Causes of Advanced Cerebellar Atrophy
Advanced cerebellar atrophy results from multiple etiologies including hereditary neurodegenerative disorders (spinocerebellar ataxias, Friedreich ataxia), acquired toxic-metabolic causes (chronic alcohol use, drug toxicity), immune-mediated conditions (paraneoplastic cerebellar degeneration, anti-GAD antibodies), neurodegenerative diseases (multiple system atrophy-cerebellar type), vascular disease, infectious/post-infectious cerebellitis, and nutritional deficiencies (vitamin E, thiamine). 1
Hereditary/Genetic Causes
Autosomal dominant spinocerebellar ataxias (SCAs) represent a genetically heterogeneous group with variable phenotypic expression and progressive cerebellar hemispheric and vermian volume loss. 2, 3 Recent genetic discoveries include short-tandem repeat (STR) expansions in RFC1 (causing CANVAS syndrome), FGF14-GAA (causing SCA27B), THAP11, and ZFHX3 (causing SCA4). 4
Autosomal recessive conditions include Friedreich ataxia and ataxia-telangiectasia, both causing progressive cerebellar degeneration with characteristic imaging findings. 2, 3 These hereditary disorders show progressive clinical course with varying progression of cerebellar volume loss, and imaging in early childhood may be normal or subtly abnormal with abnormalities becoming more apparent on follow-up. 2
Acquired Toxic-Metabolic Causes
Alcohol-related cerebellar degeneration is a major toxic cause that should be considered even without obvious history, presenting with isolated cerebellar signs and progressive atrophy. 5, 1
Drug-induced cerebellar toxicity includes phenytoin and other medications that can cause irreversible cerebellar damage with chronic use. 1, 6
Nutritional deficiencies causing cerebellar atrophy include:
- Vitamin E deficiency, which causes cerebellar ataxia with potential spinal cord involvement 5
- Thiamine deficiency (Wernicke's encephalopathy), which can present acutely with ataxia and lead to chronic changes if untreated 5
Heavy metal poisoning is recognized as a significant toxic cause of acquired cerebellar degeneration. 5
Immune-Mediated Causes
Paraneoplastic cerebellar degeneration (PCD) is associated with antibodies against intracellular antigens and commonly linked to small cell lung cancer, breast, ovarian, and testicular cancers, with poor response to immunotherapy and poor prognosis. 5
Anti-GAD (glutamic acid decarboxylase) antibody-associated cerebellar ataxia presents with subacute progressive ataxia and normal initial MRI, but develops atrophy over time. 5
Non-paraneoplastic autoimmune cerebellar syndromes associated with antibodies to neuronal surface antigens are generally responsive to immunotherapy but can still result in atrophy if treatment is delayed. 5
Neurodegenerative Disorders
Multiple system atrophy-cerebellar type (MSA-C) is a late-onset sporadic neurodegenerative disorder characterized by autonomic failure and cerebellar ataxia, with neuropathological findings of widespread α-synuclein-positive glial cytoplasmic inclusions and olivopontocerebellar neurodegeneration. 7 This presents a unique diagnostic challenge in distinguishing it from other causes of adult-onset cerebellar ataxia. 7
Infectious/Post-Infectious Causes
Cerebellitis can lead to late-stage cerebellar atrophy, with MR images demonstrating generalized cerebellar atrophy and slightly high intensities in affected cerebellar cortices on FLAIR images. 6 Post-infectious cerebellar ataxia is the most common cause of acute ataxia in children (approximately 50% of pediatric emergency presentations), and severe cases can progress to chronic atrophy. 3
Acute cerebellitis presents with truncal ataxia, dysmetria, and headache, with severe cases developing altered consciousness or increased intracranial pressure that may result in permanent cerebellar damage. 3
Vascular Causes
Posterior circulation stroke and vertebrobasilar insufficiency can cause acute cerebellar damage that evolves into chronic atrophy. 5, 3 Cerebellar hemorrhage is another vascular cause that may result in residual atrophy. 5
Diagnostic Approach to Identify Etiology
MRI head without IV contrast is the preferred initial imaging modality, showing volume loss in the cerebellum and/or brainstem, signal alterations, and patterns of parenchymal injury that may suggest specific ataxia subtypes. 1 Key imaging findings include cerebellar hemispheric and vermian volume loss, with associated signal abnormality and atrophy of the spinal cord in certain conditions. 2
Clinical history is critical to distinguish between causes:
- Age of presentation (childhood vs. adult-onset) 8
- Time course (acute, subacute, chronic progressive) 3
- Family history (suggests hereditary causes) 8
- Exposure history (alcohol, medications, toxins) 1
- Associated symptoms (autonomic dysfunction suggests MSA-C, telangiectasias suggest ataxia-telangiectasia) 3, 7
Genetic testing should include targeted evaluation of STR expansions for common SCAs, Friedreich ataxia, and fragile X-associated tremor/ataxia syndrome, followed by next-generation sequencing (targeted gene panels, whole exome, or whole genome sequencing) for conventional variants. 4
Laboratory evaluation should assess for anti-GAD antibodies, paraneoplastic antibodies, vitamin E and thiamine levels, and thyroid function to exclude hypothyroidism as a cause. 5, 6
Common Pitfalls
Conventional MRI may be unremarkable in early degenerative ataxia, drug-induced ataxia, and immune-mediated ataxia, requiring advanced MRI techniques (diffusion-tensor imaging, spectroscopy) to detect early changes, though these are not routinely available. 5 Because of phenotypic heterogeneity and progressive nature of hereditary cerebellar ataxias, imaging in early childhood may be normal or subtly abnormal. 2
Do not assume all cerebellar atrophy is genetic—acquired causes including alcohol, medications, nutritional deficiencies, and immune-mediated conditions must be systematically excluded as these may be treatable or preventable. 1