Emerging Mechanisms in the Pathogenesis of Menière's Disease: Evidence for the Involvement of Ion Homeostatic or Blood-Labyrinthine Barrier Dysfunction in Human Temporal Bones.

HYPOTHESIS: Analysis of human temporal bone specimens of patients with Menière's disease (MD) may demonstrate altered expression of gene products related to barrier formation and ionic homeostasis within cochlear structures compared with control specimens. BACKGROUND: MD represents a challenging otologic disorder for investigation. Despite attempts to define the pathogenesis of MD, there remain many gaps in our understanding, including differences in protein expression within the inner ear. Understanding these changes may facilitate the identification of more targeted therapies for MD. METHODS: Human temporal bones from patients with MD (n = 8) and age-matched control patients (n = 8) were processed with immunohistochemistry stains to detect known protein expression related to ionic homeostasis and barrier function in the cochlea, including CLDN11, CLU, KCNJ10, and SLC12A2. Immunofluorescence intensity analysis was performed to quantify protein expression in the stria vascularis, organ of Corti, and spiral ganglion neuron (SGN). RESULTS: Expression of KCNJ10 was significantly reduced in all cochlear regions, including the stria vascularis (9.23 vs 17.52, p = 0.011), OC (14.93 vs 29.16, p = 0.014), and SGN (7.69 vs 18.85, p = 0.0048) in human temporal bone specimens from patients with MD compared with control, respectively. CLDN11 (7.40 vs 10.88, p = 0.049) and CLU (7.80 vs 17.51, p = 0.0051) expression was significantly reduced in the SGN. CONCLUSION: The results of this study support that there may be differences in the expression of proteins related to ionic homeostasis and barrier function within the cochlea, potentially supporting the role of targeted therapies to treat MD.

Volume ratio and distribution rate in patients with orthostatic vertigo/dizziness using MR imaging: a comparison with vertiginous diseases.

BACKGROUND: Orthostatic dizziness/vertigo (ODV) is characterized by lightheadedness owing to postural changes. AIMS/OBJECTIVES: To measure the endolymphatic space (ELS)/total fluid space (TFS) volume ratio and the distribution rate of endolymphatic fluid (ELF) of patients with ODV and compare them with those of control subjects (CS). MATERIALS AND METHODS: This study included 22 patients (44 ears) with ODV and 52 controls (104 ears, CS). The ELS/TFS volume ratio (%) and distribution rate (%) of the inner ear components were measured using 3-dimensional magnetic resonance imaging. RESULTS: In the ODV group, the mean ELS/TFS volume ratios of the cochlea, vestibule, and semi-circular canals (SCCs) were 12.1%, 18.6%, and 18.1%, respectively; the mean ELS distribution rates for the cochlea, vestibule, and SCCs were 27.3%, 26.2%, and 46.6%, respectively. The ELS distribution rate of the vestibule was significantly lower (p < .01) and the ELS distribution rate of the SCCs was significantly higher in the ODV than in the CS group (p < .01). CONCLUSIONS AND SIGNIFICANCE: The ELS distribution rate in the vestibule + SCCs among patients with ODV did not differ from that in the CS; ELF in the vestibule moved to the SCCs, and a large amount of ELF was distributed only in the SCCs.

Evaluation of changes in endolymphatic hydrops volume after medical treatments for Meniere's disease using 3D magnetic resonance imaging.

OBJECTIVE: To elucidate the relationship between vertigo and EH volume after medical treatment, we investigated changes in endolymphatic hydrops (EH) volume using inner ear magnetic resonance imaging (ieMRI) in relation to clinical results for vertigo and hearing after administration of the anti-vertiginous medications betahistine, adenosine triphosphate (ATP), isosorbide (ISO), and saireito (SAI) for Meniere's disease (MD). METHODS: We retrospectively enrolled 202 consecutive patients diagnosed with unilateral MD from 2015 to 2021 and assigned them to four groups: Group I (G-I), symptomatic oral medication with betahistine only (CONT); Group II (G-II), inner ear vasoactive oral medication (ATP); Group III (G-III), osmotic diuretic oral medication (ISO); and Group IV (G-IV), kampo oral medication (SAI). In total, 172 patients completed the planned one-year-follow-up, which included the assessment of vertigo frequency, hearing improvement, and changes in EH using ieMRI (G-I, n=40; G-II, n=42; G-III, n=44; G-IV, n=46). We constructed 3D MRI images semi-automatically and fused the 3D images of the total fluid space (TFS) of the inner ear and endolymphatic space (ELS). After fusing the images, we calculated the volume ratios of the TFS and ELS (ELS ratios). RESULTS: One year after treatment, vertigo was controlled with zero episodes per month in 57.5% (23/40) of patients in G-I, 78.6% (33/42) in G-II, 81.8% (36/44) in G-III, and 82.6% (38/46) in G-IV (statistical significance: G-I 10 dB in 5.0% (2/40) of patients in G-I, 16.7% (7/42) in G-II, 18.2% (8/44) in G-III, and 21.7% (10/46) in G-IV (statistical significance: G-I=G-II=G-III=G-IV). ELS ratios were significantly reduced after treatment only in the vestibule for G-II, G-III, and G-IV when compared with G-I. Especially among patients with complete control of vertigo after treatment, ELS ratios were significantly reduced after treatment in the vestibule and total inner ear for G-II; in the cochlea, vestibule, and total inner ear for G-III; and in the cochlea, vestibule, and total inner ear for G-IV compared with G-I. However, there were no significant findings in the relationship between hearing results and changes in ELS ratios. CONCLUSION: These results indicate that daily administration of anti-vertiginous medications including ATP, ISO, and SAI could be an effective treatment option for patients with MD at an early stage before it becomes intractable. Treatments to reduce EH might offer better control of vertigo rather than improve hearing.

Aldosterone inhibits Dot1l expression in guinea pig cochlea.

BACKGROUND: Aldosterone relieves transcriptional repression of epithelial sodium channel (ENaC) by inhibiting Dot1a and Af9 expression and their interaction with ENaC promoter in various tissues. Expressions of ENaC and Af9 in inner ear have been identified. However, it is not known how Dot1l is regulated by aldosterone in inner ear. METHODS: Twenty-eight adult guinea pigs were randomly divided into the control group and treatment group. Aldosterone 1 mg/kg/d was injected intraperitoneally in the treatment group and saline in the control group for 7 days. Animals were killed 1 month later following auditory brainstem response examination. Histomorphology of cochlea was detected with hematoxylin-eosin staining, and Dot1l expression was examined with immunohistochemistry and Western blot. RESULTS: There was no significant difference in ABR thresholds before and after injection of aldosterone or saline in either group. Endolymphatic hydrops was found in 75% of animals in the treatment group. Dot1l was found in both groups in the stria vascularis, Reissner's membrane, spiral limbus, organ of Corti and spiral ligament. Dot1l expression in the treatment group was decreased by aldosterone. CONCLUSIONS: Dot1l in guinea pig cochlea is inhibited by aldosterone with induction of endolymphatic hydrops. Dot1l may be closely related to endolymph regulation by aldosterone and to pathogenesis of Meniere's disease.

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.

Progression of endolymphatic hydrops and vertigo during treatment in Meniere's disease.

BACKGROUND: Patients with Meniere's disease (MD) receive treatment to reduce vertigo. PURPOSE: To explore the fluctuation of vertigo symptoms and the changes in endolymphatic hydrops (EHs) in MD patients during long-term regular medication. MATERIALS AND METHODS: We enrolled MD patients who had received two magnetic resonance imaging with intravenous contrast agents. RESULTS: Of the 42 patients in the study, 18(42.9%) had progressive EHs and 3(7.1%) had remission. The change value of the signal intensity ratio (SIR; cochlear perilymph/cerebellum) on the affected side (1.2) was larger than that on the healthy side (0.9), but there was no statistical difference. Among the 30 patients followed up, two patients had complete control of vertigo, two patients had substantial control, and three patients had worse control. The other 23 patients had insignificant control of vertigo symptoms before and after treatment. The correlation between the progression of cochlear and vestibular hydrops and the improvement of vertigo symptoms in MD patients was not significant. CONCLUSIONS AND SIGNIFICANCE: In treated patients with MD, EHs may progress or relieve over the long course of the disease. But there was no correlation between the development of EHs and changes in vertigo symptoms.

The Diagnostic Value of 1.5T Versus 3.0T Magnetic Resonance Imaging Intratympanic Gadolinium Inner Ear Enhancement in Patients with Meniere's Disease.

BACKGROUND: A comparative study of 1.5T and 3.0T magnetic resonance imaging inner ear gadolinium enhancement was carried out to further explore the practicality and universality of 1.5T magnetic resonance imaging in the diagnosis of inner ear labyrinthine hydrops positive imaging. METHODS: This dual case-control study was conducted on 25 patients with Meniere's disease (experimental group), diagnosed by People's Hospital of Ordos Dongsheng District between April 2017 and April 2019 and 51 patients with Meniere's disease (control group), diagnosed by People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine between March 2010 and February 2011 and published on Chinese Medical Journal in 2011. Both groups were injected with gadolinium diluent into bilateral tympanic chambers through the tympanic membrane, and 3 dimensional-Fluid Attenuated Inversion Recovery (FLAIR) magnetic resonance imaging scanning of the inner ear was performed 24 hours later. The results of the 2 groups were observed, calculated, and statistically processed. RESULTS: The positive rate of membranous labyrinthine hydrops was 96% (24/25) in the experimental group and 96.1% (49/51) in the control group. The results are very close. CONCLUSION: In clinical diagnoses of Meniere's disease, 1.5T magnetic resonance imaging and 3.0T magnetic resonance imaging have the same value and significance.

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.

Magnetic resonance imaging of endolymphatic hydrops in patients with unilateral Meniere's disease: volume ratio and distribution rate of the endolymphatic space.

BACKGROUND: Endolymphatic hydrops (ELH), which is a pathological feature of Meniere's disease (MD), is characterized by an extended endolymphatic space (ELS). AIMS/OBJECTIVES: We aimed to perform a quantitative volumetric analysis of inner-ear ELH in patients with unilateral MD (uMD). MATERIAL AND METHODS: This study included 97 patients with definite uMD and 49 control subjects (CS). The ELS/total fluid space (TFS) volume ratio (%) and the distribution rate of the inner-ear components in the ELS (%) were measured using 3D magnetic resonance imaging and compared between patients with uMD and CS. RESULTS: Compared to CS, patients with uMD had significantly higher mean ELS/TFS volume ratios for inner-ear components. The mean distribution rate of the inner-ear components in the ELS was not significantly different between the two groups. CONCLUSIONS AND SIGNIFICANCE: In patients with uMD, ELH was noted to be spread throughout the entire inner ear and the endolymph was evenly distributed in the total ELS. These findings should be useful as a standard reference for further research.

Validation of inner ear MRI in patients with Ménière's disease by comparing endolymphatic hydrops from histopathologic specimens.

Intravenous gadolinium-enhanced inner-ear magnetic resonance imaging (IV-Gd inner-ear MRI) has been used to visualize endolymphatic hydrops (EH) in clinical diagnosis of Ménière's disease (MD). However, lack of histological validation has led to several concerns regarding how best to interpret the resulting images. Here, we compared hydropic changes in temporal bone specimens with the results of IV-Gd inner-ear MRI in patients with MD. Histopathologic images of temporal bones from 37 patients with MD and 10 healthy controls were collected from the National Temporal Bone Bank of the Massachusetts Eye and Ear Infirmary in the United States. The EH ratios in the vestibule and cochlea were calculated from temporal bones using the methods used for IV-Gd inner-ear MRI, and the degree to which the saccular and utricular hydrops contributed to vestibular hydrops was measured. The presence of hydropic change in each semicircular canal was assessed using temporal bone images and compared with IV-Gd inner-ear MRI scans of 74 patients with MD. Based on human temporal bone imagery, the EH ratios in the cochlea and the vestibule on the affected side were 0.314 and 0.757, respectively. In the healthy control group, the ratio was 0.064 for the cochlea and 0.289 for the vestibule; these values were significantly different from those for the affected side of MD patients. The values for the affected ear were similar to the ratios from the IV-Gd inner-ear MRI scans in MD patients. In the vestibule, saccular hydrops were more common than utricular hydrops. The average EH ratios in the saccule and utricle were 0.513 and 0.242, respectively. No significant hydropic change from each of three semicircular canals was evident in temporal bone histopathology. However, herniation of otolithic organs (saccule or utricle) into the lateral semicircular canal was found in 44.4% of the patients, with saccular herniation (24.8%) more common than utricular herniation (16.7%). Although IV-Gd inner-ear MRI might not reflect fully the results of actual histopathology due to the limited resolution of MRI and image-processing techniques, the measured EH ratios from temporal bone specimens and IV-Gd inner-ear MRI scans were similar. Hydropic change in the three semicircular canals was not significant at either the ampullated or nonampullated end. Canal invasion of vestibular hydrops seen on MRI also appeared in temporal bone histopathology, and saccular invasion was dominant.

3D-reconstructions of Bast's Valve and Membranous Labyrinth: Insights for Vestibular Implantation and Meniere's Disease.

HYPOTHESIS/BACKGROUND: Bast's valve is a poorly understood inner ear structure located at the junction between pars superior and inferior in the membranous labyrinth. Anatomically precise three-dimensional reconstructions (3D-reconstructions) of Bast's valve can help illuminate the morphology of the valve, and point toward its role in normal physiology and pathological states such as endolymphatic hydrops. This is of particular relevance to the development of a vestibular implant, a device intended to rehabilitate deficits in the vestibular system. METHODS: Six postmortem human temporal bones from healthy donors were scanned using a micro-computed tomography (microCT) scanner. The microCT data allowed 3D-reconstructions of the membranous labyrinth, with a particular focus on Bast's valve, vestibule, and cochlear duct. RESULTS: The microCT images of Bast's valve showed a rigid lip containing a core of soft tissue, opposing the thin membranous wall of the utricle. The maximum recorded length and width of the rigid lip were 440.4 µm and 88 µm, respectively. The 3D-reconstructions illustrated the slit-like opening of Bast's valve into the utricle, the twisting course of the basal turn of the cochlear duct, and the spatial orientation of utricle and saccule with respect to the stapes footplate. CONCLUSIONS: The present study provided a novel anatomical perspective on the microscopic structure of Bast's valve. The interplay between endolymphatic hydrops and Bast's valve is an ongoing area of research, but defining this anatomy in 3D will play a key role in furthering our understanding of the disease process. Implications for vestibular implantation are explored through the various 3D-reconstructions.

Estudo da eficácia de encapsulação da Cinarizina em cubossomos não-iônicos: caracterização estrutural e citotóxica / Study of the encapsulation efficacy of Cinnarizine in non-ionic cubosomes: structural and cytotoxic characterization

Os cubossomos são partículas nanoestruturadas em forma de bicamada lipídica, bicontínuas e altamente curvadas, as quais devem ser estabilizadas por um polímero não-iônico, neste caso o Pluronic® F-127. Podem ser compostos por alguns tipos de lipídios específicos que possuem a capacidade de se auto associar em estruturas cúbicas quando estão em excesso de água, como o fitantriol (PHY) e a monoleína (GMO). Devido a sua estrutura única, cubossomos possuem um grande potencial para serem considerados como sistemas drug delivery. Os sistemas drug delivery são amplamente utilizados na pesquisa farmacêutica e em contextos clínicos para aumentar a eficácia de compostos utilizados para diagnóstico e de fármacos. No caso da cinarizina (CNZ), fármaco já aprovado para o tratamento de náuseas, vômitos e vertigens causadas pela doença de Ménière, existem inúmeros efeitos colaterais associados a sua baixa solubilidade. Desta forma, a encapsulação em cubossomos se torna uma abordagem promissora para resolver os problemas de atividade farmacológica relacionados ao fármaco. Neste trabalho, realizamos uma caracterização biofísica da interação da CNZ em cubossomos (contendo PHY ou myverol, MYV, sendo este composto por 80% de GMO). As técnicas biofísicas utilizadas foram: espalhamento de raios-X em baixos ângulos (SAXS), espalhamento dinâmico de luz (DLS), microscopia eletrônica de transmissão (TEM), crio microscopia eletrônica de transmissão (Crio-TEM), análise de rastreamento de nanopartículas (NTA) e potencial zeta. A cromatografia líquida de alta eficiência (HPLC) foi realizada para verificar a porcentagem de eficiência de encapsulação (%EE) da CNZ nos cubossomos, enquanto que a citotoxicidade foi avaliada em eritrócitos através da análise da atividade hemolítica. Inicialmente, a influência de diferentes solventes (acetona, clorofórmio, etanol e octano) nas propriedades estruturais de cubossomos de PHY foi investigada, a fim de se minimizar os efeitos do solvente utilizados para a encapsulação da CNZ. Para amostras com acetona, descobriu-se que apenas altas concentrações tiveram influência na estrutura cristalográfica das nanopartículas, sendo o resultado foi totalmente reversível após 24h. O etanol fez com que o parâmetro de rede aumentasse de 10-15%. O clorofórmio e o octano tiveram efeitos diferentes sobre cubossomos de PHY em comparação com a acetona e o etanol; ambos induziram uma transição cúbico-hexagonal-micelar. Posteriormente, constatamos que as nanopartículas de PHY e MYV apresentaram diferentes estruturas cristalográficas, sendo elas Pn3m e Im3m, respectivamente. Devido a problemas com a baixa solubilidade de CNZ em PHY os estudos para esse lipídio foram suspensos. Nos testes para cubossomos de MYV ao incorporar a CNZ foi observado uma alteração da estrutura cúbica de Im3m para Pn3m e os valores dos parâmetros de rede se alteraram de acordo com a estrutura cristalina encontrada, porém os valores não apresentaram diferenças significativas de tamanho quando se trata da mesma estrutura, sugerindo que a CNZ não interferiu no parâmetro de rede. Os tamanhos das nanopartículas apresentaram uma população monodispersa com ~200 nm. DLS mostrou uma interferência da CNZ no tamanho dos cubossomos, variando de forma diretamente proporcional a concentração de CNZ na amostra, enquanto as técnicas de NTA e microscopia apresentaram nanopartículas de tamanhos bastante variados, mas independente da interferência da CNZ. A encapsulação de CNZ também foi dosada por HLPC em cubossomos de MYV, obtendo um limite superior de 0,6 mg/mL. A atividade citotóxica dos cubossomos foi testada em eritrócitos, revelando uma taxa de hemólise bastante inferior em cubossomos com CNZ em relação a cubossomos puros. Acreditamos que os cubossomos podem sim ser utilizados como sistemas carreadores de CNZ

Cubosomes are nanostructured particles in the form of a lipid bilayer, bicontinuous and highly curved, which must be stabilized by a non-ionic polymer, in this case Pluronic® F-127. They can be composed of some types of specific lipids that have the ability to self-associate in cubic structures when they are in excess of water, such as phytantriol (PHY) and monolein (GMO). Due to their unique structure, cubosomes have a great potential to be considered as drug delivery systems. Drug delivery systems are widely used in pharmaceutical research and clinical settings to increase the efficacy of compounds used for diagnostics and drugs. In the case of cinnarizine (CNZ), a drug already approved for the treatment of nausea, vomiting and vertigo caused by Ménière's disease, there are numerous side effects associated with its low solubility. Thus, cubosomal encapsulation becomes a promising approach to solve drug-related problems of pharmacological activity. In this work, we performed a biophysical characterization of the CNZ interaction in cubosomes (containing PHY or myverol, MYV, which is composed of 80% GMO). The biophysical techniques used were: low angle X-ray scattering (SAXS), dynamic light scattering (DLS), transmission electron microscopy (TEM), cryo transmission electron microscopy (Crio-TEM), nanoparticle tracking analysis (NTA) and zeta potential. High performance liquid chromatography (HPLC) was performed to verify the percentage of encapsulation efficiency (%EE) of CNZ in cubosomes, while cytotoxicity was evaluated in erythrocytes by analyzing the hemolytic activity. Initially, the influence of different solvents (acetone, chloroform, ethanol and octane) on the structural properties of PHY cubosomes was investigated in order to minimize the effects of the solvent used for the encapsulation of CNZ. For samples with acetone, it was found that only high concentrations had an influence on the crystallographic structure of the nanoparticles, with the result being fully reversible after 24h. Ethanol caused the network parameter to increase by 10-15%. Chloroform and octane had different effects on PHY cubosomes compared to acetone and ethanol; both induced a cubic-hexagonal-micellar transition. Later, we found that PHY and MYV nanoparticles presented different crystallographic structures, being Pn3m and Im3m, respectively. Due to problems with the low solubility of CNZ in PHY, studies for this lipid were suspended. In the tests for MYV cubosomes when incorporating CNZ, a change in the cubic structure from Im3m to Pn3m was observed and t he lattice parameters changed according to the crystal structure found, but the differences observed were not significant when it comes to the same structure, suggesting that the CNZ did not interfere with the network parameter. The nanoparticle sizes showed a monodisperse population with ~200 nm. DLS showed an interference of CNZ in the size of the cubosomes, varying directly proportionally to the concentration of CNZ in the sample, while NTA and microscopy techniques showed nanoparticles of widely varying sizes, but independent of CNZ interference. CNZ encapsulation was also dosed by HLPC in MYV cubosomes, obtaining an upper limit of 0.6 mg/ml. The cytotoxic activity of cubosomes was tested in erythrocytes, revealing a much lower rate of hemolysis in cubosomes with CNZ compared to pure cubosomes. We believe that cubosomes can indeed be used as CNZ carrier systems

Vestibular mapping in patients with unilateral peripheral-vestibular deficits.

OBJECTIVE: To test the hypothesis that patterns of semicircular canal (SCC) and otolith impairment in unilateral vestibular loss depend on the underlying disorders, we analyzed peripheral-vestibular function of all 5 vestibular sensors. METHODS: For this retrospective case series, we screened the hospital video-head-impulse test database (n = 4,983) for patients with unilaterally impaired SCC function who also received ocular vestibular-evoked myogenic potentials and cervical vestibular-evoked myogenic potentials (n = 302). Frequency of impairment of vestibular end organs (horizontal/anterior/posterior SCC, utriculus/sacculus) was analyzed with hierarchical cluster analysis and correlated with the underlying etiology. RESULTS: Acute vestibular neuropathy (AVN) (37.4%, 113 of 302), vestibular schwannoma (18.2%, 55 of 302), and acute cochleovestibular neuropathy (6.6%, 20 of 302) were most frequent. Horizontal SCC impairment (87.4%, 264 of 302) was more frequent (p < 0.001) than posterior (47.4%, 143 of 302) and anterior (37.8%, 114 of 302) SCC impairment. Utricular damage (58%, 175 of 302) was noted more often (p = 0.003) than saccular impairment (32%, 98 of 302). On average, 2.6 (95% confidence interval 2.48-2.78) vestibular sensors were deficient, with higher numbers (p ≤ 0.017) for acute cochleovestibular neuropathy and vestibular schwannoma than for AVN, Menière disease, and episodic vestibular syndrome. In hierarchical cluster analysis, early mergers (posterior SCC/sacculus; anterior SCC/utriculus) pointed to closer pathophysiologic association of these sensors, whereas the late merger of the horizontal canal indicated a more distinct state. CONCLUSIONS: While the extent and pattern of vestibular impairment critically depended on the underlying disorder, more limited damage in AVN and Menière disease was noted, emphasizing the individual range of loss of function and the value of vestibular mapping. Likely, both the anatomic properties of the different vestibular end organs and their vulnerability to external factors contribute to the relative sparing of the vertical canals and the sacculus.

Current status on researches of Meniere's disease: a review.

Background: Meniere's disease (MD) is a complex and multifactorial inner ear disease. The etiology of MD is unclear. Significant progress had been made in diagnosis and treatment. Complete cure for this disease is still impossible.Objectives: This review covers the updated research results in MD in the past decades.Material and methods: Recent publications were critically reviewed.Results: The relationship between Endolymphatic hydrops and Meniere symptoms requires further study. Direct visualization of EH is achieved by special sequences of inner ear MRI. Appearance of EH could be observed in MD patients both in symptomatic and asymptomatic ears. Visualization of EH in vivo might make a great substantial improvement in diagnose of MD. The first goal of the management of MD is to reduce the attack frequency. Several safe and effective medical and surgical therapies are practiced to help patients to control vertigo and preserve hearing.Conclusions and significance: There has been no major breakthrough in the pathogenesis research of MD in recent years. Visualization of EH in vivo might make a great substantial improvement in diagnose of MD. Clinicians still have few effective ways to alleviate the progress of the disease.

Inner-Ear Disorders Presenting with Air-Bone Gaps: A Review.

Air-bone gaps (ABGs) are commonly found in patients with conductive or mixed hearing loss generally due to outer- and/or middle-ear diseases such as otitis externa, tympanic membrane perforation, interruption or fixation of the ossicular chain, and chronic suppurative otitis media. ABGs can also be found in correlation with inner-ear disorders, such as endolymphatic hydrops, enlarged vestibular aqueduct syndrome, semicircular canal dehiscence, gusher syndrome, cochlear dehiscence, and Paget disease's as well cerebral vascular anomalies including dural arteriovenous fistula. The typical clinical presentation of inner-ear conditions or cerebral vascular anomalies causing ABGs includes audiological and vestibular symptoms like vertigo, oscillopsia, dizziness, imbalance, spinning sensation, pulsatile or continuous tinnitus, hyperacusis, autophony, auricular fullness, Tullio's phenomenon, and Hennebert's sign. Establishing a definitive diagnosis of the underlying condition in patients presenting with an ABG is often challenging to do and, in many patients, the condition may remain undefined. Results from an accurate clinical, audiological, and vestibular evaluation can be suggestive for the underlying condition; however, radiological assessment by computed tomography and/or magnetic resonance imaging is mandatory to confirm any diagnostic suspicion. In this review, we describe and discuss the most recent updates available regarding the clinical presentation and diagnostic workup of inner-ear conditions that may present together with ABGs.

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.

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.

Early Detection of Endolymphatic Hydrops using the Auditory Nerve Overlapped Waveform (ANOW).

Endolymphatic hydrops is associated with low-frequency sensorineural hearing loss, with a large body of research dedicated to examining its putative causal role in low-frequency hearing loss. Investigations have been thwarted by the fact that hearing loss is measured in intact ears, but gold standard assessments of endolymphatic hydrops are made postmortem only; and that no objective low-frequency hearing measure has existed. Yet the association of endolymphatic hydrops with low-frequency hearing loss is so strong that it has been established as one of the important defining features for Ménière's disease, rendering it critical to detect endolymphatic hydrops early, regardless of whether it serves a causal role or is the result of other disease mechanisms. We surgically induced endolymphatic hydrops in guinea pigs and employed our recently developed objective neural measure of low-frequency hearing, the Auditory Nerve Overlapped Waveform (ANOW). Hearing loss and endolymphatic hydrops were assessed at various time points after surgery. The ANOW detected low-frequency hearing loss as early as the first day after surgery, well before endolymphatic hydrops was found histologically. The ANOW detected low-frequency hearing loss with perfect sensitivity and specificity in all ears after endolymphatic hydrops developed, where there was a strong linear relationship between degree of endolymphatic hydrops and severity of low-frequency hearing loss. Further, histological data demonstrated that endolymphatic hydrops is seen first in the high-frequency cochlear base, though the ANOW demonstrated that dysfunction begins in the low-frequency apical cochlear half. The results lay the groundwork for future investigations of the causal role of endolymphatic hydrops in low-frequency hearing loss.

Solute carrier family 4 member 1 might participate in the pathogenesis of Meniere's disease in a murine endolymphatic hydrop model.

Background: To date, the pathogenesis of Meniere's disease (MD) remains unclear. Previous research found that the SLC4A1 gene significantly down-regulated. Aims: This study sought to understand the effect of SLC4A1 on the pathogenesis of MD. ELH C57 mice models were induced by intraperitoneal injection of AVP. Material and methods: The mRNA expression levels of SLC4A1, SLC4A10 and SLC26A4 were monitored by real-time quantitative PCR, the protein expression levels of SLC4A1 were monitored by immunoblotting and immunofluorescence before and after the ELH. DIDS is an inhibitor of SLC4A1. The expression levels of SLC4A1 were also monitored in the AVP + DIDS group. Results: We successfully established the model of ELH after applied AVP. The results of HE staining showed displacement of Reissner's membrane with bulge to scala vestibule in ears of the AVP group. Cochlea/ELS SLC4A1 protein and SLC4A1, SLC4A10, SLC26A4 mRNA expressions were reduced significantly in C57 mice of the AVP group. The SLC4A1 protein expression levels and SLC4A1, SLC4A10, SLC26A4 mRNA expression levels declined more obvious in the cochlea and ELS in C57 mice of the AVP + DIDS group. Conclusions and significance: SLC4A1 was a protective factor in the pathogenesis of MD, but the mechanisms were unknown.