Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late onset, slowly progressive autosomal recessive disorder with cerebellar ataxia, sensory neuronopathy and bilateral vestibulopathy. It is caused by biallelic AAGGG repeat expansion in RFC1.

It is among the commonest causes of late onset recessive ataxia. About 1 in 20 to 1 in 30 people of European ancestry carry a pathogenic expansion. Onset is usually after 50 years.

Features beyond the triad. Chronic dry cough (often years before ataxia), autonomic failure with orthostatic hypotension, constipation and erectile dysfunction, and sometimes parkinsonism.

Pathophysiology. The repeat expansion causes loss of function with neuronal loss in the cerebellum (vermis and hemispheres), dorsal root ganglia and vestibular ganglia.

Presentation is progressive unsteadiness, oscillopsia on head movement, numbness or tingling of feet with loss of vibration and proprioception, and falls, especially in the dark. Examination shows impaired visually enhanced vestibulo ocular reflex with abnormal head impulse test, gaze evoked nystagmus, dysarthria, limb dysmetria, sensory ataxia and absent ankle reflexes. Dysphagia and orthostatic dizziness are common.

Genetic testing for the RFC1 repeat expansion by repeat primed PCR or long read sequencing is the key test (conventional short read panels miss it). Nerve conduction studies show absent sensory nerve action potentials with normal motor studies. MRI shows cerebellar atrophy (vermis and anterior lobe). Video head impulse testing or caloric testing confirms bilateral vestibulopathy. Test for autonomic failure with lying and standing blood pressure.

Differential diagnosis.

• Sjogren syndrome and other immune sensory neuronopathies, paraneoplastic sensory neuronopathy.
• Cisplatin and pyridoxine toxicity, vitamin E and B12 deficiency.
• Friedreich ataxia, spinocerebellar ataxias and multiple system atrophy.
• Aminoglycoside vestibulotoxicity.

No treatment changes the course. Management is supportive.

Balance and falls. Vestibular and balance rehabilitation, visual and proprioceptive strategies, gait aids, home safety assessment and avoidance of vestibulotoxic drugs (gentamicin and other aminoglycosides).

Orthostatic hypotension. Compression stockings, abdominal binder, fluid 2 to 3 litres daily and salt, raising the head of the bed by 10 degrees. Fludrocortisone 0.1 mg daily, increased to a maximum of 0.3 mg daily, with monitoring of potassium and supine hypertension. Midodrine 2.5 mg three times daily, increased to 10 mg three times daily, taken at least 4 hours before bedtime.

Cough. Gabapentin 100 to 300 mg three times daily, titrated to effect, or low dose amitriptyline 10 to 25 mg at night. Adjust gabapentin to renal function.

Swallowing and speech. Speech and language therapy, with videofluoroscopy for dysphagia.

Other. Occupational therapy and genetic counselling.

Monitoring. Falls, lying and standing blood pressure, swallowing and neuropathy annually.

Referral and escalation. Refer to neurology, with vestibular and balance services. Refer urgently for rapid progression.