Vestibular Syndrome Research Articles

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.

The future of AVS, dizziness, and vertigo in emergency departments Part iii: A tyranny of distance – the persistence of rural health inequity

The future of AVS, dizziness, and vertigo in emergency departments Part iii: A tyranny of distance – the persistence of rural health inequity In the third article of this five-part series, Dr Millie Nakatsuka discusses the impact of isolation on health equity and the medical decision-making for emergency presentations of acute vestibular syndrome (AVS). People in rural and remote areas bear a significantly higher burden of disease and have poorer health outcomes. They have greater socio-economic disadvantage with lower levels of educational attainment, lower rates of employment, lower income and exhibit more health risk factors with markedly increased rates of obesity, tobacco smoking and alcohol consumption.

Advances in vestibular function and rehabilitation of large vestibular aqueduct syndrome

Large vestibular aqueduct syndrome（LVAS） is a common recessive hereditary hearing loss disease, and some patients may also experience vestibular dysfunction. With the wide application of cochlear implant（CI） and the development of vestibular medicine, the pathophysiological mechanism of LVAS and the influence mechanism of CI on vestibular function are gradually elucidated. Consequently, the evaluation and rehabilitation of vestibular dysfunction function have also become research hotspots. This article reviews studies on vestibular function and related rehabilitation in patients with large vestibular aqueduct syndrome.

Effects of Vestibular vs. Somatosensory Rehabilitation on Balance and Quality of Life of Sub-acute Stroke Patients with Vestibular Syndrome

Background: Stroke is one of the most common causes of disability worldwide, affecting millions of people per year, and it has a large burden on health care systems. In the early subacute phase, patients who survive a stroke usually show impairments in balance, often due to sensory and vestibular deficits; this influences their quality of life. Methods: A double-blind, randomized controlled trial was conducted to assess the effectiveness of vestibular and somatosensory interventions on balance and quality of life in early subacute stroke patients with vestibular syndrome. Fifty-two patients were randomly divided into a vestibular or somatosensory rehabilitation group or a control group receiving usual care. The trial was completed by 49 patients who were evaluated onon the Berg Balance Scale and the Vestibular Quality of Life Questionnaire at baseline and 12 weeks post-intervention. Results: The study found that both vestibular and somatosensory rehabilitation interventions led to significant improvements in balance, as indicated by the Berg Balance Scale scores, and quality of life, based on vestibular Quality of Life Questionnaire scores, compared to the control group (p<0.05). There was no significant difference between the two intervention groups in terms of their impact on either balance or quality of life outcomes. Conclusion: Vestibular and somatosensory rehabilitation interventions represent effective strategies for improving balance and quality of life in early subacute stroke patients with vestibular syndrome. These findings underline the importance of including targeted rehabilitation approaches within stroke care protocols to achieve optimal functional outcomes and long-term recovery. Keywords: Balance, Stroke, Quality of Life, Vestibular Symptoms.

Predictive accuracy of wideband absorbance in children with large vestibular aqueduct syndrome: A single-center retrospective study

ObjectivesThis study aimed to assess the clinical significance of Wideband Absorbance (WBA) in children with Large Vestibular Aqueduct Syndrome (LVAS), which could potentially serve as diagnostic and predictive markers for LVAS in children. DesignThis was a single-center retrospective case-control study. Audiological measurements and Wideband Acoustic Immittance (WAI) were performed. Propensity score matching (PSM) was considered to treat group imbalance. The Receiver Operating Characteristic (ROC) curves and area under the ROC curve (AUC) were used to evaluate the sensitivity and specificity of WBA. Study sampleParticipants included 42 children with LVAS and 163 normal children aged 6 months −11 years recruited from clinical audiology settings between 2019 and 2021. ResultsThe WBA at Tympanometric Peak Pressure (WBATPP) and Ambient Pressure (WBAA) in the LVAS group were significantly lower than those of the control group at 1259–2000 Hz but higher at 4000–6349 Hz (p < 0.05, power >0.8). The WBAA (1587 Hz) AUC value was 0.805, identifying a score ≤0.565 as indicative of a LVAS risk. ConclusionsWBA holds promise in distinguishing LVAS from the normal condition and warrants further exploration as a tool to examine the influence of inner ear pressure on acoustic energy transmission in the middle ear.

Analysis and occurrence of biallelic pathogenic repeat expansions in RFC1 in a German cohort of patients with a main clinical phenotype of motor neuron disease

Biallelic pathogenic repeat expansions in RFC1 were recently identified as molecular origin of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) as well as of one of the most common causes of adult-onset ataxia. In the meantime, the phenotypic spectrum has expanded massively and now includes mimics of multiple system atrophy or parkinsonism. After identifying a patient with a clinical diagnosis of amyotrophic lateral sclerosis (ALS) as a carrier of biallelic pathogenic repeat expansions in RFC1, we studied a cohort of 106 additional patients with a clinical main phenotype of motor neuron disease (MND) to analyze whether such repeat expansions are more common in MND patients. Indeed, two additional MND patients (one also with ALS and one with primary lateral sclerosis/PLS) have been identified as carrier of biallelic pathogenic repeat expansions in RFC1 in the absence of another genetic alteration explaining the phenotype, suggesting motor neuron disease as another extreme phenotype of RFC1 spectrum disorder. Therefore, MND might belong to the expanding phenotypic spectrum of pathogenic RFC1 repeat expansions, particularly in those MND patients with additional features such as sensory and/or autonomic neuropathy, vestibular deficits, or cerebellar signs. By systematically analyzing the RFC1 repeat array using Oxford nanopore technology long-read sequencing, our study highlights the high intra- and interallelic heterogeneity of this locus and allows the identification of the novel repeat motif ‘ACAAG’.

An Updated Canvas of the RFC1-mediated CANVAS (Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome).

Proliferation of specific nucleotide sequences within the coding and non-coding regions of numerous genes has been implicated in approximately 40 neurodegenerative disorders. Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), a neurodegenerative disorder, is distinguished by a pathological triad of sensory neuropathy, bilateral vestibular areflexia and cerebellar impairments. It manifests in adults gradually and is autosomal recessive and multi-system ataxia. Predominantly, CANVAS is associated with biallelic AAGGG repeat expansions in intron 2 of the RFC1 gene. Although various motifs have been identified, only a subset induces pathological consequences, by forming stable secondary structures that disrupt gene functions both in vitro and in vivo. The pathogenesis of CANVAS remains a subject of intensive research, yet its precise mechanisms remain elusive. Herein, we aim to comprehensively review the epidemiology, clinical ramifications, molecular mechanisms, genetics, and potential therapeutics in light of the current findings, extending an overview of the most significant research on CANVAS.

Common Neurologic Diseases in Geriatric Dogs.

The increase in the canine geriatric population means that veterinarians are more often confronted with diseases that are more prevalent in patients in this age group. As in other organ systems, degenerative, neoplastic, and vascular diseases are the most prevalent neurologic disorders in older dogs. A neurological disease in an older dog poses a challenge for the clinician due to the presence of concomitant diseases and age-related changes that make it difficult to interpret the neurological examination. In addition, given the age of the patients, some owners do not allow advanced imaging tests, and it is necessary to establish the most likely presumptive diagnosis to initiate treatment. Although many of these diseases can cause clinical signs that can be very upsetting, some of them can be managed with symptomatic therapy and have a good prognosis, such as idiopathic vestibular syndrome. Moreover, advances in and the greater availability of therapeutic options such as surgery and radiation therapy may increase survival and quality of life in diseases with a more serious prognosis, such as tumours. The aim of this review is to summarize the clinical presentation, diagnosis, and treatment of the more frequent diseases affecting the central nervous systems of geriatric dogs.

Pathologic RFC1 repeat expansions do not contribute to the development of inflammatory neuropathies.

Biallelic expansions of the AAGGG repeat in the replication factor C subunit 1 (RFC1) have recently been described to be responsible for cerebellar ataxia, peripheral neuropathy and vestibular areflexia syndrome. This genetic alteration has also allowed genetic classification in up to one-third of cases with idiopathic sensory neuropathy. Here, we screened a well-characterized cohort of inflammatory neuropathy patients for RFC1 repeat expansions to explore whether RFC1 was increased from background rates and possibly involved in the pathogenesis of inflammatory neuropathy. A total of 259 individuals with inflammatory neuropathy and 243 healthy controls were screened for the AAGGG repeat expansion using short-range flanking PCR and repeat-primed PCR. Cases without amplifiable PCR product on flanking PCR and positive repeat-primed PCR were also tested for the mostly non-pathogenic expansions of the AAAGG and AAAAG repeat units. None of the patients showed biallelic AAGGG expansion of RFC1, and their carrier frequency for AAGGG was comparable with controls [n = 27 (5.2%) and n = 23 (4.7%), respectively; P > 0.5]. Data suggest that the pathologic expansions of AAGGG repeats do not contribute to the development of inflammatory neuropathies nor lead to misdiagnosed cases. Accordingly, routine genetic screening for RFC1 repeat expansion is not indicated in this patient population.

RFC1 Repeat Distribution in the Cypriot Population: Study of a Large Cohort of Patients With Undiagnosed Ataxia and Non-Disease Controls.

The intronic biallelic AAGGG expansion in the replication factor C subunit 1 (RFC1) gene was recently associated with a phenotype combining cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, as well as with late-onset ataxia. Following this discovery, studies in multiple populations extended the phenotypic and genotypic spectrum of this locus. Multiple benign and additional pathogenic configurations are currently known. Our main objectives were to study the prevalence of the pathogenic AAGGG expansion in the Cypriot population, to further characterize the RFC1 repeat locus allele distribution, and to search for possible novel repeat configurations. Cypriot undiagnosed patients, in the majority presenting at least with cerebellar ataxia and non-neurologic disease controls, were included in this study. A combination of conventional methods was used, including standard PCR flanking the repeat region, repeat-primed PCR, long-range PCR, and Sanger sequencing. Bioinformatics analysis of already available in-house short-read whole-genome sequencing data was also performed. A large group of undiagnosed patients (n = 194), mainly presenting with pure ataxia or with ataxia accompanied by neuropathy or additional symptoms, as well as a group of non-disease controls (n = 100), were investigated in the current study. Our findings include the diagnosis of 10 patients homozygous for the pathogenic AAGGG expansion and a high percentage of heterozygous AAGGG carriers in both groups. The benign AAAAGn, AAAGGn, and AAGAGn configurations were also identified in our cohorts. We also report and discuss the identification of 2 recently reported novel and possibly benign repeat configurations, AAAGGGn and AAGACn, thus confirming their existence in another distinct population, and we highlight an increased frequency of the AAAGGGn in the patient group, including a single case of homozygosity. Our findings indicate the existence of genetic heterogeneity regarding the RFC1 repeat configurations and that the AAGGG pathogenic expansion is a frequent cause of ataxia in the Cypriot population.

Profiling complex repeat expansions in RFC1 in Parkinson’s disease

A biallelic (AAGGG) expansion in the poly(A) tail of an AluSx3 transposable element within the gene RFC1 is a frequent cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), and more recently, has been reported as a rare cause of Parkinson’s disease (PD) in the Finnish population. Here, we investigate the prevalence of RFC1 (AAGGG) expansions in PD patients of non-Finnish European ancestry in 1609 individuals from the Parkinson’s Progression Markers Initiative study. We identified four PD patients carrying the biallelic RFC1 (AAGGG) expansion and did not identify any carriers in controls.

Use of the Head Impulse, Nystagmus, Test of Skew ('HINTS') assessment to aid differential diagnosis in acute vestibular syndrome in the hyperacute stroke setting.

Differential diagnosis of acute vertigo syndrome is challenging given the similarities between clinical presentations of posterior circulation stroke and peripheral vestibular dysfunction. The Head Impulse, Nystagmus, Test of Skew ('HINTS') assessment is a clinical bedside test used to aid diagnosis. Comprehensive training on use of the Head Impulse, Nystagmus, Test of Skew assessment was provided to one stroke consultant, and the effectiveness of the test in that setting was assessed. Further education was completed with more members of the stroke and emergency department multi-disciplinary team. Quality improvement measures including magnetic resonance imaging use and bed utilisation were explored. Following training of one stroke consultant, the Head Impulse, Nystagmus, Test of Skew assessment was found to be a feasible, accurate bedside test within this acute stroke service. Further training for the multi-disciplinary team was completed, but outcome measures were not explored because of the coronavirus disease 2019 pandemic and maternity leave. There is a role for trained members of the multi-disciplinary team to successfully use the Head Impulse, Nystagmus, Test of Skew assessment in hyperacute stroke settings, to aid diagnosis in acute vertigo syndrome.

Recognizing Posterior Circulation Transient Ischemic Attacks Presenting as Episodic Isolated Dizziness

Diagnosing patients presenting to the emergency department with self-limited episodes of isolated dizziness (the episodic vestibular syndrome, or EVS) requires a broad differential diagnosis that includes posterior circulation transient ischemic attack (pc-TIA). Because these patients are by definition, asymptomatic without new neurological findings on exam, the diagnosis, largely based on history and epidemiological context, can be challenging. We review literature that addresses the frequency of pc-TIA in this group of patients, compared to other potential causes of the EVS. We present ways of distinguishing pc-TIA from vestibular migraine, the most common cause of the EVS. We also present a diagnostic algorithm that may help clinicians to work their way through the differential diagnosis.

Multifrekvenční testování pacientů po akutním izolovaném vestibulárním deficitu

Summary Introduction: Acute unilateral vestibulopathy (AUVP) is defined as an acute peripheral vestibular syndrome without evidence of central neurological or audiological symptoms. Currently, there is no uniform instrumental testing protocol for the diagnosis and follow-up of patients with AUVP. Vestibular tests provide information in different frequency bands of the vestibuloocular reflex (VOR); therefore, the aim of our study is to evaluate the contribution of multifrequency VOR testing in the evaluation of patients with AUVP. Methods: 22 patients (9 females and 13 males) with a diagnosis of AUVP were prospectively examined. Multifrequency testing included spontaneous nystagmus with visual fixation cancellation (SPN), Head Shaking Test (HST), bithermal air caloric test, and video Head Impulse Test (vHIT). The first examination was performed within one week of AUVP; follow-up examinations were performed 3 and 6 months apart. On the third examination, the Dizziness handicap inventory (DHI) questionnaire was completed. Results: The rate of the slow component of spontaneous and induced nystagmus during HST and the values of unilateral weakness (UW) during caloric testing decreased during follow-up with a statistically significant difference (P &lt;0.05) between both the first and second and between the second and third examinations. On vHIT, there was a statistically significant increase in the gains of individual channels during follow-up. Dissociation of vHIT and caloric test results was found in 22.73% of patients on the second and 18.18% of patients on the third examination. There was a statistically significant difference in the changes in test results of patients with different DHI. Conclusion: Multifrequency VOR testing provides a comprehensive overview of the status of vestibular function, recovery dynamics, and clinical impact of residual vestibular dysfunction after AUVP. Key words acute unilateral vestibulopathy – vestibuloocular reflex – video Head Impulse Test – caloric test – spontaneous nystagmus – Head Shaking Test

Update on diagnostic procedures in third window syndromes. German version

The diagnosis of third window syndromes often poses achallenge in clinical practice. This paper provides an up-to-date overview of diagnostic procedures in third window syndromes, with special emphasis on superior canal dehiscence syndrome(SCDS), large vestibular aqueduct syndrome(LVAS), andX-chromosomal malformation of the cochlea. Aliterature search was performed in PubMed up to December 2023. Furthermore, aselection of the authors' own cases is presented. Audiovestibular tests for the diagnosis of third window syndromes are most often reported for patients with SCDS in the literature. In this context, cut-off values with different sensitivities and specificities have been defined for different outcome parameters of vestibular evoked myogenic potentials. Current developments include the application of electrocochleography, broadband tympanometry, video head impulse testing, and vibration-induced nystagmus. Genetic analyses are increasingly applied in LVAS. The diagnosis of third window syndromes is always based on the synthesis of patients' symptoms, clinical signs, audiovestibular test results, and imaging.

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

IntroductionA 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. AimIn 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). MethodsClinical 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. ResultsPrevalence 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. ConclusionGenetic 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.

Clinical Assessment of the Nystagmus Fixation Suppression Test: An Experimental Study.

Assessment of nystagmus fixation suppression can be used as an additional diagnostic tool for patients with an acute vestibular syndrome to distinguish between a central or peripheral cause. We investigated the ability of physicians to detect fixation suppression using a nystagmus simulation model. We used a nystagmus simulator to measure the accuracy of the nystagmus fixation suppression test. Fixation suppression was assessed randomly in 6170 trials by 20 otorhinolaryngologists and neurologists, segregated into 2 groups based on their neurootological experience, a beginner and an experienced group. The simulator presented random nystagmus slow velocity (SPV) reductions and presented 3 conditions with either changed nystagmus frequency, amplitude, or both. The cutoff for the discernment of fixation suppression ranged from 1.2 to 14°/s nystagmus velocity difference. The more intense the baseline nystagmus was, the more difficult was the detection of fixation suppression. There was not significant difference (P >.05) in the cutoff values in the experts group compared to the novices for all 3 different conditions. Both, novices and experts, detected frequency changes easier than differences of the nystagmus amplitude. Test sensitivity was very low (19%-65%) for discernment of small nystagmus velocity differences of <2°/s by experts. In our study, there was no difference between experts and novices in detection of nystagmus suppression by visual fixation. The examiners could only detect large suppression effects at low-intensity baseline nystagmus. Overall, the sensitivity and accuracy of a clinical fixation suppression test is low and the assistance with a video-oculography device is highly recommended.

Altered Functional Connectivity of the Multisensory Vestibular Cortex in Patients with Chronic Unilateral Vestibulopathy.

Background: Chronic unilateral vestibulopathy (CUVP) is a common chronic vestibular syndrome; the mechanisms of central vestibular compensation in CUVP are rarely studied. Methods: This study analyzed the data of 18 patients with CUVP and 18 healthy controls (HCs) and used seed-based functional connectivity (FC) and voxel-mirrored homotopic connectivity (VMHC) analyses to explore the FC alterations. Results: Compared with HCs, patients with CUVP showed decreased FC between the left dorsolateral superior frontal gyrus and the right hippocampus; the left middle frontal gyrus and the right posterior cingulate gyrus, the right hippocampus, the right parahippocampal gyrus. There is also a reduction in FC betweenthe left and right insula. There was enhanced FC between the left supplementary motor area (SMA) and the bilateral superior occipital gyrus, the left hippocampus and the left posterior cingulate gyrus, as wellas a the left middle temporal gyrus (p = 0.03). Additionally,VMHC was decreased betweenthe bilateral medial superior frontal gyrus, the bilateral precentral gyrus, and the bilateral postcentral gyrus (p = 0.001). The zVMHC values in the bilateral superior frontal gyrus and the precentral gyrus were both negatively corrected with the Dizziness Handicap Inventory (DHI) score.wellas Conclusions: Altered FC in regions of bilateral multisensory vestibular cortex existed in patients with CUVP. Decreased FC and VMHC in the bilateral multisensory vestibular cortex may affect vestibular information integration, thus affecting self-motion perception, spatial orientation, and postural control.

Bilateral vestibulopathy as the initial presentation of CANVAS

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a slowly progressing autosomal recessive ataxic disorder linked to an abnormal biallelic intronic (most commonly) AAGGG repeat expansion in the replication factor complex subunit 1 (RFC1). While the clinical diagnosis is relatively straightforward when the three components of the disorder are present, it becomes challenging when only one of the triad (cerebellar ataxia, neuropathy or vestibular areflexia) manifests. Isolated cases of Bilateral Vestibulopathy (BVP) or vestibular areflexia that later developed the other components of CANVAS have not been documented. We report four cases of patients with chronic imbalance and BVP that, after several years, developed cerebellar and neuropathic deficits with positive genetic testing for RFC1. Our report supports the concept that CANVAS should be considered in every patient with BVP of unknown etiology, even without the presence of the other triad components. This is especially important given that about 50% of cases in many BVP series are diagnosed as idiopathic, some of which may be undiagnosed CANVAS.

Digital biomarkers from gaze tests for classification of central and peripheral lesions in acute vestibular syndrome.

Acute vestibular syndrome (AVS) is characterised by a sudden vertigo, gait instability, nausea and nystagmus. Accurate and rapid triage of patients with AVS to differentiate central (potentially sinister) from peripheral (usually benign) root causes is a challenge faced across emergency medicine settings. While there exist bedside exams which can reliably differentiate serious cases, they are underused due to clinicians' general unfamiliarity and low confidence interpreting results. Nystagmus is a fundamental part of AVS and can facilitate triaging, but identification of relevant characteristics requires expertise. This work presents two quantitative digital biomarkers from nystagmus analysis, which capture diagnostically-relevant information. The directionality biomarker evaluates changes in direction to differentiate spontaneous and gaze-evoked (direction-changing) nystagmus, while the intensity differential biomarker describes changes in intensity across eccentric gaze tests. In order to evaluate biomarkers, 24 sets of three gaze tests (left, right, and primary) are analysed. Both novel biomarkers were found to perform well, particularly directionality which was a perfect classifier. Generally, the biomarkers matched or eclipsed the performance of quantitative nystagmus features found in the literature. They also surpassed the performance of a support vector machine classifier trained on the same dataset, which achieved an accuracy of 75%. In conclusion, these biomarkers simplify the diagnostic process for non-specialist clinicians, bridging the gap between emergency care and specialist evaluation, ultimately benefiting patients with AVS.