can detect cerebellar atrophy, structural abnormalities, demyelination, and vascular lesions 4
• CT head without contrast has inferior soft tissue contrast and should be reserved for emergency settings when MRI is unavailable 1

Step 3: Assess Family History

• Positive family history: Pursue genetic testing with next-generation sequencing, which yields positive results in 32% of tested patients and 57% of familial ataxias 5
• Negative family history: Consider acquired causes first, but note that 13% of sporadic cases have an identifiable genetic cause 5

Step 4: Targeted Laboratory Evaluation

• Exclude acquired causes: Vitamin E (expressed as ratio to lipids), vitamin B12, thyroid function, anti-GAD antibodies, anti-gliadin antibodies for gluten ataxia 4, 5
• Consider paraneoplastic antibody panel if subacute onset in appropriate age group 2, 4
• Genetic testing using next-generation sequencing when hereditary ataxia suspected 5, 6

Step 5: Additional Imaging When Indicated

• MRI cervical and thoracic spine without contrast for suspected spinocerebellar ataxias (particularly SCA1, SCA7) or when spinal cord signs present 3
• Serial imaging may be necessary in hereditary ataxias where initial scans appear normal or subtly abnormal 1, 3

Critical Diagnostic Pitfalls to Avoid

Do not assume all progressive ataxia is benign hereditary disease—always exclude tumors, inflammatory conditions, and paraneoplastic syndromes first, as these are treatable and directly impact mortality. 3

• Conventional MRI may be unremarkable in early degenerative ataxia, drug-induced ataxia, and immune-mediated ataxia 4
• Diagnosis relies on combination of history, thorough neurologic examination, imaging, and confirmatory laboratory and/or genetic testing 1
• Early imaging in hereditary cerebellar ataxias may be normal or subtly abnormal, with abnormalities becoming more apparent on follow-up due to progressive nature 1, 3
• Do not overlook immune-mediated ataxias, which are common and potentially treatable 5
• Gluten ataxia should be considered even without obvious gastrointestinal symptoms 5
• Alcohol-related cerebellar degeneration should be considered even without obvious history 4

Management Considerations

Treatment of underlying causes is crucial and varies by etiology:

• Cessation of toxic agents (alcohol, medications) for toxic causes 4
• Vitamin supplementation: Vitamin E 100-400 IU daily for maintenance (more for repletion), with intramuscular injections for deficiency unresponsive to oral therapy 4
• Immunotherapy for non-paraneoplastic autoimmune cerebellar syndromes, which generally have better prognosis than paraneoplastic syndromes 4
• Gluten-free diet for gluten ataxia 5
• Emerging therapies: Antisense oligonucleotides for polyglutamine SCAs and viral gene therapy for Friedreich ataxia 6
• Intensive physical therapy appears helpful for symptomatic management 7