VEMPs and Dysautonomia Assessment in Definite Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS): a Case Series Study.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recently described slowly progressive ataxia with severe imbalance due to the compromise of three of the four sensory inputs for balance, leaving only vision unaffected. Bilateral vestibulopathy is present but saccular and utricular function, measured by vestibular evoked myogenic potentials (VEMPs), has not been widely studied in these patients. Dysautonomia has been reported but is not among the diagnostic criteria. We performed a database analysis to identify patients evaluated between 2003 and 2019 with probable diagnosis of CANVAS by using key words "bilateral vestibulopathy and/or cerebellar ataxia and/or sensory polyneuropathy." Five out of 842 met all conditions. Patients underwent neurological/neurootological exam, brain MRI, visually enhanced vestibulo-ocular reflex (VVOR) exam by high-speed video-oculography using video-Head Impulse Test (vHIT), VEMPs, neurophysiological studies, and genetic tests to exclude other causes of ataxia. Dysautonomia was addressed by the standardized survey of autonomic symptoms. All patients had clinically definite CANVAS as brain MRI showed vermal cerebellar atrophy, neurophysiological studies showed a sensory neuronopathy pattern (absent sensory action potentials), VVOR was abnormal bilaterally, and genetic tests ruled out other causes of ataxia including SCA 3 and Friedreich ataxia. Patients had at least 3 dysautonomic symptoms, including xerostomia/xerophthalmia (5/5). VEMP results varied among patients, ranging from normal to completely abnormal. We found inconsistent results with VEMPs. The utilization of VEMPs in more CANVAS cases will determine its utility in this syndrome. Dysautonomia may be included in the diagnostic criteria.

Effects of galvanic vestibular stimulation on resting state brain activity in patients with bilateral vestibulopathy.

We examined the effect of galvanic vestibular stimulation (GVS) on resting state brain activity using fMRI (rs-fMRI) in patients with bilateral vestibulopathy. Based on our previous findings, we hypothesized that GVS, which excites the vestibular nerve fibers, (a) increases functional connectivity in temporoparietal regions processing vestibular signals, and (b) alleviates abnormal visual-vestibular interaction. Rs-fMRI of 26 patients and 26 age-matched healthy control subjects was compared before and after GVS. The stimulation elicited a motion percept in all participants. Using different analyses (degree centrality, DC; fractional amplitude of low frequency fluctuations [fALFF] and seed-based functional connectivity, FC), group comparisons revealed smaller rs-fMRI in the right Rolandic operculum of patients. After GVS, rs-fMRI increased in the right Rolandic operculum in both groups and in the patients' cerebellar Crus 1 which was related to vestibular hypofunction. GVS elicited a fALFF increase in the visual cortex of patients that was inversely correlated with the patients' rating of perceived dizziness. After GVS, FC between parietoinsular cortex and higher visual areas increased in healthy controls but not in patients. In conclusion, short-term GVS is able to modulate rs-fMRI in healthy controls and BV patients. GVS elicits an increase of the reduced rs-fMRI in the patients' right Rolandic operculum, which may be an important contribution to restore the disturbed visual-vestibular interaction. The GVS-induced changes in the cerebellum and the visual cortex were associated with lower dizziness-related handicaps in patients, possibly reflecting beneficial neural plasticity that might subserve visual-vestibular compensation of deficient self-motion perception.

Increased brain responsivity to galvanic vestibular stimulation in bilateral vestibular failure.

In this event-related functional magnetic resonance imaging (fMRI) study we investigated how the brain of patients with bilateral vestibular failure (BVF) responds to vestibular stimuli. We used imperceptible noisy galvanic vestibular stimulation (GVS) and perceptible bi-mastoidal GVS intensities and related the corresponding brain activity to the evoked motion perception. In contrast to caloric irrigation, GVS stimulates the vestibular organ at its potentially intact afferent nerve site. Motion perception thresholds and cortical responses were compared between 26 BVF patients to 27 age-matched healthy control participants. To identify the specificity of vestibular cortical responses we used a parametric design with different stimulus intensities (noisy imperceptible, low perceptible, high perceptible) allowing region-specific stimulus response functions. In a 2 × 3 flexible factorial design all GVS-related brain activities were contrasted with a sham condition that did not evoke perceived motion. Patients had a higher motion perception threshold and rated the vestibular stimuli higher than the healthy participants. There was a stimulus intensity related and region-specific increase of activity with steep stimulus response functions in parietal operculum (e.g. OP2), insula, superior temporal gyrus, early visual cortices (V3) and cerebellum while activity in the hippocampus and intraparietal sulcus did not correlate with vestibular stimulus intensity. Using whole brain analysis, group comparisons revealed increased brain activity in early visual cortices (V3) and superior temporal gyrus of patients but there was no significant interaction, i.e. stimulus-response function in these regions were still similar in both groups. Brain activity in these regions during (high)GVS increased with higher dizziness-related handicap scores but was not related to the degree of vestibular impairment or disease duration. nGVS did not evoke cortical responses in any group. Our data indicate that perceptible GVS-related cortical responsivity is not diminished but increased in multisensory (visual-vestibular) cortical regions despite bilateral failure of the peripheral vestibular organ. The increased activity in early visual cortices (V3) and superior temporal gyrus of BVF patients has several potential implications: (i) their cortical reciprocal inhibitory visuo-vestibular interaction is dysfunctional, (ii) it may contribute to the visual dependency of BVF patients, and (iii) it needs to be considered when BVF patients receive peripheral vestibular stimulation devices, e.g. vestibular implants or portable GVS devices. Imperceptible nGVS did not elicit cortical brain responses making it unlikely that the reported balance improvement of BVF by nGVS is mediated by cortical mechanisms.

Nerve ultrasound as a diagnostic tool for sensory neuronopathy in spinocerebellar ataxia syndrome.

OBJECTIVE: The objective was to assess if nerve ultrasound has a role in diagnosing sensory neuronopathy in spinocerebellar ataxia syndrome (SCA) by examining if proposed diagnostic cut-off criteria of ultrasound in sensory neuronopathy caused by cerebellar ataxia neuropathy vestibular areflexia syndrome (CANVAS) were also discriminatory for SCA-related sensory neuronopathy. METHODS: Optimal diagnostic cut-off criteria for nerve size measured by diagnostic ultrasound were developed in 14 patients with CANVAS and 42 healthy controls using six peripheral nerve sites; and logistic regression and receiver operating characteristic (ROC) curves. These proposed cut-off values were tested in seven patients with spinocerebellar ataxia type 2 (SCA2) patients with sensory neuronopathy. RESULTS: Ultrasound of upper limb nerves was highly accurate in differentiating between CANVAS and healthy controls with areas under the ROC curves between 0.97 and 0.99. Optimal cut-off measurements from the CANVAS patients also accurately diagnosed sensory neuronopathy in all patients with SCA2. CONCLUSIONS: Upper limb ultrasound is a sensitive tool for detecting sensory neuronopathy in established cases of CANVAS and SCA2. SIGNIFICANCE: Ultrasound could aid the diagnosis of sensory neuronopathy in spinocerebellar ataxias.

High prevalence of congenital deafness on Reunion Island is due to a founder variant of LHFPL5.

Reunion Island is a French oversea department in the Indian Ocean with 1.6/1000, an estimated prevalence of deafness that is almost double as compared to the mainland France. Twelve children having isolated bilateral prelingual profound deafness along with motor delay attributed to vestibular areflexia were enrolled. Their mean walking age was 19 months. Electroretinography and temporal bone CT-scans were normal in all cases. A novel homozygous frameshift lipoma HMGIC fusion partner-like 5 (LHFPL5) variant c.185delT p.(Phe62Serfs*23) was identified using whole-exome sequencing. It was found in seven families. Four patients from two different families from both Reunion Island and mainland France, were compound heterozygous: c.185delT p.(Phe62Serfs*23) and c.472C > T p.(Arg158Trp). The phenotype observed in our patients completely mimics the hurry-scurry (hscy) murine Tmhs knock-out model. The recurrent occurrence of same LHFPL5 variant in Reunion Island is attributed to common ancestor couple born in 1693.

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) with chronic cough and preserved muscle stretch reflexes: evidence for selective sparing of afferent Ia fibres.

The aim of this study was to describe five patients with cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) with chronic cough and preserved limb muscle stretch reflexes. All five patients were in the seventh decade of age, their gait imbalance having been initiated in the fifth decade. In four patients cough antedated gait imbalance between 15 and 29 years; cough was spasmodic and triggered by variable factors. Established clinical picture included severe hypopallesthesia predominating in the lower limbs with postural imbalance, and variable degree of cerebellar axial and appendicular ataxia, dysarthria and horizontal gaze-evoked nystagmus. Upper- and lower-limb tendon jerks were preserved, whereas jaw jerk was absent. Vestibular function testing showed bilateral impairment of the vestibulo-ocular reflex. Nerve conduction studies demonstrated normal motor conduction parameters and absence or severe attenuation of sensory nerve action potentials. Somatosensory evoked potentials were absent or severely attenuated. Biceps and femoral T-reflex recordings were normal, while masseter reflex was absent or attenuated. Sympathetic skin responses were normal. Cranial MRI showed vermian and hemispheric cerebellar atrophy predominating in lobules VI, VII and VIIa. We conclude that spasmodic cough may be an integral part of the clinical picture in CANVAS, antedating the appearance of imbalance in several decades and that sparing of muscle spindle afferents (Ia fibres) is probably the pathophysiological basis of normoreflexia.

Pathogenetic Role of Endothelial Dysfunction in Idiopathic Vestibulopathy.

Comparative analysis of the groups of patients with idiopathic bilateral vestibular hypofunction and a group of vestibulopathy patients with vertebrobasilar insufficiency demonstrated identity of the basic and additional diagnostic parameters in these syndromes as well as similarity in clinical diagnostic and anamnesis data. In all cases, functional assessment of endothelium-dependent vasodilation and selected biochemical marker sICAM-1 revealed endothelial dysfunction. Drug correction of endothelial dysfunction positively affected the manifestations of major and minor features of the syndrome, which confirmed the contribution of endothelial functional disturbances to the pathogenesis of bilateral vestibular hypofunction.

Peripheral nerves are pathologically small in cerebellar ataxia neuropathy vestibular areflexia syndrome: a controlled ultrasound study.

BACKGROUND AND PURPOSE: Sensory neuronopathy is a cardinal feature of cerebellar ataxia neuropathy vestibular areflexia syndrome (CANVAS). Having observed that two patients with CANVAS had small median and ulnar nerves on ultrasound, we set out to examine this finding systematically in a cohort of patients with CANVAS, and compare them with both healthy controls and a cohort of patients with axonal neuropathy. We have previously reported preliminary findings in seven of these patients with CANVAS and seven healthy controls. METHODS: We compared the ultrasound cross-sectional area of median, ulnar, sural and tibial nerves of 14 patients with CANVAS with 14 healthy controls and 14 age- and gender-matched patients with acquired primarily axonal neuropathy. We also compared the individual nerve cross-sectional areas of patients with CANVAS and neuropathy with the reference values of our laboratory control population. RESULTS: The nerve cross-sectional area of patients with CANVAS was smaller than that of both the healthy controls and the neuropathy controls, with highly significant differences at most sites (P < 0.001). Conversely, the nerve cross-sectional areas in the upper limb were larger in neuropathy controls than healthy controls (P < 0.05). On individual analysis, the ultrasound abnormality was sufficiently characteristic to be detected in all but one patient with CANVAS. DISCUSSION: Small nerves in CANVAS probably reflect nerve thinning from loss of axons due to ganglion cell loss. This is distinct from the ultrasound findings in axonal neuropathy, in which nerve size was either normal or enlarged. Our findings indicate a diagnostic role for ultrasound in CANVAS sensory neuronopathy and in differentiating neuronopathy from neuropathy.

Hippocampal gray matter volume in bilateral vestibular failure.

Bilateral vestibular failure (BVF) is a severe chronic disorder of the labyrinth or the eighth cranial nerve characterized by unsteadiness of gait and disabling oscillopsia during head movements. According to animal data, vestibular input to the hippocampus is proposed to contribute to spatial memory and spatial navigation. Except for one seminal study showing the association of impaired spatial navigation and hippocampal atrophy, patient data in BVF are lacking. Therefore, we performed a voxel-wise comparison of the hippocampal gray matter volume (GMV) in a clinically representative sample of 27 patients with incomplete BVF and 29 age- and gender-matched healthy controls to test the hypothesis of hippocampal atrophy in BVF. Although the two groups did not generally differ in their hippocampal GMV, a reduction of GMV in the bilateral hippocampal CA3 region was significantly correlated with increased vestibulopathy-related clinical impairment. We propose that GMV reduction in the hippocampus of BVF patients is related to the severity of vestibular-induced disability which is in line with combined hippocampal atrophy and disorders of spatial navigation in complete vestibular deafferentation due to bilateral nerve section. Clinically, however, the most frequent etiologies of BVF cause incomplete lesions. Accordingly, hippocampus atrophy and deficits in spatial navigation occur possibly less frequently than previously suspected. Hum Brain Mapp 37:1998-2006, 2016. © 2016 Wiley Periodicals, Inc.