Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): diagnostic contribution of vestibular function tests

Background

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a type of autosomal recessive ataxia with a late onset (fifth to seventh decade of life).1 This syndrome was first described by Szmulewicz et al in 2011,2 and clinical diagnostic criteria were established in 2016.3 The genetic background of CANVAS was recently characterised in 2019 by the identification of a biallelic intronic pentanucleotide (AAGGG) repeat expansion in replication factor complex subunit 1 (RFC1).1 4 Sporadic and familial cases have been reported5 and although its exact prevalence remains unknown, CANVAS is very likely underdiagnosed.1 5 A recent European multicentric study reported the results of a large natural history study in RFC1 disease and demonstrated that it is frequent and occurs across continents.6

The RFC1 gene encodes the large subunit of replication factor C, a 5-subunit DNA polymerase accessory protein required for the coordinated synthesis of both DNA strands during replication or after DNA damage.1 Mutations in DNA repair genes have been associated with some degenerative neurological disorders7 that typically present as ataxia and neuropathy, suggesting a particular susceptibility of the cerebellum and peripheral nerves to DNA damage.1

The disease is slowly progressive, with typical symptoms including gait imbalance (worsened in darkness), limb dysesthesia and oscillopsia with frequent falls.8 Chronic cough has been recognised as a prodromal symptom of CANVAS and can precede gait ataxia by several decades.5 8 9 In addition, dysarthria, dysphagia, dysautonomic signs and neuropathic pain are frequently observed.10–12

CANVAS affects multiple neurological systems, compromising three of the four pillars of balance: cerebellar, proprioceptive and vestibular functions (only vision remains intact). Patients with CANVAS have impaired, slow stabilising eye movements (vestibulo-ocular reflex (VOR), smooth pursuit and optokinetic reflex) responsible for gaze stabilisation during head motion, causing a deficient visually enhanced vestibulo-ocular reflex (VVOR) with clinically detectable catch-up saccades, a characteristic clinical sign.13 14

CANVAS is likely to be underdiagnosed due to its variability of symptoms (type and onset) and the potential need for multiple specialties for a definite diagnosis. Furthermore, particular expertise is required in interpreting diagnostic tests, which may not be available in every setting. In particular, vestibular deficits may go unrecognised if vestibular function tests are not performed.12

We present a case of CANVAS and highlight the importance of comprehensive clinical and diagnostic investigations with a special emphasis on vestibular function tests to confirm bilateral vestibulopathy. This condition has rarely been reported in Portugal, and to the best of our knowledge, this is the only case reported after Malaquias et al described the first four cases of Portuguese familial CANVAS with pathogenic RFC1 expansion and autosomal recessive inheritance.15

Case presentation

A man in his 60s presented to the otolaryngology department on referral by his neurologist for imbalance, gait disturbance and falls over the last 10 years. His symptoms were slowly progressive, initially with walking difficulty and unsteady gait that gradually worsened, mostly in the dark and on uneven ground, with increasing occasional falls. He also presented with a long-standing chronic cough since the age of 30 years that usually came in bursts without apparent triggering factors. He had no dysphagia, dysarthria or symptoms of autonomic dysfunction. His personal medical history included depression, for which he was taking 150 mg of venlafaxine daily. He was unaware of other relatives with similar symptoms.

Neurological examination showed wide-based truncal ataxia, impossible tandem gait and instability in the Romberg test. Downbeat nystagmus was present, the clinical head-impulse test was pathological bilaterally, and saccadic eye movements were observed while examining for VVOR. Upper-limb and lower-limb tendon jerks were preserved, and the flexor plantar reflex was present. Vibration sensation was impaired distally (upper and lower extremities), but pinprick and joint position sensations were intact. Muscle strength was normal. He had slight bilateral heel-knee and finger-to-nose dysmetria.

The patient had been previously investigated as a neurology outpatient with nerve conduction studies that revealed the absence of sensory nerve action potentials in all limbs and normal motor nerve conduction studies, suggesting a sensory neuronopathy. Brain MRI revealed atrophy of the anterior and dorsal vermis (predominantly in lobules V, VI, VIIA and VIIB) and widening of the superior posterior and horizontal fissures of the cerebellar hemispheres (mild atrophy of Crus I), without signal changes; the cerebrum and brainstem parenchyma were unremarkable (figure 1). Given these findings, causes of acquired cerebellar degeneration were investigated with extensive laboratory testing, including protein electrophoresis; vitamins B1, B6, B12 and E; thyroid hormones; an immunology panel containing antineuronal antibodies (Hu, Yo, Ri, CV2, PNMA2, amphiphysin), antigliadin, and anti-t-transglutaminase; and infectious serologies, which were unremarkable. He was genetically tested for Friedreich’s ataxia and the most common spinocerebellar ataxias (SCAs) by a genetic panel (144 genes) that included ATXN1 (SCA1), ATXN2 (SCA2), ATXN3/DMJ (SCA3), CACNA1A (SCA6), ATXN7 (SCA7), TBP (SCA17) and ATN1 (DRPLA), which were all negative. His chronic cough had also been previously investigated by the pneumology department, but no organic cause was found.

Investigations

In order to establish a diagnosis, a comprehensive audiovestibular assessment, including pure-tone audiometry, videonystagmography with bithermal caloric test, video head impulse test (vHIT) and ocular and cervical vestibular evoked myogenic potentials (oVEMP and cVEMP), was conducted at the otolaryngology department. Audiometry demonstrated normal hearing for age. Videonystagmography showed downbeat nystagmus, saccadic horizontal and vertical pursuit, hypermetric saccades and impaired VVOR (figure 2). He had caloric areflexia, and vHIT showed decreased VOR gains for all semicircular canals with compensatory saccades (figure 3). cVEMP revealed absent responses on the left side and low amplitude responses with a high threshold on the right (figure 4A). oVEMP responses were absent on the left side and normal on the right (figure 4B).

These findings of bilateral vestibulopathy associated with cerebellar ataxia and sensory neuronopathy suggested CANVAS, which was confirmed by the biallelic repeat expansion in the RFC1 gene on genetic testing.

Differential diagnosis

The association of cerebellar ataxia, vestibular deficit and sensory neuropathy may be observed in hereditary ataxias, such as Friedreich’s ataxia and SCAs (particularly SCA1 and SCA3), as well as in mitochondrial diseases,12 16 and affected patients may have clinical features similar to CANVAS. In addition, since autonomic dysfunction can be a feature of CANVAS,11 multiple system atrophy with predominant cerebellar ataxia (MSA-C) should also be considered as a differential diagnosis, especially in patients who present with ataxia and autonomic failure (which was not the case in this patient). The absence of a vestibular deficit, more rapid disease progression and brainstem atrophy may help differentiate MSA-C from CANVAS.11

Infectious, metabolic, paraneoplastic and immune-mediated peripheral neuropathies should also be considered and laboratory investigations must be carried out accordingly,17 as was done in this patient’s case.

In addition, peripheral neuropathy and cerebellar ataxia can be associated with chronic alcoholic intoxication, and vestibular deficits have been observed in Wernicke’s encephalopathy due to thiamine deficiency.18 This should be explored in the patient’s history and with laboratory testing, which excluded this diagnosis in our case.

Treatment

The patient was referred to physiotherapy and started a personalised rehabilitation programme (two times per week over 8 weeks), which focused on balance and gait training and consisted of static and dynamic balance exercises (eg, standing on one leg, standing heel to toe, sidesteps, climbing stairs, sitting on a Swiss ball), and whole-body movements to train trunk-limb coordination. Strength and flexibility training were also performed to improve muscle strength and range of motion. The patient was encouraged to continue exercises at home according to an individual written training schedule of safe tasks. Fall prevention strategies were also implemented by identifying and avoiding potential environmental and home fall hazards, improving lighting conditions and wearing appropriate footwear.

Outcome and follow-up

After 1 year of follow-up and customised physical rehabilitation, the patient maintains gait instability but is able to walk without assistance. Physiotherapy has not improved gait disturbance but has helped with physical conditioning and muscle strengthening. The patient’s disability level has not worsened, allowing him to continue his work activities.