What causes cerebellar atrophy?

Causes of Cerebellar Atrophy

Cerebellar atrophy results from a diverse array of genetic, immune-mediated, toxic, vascular, and degenerative disorders, with immune-mediated causes (particularly gluten ataxia) being the most common in sporadic cases, accounting for 25% of presentations, followed by genetic causes (13% of sporadic, 57% of familial), alcohol excess (12%), and multiple system atrophy (11%). 1

Categorization by Etiology

Acquired/Sporadic Causes

Immune-Mediated Disorders (Most Common Sporadic Category)

• Gluten ataxia represents the single most common cause of sporadic cerebellar atrophy at 25% of cases 1
• Anti-GAD antibody-associated cerebellar ataxia presents with subacute progressive ataxia and initially normal MRI 2
• Paraneoplastic cerebellar degeneration associated with antibodies against intracellular antigens, commonly linked to SCLC, breast, ovarian, and testicular cancers, with poor immunotherapy response 2
• Non-paraneoplastic autoimmune cerebellar syndromes with antibodies to neuronal surface antigens show better immunotherapy response 2

Toxic/Metabolic Causes

• Alcohol-related cerebellar degeneration accounts for 12% of sporadic cases and should be considered even without obvious history 2, 1
• Drug-induced cerebellar toxicity from various medications 2
• Heavy metal poisoning 2
• Vitamin E deficiency causing cerebellar ataxia with potential spinal cord involvement 2
• Thiamine deficiency (Wernicke's encephalopathy) presenting acutely with ataxia 2

Vascular Causes

• Posterior circulation stroke requiring immediate recognition 3
• Vertebrobasilar insufficiency presenting with episodic or progressive ataxia 3
• Cerebellar hemorrhage 2

Infectious/Postinfectious

• Acute cerebellitis presenting with truncal ataxia, dysmetria, and headache 3
• Postinfectious cerebellar ataxia (most common acute ataxia in children, ~50% of pediatric emergency presentations) 3
• Miller Fisher syndrome with classic triad of ataxia, areflexia, and ophthalmoplegia 3

Degenerative Disorders

• Multiple system atrophy (cerebellar variant) accounts for 11% of sporadic cases 1
• Sporadic adult-onset ataxias 4

Other Acquired Causes

• Neoplasias and paraneoplastic syndromes 4
• Traumatic causes 4
• Endocrine disorders affecting the cerebellum 4

Genetic/Hereditary Causes

Autosomal Recessive Ataxias

• Friedreich ataxia is the most common genetic ataxia overall at 22% of familial cases, notably showing normal cerebellar volume on MRI but sometimes spinal cord atrophy 1, 5
• Ataxia-telangiectasia with characteristic telangiectasias 3, 5
• Ataxia with oculomotor apraxia types I and II (DNA repair defects) 5
• Vitamin E-responsive ataxia (treatable) 5
• Coenzyme Q10 synthesis defects 5

Autosomal Dominant Ataxias (Spinocerebellar Ataxias)

• SCA6 accounts for 14% of familial cases 1
• Episodic ataxia type 2 (EA2) is the most common ataxia identified by next-generation sequencing at 13% of familial cases 1, 6
• SPG7 accounts for 10% of familial cases 1
• SCA27B caused by FGF14-GAA short-tandem repeat expansion 6
• SCA4 caused by ZFHX3 short-tandem repeat expansion 6
• CANVAS (cerebellar ataxia, neuropathy, vestibular areflexia syndrome) caused by RFC1 expansions 6
• SCA2 and SCA7 may begin in childhood or infancy 5

Mitochondrial Disorders

• Account for 10% of familial cases with mitochondrial inheritance patterns 1

X-Linked Ataxias

• Fragile X-associated tremor/ataxia syndrome 6

Diagnostic Approach Algorithm

Step 1: Temporal Classification

• Acute/subacute onset: prioritize stroke, hemorrhage, infection, toxic causes 3
• Chronic/progressive: focus on inherited causes, degenerative disorders, immune-mediated 3

Step 2: Age and Family History

• Pediatric with family history: consider autosomal recessive ataxias, particularly Friedreich ataxia 5
• Adult sporadic: prioritize gluten ataxia, alcohol, immune causes, then genetic testing 1
• Adult with family history: autosomal dominant SCAs, particularly SCA6, EA2, SPG7 1

Step 3: Initial Imaging

• MRI head without IV contrast is the preferred initial modality 3, 7
• Look for cerebellar atrophy pattern, brainstem involvement, signal changes 2
• Critical pitfall: Friedreich ataxia shows normal cerebellar volume despite being a major genetic cause 5
• Early degenerative, drug-induced, and immune-mediated ataxias may show normal initial MRI 2

Step 4: Laboratory and Genetic Testing

• Screen for gluten antibodies (anti-gliadin, anti-tissue transglutaminase) given 25% prevalence 1
• Anti-GAD antibodies for immune ataxia 2
• Vitamin E and thiamine levels for nutritional causes 2
• Next-generation sequencing yields positive results in 32% of tested patients, with overall diagnostic yield of 63% when combined with clinical evaluation 1
• Test for short-tandem repeat expansions in RFC1, FGF14, ZFHX3, and traditional SCA genes 6

Critical Clinical Distinctions

Key Examination Features

• Unsteadiness does NOT worsen with eye closure (distinguishes from sensory ataxia) 3, 7
• Truncal ataxia particularly suggests cerebellar vermian pathology 3, 7
• Associated telangiectasias indicate ataxia-telangiectasia 7
• Peripheral neuropathy suggests CANVAS, ataxia with oculomotor apraxia, or Friedreich ataxia 1, 5

Common Pitfalls

• Missing gluten ataxia as the most common sporadic cause by not screening antibodies 1
• Assuming normal MRI excludes cerebellar disease (Friedreich ataxia, early immune/degenerative causes) 2, 5
• Not considering alcohol-related degeneration without obvious history 2
• Overlooking treatable causes: vitamin E deficiency, coenzyme Q10 defects, gluten ataxia, immune ataxias 2, 1, 5