Neuroimaging Insights: Structural Changes and Classification in Ménière's Disease.

OBJECTIVES: This study aimed to comprehensively investigate the neuroanatomical alterations associated with idiopathic Ménière's disease (MD) using voxel-based morphometry and surface-based morphometry techniques. The primary objective was to explore nuanced changes in gray matter volume, cortical thickness, fractal dimension, gyrification index, and sulcal depth in MD patients compared with healthy controls (HC). Additionally, we sought to develop a machine learning classification model utilizing these neuroimaging features to effectively discriminate between MD patients and HC. DESIGN: A total of 55 patients diagnosed with unilateral MD and 70 HC were enrolled in this study. Voxel-based morphometry and surface-based morphometry were employed to analyze neuroimaging data and identify structural differences between the two groups. The selected neuroimaging features were used to build a machine learning classification model for distinguishing MD patients from HC. RESULTS: Our analysis revealed significant reductions in gray matter volume in MD patients, particularly in frontal and cingulate gyri. Distinctive patterns of alterations in cortical thickness were observed in brain regions associated with emotional processing and sensory integration. Notably, the machine learning classification model achieved an impressive accuracy of 84% in distinguishing MD patients from HC. The model's precision and recall for MD and HC demonstrated robust performance, resulting in balanced F1-scores. Receiver operating characteristic curve analysis further confirmed the discriminative power of the model, supported by an area under the curve value of 0.92. CONCLUSIONS: This comprehensive investigation sheds light on the intricate neuroanatomical alterations in MD. The observed gray matter volume reductions and distinct cortical thickness patterns emphasize the disease's impact on neural structure. The high accuracy of our machine learning classification model underscores its diagnostic potential, providing a promising avenue for identifying MD patients. These findings contribute to our understanding of MD's neural underpinnings and offer insights for further research exploring the functional implications of structural changes.

Temporal changes in endolymphatic hydrops on MRI with or without intervention: A systematic review.

OBJECTIVE: The pathophysiology of Meniere's Disease (MD) involves endolymphatic hydrops (ELH) of the inner ear. Magnetic Resonance Imaging (MRI) has been shown to detect ELH, but changes in ELH have been poorly described using this modality. Our objective was to review MRI-measured changes in ELH over time and after medical and/or surgical intervention in patients with MD. We secondarily aim to associate changes in ELH with changes in MD symptomatology. DATABASES REVIEWED: Medline, Web of Science, and Embase databases. METHODS: A systematic review of articles was performed to identify studies utilizing MRI to measure ELH changes over time, and after medical or surgical treatment. Articles on non-human subjects and without direct measurement of ELH were excluded. RESULTS: Of 532 studies identified, 12 were included, involving 170 patients (mean age 56.3 years). Ten studies were prospective; two were retrospective. Five studies strictly utilized medical means of intervention, four utilized surgical treatments, one utilized both, and two observed temporal changes without treatment. Across all interventions, 72.1 % of patients exhibited the same or worsening ELH on imaging. In studies reporting vertigo outcomes, 95.9 % of patients exhibited improvement after the treatment period. CONCLUSION: Medical and surgical interventions often yield symptomatic relief of vertigo in MD patients despite stable or increasing ELH volume. MRI may have greater clinical utility in diagnosing ELH as opposed to assessing treatment response.

Diagnosis of Menière's disease on MRI: feasibility at 1.5 Tesla.

BACKGROUND: Menière's disease (MD) is clinically characterized by the triad sensorineural hearing loss, tinnitus and/or aural fullness, and vertigo. Endolymphatic hydrops (EH) is the histopathological basis associated with MD, which can be demonstrated on magnetic resonance imaging (MRI). Currently, most studies are done on a 3-T MRI scanner and to date it is believed that EH can only be demonstrated on a 3-T magnet. We report the feasibility of demonstrating EH on a 1.5-T scanner using the standard 20-channel head and neck coil and the current standard 4-h delayed intravenous gadolinium-enhanced three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) sequence. PURPOSE: To investigate whether current standard 4-h delayed intravenous gadolinium-enhanced 3D-FLAIR imaging can demonstrate endolymphatic hydrops on a 1.5-T MRI scanner. MATERIAL AND METHODS: The 3D-FLAIR sequence was taken from a 3-T MRI protocol and tested on a volunteer patient with clinically "definite" MD, after 4-h delayed intravenous contrast injection. Good image quality was obtained after reducing both the matrix and the bandwidth, with clear demonstration of EH. Subsequently, eight more patients with unilateral disease were imaged. Five patients had "definite" MD and four had "probable" MD. RESULTS: We imaged nine patients with unilateral disease and detected EH in eight of nine ears. One patient with "probable" MD did not show any abnormality, but the images were degraded by motion artifacts. CONCLUSION: At a cost of 2 min extra scanning time compared to a 3-T scanner, EH can be confidently demonstrated with the current standard 3D-FLAIR sequence on a 1.5-T magnet.

Enrichment of damaging missense variants in genes related with axonal guidance signalling in sporadic Meniere's disease.

INTRODUCTION: Meniere's disease (MD) is a rare inner ear disorder with a significant genetic contribution defined by a core phenotype: episodic vertigo, sensorineural hearing loss and tinnitus. It has been mostly described in sporadic cases, familial cases being around 10% of the observed individuals. It is associated with an accumulation of endolymph in the inner ear, but the molecular underpinnings remain largely unknown. The main molecular pathways showing higher differentially expressed genes in the supporting cells of the inner ear are related to cochlea-vestibular innervation, cell adhesion and leucocyte extravasation. In this study, our objective is to find a burden of rare variants in genes that interact with the main signalling pathways in supporting cells of the inner ear in patients with sporadic MD. METHODS: We designed a targeted-sequencing panel including genes related with the main molecular pathways in supporting cells and sequenced 860 Spanish patients with sporadic MD. Variants with minor allele frequencies <0.1 in the gene panel were compared with three independent reference datasets. Variants were classified as loss of function, missense and synonymous. Missense variants with a combined annotation-dependent depletion score of >20 were classified as damaging missense variants. RESULTS: We have observed a significant burden of damaging missense variants in few key genes, including the NTN4 gene, associated with axon guidance signalling pathways in patients with sporadic MD. We have also identified active subnetworks having an enrichment of rare variants in sporadic MD. CONCLUSION: The burden of missense variants in the NTN4 gene suggests that axonal guidance signalling could be a novel pathway involved in sporadic MD.

The vestibular aqueduct sign: Magnetic resonance imaging can detect abnormalities in both ears of patients with unilateral Meniere's disease.

BACKGROUND AND PURPOSE: In patients with Meniere's disease (MD), saccular hydrops can only be studied by magnetic resonance imaging (MRI) at a late stage when the disease is already responsible for moderate to severe hearing loss. However, these patients may also present vestibular aqueduct (VA) abnormalities. MATERIALS AND METHODS: In this prospective study (38RC14.428 for healthy subjects/38RC15.173 for patients), imaging was carried out on a 3T MRI scanner. Twenty healthy subjects (13 women, median age 53.5 [52.2-66.7]) and twenty MD patients (9 women, median age 54.5 [52-66.7]) had MRI scans with 3D-FLAIR sequences without injection, then 4 hours after a single intra-venous dose of contrast agent. Two radiologists independently ranked the morphology of the VA in the healthy subjects and in MD patients, using a three-level score (completely visible, discontinuous and not visible). Each subject was then graded, based on both the VA's appearance and on saccular hydrops presence. Inter-reader agreement tests were performed. RESULTS: In controls and patients, VA modifications were symmetrical without significant difference between the symptomatic and asymptomatic ears. The presence of at least one ear with discontinuous VA showed a correlation with clinical MD (P < 0.001) with a sensitivity of 90%. Ten patients had saccular hydrops, but only in the symptomatic ears. The evaluation of VA did not differ between MRI, both within MRI series or between the two radiologists (kappa without and with contrast agent = 0.9 and 0.92 respectively). CONCLUSION: Analysis of the vestibular aqueduct by MRI detects abnormalities in both ears of patients with unilateral MD.

Inner ear pathologies impair sodium-regulated ion transport in Meniere's disease.

Meniere's disease (MD), a syndromal inner ear disease, is commonly associated with a pathological accumulation of endolymphatic fluid in the inner ear, termed "idiopathic" endolymphatic hydrops (iEH). Although numerous precipitating/exacerbating factors have been proposed for MD, its etiology remains elusive. Here, using immunohistochemistry and in situ protein-protein interaction detection assays, we demonstrate mineralocorticoid-controlled sodium transport mechanisms in the epithelium of the extraosseous portion of the endolymphatic sac (eES) in the murine and human inner ears. Histological analysis of the eES in an extensive series of human temporal bones consistently revealed pathological changes in the eES in cases with iEH and a clinical history of MD, but no such changes were found in cases with "secondary" EH due to other otological diseases or in healthy controls. Notably, two etiologically different pathologies-degeneration and developmental hypoplasia-that selectively affect the eES in MD were distinguished. Clinical records from MD cases with degenerative and hypoplastic eES pathology revealed distinct intergroup differences in clinical disease presentation. Overall, we have identified for the first time two inner ear pathologies that are consistently present in MD and can be directly linked to the pathogenesis of EH, and which potentially affect the phenotypical presentation of MD.

3D-real IR MRI of Meniere's disease with partial endolymphatic hydrops.

OBJECTIVES: A three-dimensional inversion-recovery sequence with real reconstruction (3D-real IR) sequence 4 h after intravenous gadolinium injection (IV) has been used to visualize the endolymphatic hydrops (ELH) in Meniere's disease (MD). This study was designed to explore the pathology of MD with partial ELH. METHODS: We collected 338 patients with definite MD, all of whom underwent the IV method. Patients who were found to have partial ELH (vestibular or cochlear) were enrolled. The hearing thresholds of the enrolled patients were analyzed, the regions of interest of the cochlear perilymph and the cerebellum white matter were determined, and the signal intensity ratio in the former to the latter (CC ratio) for both sides in the patients was subsequently evaluated. RESULTS: Of the 338 collected patients with definite MD, 19 patients (5.6%) had unilateral vestibular ELH (N = 18) or cochlear ELH (N = 1), and 4 patients (1.2%) with bilateral ELH had contralateral cochlear ELH. The CC ratio of the affected side (1.44 ±â€¯0.46) was higher than that of the unaffected side (1.15 ±â€¯0.33, P < 0.05) in the 19 patients with unilateral ELH. Conversely, there was no difference between the ratio of the contralateral side (1.18 ±â€¯0.16) and the unaffected side (P > 0.05) in the 4 patients with bilateral ELH. CONCLUSIONS: Partial vestibular ELH was more common than partial cochlear ELH in MD. Moreover, vestibular ELH, rather than cochlear ELH, may correlate with the elevated contrast effect in the affected side, which may better reflect the pathologic mechanism of MD.

Quantitative analysis of cochlear signal intensity on three-dimensional and contrast-enhanced fluid-attenuated inversion recovery images in patients with Meniere's disease: Correlation with the pure tone audiometry test.

PURPOSE: The purpose of this study was to correlate the quantitative analysis of cochlear signal intensity (SI) on 3-dimensional fluid-attenuated inversion recovery (3D-FLAIR) and contrast-enhanced (CE) 3D-FLAIR images with results of the pure tone audiometry (PTA) test in patients with Meniere's disease (MD). MATERIALS AND METHODS: Over a 3-year period, 123 patients with MD underwent 3-Tesla (3 T) temporal magnetic resonance imaging (MRI), including 3D-FLAIR and CE-FLAIR sequences. The SI of membranous labyrinth of the cochlea in both ears of each patient was measured by drawing a region of interest (ROI) with a seed growing technique. The correlation between measured cochlear SIs on 3D-FLAIR and CE-FLAIR images, contrast enhancement index (CEI), and contrast enhancement ratio (CER) and clinical findings and pre- and post-treatment PTA results were assessed. RESULTS: Cochlear signal ratios of symptomatic ears on 3D-FLAIR and CE-FLAIR images were significantly higher than those of asymptomatic ears (P < 0.001). The area under the curve, from the receiver operating characteristic curve of cochlear SIs on 3D-FLAIR and CE-FLAIR images for discrimination between symptomatic and asymptomatic ears, was 0.729 and 0.728, respectively. Cochlear SIs on 3D-FLAIR and CE-FLAIR images were significantly correlated with patients' sex (P < 0.05 and P < 0.01, respectively), symptomatic ear (both P < 0.0001), and pre-treatment PTA (P < 0.0001 and P < 0.005, respectively), but were not significantly correlated with patients' age, post-treatment PTA or hearing threshold level at 0.5, 1.0, 2.0, or 4.0 kHz. CONCLUSION: Quantitative analysis of cochlear SI on 3D-FLAIR and CE-FLAIR images may be a helpful diagnostic adjunct for MD, but may be of little value in predicting the prognosis of MD.

RNA-sequencing study of peripheral blood mononuclear cells in sporadic Ménière's disease patients: possible contribution of immunologic dysfunction to the development of this disorder.

To date, the pathogenesis of Ménière's disease (MD) remains unclear. This study aims to investigate the possible relationship between potential immune system-related genes and sporadic MD. The whole RNA-sequencing (RNA-seq) technology was used to analyse the transcriptome of peripheral blood mononuclear cells of three MD patients and three control individuals. Of 366 differentially expressed genes (DEGs), 154 genes were up-regulated and 212 genes were down-regulated (|log2 fold change| > 1 and P < 0·05). Gene ontology (GO) enrichment analysis illustrated that immune relevant factors played a key role in the pathogenesis of MD. Of 366 DEGs, we focused upon analysing the possible immune-related genes, among which the significantly up-regulated genes [glutathione S-transferase mu 1 (GSTM1), transmembrane protein 176 (TMEM176)B, TMEM176A] and down-regulated genes [solute carrier family 4 member (SLC4A)10 and SLC4A1] especially drew our attention. The mRNA expression levels of GSTM1, TMEM176B, TMEM176A, SLC4A1 and SLC4A10 were analysed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The serum concentration of GSTM1, TMEM176B and SLC4A10 proteins were measured by enzyme-linked immunosorbent assay (ELISA). Considering the results of qRT-PCR and ELISA, it was noteworthy that GSTM1 exhibited the highest fold change between two groups, which was consistent with the deep sequencing results by RNA-seq. In conclusion, our study first offers a new perspective in MD development on the basis of RNA expression patterns, suggesting that immune factors might be involved in the MD pathogenesis. Remarkably, GSTM1 might be a possible candidate gene for the diagnostic biomarker of MD and provides the basis for further biological and functional investigations.

A pipeline combining multiple strategies for prioritizing heterozygous variants for the identification of candidate genes in exome datasets.

BACKGROUND: The identification of disease-causing variants in autosomal dominant diseases using exome-sequencing data remains a difficult task in small pedigrees. We combined several strategies to improve filtering and prioritizing of heterozygous variants using exome-sequencing datasets in familial Meniere disease: an in-house Pathogenic Variant (PAVAR) score, the Variant Annotation Analysis and Search Tool (VAAST-Phevor), Exomiser-v2, CADD, and FATHMM. We also validated the method by a benchmarking procedure including causal mutations in synthetic exome datasets. RESULTS: PAVAR and VAAST were able to select the same sets of candidate variants independently of the studied disease. In contrast, Exomiser V2 and VAAST-Phevor had a variable correlation depending on the phenotypic information available for the disease on each family. Nevertheless, all the selected diseases ranked a limited number of concordant variants in the top 10 ranking, using the three systems or other combined algorithm such as CADD or FATHMM. Benchmarking analyses confirmed that the combination of systems with different approaches improves the prediction of candidate variants compared with the use of a single method. The overall efficiency of combined tools ranges between 68 and 71% in the top 10 ranked variants. CONCLUSIONS: Our pipeline prioritizes a short list of heterozygous variants in exome datasets based on the top 10 concordant variants combining multiple systems.

Saccular measurements in routine MRI can predict hydrops in Menière's disease.

Most patients with suspicion of hydrops do not have access to MRI with 3D reconstruction of the endolymphatic space. Our main objective was to show that measurements of the saccule on a non-enhanced 3D-T2 MRI could show hydrops and help diagnose Menière disease. We conducted a prospective study from 2015 to 2016 to compare consecutive patients consulting for Menière's disease to a control group (patients with unilateral non-hydrops disorders and contralateral healthy ears). They all received full auditory and vestibular testing. They also underwent a 3-Tesla 3D-T2 MRI using CISS sequence (0.4 mm thick slices), which were blindly evaluated by two independent neuroradiologists. The saccular height and width were measured in a coronal plane and Menière's disease patients' symptomatic ears were compared to asymptomatic and control ears. 36 patients with definite Menière's disease and 36 control patients were studied, including 42 symptomatic Menière, 30 asymptomatic Menière and 72 control ears. Saccular measurements were significantly different between symptomatic Menière ears compared to healthy ears (1.59 vs 1.32 mm, p < 0.001 for height; 1.13 vs 0.90 mm, p < 0.001 for width). Symptomatic and asymptomatic Menière ears' measurements were not significantly different (p = 0.307 and p = 0.109). Using ROC curve, we found cut-off values for saccular height 1.51 mm, Se = 63%, Sp = 95% and width 1.05 mm, Se = 41%, Sp = 95%. Routine 3D-T2 MRI, which patients must undergo for differential diagnosis, could help diagnose hydrops with high specificity using saccular measurements.

SLC44A2 single nucleotide polymorphisms, isoforms, and expression: Association with severity of Meniere's disease?

SLC44A2 was discovered as the target of an antibody that causes hearing loss. Knockout mice develop age related hearing loss, loss of sensory cells and spiral ganglion neurons. SLC44A2 has polymorphic sites implicated in human disease. Transfusion related acute lung injury (TRALI) is linked to rs2288904 and genome wide association studies link rs2288904 and rs9797861 to venous thromboembolism (VTE), coronary artery disease and stroke. Here we report linkage disequilibrium of rs2288904 with rs3087969 and the association of these SLC44A2 SNPs with Meniere's disease severity. Tissue-specific isoform expression differences suggest that the N-terminal domain is linked to different functions in different cell types. Heterozygosity at rs2288904 CGA/CAA and rs3087969 GAT/GAC showed a trend for association with intractable Meniere's disease compared to less severe disease and to controls. The association of SLC44A2 SNPs with VTE suggests that thrombi affecting cochlear vessels could be a factor in Meniere's disease.

Expression of histamine receptors in the human endolymphatic sac: the molecular rationale for betahistine use in Menieres disease.

The human endolymphatic sac (ES) is situated in a duplicature of the dura in the posterior cranial fossa and constitutes a part of the inner ear. The sac possesses immunological capacities and is responsible for a major part of the trans-epithelial ion transport occurring within the inner ear, via molecular mechanisms similar to that of the kidney collecting duct epithelia. Dysfunction of the trans-epithelial ion transport has been hypothesized as the reason for the endolymphatic hydrops occurring in Menieres diseases. Thus, candidate drug selection for medical treatment of Menieres disease has been based on a potential capability of improving trans-epithelial ion transport. However, recent human studies seems to rule out diuretic therapy and The Committee for Medicinal Products for Human Use redrew the recommendation for trimetazidine (Vastarel) treatment in the management of Meniere disease in 2012. This leaves betahistine (Betaserc) as the only drug for potential prevention of the incapacitating attacks of dizziness, tinnitus and hearing loss. However, the histamine receptors targeted by betahistine have never been demonstrated in the human ES. Accordingly, this study aims to investigate the expression of histamine receptors of the human ES epithelium and sub-epithelial stroma. Following sampling of human endolymphatic sac tissue during translabyrinthine surgery, the expression of histamine receptor genes was determined by cDNA microarray analysis. Results were subsequently verified by immuno-histochemistry. The combined results of microarrays and immuno-histochemistry showed expression of the histamine receptor HRH1 in the epithelial lining of the ES, whereas HRH3 was expressed exclusively in the sub-epithelial capillary network. Receptors HRH2 and -4 were not expressed. The present data provide the first direct evidence of a molecular rationale for betahistine treatment in Menieres disease. A potential betahistine effect in Menieres disease may primarily be through the H3-receptor antagonism, leading to inhibition of vestibular neuro-transmission and central vaso-dilation. The H1-receptor localization in the ES epithelium suggests an immuno-regulatory effect.

Recovery of Hearing in Meniere's Disease after Antiviral Treatment.

OBJECTIVE: Determine the outcome of hearing in Meniere's Disease (MD) after antiviral treatment. STUDY DESIGN: Prospective study. SETTING: University Hospital. METHODS: Thirty one new patients with a diagnosis of MD were treated with antiviral drugs during 2012. Acyclovir or valacyclovir was used depending on insurance coverage and cost. A standard dose of 800 mg (acyclovir) or 1g (valacyclovir) 3 times a day for 3 weeks was used. The dose was decreased to twice daily for three weeks, and finally once daily for a year or longer. Hearing test including pure tone average (PTA) and speech discrimination (SD) was performed prior to treatment and 1-2 months, 6 months and 1 year after the initiation of treatment. Effect on dizziness was recorded at each evaluation, hearing was judged to be improved if PTA was lowered by at least 15 db and/or an increase in SD of 20% or greater. RESULTS: Hearing was improved in twelve and not improved in nineteen patients. Complete control of vertigo was achieved in those patients with improved hearing. The nineteen patients with no improvement in hearing were divided into 2 groups based on the level of hearing at diagnosis. Nine patients presenting with a PTA of 50 db and SD of 50% or better experienced good control of vertigo (6 out of 7; 2 with no follow-up). Ten patients with PTA of 60 db or more and SD below 50% exhibited poor control of vertigo with antivirals (3 out of 10). The duration of MD in the group with hearing improvement was shorter (2.4 years) than the group with no improvement (5.5 years). CONCLUSION: Significant hearing and balance control in patients with MD can be achieved with orally administered antiviral drugs.

Endolymphatic sac surgery versus tenotomy of the stapedius and tensor tympani muscles in the management of patients with unilateral definite Meniere's disease.

This study aims to compare the outcomes of patients with Meniere's disease submitted to either endolymphatic mastoid shunt (ES) or tenotomy of the stapedius and tensor tympani muscles (TSTM). This is a retrospective chart review of patients treated with ES or TSTM between 2000 and 2010 and followed up for at least 12 months. The main outcomes were represented by: (1) vertigo class, hearing stage and functional level according to the American Academy of Otolaryngology-Head and Neck Surgery criteria; (2) adjustment of dizziness handicap inventory (DHI) and (3) complete and substantial vertigo control using the Kaplan-Meier survival method. Sixty-three patients met the inclusion criteria: 34 underwent ES and 29 TSTM. The baseline demographic characteristics, the hearing stage, the functional level, the DHI and hearing levels were not different between the two groups. No significant difference in vertigo class was demonstrated: 66 % of TSTM patients attained class A compared to 44 % in the ES group (p = 0.14). Kaplan-Meier survival curves specific to class A showed significant differences, favoring TSTM (log-rank test, p = 0.022). TSTM patients demonstrated significantly improved functional level (p = 0.0004) and improved DHI scores (p = 0.001). Eight ES patients (25 %) demanded a second surgical attempt compared to none in the TSTM. Aural fullness was significantly improved in TSTM group (p = 0.01), while the difference in tinnitus improvement was non-significant. Hearing preservation was significantly better in TSTM group (p = 0.001). TSTM is a safe surgical procedure, with significant vertigo control rates, and important hearing preservation rates. More patients and longer follow-up are needed to support our preliminary findings.

Association Between Vestibular Aqueduct Morphology and Meniere's Disease.

OBJECTIVE: To investigate the relationship between vestibular aqueduct (VA) morphology and Meniere's disease (MD) using ultrahigh-resolution computed tomography (U-HRCT). METHODS: Retrospective data were collected from 34 patients (40 ears) diagnosed with MD in our hospital who underwent temporal bone U-HRCT with isotropic 0.05-mm resolution, magnetic resonance with gadolinium-enhanced, and pure-tone audiometry; 34 age- and sex-matched controls (68 ears) who underwent U-HRCT were also included. VA patency was qualitatively classified as locally not shown (grade 1), locally faintly shown (grade 2), or clearly shown throughout (grade 3). The width of the outer orifice and VA length and angle were quantitatively measured. Differences in VA morphology between the MD and control groups were analyzed. The correlations between VA morphology and the degrees of hearing loss and endolymphatic hydrops (EH) were also analyzed. RESULTS: VA was classified as grades 1-3 in 11, 17, and 12 ears in the MD group and 5, 26, and 37 ears in the control group, respectively. The patency differed significantly between the groups (p < 0.01). The width of the outer orifice and length of VA were significantly smaller in the MD group than those in the control group (p < 0.05). Both VA patency and length were correlated with the degree of EH in the cochlea and the vestibule (p < 0.05). No difference was found between VA morphology and the degree of hearing loss (p > 0.05). CONCLUSION: The morphological characteristics of VA were found to be associated with the occurrence of MD and the degree of EH. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3349-3354, 2024.

Morphological and functional changes in a new animal model of Ménière's disease.

The purpose of this study was to clarify the underlying mechanism of vertiginous attacks in Ménière's disease (MD) while obtaining insight into water homeostasis in the inner ear using a new animal model. We conducted both histopathological and functional assessment of the vestibular system in the guinea-pig. In the first experiment, all animals were maintained 1 or 4 weeks after electrocauterization of the endolymphatic sac of the left ear and were given either saline or desmopressin (vasopressin type 2 receptor agonist). The temporal bones from both ears were harvested and the extent of endolymphatic hydrops was quantitatively assessed. In the second experiment, either 1 or 4 weeks after surgery, animals were assessed for balance disorders and nystagmus after the administration of saline or desmopressin. In the first experiment, the proportion of endolymphatic space in the cochlea and the saccule was significantly greater in ears that survived for 4 weeks after surgery and were given desmopressin compared with other groups. In the second experiment, all animals that underwent surgery and were given desmopressin showed spontaneous nystagmus and balance disorder, whereas all animals that had surgery but without desmopressin administration were asymptomatic. Our animal model induced severe endolymphatic hydrops in the cochlea and the saccule, and showed episodes of balance disorder along with spontaneous nystagmus. These findings suggest that administration of desmopressin can exacerbate endolymphatic hydrops because of acute V2 (vasopressin type 2 receptor)-mediated effects, and, when combined with endolymphathic sac dysfunction, can cause temporary vestibular abnormalities that are similar to the vertiginous attacks in patients with MD.

Allelic variants in TLR10 gene may influence bilateral affectation and clinical course of Meniere's disease.

Toll-like receptors trigger the innate immune response by activating various cell types such us macrophages and lymphocytes. We genotyped SNV of TLR3, TRL7, TLR8 and TLR10 in 863 Spanish and 150 Italian patients with Meniere's disease (MD) and 1,013 controls by using Taqman assays. Real-Time qPCR was used to measure the expression level of TLR10 in peripheral blood leukocytes. The overall dataset showed that the C allele and the CC genotype of rs11096955 in TLR10 gene were more commonly observed in controls than patients (corrected p = 1 × 10(-3), OR = 0.68 [95 % confidence interval, 0.54-0.84] for CC genotype; corrected p = 1.5 × 10(-5), OR = 0.75 [0.66-0.85] for allele C). Moreover, the CC genotype was more frequent in patients with uni- (19 %) than bilateral sensorineural hearing loss (SNHL) (13 %). Logistic regression demonstrated that the time since the onset of MD, Tumarkin crises, hearing stage and rs11096955 were independent factors influencing the risk of bilateral SNHL. In addition, rs11096955 influenced hearing loss progression in patients with bilateral MD. No change in expression of TLR10 was observed according to CC, CA or AA genotypes. Our data suggest that allelic variants of TLR10 gene may influence the susceptibility and time-course of hearing loss of MD in the European population.

Experimental hyperactivity of the endolymphatic sac.

Injury to the endolymphatic sac may play an important role in the pathogenesis of Ménière's disease, an inner ear disorder characterized by hearing loss, tinnitus and attacks of vertigo. Isoimmunization of 16 inbred Lewis rats with a crude endolymphatic sac extract and complete Freund's adjuvant induced hyperactivity of the endolymphatic sac. One group of rats was immunized by a single dose whereas a second group was immunized twice. Control animals were injected with Freund's adjuvant in saline only. Serum was collected from all rats by the end of the study and harvested autoantibodies were tested by immunohistochemistry. The endolymphatic sacs were investigated by transmission electron microscopy. Endolymphatic sac stimulation was observed in all immunized rats. Based on detailed ultrastructural observations, the degree of reactivity seemed proportional to the number of injections and the extent of immunization. Moreover, the ribosome-rich cells seemed hyperactive with an extravagant content of intracellular components: numerous rough endoplasmic reticulum and free ribosomes, morphological signs of extensive endo- and exocytosis, vesicles of material with a density similar to the homogeneous substance of which many were observed to fuse with primary lysozymes. Basolateral foldings were numerous and in the subepithelial capillaries formation of multiple and apposing fenestrations were observed. No endolymphatic sac stimulation was observed in the control animals. Specific ribosome-rich cell alterations identical to those present in the endolymphatic sac of Ménière's disease were observed 21 days after the first immunization. The observations suggest that either an autoantigen or a trophic factor, capable of inducing a hyperactivity of the ribosome-rich cells and an imbalance of the homogeneous substance metabolism, exists in the endolymphatic sac of the rat.

Association between MIF gene variation and Meniere's disease.

Several pieces of evidence support the involvement of immune system in Menière's disease (MD). Macrophage migration inhibitory factor (MIF) plays a key role in immune-mediated reactions. Several studies have shown an association between MIF gene polymorphisms and susceptibility to various inflammatory and autoimmune disorders. The aim of this study was to explore the association between MIF-173 G/C polymorphism and MD in an Iranian population. In this case-control association study, MD cases (N = 72) were recruited and were comprised of definitive MD (N = 58) and probable MD (N = 14) subjects. Normal healthy subjects (N = 100) were also included. Genotyping for MIF-173 G/C polymorphism was carried out using PCR-RFLP technique. There was a significant increase in genotype GG in patients with MD compared with the control group. (GG vs. GC + CC, P = 0.02, OR = 2.08, 95% CI: 1.02-4.3). This was more significant when definitive MD was stratified and compared with the controls (GG vs. GC + CC, P = 0.009, OR = 2.6, 95% CI = 1.19-6.18). This study's result indicates the potential role of MIF in MD of which further evaluation is required. Also, the more significant association between MIF gene polymorphism and definitive MD designates the involvement of specific pathogenic mechanisms which may be considered as a marker for diagnosis.