Cerebellar disorders
Description
- Cerebellar signs are IPSILATERAL - the output decussates twice
- DANISH: Dysdiadochokinesia | Ataxia | Nystagmus | Intention tremor | Scanning dysarthria | Hypotonia + hyporeflexia (pendular)
Anatomy determines the syndrome
| Region | Signs |
|---|---|
| Cerebellar hemisphere | Ipsilateral limb ataxia, dysmetria, intention tremor, dysdiadochokinesia, rebound |
| Vermis / midline | Truncal and gait ataxia with relatively normal limb coordination; titubation |
| Rostral (anterior superior) vermis | Gait ataxia confined to the legs, arms spared - the alcohol signature |
| Flocculonodular | Nystagmus, vertigo, gaze-holding failure, imbalance |
Individual signs
- Nystagmus - jerky, horizontal, fast phase towards the side of the lesion, amplitude greater on gaze to that side
- Saccades - hypermetric/hypometric, overshoot; broken (saccadic) smooth pursuit
- Dysarthria - explosive, irregular, scanning; test with "British constitution", "West Register Street", "hippopotamus"
- Dysmetria + intention tremor on finger-nose (worse the closer to the target); past-pointing; positive rebound
- Heel-shin ataxia; broad-based, veering gait; unable to tandem walk
- Hypotonia and pendular reflexes
- Romberg is negative in pure cerebellar disease - Romberg tests proprioception, not the cerebellum
Epidemiology
- Alcohol is the commonest cause of chronic acquired cerebellar degeneration in Australia
- Friedreich ataxia = commonest inherited ataxia; ~1 in 50,000; AR; onset usually <25 (mean 10-15)
- Autosomal dominant spinocerebellar ataxias: SCA3 (Machado-Joseph) commonest worldwide; SCA6 = late-onset, pure cerebellar
- Vestibular schwannoma = ~80% of cerebellopontine angle tumours
- Cerebellar stroke ~2-3% of all strokes but disproportionate mortality (posterior fossa oedema)
Aetiopathogenesis
By pattern - the exam's organising axis
### Unilateral (hemispheric)
- Space-occupying lesion - tumour (metastasis, haemangioblastoma, medulloblastoma), abscess, granuloma
- Vertebrobasilar ischaemia / cerebellar infarct (PICA, AICA, SCA territories)
- Multiple sclerosis
- Trauma; cerebellar haemorrhage
### Bilateral / global
- Alcohol - acute intoxication and chronic rostral vermis atrophy (+ thiamine deficiency)
- Drugs - phenytoin (may be permanent), carbamazepine, lithium, amiodarone, metronidazole, 5-FU, cytarabine, calcineurin inhibitors
- Hereditary - Friedreich ataxia, SCAs, ataxia-telangiectasia, fragile X tremor-ataxia (FXTAS), episodic ataxias, mitochondrial disease
- Hypothyroidism
- Paraneoplastic cerebellar degeneration - subacute, rapidly progressive, often precedes the cancer
- Anti-Yo (breast, ovary), anti-Hu (SCLC), anti-Tr/DNER (Hodgkin lymphoma), anti-Ri, anti-CV2/CRMP5
- Multiple system atrophy (MSA-C)
- Nutritional - vitamin B12, vitamin E (abetalipoproteinaemia), thiamine
- Infective/post-infectious - varicella cerebellitis (children), TB, Whipple disease, HIV, Creutzfeldt-Jakob disease
- Coeliac disease (gluten ataxia)
- Chiari malformation; superficial siderosis; hypoxic-ischaemic injury; heat stroke; heavy metals (mercury, lead)
### Midline (vermis)
- Paraneoplastic or midline tumour (medulloblastoma, ependymoma) - these two above all
- Alcohol (rostral vermis)
Mechanisms worth knowing
- Friedreich ataxia - AR, *GAA trinucleotide expansion in intron 1 of FXN*** (chr 9q21) -> reduced frataxin -> mitochondrial iron accumulation and oxidative damage
- Repeat length inversely correlates with age of onset; affects dorsal root ganglia, dorsal columns, corticospinal tracts, dentate nucleus, heart, pancreatic beta cells
- SCAs - mostly CAG (polyglutamine) expansions, autosomal dominant, anticipation
- Episodic ataxia type 2 - CACNA1A, attacks of ataxia and vertigo, responds to acetazolamide (allelic with familial hemiplegic migraine and SCA6)
Diagnosis
Distinguish the three ataxias at the bedside
| Cerebellar | Sensory | Vestibular | |
|---|---|---|---|
| Romberg | Negative | Positive | Positive |
| Eyes closed | Little change | Much worse | Worse |
| Nystagmus | Yes, gaze-evoked | No | Yes, unidirectional |
| Proprioception | Normal | Lost | Normal |
| Gait | Broad-based, veering | High-stepping, stamping | Veers to one side |
Friedreich ataxia - the classic exam long case
- Bilateral cerebellar signs, four-limb ataxia, nystagmus, dysarthria
- Absent reflexes WITH extensor plantars (peripheral neuropathy + corticospinal involvement)
- Posterior column loss - vibration and proprioception
- Pes cavus, kyphoscoliosis, distal wasting
- Normal cognition - distinguishes it from most other progressive ataxias
- >60% have ECG abnormalities from hypertrophic cardiomyopathy; diabetes in ~10-30%; optic atrophy, sensorineural deafness
Cerebellopontine angle lesion
- Ipsilateral cerebellar signs + LMN VII palsy + SNHL (Weber lateralises AWAY, Rinne normal/positive) + early loss of the corneal reflex (V1)
- Progression to IX-XII or long-tract signs = brainstem compression
- Bilateral vestibular schwannomas = NF2
Acute vertigo: is it a cerebellar stroke?
- HINTS in acute vestibular syndrome (only valid with continuous vertigo AND nystagmus)
- Normal head impulse test, direction-changing nystagmus, or skew deviation -> central
- HINTS outperforms early MRI in the first 24-48 h
- Inability to sit or walk unaided, severe headache, or other brainstem signs -> image
- A normal CT does not exclude posterior fossa infarct
Investigation
- MRI brain (posterior fossa; CT is inadequate) +/- MRA; contrast if tumour or MS suspected
- Bloods: TSH, B12, vitamin E, coeliac serology, LFT/GGT, glucose/HbA1c, caeruloplasmin, ESR/CRP, HIV, syphilis, ANA/ENA, alpha-fetoprotein (ataxia-telangiectasia)
- Anti-neuronal/paraneoplastic antibody panel + CT chest/abdomen/pelvis +/- PET for subacute progressive ataxia
- Search hard: the cancer may be found only on PET or at a later scan
- CSF - cells, protein, oligoclonal bands, cytology, 14-3-3/RT-QuIC if CJD suspected
- NCS/EMG - the sensorimotor axonal neuropathy of Friedreich ataxia; separates sensory from cerebellar ataxia
- ECG + echocardiogram (Friedreich cardiomyopathy), fasting glucose/OGTT
- Genetic testing: FXN GAA repeat, SCA panel, FMR1 premutation (FXTAS in older men with tremor + ataxia + MRI middle cerebellar peduncle sign)
Management
A. Treat the reversible causes first - the whole point of the work-up
- Alcohol - cessation, parenteral thiamine before any glucose, nutrition; gait may partially recover over months
- Drug-induced - stop or reduce (phenytoin, lithium, metronidazole); check levels. Phenytoin ataxia may be permanent if chronic
- Hypothyroidism - thyroxine
- B12, vitamin E, thiamine, copper - replace
- Coeliac disease - gluten-free diet
- Episodic ataxia type 2 - acetazolamide, or 4-aminopyridine
- Wilson disease - chelation
B. Cerebellar stroke - the time-critical scenario
- Standard acute stroke pathway - thrombolysis and thrombectomy assessment (basilar occlusion has an extended window)
- Watch for malignant cerebellar oedema at days 2-4: declining conscious state, new hydrocephalus from 4th ventricle compression
- Neurosurgical referral early - suboccipital decompressive craniectomy +/- EVD is life-saving
- The posterior fossa has no room; deterioration is abrupt
- Cerebellar haemorrhage >3 cm or with brainstem compression/hydrocephalus -> urgent evacuation
C. Structural lesions
- Vestibular schwannoma - observation with serial MRI for small tumours, stereotactic radiosurgery, or microsurgical resection; hearing preservation is the trade-off
- Tumour/abscess - neurosurgery, oncology, antimicrobials as appropriate
- Chiari I with symptoms or syrinx -> posterior fossa decompression
D. Immune-mediated
- Paraneoplastic cerebellar degeneration: find and treat the tumour - that is the treatment; immunotherapy (steroid, IVIg, plasma exchange, rituximab) has limited benefit once Purkinje cells are lost
- Treat early and empirically while searching - waiting for the cancer costs neurons
- MS - acute steroid, then disease-modifying therapy
- Gluten ataxia, anti-GAD ataxia - diet, immunotherapy
E. Friedreich ataxia and the genetic ataxias - anticipatory care
- Omaveloxolone - the first approved disease-modifying therapy for Friedreich ataxia, age >=16; 150 mg daily, taken without food; modest slowing of mFARS progression
- Monitor LFTs and BNP; reduce dose in hepatic impairment. Not currently PBS-listed in Australia
- Annual ECG and echocardiogram - cardiomyopathy is the leading cause of death; treat heart failure and arrhythmia conventionally
- Annual OGTT/HbA1c for diabetes
- Scoliosis surveillance and surgery; orthopaedic care of pes cavus
- Audiology, ophthalmology, swallow assessment
- Genetic counselling and cascade testing
F. Symptomatic and rehabilitative - for everyone
- Physiotherapy and balance training are the highest-yield intervention in any chronic ataxia
- OT: home modification, weighted utensils, falls prevention
- Speech pathology - dysarthria and dysphagia; communication aids
- Tremor: poorly responsive; trials of propranolol, clonazepam, topiramate; thalamic DBS rarely, for severe intention tremor
- Nystagmus/oscillopsia: 4-aminopyridine, gabapentin, memantine
- Spasticity, bladder, mood, driving assessment, ataxia support groups
Associations
- Alcohol use disorder - cerebellar degeneration + Wernicke-Korsakoff + peripheral neuropathy
- Friedreich ataxia - hypertrophic cardiomyopathy, diabetes, scoliosis, pes cavus, optic atrophy, deafness
- Paraneoplastic - breast and ovarian (anti-Yo), small cell lung (anti-Hu), Hodgkin lymphoma (anti-Tr/DNER)
- Multiple sclerosis - INO, optic neuritis, cerebellar signs
- MSA-C - autonomic failure, stridor
- Coeliac disease, hypothyroidism, vitamin E deficiency/abetalipoproteinaemia
- Ataxia-telangiectasia - oculocutaneous telangiectasia, immunodeficiency, inc AFP, lymphoid malignancy, radiation sensitivity
- FXTAS - FMR1 premutation; older men, intention tremor + ataxia + parkinsonism; grandchildren at risk of fragile X
- NF2 - bilateral vestibular schwannomas
- von Hippel-Lindau - cerebellar haemangioblastoma, renal cell carcinoma, phaeochromocytoma
Natural history & complications
- Depends entirely on the cause - the reason the work-up is worth doing
- Reversible: drug, thyroid, nutritional, coeliac - substantial recovery
- Alcohol: stabilises with abstinence, partial gait recovery
- Stroke: maximal deficit at onset, then improves; the danger period is days 2-4, not day 1
- Paraneoplastic: rapidly progressive over weeks-months, then plateaus at severe disability
- Degenerative/genetic: relentless
Friedreich ataxia
- Gait ataxia -> wheelchair typically 10-15 years after onset
- Death most often from hypertrophic cardiomyopathy and arrhythmia; median survival into the 40s-50s
- Later-onset and compound heterozygotes run milder courses
Complications of any chronic ataxia
- Falls and fractures; aspiration pneumonia; malnutrition and weight loss
- Loss of independence, driving and employment; carer burden
- Pressure injury and contracture in advanced disease
- Depression - common and under-treated
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