Streamlined two-step fragment analysis PCR and exome sequencing of RFC1 for diagnostic testing of suspected CANVAS patients.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is caused by biallelic pathogenic expansions, or compound heterozygosity with other pathogenic variants in the RFC1 gene. CANVAS is estimated to be underdiagnosed, both because of the lack of formal diagnostic criteria and molecular challenges that translate to lesser access and high cost of routine testing. Our aim was to address the need for making CANVAS genetic testing routine, by designing a streamlined two-step PCR consisting of a short-allele screening PCR and a confirmatory PCR with fragment capillary electrophoresis detection. Exome sequencing of RFC1 was additionally foreseen to resolve potential compound heterozygosity cases. Specificity of our approach was evaluated using ataxia patients with known non-CANVAS diagnoses, and optimized using Southern blot confirmed CANVAS patients. We evaluated our approach by testing patients consecutively referred for clinically suspected CANVAS using first the two-step PCR, followed by exome sequencing. Our approach was able to accurately identify negative and confirm positive cases in prospectively collected suspected CANVAS patients presenting with at least three typical clinical signs. The proposed testing approach provides an alternative method able to clearly distinguish between CANVAS negative and positive cases and can be easily incorporated into the genetic diagnostic laboratory workflow.

Serum Neurofilament Light Chain in Replication Factor Complex Subunit 1 CANVAS and Disease Spectrum.

BACKGROUND: Biallelic intronic AAGGG repeat expansions in the replication factor complex subunit 1 (RFC1) gene were identified as the leading cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome. Patients exhibit significant clinical heterogeneity and variable disease course, but no potential biomarker has been identified to date. OBJECTIVES: In this multicenter cross-sectional study, we aimed to evaluate neurofilament light (NfL) chain serum levels in a cohort of RFC1 disease patients and to correlate NfL serum concentrations with clinical phenotype and disease severity. METHODS: Sixty-one patients with genetically confirmed RFC1 disease and 48 healthy controls (HCs) were enrolled from six neurological centers. Serum NfL concentration was measured using the single molecule array assay technique. RESULTS: Serum NfL concentration was significantly higher in patients with RFC1 disease compared to age- and-sex-matched HCs (P < 0.0001). NfL level showed a moderate correlation with age in both HCs (r = 0.4353, P = 0.0020) and patients (r = 0.4092, P = 0.0011). Mean NfL concentration appeared to be significantly higher in patients with cerebellar involvement compared to patients without cerebellar dysfunction (27.88 vs. 21.84 pg/mL, P = 0.0081). The association between cerebellar involvement and NfL remained significant after controlling for age and sex (ß = 0.260, P = 0.034). CONCLUSIONS: Serum NfL levels are significantly higher in patients with RFC1 disease compared to HCs and correlate with cerebellar involvement. Longitudinal studies are warranted to assess its change over time.

Catch-Up Saccades in Vestibular Hypofunction: A Contribution of the Cerebellum?

Long-term deficits of the vestibulo-ocular reflex (VOR) elicited by head rotation can be partially compensated by catch-up saccades (CuS). These saccades are initially visually guided, but their latency can greatly decrease resulting in short latency CuS (SL-CuS). It is still unclear what triggers these CuS and what are the underlying neural circuits. In this study, we aimed at evaluating the impact of cerebellar pathology on CuS by comparing their characteristics between two groups of patients with bilateral vestibular hypofunction, with or without additional cerebellar dysfunction. We recruited 12 patients with both bilateral vestibular hypofunction and cerebellar dysfunction (BVH-CD group) and 12 patients with isolated bilateral vestibular hypofunction (BVH group). Both groups were matched for age and residual VOR gain. Subjects underwent video head impulse test recording of the horizontal semicircular canals responses as well as recording of visually guided saccades in the step, gap, and overlap paradigms. Latency and gain of the different saccades were calculated. The mean age for BVH-CD and BVH was, respectively, 67.8 and 67.2 years, and the mean residual VOR gain was, respectively, 0.24 and 0.26. The mean latency of the first catch-up saccade was significantly longer for the BVH-CD group than that for the BVH group (204 ms vs 145 ms, p < 0.05). There was no significant difference in the latency of visually guided saccades between the two groups, for none of the three paradigms. The gain of covert saccades tended to be lower in the BVH-CD group than in BVH group (t test; p = 0.06). The mean gain of the 12° or 20° visually guided saccades were not different in both groups. Our results suggest that the cerebellum plays a role in the generation of compensatory SL-CuS observed in BVH patients.

Nerve ultrasound in CANVAS-spectrum disease: Reduced nerve size distinguishes genetically confirmed CANVAS from other axonal polyneuropathies.

BACKGROUND AND AIMS: Ultrasound nerve cross-sectional area (CSA) of patients affected with axonal neuropathy usually shows normal value. Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) seems to represent an exception, showing smaller CSA, but previous reports did not test for biallelic RFC1 gene repeat expansions. METHODS: We compared nerve CSA from CANVAS patients (tested positive for biallelic RFC1 gene repeat expansions) with the CSA from a group of patients with chronic idiopathic axonal polyneuropathy (CIAP) who tested negative for RFC1 gene repeat expansions, hereditary axonal neuropathy (Charcot-Marie-Tooth type 2, CMT2), and Friedreich ataxia (FRDA). RESULTS: We enrolled 15 CANVAS patients (eight men, mean age 66.3 ± 11.5 years, mean disease duration 9.3 ± 4.1 years), affected with sensory axonal neuronopathy. Controls consisted of 13 CIAP (mean age 68.5 ± 12.8 years, seven men), seven CMT2 (mean age 47.9 ± 18.1 years, four men), 12 FRDA (mean age 33.7 ± 8.8, five men). Nerve ultrasound was performed at median, ulnar, sciatic, sural, and tibial nerves and brachial plexus, bilaterally. The nerve CSA from CANVAS patients was significantly smaller than the one from the other cohorts at several sites with significant and high accuracy at Receiver-operating characteristic (ROC) curve analyses. RFC1 AAGGG pentanucleotide expansion, disease duration, and disability did not correlate with CSA at any site, after Bonferroni correction. INTERPRETATION: Decreased sonographic nerve sizes, in arms and legs, in patients with sensory neuropathy and normal motor conduction studies could point to CANVAS-spectrum disease and help guide appropriate genetic testing.

Ultrasound of peripheral nerves distinguishes inherited sensory neuronopathy of cerebellar ataxia with neuropathy and vestibular areflexia syndrome from inherited axonopathy.

Introduction/Aims Recent studies have shown that ultrasound of peripheral nerves can distinguish inherited sensory neuronopathy from acquired axonopathy with a high degree of accuracy. In this study we aimed to determine whether ultrasound can also distinguish inherited sensory neuronopathy from inherited axonopathy. Methods We compared the ultrasound cross-sectional areas (CSAs) of the median, ulnar, sural, and tibial nerves of retrospectively recruited patients with cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS), in whom sensory neuronopathy is a cardinal feature, with Charcot-Marie-Tooth type 2 (CMT2) disease patients, who have an inherited axonopathy, using the Kruskal-Wallis test and receiver-operating characteristic curves. Results There were 17 patients with CANVAS and 18 with CMT2. The upper limb nerve CSAs were significantly smaller in CANVAS than in CMT2 (P < .001), with the CSAs of the median nerve at mid-forearm and ulnar nerve at mid-arm being a third or less the size of those of the CMT2 patients. Nerve ultrasound reliably distinguished CANVAS from CMT2 with ROC areas under the curve between 0.97 and 0.99. The lower limb CSAs of the two patient groups were not significantly different. Discussion Ultrasound of the upper limb nerves distinguishes CANVAS sensory neuronopathy from inherited axonopathy with high accuracy and can therefore be proposed as a reliable additional tool in the investigation of these diseases.

Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied. To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION. We identified 16 patients from 11 families, of whom seven had ACAGG expansions [(ACAGG)exp/(ACAGG)exp] (ACAGG homozygotes), two had ACAGG and AAGGG expansions [(ACAGG)exp/(AAGGG)exp] (ACAGG/AAGGG compound heterozygotes) and seven had AAGGG expansions [(AAGGG)exp/(AAGGG)exp] (AAGGG homozygotes). The overall detection rate was 5.2% (11/212 families including one family having two expansion genotypes). Long-read sequencers revealed the entire sequence of both AAGGG and ACAGG repeat expansions at the nucleotide level of resolution. Clinical assessment and neuropathology results suggested that patients with ACAGG expansions have similar clinical features to previously reported patients with homozygous AAGGG expansions, although motor neuron involvement was more notable in patients with ACAGG expansions (even if one allele was involved). Furthermore, a later age of onset and slower clinical progression were implied in patients with ACAGG/AAGGG compound heterozygous expansions compared with either ACAGG or AAGGG homozygotes in our very limited cohort. Our study clearly shows the occurrence of repeat conformation heterogeneity, with possible different impacts on the affected nervous systems. The difference in disease onset and progression between compound heterozygotes and homozygotes might also be suspected but with very limited certainty due to the small sample number of cases in our study. Studies of additional patients are needed to confirm this.

Optimized Signal Analysis to Quantify the Non-Linear Behaviour of the Electrically Evoked Vestibulo-Ocular Reflex in Patients with a Vestibular Implant.

INTRODUCTION: Different eye movement analysis algorithms are used in vestibular implant research to quantify the electrically evoked vestibulo-ocular reflex (eVOR). Often, standard techniques are used as applied for quantification of the natural VOR in healthy subjects and patients with vestibular loss. However, in previous research, it was observed that the morphology of the VOR and eVOR may differ substantially. In this study, it was investigated if the analysis techniques for eVOR need to be adapted to optimize a truthful quantification of the eVOR (VOR gain, orientation of the VOR axis, asymmetry, and phase shift). METHODS: "Natural" VOR responses were obtained in six age-matched healthy subjects, and eVOR responses were obtained in eight bilateral-vestibulopathy patients fitted with a vestibular implant. Three conditions were tested: "nVOR" 1-Hz sinusoidal whole-body rotations of healthy subjects in a rotatory chair, "eVOR" 1-Hz sinusoidal electrical vestibular implant stimulation without whole-body rotations in bilateral-vestibulopathy patients, and "dVOR" 1-Hz sinusoidal whole-body rotations in bilateral-vestibulopathy patients using the chair-mounted gyroscope output to drive the electrical vestibular implant stimulation (therefore also in sync 1 Hz sinusoidal). VOR outcomes were determined from the obtained VOR responses, using three different eye movement analysis paradigms: (1) peak eye velocity detection using the raw eye traces; (2) peak eye velocity detection using full-cycle sine fitting of eye traces; (3) peak eye velocity detection using half-cycle sine fitting of eye traces. RESULTS: The type of eye movement analysis algorithm significantly influenced VOR outcomes, especially regarding the VOR gain and asymmetry of the eVOR in bilateral-vestibulopathy patients fitted with a vestibular implant. Full-cycle fitting lowered VOR gain in the eVOR condition (mean difference: 0.14 ± 0.06 95% CI, p = 0.018). Half-cycle fitting lowered VOR gain in the dVOR condition (mean difference: 0.08 ± 0.04 95% CI, p = 0.009). In the eVOR condition, half-cycle fitting was able to demonstrate the asymmetry between the excitatory and inhibitory phases of stimulation in comparison with the full-cycle fitting (mean difference: 0.19 ± 0.12 95% CI, p = 0.024). The VOR axis and phase shift did not differ significantly between eye movement analysis algorithms. In healthy subjects, no clinically significant effect of eye movement analysis algorithms on VOR outcomes was observed. CONCLUSION: For the analysis of the eVOR, the excitatory and inhibitory phases of stimulation should be analysed separately due to the inherent asymmetry of the eVOR. A half-cycle fitting method can be used as a more accurate alternative for the analysis of the full-cycle traces.

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion.

Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist.

A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive late-onset, neurological disease. Recently, a pentanucleotide expansion in intron 2 of RFC1 was identified as the genetic cause of CANVAS. We screened an Asian-Pacific cohort for CANVAS and identified a novel RFC1 repeat expansion motif, (ACAGG)exp, in three affected individuals. This motif was associated with additional clinical features including fasciculations and elevated serum creatine kinase. These features have not previously been described in individuals with genetically-confirmed CANVAS. Haplotype analysis showed our patients shared the same core haplotype as previously published, supporting the possibility of a single origin of the RFC1 disease allele. We analysed data from >26 000 genetically diverse individuals in gnomAD to show enrichment of (ACAGG) in non-European populations.

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.

Bayesian quantification of sensory reweighting in a familial bilateral vestibular disorder (DFNA9).

DFNA9 is a rare progressive autosomal dominantly inherited vestibulo-cochlear disorder, resulting in a homogeneous group of patients with hearing impairment and bilateral vestibular function loss. These patients suffer from a deteriorated sense of spatial orientation, leading to balance problems in darkness, especially on irregular surfaces. Both behavioral and functional imaging studies suggest that the remaining sensory cues could compensate for the loss of vestibular information. A thorough model-based quantification of this reweighting in individual patients is, however, missing. Here we psychometrically examined the individual patient's sensory reweighting of these cues after complete vestibular loss. We asked a group of DFNA9 patients and healthy control subjects to judge the orientation (clockwise or counterclockwise relative to gravity) of a rod presented within an oriented square frame (rod-in-frame task) in three different head-on-body tilt conditions. Our results show a cyclical frame-induced bias in perceived gravity direction across a 90° range of frame orientations. The magnitude of this bias was significantly increased in the patients compared with the healthy control subjects. Response variability, which increased with head-on-body tilt, was also larger for the patients. Reverse engineering of the underlying signal properties, using Bayesian inference principles, suggests a reweighting of sensory signals, with an increase in visual weight of 20-40% in the patients. Our approach of combining psychophysics and Bayesian reverse engineering is the first to quantify the weights associated with the different sensory modalities at an individual patient level, which could make it possible to develop personal rehabilitation programs based on the patient's sensory weight distribution. NEW & NOTEWORTHY It has been suggested that patients with vestibular deficits can compensate for this loss by increasing reliance on other sensory cues, although an actual quantification of this reweighting is lacking. We combine experimental psychophysics with a reverse engineering approach based on Bayesian inference principles to quantify sensory reweighting in individual vestibular patients. We discuss the suitability of this approach for developing personal rehabilitation programs based on the patient's sensory weight distribution.

Are Covert Saccade Functionally Relevant in Vestibular Hypofunction?

The vestibulo-ocular reflex maintains gaze stabilization during angular or linear head accelerations, allowing adequate dynamic visual acuity. In case of bilateral vestibular hypofunction, patients use saccades to compensate for the reduced vestibulo-ocular reflex function, with covert saccades occurring even during the head displacement. In this study, we questioned whether covert saccades help maintain dynamic visual acuity, and evaluated which characteristic of these saccades are the most relevant to improve visual function. We prospectively included 18 patients with chronic bilateral vestibular hypofunction. Subjects underwent evaluation of dynamic visual acuity in the horizontal plane as well as video recording of their head and eye positions during horizontal head impulse tests in both directions (36 ears tested). Frequency, latency, consistency of covert saccade initiation, and gain of covert saccades as well as residual vestibulo-ocular reflex gain were calculated. We found no correlation between residual vestibulo-ocular reflex gain and dynamic visual acuity. Dynamic visual acuity performance was however positively correlated with the frequency and gain of covert saccades and negatively correlated with covert saccade latency. There was no correlation between consistency of covert saccade initiation and dynamic visual acuity. Even though gaze stabilization in space during covert saccades might be of very short duration, these refixation saccades seem to improve vision in patients with bilateral vestibular hypofunction during angular head impulses. These findings emphasize the need for specific rehabilitation technics that favor the triggering of covert saccades. The physiological origin of covert saccades is discussed.

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.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) - a case report and review of literature.

CANVAS (cerebellar ataxia with neuropathy and vestibular areflexia syndrome) is a rare neurological syndrome of unknown etiology. The main clinical features include bilateral vestibulopathy, cerebellar ataxia and sensory neuropathy. An abnormal visually enhanced vestibulo-ocular reflex is the hallmark of the disease. We present a case of 58-year-old male patient who has demonstrated gait disturbance, imbalance and paresthesia of feet for 2 years. On examination ataxia of gait, diminished knee and ankle reflexes, absence of plantar reflexes, fasciculations of thigh muscles, gaze-evoked downbeat nystagmus and abnormal visually enhanced vestibulo-ocular reflex were found. Brain magnetic resonance imaging revealed cerebellar atrophy. Vestibular function testing showed severely reduced horizontal nystagmus in response to bithermal caloric stimulation. Nerve conduction study revealed loss of upper and lower limb sensory nerve action potentials. The course of illness was progressive with ataxic gait and unsteadiness as the most disabling symptoms. We report 4-year follow-up of the patient since the beginning of the disease.

[Subacute ataxia associated with cerebellar ataxia, neuropathy and vestibular areflexia (CANVAS)]. / Ataxia subaguda asociada a ataxia cerebelosa, neuropatía y arreflexia vestibular (CANVAS).

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is a late onset neurodegenerative disorder. Its genetic basis has recently been identified in the gene encoding a subunit of the Replication Factor C (RFC1). We present the case of a 62-year-old woman who experienced a history of a biphasic presentation of imbalance and gait disorders, with rapid onset of symptoms followed by slow and progressive neurological deterioration. The diagnostic process was challenging, and numerous tests were conducted to rule out acquired and genetic causes of ataxia, leading to a diagnosis of late-onset idiopathic cerebellar ataxia. Subsequently, vestibular function tests identified severe bilateral vestibulopathy. This led to considering CANVAS among the diagnoses, which was ultimately confirmed through genetic testing (biallelic expansion of the pentanucleotide AAGGG in the RFC1 gene). This case highlights the importance of this new described genetic disease and its subacute presentation variant, emphasizing the relevance of objective vestibular function tests in idiopathic ataxias to achieve proper diagnosis and eventual genetic counseling for offspring.

El síndrome de ataxia cerebelosa, neuropatía y arreflexia vestibular (CANVAS) es un trastorno neurodegenerativo progresivo que se manifiesta en etapas tardías de la vida. Su base genética ha sido recientemente identificada en el gen que codifica la subunidad 1 del factor C de replicación (RFC1). Presentamos el caso de una mujer de 62 años con una historial de desequilibrio y deterioro de la marcha de presentación bifásica, con un inicio rápido de los síntomas seguido de un deterioro neurológico lento y progresivo. El proceso diagnóstico fue complejo y se realizaron numerosas pruebas para descartar causas adquiridas y genéticas de la ataxia, arribando al diagnóstico de ataxia cerebelosa de inicio tardío idiopática. Ulteriormente, las pruebas de función vestibular identificaron una grave vestibulopatía bilateral. Esto llevó a considerar el CANVAS entre los diagnósticos, que finalmente fue confirmado mediante pruebas genéticas (expansión bialélica del penta-nucleótido AAGGG en el gen RFC1). Este caso subraya la importancia de esta nueva enfermedad genética y su variante de presentación subaguda y enfatiza la relevancia de las pruebas objetivas de función vestibular en las ataxias consideradas idiopáticas para lograr un diagnóstico adecuado y un eventual asesoramiento genético a la descendencia.

Functional impact of bilateral vestibular loss and the unexplained complaint of oscillopsia.

Introduction: The vestibulo-ocular reflex (VOR) stabilizes vision during head movements. VOR disorders lead to symptoms such as imbalance, dizziness, and oscillopsia. Despite similar VOR dysfunction, patients display diverse complaints. This study analyses saccades, balance, and spatial orientation in chronic peripheral and central VOR disorders, specifically examining the impact of oscillopsia. Methods: Participants involved 15 patients with peripheral bilateral vestibular loss (pBVL), 21 patients with clinically and genetically confirmed Machado-Joseph disease (MJD) who also have bilateral vestibular deficit, and 22 healthy controls. All pBVL and MJD participants were tested at least 9 months after the onset of symptoms and underwent a detailed clinical neuro-otological evaluation at the Dizziness and Eye Movements Clinic of the Meir Medical Center. Results: Among the 15 patients with pBVL and 21 patients with MJD, only 5 patients with pBVL complained of chronic oscillopsia while none of the patients with MJD reported this complaint. Comparison between groups exhibited significant differences in vestibular, eye movements, balance, and spatial orientation. When comparing oscillopsia with no-oscillopsia subjects, significant differences were found in the dynamic visual acuity test, the saccade latency of eye movements, and the triangle completion test. Discussion: Even though there is a significant VOR gain impairment in MJD with some subjects having less VOR gain than pBVL with reported oscillopsia, no individuals with MJD reported experiencing oscillopsia. This study further supports that subjects experiencing oscillopsia present a real impairment to stabilize the image on the retina, whereas those without oscillopsia may utilize saccade strategies to cope with it and may also rely on visual information for spatial orientation. Finding objective differences will help to understand the causes of the oscillopsia experience and develop coping strategies to overcome it.

Molecular Imaging in CANVAS: A Contribution for Differential Diagnosis?

BACKGROUND: Phenotypes of CANVAS are increasingly diversified, including bradykinesia and dysautonomia, so that its primary differential diagnoses are multiple system atrophy-cerebellar type (MSA-c), and spinocerebellar ataxia type 3 (SCA3). This case series aims to highlight key molecular imaging findings in CANVAS. CASES: We report a case series of six patients with CANVAS who underwent nuclear medicine examinations in our center and 13 patients from the literature. These include 18F-FDG brain positron emission tomography (PET), single photon emission computed tomography (SPECT) of dopamine transporter (DaT) activity, and 123I-MIBG cardiac scintigraphy of noradrenergic transmission. CONCLUSIONS: In CANVAS, 18F-FDG brain PET mainly shows cerebellar hypometabolism, with preserved brainstem and striatum metabolism, contrasting with SCA3 and MSA-c. Dopaminergic denervation on scintigraphy seems to be associated with clinical parkinsonism, ranging from normal to severely impaired DaT SPECT. Additionally, 123I-MIBG cardiac scintigraphy might show denervation in CANVAS, similar to SCA3, but not in most MSA-c patients.

Systematic review and meta-analysis of the diagnostic value of optokinetic after-nystagmus in vestibular disorders.

Introduction: To date, no systematic review or meta-analysis has critically evaluated the relevance of using optokinetic after-nystagmus (OKAN) in diagnosis of vestibular disorders. To assess the role of OKAN in diagnosis of vestibular disorders, the OKAN time constant (TC) between patients with vestibular disorders and healthy participants will be compared. Methods: Automated search strategies were carried out in the Embase, Medline PubMed, Web of Science, and Scopus databases from inception to December 2023. The following inclusion criteria were applied: (1) evaluation of OKAN in individuals with vestibular disorders, (2) clinical trials, and (3) inclusion of healthy individuals as the control group. Exclusion criteria were: (1) animal studies, (2) non-clinical trial study designs, (3) assessment of non-vestibular disorders, (4) no examination of OKAN TC, (5) only examination of healthy participants, (6) studies published in a language other than English, (7) no healthy participants as control group, (8) case reports, and (9) only abstract available. The random-effects model was used to pool the data. The Joanna Briggs Institute (JBI) Critical Appraisal Tools was used to assess the risk of bias. The quality assessment was performed with the aid of the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, provided by NHLBI. The PRISMA guidelines were used as reporting guidelines. The main outcome of this study was the between-group mean difference (MDbetween) in OKAN TC and its 95% confidence interval between patients with vestibular disorders and healthy participants. Results: Seven out of 244 screened articles were included that studied 289 participants. The overall mean difference (MD = -7.08) with a 95% CI of [-10.18; -3.97] was significant (p = 0.014). The heterogeneity was significant (p = 0.02). Quality assessment was generally good (76%). The risk of bias was low in five studies and moderate in two studies. Conclusion: The results demonstrate that OKAN TC is significantly shorter in patients with vestibular disorders compared to healthy controls. This finding is important for future research, particularly with the emergence of novel clinical tools and diagnostic syndromes. Systematic Review: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=442695.

Chronic Cough and Cerebellar Ataxia With Neuropathy and Bilateral Vestibular Areflexia Syndrome (CANVAS): Screening for Mutations in Replication Factor C Subunit 1 (RFC1).

INTRODUCTION: A common complaint in patients is chronic cough (CC), which may be refractory (RCC) or unexplained (UCC). Recent studies point, as a possible cause of CC, to the hereditary cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS), with an estimated carrier prevalence of 1 in 20000. AIM: In patients with CC, determine the prevalence of the biallelic (AAGGG)exp mutation in replication factor C subunit 1 (RFC1) responsible for CANVAS, test the usefulness of the Rydel-Seiffer fork test, and evaluate patient quality of life (QoL). METHODS: Clinical and functional data were collected for the 33 included patients undergoing CC studies in our specialized unit. Performed were an etiological study of CC following European Respiratory Society recommendations, a genetic study of RFC1 mutations, and Rydel-Seiffer fork testing to detect possible peripheral vibratory sensitivity impairment. Administered to evaluate QoL were 4 questionnaires. RESULTS: Prevalence of biallelic (AAGGG)exp in RFC1 was 6.1% (n=2) overall, increasing to 7.1% in the RCC subgroup, and to 33.3% in the Rydel-Seiffer fork altered results subgroup. Prevalence of monoallelic (AAGGG)exp in RFC1 was 18.2% (n=6) overall, rising to 50.0% (n=2) in the UCC subgroup. CONCLUSION: Genetic screening for (AAGGG)exp in RFC1, and also use of the Rydel-Seiffer fork test, should be considered in specialized CC consultations for patients with RCC and UCC. Detecting possible CANVAS symptoms in CC studies would identify candidates for early genetic screening, of interest in reducing the disease burden for patients and health systems alike.

Bilateral vestibulopathy and disabling vertigo: A CARE case series.

INTRODUCTION: The term bilateral vestibulopathy (BV) was recently defined by the Bárány Society. Loss of otolith function was not included in their criteria. Although spontaneous progression to complete bilateral impairment of vestibular function is expected, it is unlikely that patients with advanced BV will continue to present episodes of intense vertigo. Here, following CARE case report guidelines, we report the case of patients meeting the criteria for BV and still disabled by vertigo. CASE SERIES: Three patients evaluated in our department meeting the Bárány criteria for definite BV but still complaining of disabling rotatory vertigo were included. All underwent clinical and instrumental vestibular examination. The observations are reported. CONCLUSION: In case of BV, the conservation of a stable otolithic reference frame could allow patients to optimize postural strategy. It would be useful to revisit a classification of BV by stages, by introducing an evaluation of otolithic function and postural control for possible subsequent vestibular implantation.