Update on Cerebellar Ataxia with Neuropathy and Bilateral Vestibular Areflexia Syndrome (CANVAS)

Abstract

The syndrome of cerebellar ataxia with neuropathy and bilateral vestibular areflexia (CANVAS) has emerged progressively during the last 30 years. It was first outlined by the neurootology/neurophysiology community in the vestibular areflexic patients, through the description of patients slowly developing late-onset cerebellar ataxia and bilateral vestibulopathy. The characteristic deficit of visuo-vestibulo-ocular reflex (VVOR) due to the impaired slow stabilizing eye movements was put forward and a specific disease subtending this syndrome was suggested. The association to a peripheral sensory axonal neuropathy was described later on, with neuropathological studies demonstrating that both sensory neuropathy and vestibular areflexia were diffuse ganglionopathy. Clinical and electrophysiological criteria of CANVAS were then proposed in 2016. Besides the classical triad, frequent chronic cough, signs of dysautonomia and neurogenic pains were frequently observed. From the beginning of published cohorts, sporadic as well as familial cases were reported, the last suggestive of an autosomal recessive mode of transmission. The genetic disorder was discovered in 2019, under the form of abnormal biallelic expansion in the replication factor C subunit 1 (RFC1) in a population of late-onset ataxia. This pathological expansion was found in 100% of the familial form and 92% of sporadic ones when the triad was complete. But using the genetic criteria, the phenotype of CANVAS seems to expand, for exemple including patients with isolated neuronopathy. We propose here to review the clinical, electrophysiological, anatomical, genetic aspect of CANVAS in light of the recent discovery of the genetic aetiology, and discuss differential diagnosis, neuropathology and physiopathology.

Keywords: Bilateral vestibulopathy; Ganglionopathy; Head impulse test; Neuronopathy; RFC1; Visuo-vestibulo-ocular reflex.

Fig. 1

Exemple of typical brain MRI in a patient with CANVAS. (A) 3D T1-weighted with gadolinium MRI brain parasagittal section of a 46-year-old CANVAS. This view shows the hemispheric atrophy’s pattern with widening of the superior posterior and of the horizontal fissures, delimiting Crus I. (B) 3D T1-weighted with gadolinium MRI brain midsagittal section of a 70-year-old CANVAS. Note the predominant atrophy of the anterior and dorsal vermis and particularly in the part of the dorsal vermis between the primary fissure and the pre-pyramidal fissure corresponding to the vermal lobules VI, VIIa and VIIb

Fig. 2

Example of vHIT recording in both a normal subject and a CANVAS patient. vHIT recorded horizontal eye (grey line) and head (dark line) velocities during multiple horizontal head impulses to the right and the left. Top panels represent the responses in a normal subject and bottom panels in a CANVAS patient. For purpose of better comparison, right and left for both eye and head movements have been presented in one unique direction. In the bottom left panel, for the CANVAS patient, the residual VOR (1) does not allow stabilizing gaze during head movement. The patient trigger saccades eigher during head movement (2: covert saccade) and after eye movements (3: overt saccade)

Fig. 3

Exemples of eye movement recording during smooth pursuit (A), rotatory chair induced vestibulo-ocular reflex/visuo-vestibulo-ocular reflex (VOR/VVOR) (B) stimulations. In (A), eye position (dark line) and displacement of the triggering visual target (grey line) are plotted in a health subject (top) and a CANVAS patient (bottom). CANVAS patient shows jerky smooth pursuit. In (B) , eye position (dark line) and kinetic chair position (grey line) are plotted in a patient with isolated bilateral vestibular hypofunction (BHV) (top) and a patient with CANVAS (bottom). For purpose of better comparison, both eye and chair movements have been presented in one unique direction. In both patients VOR is deficient, but only the CANVAS patient shows the quite specific VVOR deficit