Head impulse testing in bilateral vestibulopathy in patients with genetically defined CANVAS

Abstract Background To investigate the association between disease duration and the severity of bilateral vestibulopathy in individuals with complete or incomplete CANVAS (Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome) and biallelic RFC1 repeat expansions. Methods Retrospective analysis of clinical data and the vestibulo‐ocular reflex quantified by the video head impulse test in 20 patients with confirmed biallelic RFC1 repeat expansions. Results Vestibulo‐ocular reflex gain at first admittance 6.9 ± 5.0 years after disease onset was 0.16 [0.15–0.31] (median [interquartile range]). Cross‐sectional analysis revealed that gain reduction was associated with disease duration. Follow‐up measurements were available for ten individuals: eight of them exhibited a progressive decrease of the vestibulo‐ocular reflex gain over time. At the first visit, six of all patients (30%) did not show clinical signs of cerebellar ataxia. Conclusions Our data suggest a pathological horizontal head impulse test, which can easily be obtained in many outpatient clinics, as a sign of bilateral vestibulopathy in genetically confirmed CANVAS that can precede clinically accessible cerebellar ataxia at least in a subset of patients. The presumably continuous decline over time possibly reflects the neurodegenerative character of the disease. Thus, genetic testing for RFC1 mutations in (isolated) bilateral vestibulopathy might allow disease detection before the onset of cerebellar signs. Further studies including a wider spectrum of vestibular function tests are warranted in a prospective design.


INTRODUCTION
The genetic cause of CANVAS, a previously clinically defined syndrome of cerebellar ataxia, neuropathy, and bilateral vestibulopathy, was deciphered in 2019 as a biallelic intronic repeat expansion in the RFC1 gene (Cortese et al., 2019). The mutation is detectable in > 90% of patients with the complete symptom triad (Cortese et al., 2019;Gisatulin et al., 2020). Since then, a few attempts have been performed to describe the natural history of RFC1-positive CANVAS. Their focus was on cerebellar features (Cortese et al., 2020;Traschütz et al., 2021) and neuropathy (Curro et al., 2021), but not on bilateral vestibulopathy. Hypothesizing that the vestibular organ progressively degenerates over the disease course (Ishai et al., 2021), we investigated the association between bilateral vestibulopathy and disease duration in patients with RFC1-positive CANVAS by analyzing the gain reduction of the vestibulo-ocular reflex quantified by the video head impulse test, a widely accessible method that can easily be obtained in many outpatient clinics. Quantitative analysis of the gain of the vestibulo-ocular reflex by video-oculography of the horizontal head impulse test was performed as previously described (Helmchen et al., 2017). Only the horizontal vestibulo-ocular reflex was analyzed. In brief, eye and head movements were recorded by a digital video camera (Eye-SeeCam HIT System, Autronics, Hamburg, Germany) at a sampling rate of 220 Hz. At least ten passive and rapid (peak velocity 250 • /sec) head movements of small amplitude (10-15 • ) were performed per side. Head impulses were unpredictable for direction and amplitude. The gain of the horizontal vestibulo-ocular reflex was analyzed at a narrow time interval of 60 ± 10 ms after head movement onset.

METHODS
A mean gain <0.7 was considered pathologic (Machner et al., 2021;Yip et al., 2016). If more than one video head impulse test result was available, only the first testing was used for a cross-sectional analysis to focus on the earliest disease stage possible. In seven patients with follow-up measurements, longitudinal results were analyzed on a descriptive level. The mean vestibulo-ocular reflex gain used in the present study was assessed by calculating the mean of the gain of the right and the left vestibular organ. Simple linear regression was calculated to assess the association between the mean vestibulo-ocular reflex gain and disease duration. Analysis were performed and the figure was created with GraphPad Prism 8. Data are available from the corresponding author upon reasonable request.

RESULTS
We investigated 20 RFC1-positive patients (6 female  Cross-sectional investigation of the mean vestibulo-ocular reflex gain and disease duration suggests an association between both parameters (simple linear regression, r 2 = .24, p = .027, Figure 1A). Repeated video head impulse test measurements, available for 10 subjects, depicted a vestibulo-ocular reflex gain reduction in 8 of 10 subjects over time ( Figure 1B).

DISCUSSION
IN an attempt to characterize the natural course of bilateral vestibulopathy in CANVAS, we related its most representative and easily accessible sign, that is, the abnormal video head impulse test, of  √ -present; x -absent; limb ataxia was defined by abnormal finger-nose-test and/or abnormal heal-shin-slide test; MRI -magnetic resonance imaging; ENG -electroneurography; Sensory neuropathy was clinically defined by the presence of reduced sense of vibration and the absence of the achilles deep tendon reflex; ENG was considered pathologic in the case of either a reduction or a loss of the sensory nerve action potential (SNAP) or slowing at the upper limbs using clinically established cut-off values; diagnosis of cerebellar ataxia was established by clinical examination performed by an experienced neurologist based on cerebellar oculomotor signs, limb ataxia, and/or dysarthria.

FUNDING
This study was funded by the Damp Foundation (to KL).