Early Experience with a Novel Treatment for Menière's Disease: A Long Acting Dexamethasone Formulation for Precise Delivery to the Round Window Membrane.

OBJECTIVE: To investigate the safety and feasibility of precise delivery of a long-acting gel formulation containing 6% dexamethasone (SPT-2101) to the round window membrane for the treatment of Menière's disease. STUDY DESIGN: Prospective, unblinded, cohort study. SETTING: Tertiary care neurotology clinic. PATIENTS: Adults 18 to 85 years with a diagnosis of unilateral definite Menière's disease per Barany society criteria. INTERVENTIONS: A single injection of a long-acting gel formulation under direct visualization into the round window niche. MAIN OUTCOME MEASURES: Procedure success rate, adverse events, and vertigo control. Vertigo control was measured with definitive vertigo days (DVDs), defined as any day with a vertigo attack lasting 20 minutes or longer. RESULTS: Ten subjects with unilateral Menière's disease were enrolled. Precise placement of SPT-2101 at the round window was achieved in all subjects with in-office microendoscopy. Adverse events included one tympanic membrane perforation, which healed spontaneously after the study, and two instances of otitis media, which resolved with antibiotics. The average number of DVDs was 7.6 during the baseline month, decreasing to 3.3 by month 1, 3.7 by month 2, and 1.9 by month 3. Seventy percent of subjects had zero DVDs during the third month after treatment. CONCLUSIONS: SPT-2101 delivery to the round window is safe and feasible, and controlled trials are warranted to formally assess efficacy.

Exploring causal correlations between inflammatory cytokines and Ménière's disease: a Mendelian randomization.

Objectives: Previous studies have highlighted associations between certain inflammatory cytokines and Ménière's Disease (MD), such as interleukin (IL) -13 and IL-1ß. This Mendelian randomization aims to comprehensively evaluate the causal relationships between 91 inflammatory cytokines and MD. Methods: A comprehensive two-sample Mendelian randomization (MR) analysis was conducted to determine the causal association between inflammatory cytokines and MD. Utilizing publicly accessible genetic datasets, we explored causal links between 91 inflammatory cytokines and MD risk. Comprehensive sensitivity analyses were employed to assess the robustness, heterogeneity, and presence of horizontal pleiotropy in our findings. Results: Our findings indicate that MD causally influences the levels of two cytokine types: IL-10 (P=0.048, OR=0.945, 95%CI =0.894~1.000) and Neurotrophin-3 (P=0.045, OR=0954, 95%CI =0.910~0.999). Furthermore, three cytokines exhibited significant causal effects on MD: CD40L receptor (P=0.008, OR=0.865, 95%CI =0.777-0.963), Delta and Notch-like epidermal growth factor-related receptor (DNER) (P=0.010, OR=1.216, 95%CI =1.048-1.412), and STAM binding protein (P=0.044, OR=0.776, 95%CI =0.606-0.993). Conclusion: This study suggests that the CD40L receptor, DNER, and STAM binding protein could potentially serve as upstream determinants of MD. Furthermore, our results imply that when MD is regarded as the exposure variable in MR analysis, it may causally correlate with elevated levels of IL-10 and Neurotrophin-3. Using these cytokines for MD diagnosis or as potential therapeutic targets holds great clinical significance.

[The research of the contralateral ear hearing thresholds and the hearing prognosis in unilateral Meniere's disease].

Objective:This study analyzed the pure tone audiometry results of the affected ear and the contralateral ear of unilateral Meniere's disease to investigate the correlation of the hearing threshold of the contralateral ear and the hearing prognosis of unilateral Meniere's disease. Methods:In this study, the follow-up data of 135 patients with unilateral Meniere's disease in Beijing Tongren Hospital were used to analyze the pure tone audiometry results of the affected and contralateral ears at the first visit and 1 year later. Results:①At the first visit, there was no statistically significant difference between the mean hearing thresholds of the affected ear in the normal hearing group and the high-frequency hearing loss group of the contralateral ear（P>0.05）. ②The range of improvement of hearing thresholds in the affected ear was greater in the contralateral ear normal hearing group than in the contralateral ear high-frequency hearing loss group. In the normal hearing group of the contralateral ear, the hearing thresholds of the affected ear at 0.25 kHz（P<0.01）, 0.50 kHz（P<0.01）, 1.00 kHz（P<0.01）, and 2.00 kHz（P<0.05） were significantly improved; and in the high-frequency hearing loss group of the contralateral ear, the hearing thresholds at 0.25 kHz（P<0.01） hearing thresholds improved significantly, and there was no significant difference between the rest of the frequencies before and after treatment（P>0.05）. A consistent pattern was observed in both higher and lower age groups. ③After 1 year of follow-up, the low and mid-frequency hearing of the affected ear improved. 0.25 kHz（P<0.01）, 0.50 kHz（P<0.01）, 1.00 kHz（P<0.01） hearing thresholds improved significantly; 8.00 kHz hearing thresholds decreased slightly（P<0.05）. Conclusion:After standardized treatment, the results of 1-year follow-up suggested that the low-frequency hearing of MD patients could be improved, but the high-frequency hearing was slightly decreased. The hearing prognosis of the affected ear with normal hearing threshold of the contralateral ear may be better.

[Research progress in targeted delivery of inner ear using nanocarriers].

Various inner ear diseases such as sensorineural deafness and Meniere's disease bring about problems such as speech communication disorders and decreased work efficiency, which seriously affect the life quality of patients. Due to the special anatomical structure and blood-labyrinth barrier in the inner ear, the current drug administration methods are often unable to achieve satisfactory results. Nanocarriers are the forefront and hot spot of nanotechnology research. In recent years, a lot of research progress has been made in the field of targeted delivery of the inner ear, which is expected to be eventually applied to the treatment of clinical diseases of the inner ear. This review focuses on the advantages, main research achievements and limitations of various nanocarriers in the targeted delivery of the inner ear, hoping to provide new ideas for related research.

Comparison of vestibular aqueduct visualization on computed tomography and magnetic resonance imaging in patients with Ménière's disease.

BACKGROUND: The vestibular aqueduct (VA) serves an essential role in homeostasis of the inner ear and pathogenesis of Ménière's disease (MD). The bony VA can be clearly depicted by high-resolution computed tomography (HRCT), whereas the optimal sequences and parameters for magnetic resonance imaging (MRI) are not yet established. We investigated VA characteristics and potential factors influencing MRI-VA visibility in unilateral MD patients. METHODS: One hundred patients with unilateral MD underwent MRI with three-dimensional sampling perfection with application optimized contrasts using different flip angle evolutions (3D-SPACE) sequence and HRCT evaluation. The imaging variables included MRI-VA and CT-VA visibility, CT-VA morphology and CT-peri-VA pneumatization. RESULTS: The most frequent type of MRI-VA and CT-VA visualization was invisible VA and continuous VA, respectively. The MRI-VA visibility was significantly lower than CT-VA visibility. MRI-VA visibility had a weak positive correlation with ipsilateral CT-VA visualization. For the affected side, the MRI-VA visualization was negatively correlated with the incidence of obliterated-shaped CT-VA and positively with that of tubular-shaped CT-VA. MRI-VA visualization was not affected by CT-peri-VA pneumatization. CONCLUSION: In patients with MD, the VA visualization on 3D-SPACE MRI is poorer than that observed on CT and may be affected by its osseous configuration. These findings may provide a basis for further characterization of VA demonstrated by MRI and its clinical significance.

An overload of missense variants in the OTOG gene may drive a higher prevalence of familial Meniere disease in the European population.

Meniere disease is a complex inner ear disorder with significant familial aggregation. A differential prevalence of familial MD (FMD) has been reported, being 9-10% in Europeans compared to 6% in East Asians. A broad genetic heterogeneity in FMD has been described, OTOG being the most common mutated gene, with a compound heterozygous recessive inheritance. We hypothesize that an OTOG-related founder effect may explain the higher prevalence of FMD in the European population. Therefore, the present study aimed to compare the allele frequency (AF) and distribution of OTOG rare variants across different populations. For this purpose, the coding regions with high constraint (low density of rare variants) were retrieved in the OTOG coding sequence in Non-Finnish European (NFE).. Missense variants (AF < 0.01) were selected from a 100 FMD patient cohort, and their population AF was annotated using gnomAD v2.1. A linkage analysis was performed, and odds ratios were calculated to compare AF between NFE and other populations. Thirteen rare missense variants were observed in 13 FMD patients, with 2 variants (rs61978648 and rs61736002) shared by 5 individuals and another variant (rs117315845) shared by two individuals. The results confirm the observed enrichment of OTOG rare missense variants in FMD. Furthermore, eight variants were enriched in the NFE population, and six of them were in constrained regions. Structural modeling predicts five missense variants that could alter the otogelin stability. We conclude that several variants reported in FMD are in constraint regions, and they may have a founder effect and explain the burden of FMD in the European population.

The correlation of hearing prognosis and caloric test results in Meniere's disease: a follow up study.

BACKGROUND: Hearing loss is important in the diagnosis and treatment of Meniere's disease (MD). However, little is known about the factors associated with hearing changes in MD. AIMS/OBJECTIVES: This study aimed to investigate the correlation between hearing prognosis and caloric test (CT) results in MD. MATERIAL AND METHODS: Ninety consecutive patients diagnosed with unilateral definite MD underwent pure tone audiometry (PTA) and CT at initial visits, and were re-tested PTA at the 6-month follow-up. RESULTS: Fifty-three of ninety MD patients (58.89%) had abnormal CT results. The change of PTA (cPTA = initial PTA-last PTA) was negatively correlated with canal paresis (CP) values (overall association p = 0.032 and non-linear association p = 0.413). Multivariate linear model showed that as the CP value changed from 0 to 1, the cPTA decreased by -13.31 dB (95% CI: -24.03, -2.6) (p = 0.016). Stratified analysis found that the association was present in MD patients of Stage 1 and 2 (p < 0.05) but not in patients of Stage 3 and 4 (p > 0.05). CONCLUSIONS AND SIGNIFICANCE: Elevated CP values may be linked to worse hearing outcomes in MD, especially in Stage 1 and 2 patients. Conducting a caloric test at the initial consultation may aid in assessing hearing regression in MD.

Clinical significance of posterior expansion of the utricular endolymphatic space.

BACKGROUND: Posterior expansion of the utricular endolymphatic space (ES) is a finding occasionally observed, and often occurs in bilateral ears. The clinical significance of posterior expansion of the utricular ES is not clear. OBJECTIVES: To investigate the clinical significance of posterior expansion of the utricular ES detected on magnetic resonance imaging (MRI). MATERIALS AND METHODS: Among 957 patients who underwent contrast-enhanced MRI to investigate the presence of endolymphatic hydrops (EH), clinical findings in cases with posterior expansion of the utricular ES were evaluated and the significance of their existence is considered. RESULTS: Posterior expansion of the utricular ES was detected in 30 ears from 20 cases (7 males, 13 females; mean age 48.7 years). The ears with posterior expansion had a significantly lower incidence of vestibular EH than those without, and this tendency was more prominent in cases in bilateral ears. Some cases with posterior expansion had vestibular symptoms and were diagnosed with Ménière's disease, although EH was not detected in their vestibules. CONCLUSION AND SIGNIFICANCE: Posterior expansion of the utricular ES was associated with Ménière's disease without vestibular EH. Posterior expansion of the utricular ES might not be associated with the formation of EH but may occur independently.

Machine learning models help differentiate between causes of recurrent spontaneous vertigo.

BACKGROUND: Vestibular migraine (VM) and Menière's disease (MD) are two common causes of recurrent spontaneous vertigo. Using history, video-nystagmography and audiovestibular tests, we developed machine learning models to separate these two disorders. METHODS: We recruited patients with VM or MD from a neurology outpatient facility. One hundred features from six "feature subsets": history, acute video-nystagmography and four laboratory tests (video head impulse test, vestibular-evoked myogenic potentials, caloric testing and audiogram) were used. We applied ten machine learning algorithms to develop classification models. Modelling was performed using three "tiers" of data availability to simulate three clinical settings. "Tier 1" used all available data to simulate the neuro-otology clinic, "Tier 2" used only history, audiogram and caloric test data, representing the general neurology clinic, and "Tier 3" used history alone as occurs in primary care. Model performance was evaluated using tenfold cross-validation. RESULTS: Data from 160 patients with VM and 114 with MD were used for model development. All models effectively separated the two disorders for all three tiers, with accuracies of 85.77-97.81%. The best performing algorithms (AdaBoost and Random Forest) yielded accuracies of 97.81% (95% CI 95.24-99.60), 94.53% (91.09-99.52%) and 92.34% (92.28-96.76%) for tiers 1, 2 and 3. The best feature subset combination was history, acute video-nystagmography, video head impulse test and caloric testing, and the best single feature subset was history. CONCLUSIONS: Machine learning models can accurately differentiate between VM and MD and are promising tools to assist diagnosis by medical practitioners with diverse levels of expertise and resources.

Effects of Age on the Frequency Amplitude Ratio of Cervical and Ocular Vestibular Evoked Myogenic Potentials.

PURPOSE: An increase in the 1000/500 Hz frequency amplitude ratio (FAR) of the cervical and ocular vestibular evoked myogenic potentials (cVEMP and oVEMP, respectively) may serve as a potential biomarker for diagnosing Meniere's disease (MD). However, the aging process can also result in an increased FAR for VEMPs. In older patients, distinguishing whether changes in VEMP FAR are due to MD or aging processes becomes difficult. We aimed to investigate the effects of age on VEMP FARs and establish a FAR-normative range for different age groups. METHOD: cVEMP and oVEMP were recorded from a total of 106 participants grouped as young, middle-aged, and older adults using air-conducted tone bursts at 500, 750, and 1000 Hz at 125 dB pSPL. The FAR was calculated for the cVEMP and oVEMP for the following frequencies: FAR1 = 1000/500, FAR2 = 1000/750, and FAR3 = 750/500. RESULTS: A significant age-related effect was observed on the cVEMP FAR. Although the oVEMP FAR showed an increasing trend with age, it was not statistically significant. Age-based normative FAR values are provided. CONCLUSIONS: Drawing from the normative FAR from this study, there is evidence that the existing MD diagnostic criteria would misidentify a considerable number of older adults. Therefore, to reduce false positives, we recommend a more stringent cVEMP and oVEMP FAR criterion in older adults.

Otologic disease trends in Japan post-COVID-19 outbreak: A retrospective time-series analysis.

OBJECTIVE: To evaluate the potential impact of coronavirus disease 2019 (COVID-19) and vaccinations on otologic diseases, including facial nerve paralysis (including Ramsay Hunt syndrome), vestibular neuritis, sudden sensorineural hearing loss, and Meniere's disease. METHODS: In this retrospective study, we conducted a time-series analysis employing a causal impact algorithm on a large-scale inpatient database in Japan. We compared the actual number of hospitalized patients with otologic diseases to two predictions: one without any covariates and another with a covariate accounting for the reduction in the number of hospitalized patients due to lockdown measures. Additionally, we performed Granger causality tests to ensure the robustness of our findings. RESULTS: No significant increase was noted in the number of hospitalized patients with otologic diseases following the onset of the COVID-19 pandemic in the causal impact analysis. Similarly, no notable surge was observed in hospitalizations for these diseases following the introduction of the COVID-19 vaccine. The Granger causality tests results aligned with the causal impact analysis findings. CONCLUSION: Our findings indicate that COVID-19 and vaccinations had minimal discernible effects on hospitalization of patients with otologic diseases, suggesting that otologic diseases may not be significantly impacted by COVID-19 and vaccinations, which could have implications for public health policies and the allocation of healthcare resources during a pandemic. Further research and monitoring of long-term effects are warranted to validate these findings and guide healthcare decision-making.

Assessing Cognitive Effort in Ménière's Disease: Pupillometry as a Novel Tool for Postural Control.

BACKGROUND: This study aimed to investigate the utility of pupillometry as a measure of cognitive effort in individuals with Ménière's disease experiencing chronic postural destabilization. By integrating pupillometry with static posturography, we sought to gain deeper insights into the cognitive demands and arousal levels associated with postural control in this specific patient population. METHODS: The study included 36 patients who met the diagnostic criteria for Ménière's disease and a control group comprising 36 healthy volunteers. We performed static posturography using a computerized static posturography platform to objectively assess postural imbalance. Additionally, pupillometry was recorded using infrared video-oculoscopy. Pupil dilation was measured before and after participants walked for 7 steps on-site with their vision obscured. RESULTS: Baseline tonic pupil size showed no significant difference between healthy controls and Ménière's patients. However, after walking stimulation, Ménière's patients exhibited highly significant abnormal walking-induced pupil dilation. This suggests increased arousal in response to the challenging task of walking with closed eyes, linked to static upright stance imbalance as correlated with posturography parameters. CONCLUSION: Pupillometry holds promise as an objective tool to assess cognitive effort and arousal during postural control in Ménière's disease. Implementing pupillometry in clinical practice could enhance the management of postural instability in these patients. Our findings contribute to the understanding of cognitive aspects in balance control and open new avenues for further investigations in vestibular dysfunction.

Cytokine profiling and transcriptomics in mononuclear cells define immune variants in Meniere Disease.

Meniere Disease (MD) is a chronic inner ear disorder characterized by vertigo attacks, sensorineural hearing loss, tinnitus, and aural fullness. Extensive evidence supporting the inflammatory etiology of MD has been found, therefore, by using transcriptome analysis, we aim to describe the inflammatory variants of MD. We performed Bulk RNAseq on 45 patients with definite MD and 15 healthy controls. MD patients were classified according to their basal levels of IL-1ß into 2 groups: high and low. Differentially expression analysis was performed using the ExpHunter Suite, and cell type proportion was evaluated using the estimation algorithms xCell, ABIS, and CIBERSORTx. MD patients showed 15 differentially expressed genes (DEG) compared to controls. The top DEGs include IGHG1 (p = 1.64 × 10-6) and IGLV3-21 (p = 6.28 × 10-3), supporting a role in the adaptative immune response. Cytokine profiling defines a subgroup of patients with high levels of IL-1ß with up-regulation of IL6 (p = 7.65 × 10-8) and INHBA (p = 3.39 × 10-7) genes. Transcriptomic data from peripheral blood mononuclear cells support a proinflammatory subgroup of MD patients with high levels of IL6 and an increase in naïve B-cells, and memory CD8+ T cells.

Low-sodium diet with adequate water intake improved the clinical efficacy in Ménière's disease.

BACKGROUND: Ménière's disease (MD) is a common idiopathic inner ear disorder in otorhinolaryngology characterized by recurrent episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus and ear fullness. OBJECTIVE: To study the effects of low-sodium diet with adequate water intake on the clinical efficacy in MD. METHODS: Fifty patients diagnosed with stage-3 unilateral MD were randomly divided into control group(n = 25) and experimental group(n = 25). The control group was given routine medication therapy, and the experimental group was restricted to an sodium intake of 1500 mg/d and a water intake of 35 ml/kg/d based in addition to the routine medication therapy. The two groups were assessed using pure tone audiometry, electrocochleography, Tinnitus Handicap Inventory (THI), and Dizziness Handicap Inventory (DHI). RESULTS: The pure tone audiometry and electrocochleography showed better improvements after treatment in the experimental group than the control group (p < 0.05). The THI improved values in the experimental group were significantly higher than the control group (p < 0.001). The DHI improved values in the experimental group were significantly higher than the control group (p = 0.004). CONCLUSIONS AND SIGNIFICANCE: Low-sodium diet with adequate water intake improved the hearing and alleviated vertigo and tinnitus in MD patients.

Tympanostomy tube placement for intractable Meniere's disease in the elderly.

BACKGROUND: The treatment of refractory elderly Meniere's disease is a challenge. AIM: To investigate the efficacy of tympanostomy tube placement in elderly patients with Meniere's disease. METHODS: 31 patients over 60 years old with Meniere's disease who had failed medical treatment and underwent tympanostomy tube placement. Vertigo control, hearing level, tinnitus, and ear fullness were recorded and analyzed preoperatively and postoperatively. RESULTS: All patients completed a 6-month follow-up. At 6 months postoperatively,complete control, substantial control and limited control of vertigo were achieved in 10 (32%), 13 (42%), and 6 (19%) patients respectively. Two patients (6%) reported no substantial improvement. Twelve patients completed a 2-year follow-up. At 2 years postoperatively, complete control, substantial control and limited control of vertigo were achieved in 3 (25%), 5 (42%), and 1 (8%) patients respectively. Three (25%) patients showed no significant improvement in vertigo. The majority of patients reported significant improvement in the functional level scale, the Dizziness Handicap Inventory scores, and ear fullness at 6 months and 2 years postoperatively. CONCLUSIONS AND SIGNIFICANCE: Tympanostomy tube placement may reduce vertigo attacks and improved the quality of life in elderly patients with Meniere's disease.

[Semicircular canal occlusion].

Semicircular canal occlusion（SCO） is a surgical technique widely used for treating vertigo symptoms. It is primarily aimed at treating benign paroxysmal positional vertigo（BPPV）, Ménière's disease（MD）, labyrinthine fistula, and superior semicircular canal dehiscence syndrome, among others. This review aims to comprehensively summarize the development, evolution, relevant basic research, and clinical applications of semicircular canal occlusion, especially the application of endoscopic technology in recent years, and explore its practical value in the field of surgical treatment for vertigo.