Gray-tone appearances on 4-hour delayed gadolinium-enhanced magnetic resonance imaging indicate severe inner ear pathology and symptoms in sudden sensorineural hearing loss.

Objective: Hybrid of reversed image of positive endolymph signal and negative image of perilymph signal (HYDROPS) in delayed gadolinium-enhanced magnetic resonance imaging (MRI) typically depicts normal inner ear as "white-tone" and endolymphatic hydrops as "black-transparent" appearances, whereas ears with auditory and vestibular disorders are occasionally depicted as "gray-tone." This study aimed to investigate the pathological basis of sudden sensorineural hearing loss (SSNHL) patients with "gray-tone" appearances on HYDROPS. Methods: Delayed gadolinium-enhanced MRI examinations were conducted on 29 subjects with unilateral SSNHL. We mainly analyzed positive perilymph image (PPI) and positive endolymph image (PEI), which were components HYDROPS. Results: On PPI, signal intensity (SI) values extracted from the cochlear and vestibular region of interest (ROI) were higher in the SSNHL ears with dizziness/vertigo symptom at the first visit compared to the healthy ear. Additionally, the PPI/PEI enhancement pattern in the vestibule was associated with a high prevalence of hearing and vestibular deteriorations at the first visit and poor hearing improvement after treatment. Conclusion: Enhancement on PPI/PEI may result from leakage of gadolinium into the inner ear following breakdown of the blood-labyrinth barrier, with high SI being correlated with the amount of leakage. Particularly, a significant leakage into the endolymphatic space, defined as PPI+/PEI+, indicates severe inner ear pathology. Ultimately, we emphasize that the "gray-tone" appearance in the inner ear on HYDROPS comprises enhancements on both PPI and PEI and propose a new classification for evaluating SSNHL Peri- and Endolymphatic image Enhancement pattern in Delayed gadolinium-enhanced MRI (SPEED). Level of Evidence: 4.

Hearing loss and its association with the proteome of perilymph, cerebrospinal fluid, and tumor tissue in patients with vestibular schwannoma.

This study examined the association between hearing loss in sporadic vestibular schwannoma patients and the proteome of perilymph (PL), cerebrospinal fluid (CSF), and vestibular schwannoma. Intraoperative sampling of PL and of CSF, and biopsy of vestibular schwannoma tissue, was performed in 32, 32, and 20 patients with vestibular schwannoma, respectively. Perilymph and CSF in three patients with meningioma and normal hearing were also sampled. The proteomes were identified by liquid chromatography coupled to high-resolution tandem mass spectrometry. Preoperative hearing function of the patients was evaluated with pure tone audiometry, with mean values at frequencies of 500, 1000, 2000, and 4000 Hz (PTA4) in the tumor-affected ear used to delineate three hearing groups. Analysis of the PL samples revealed significant upregulation of complement factor H-related protein 2 (CFHR2) in patients with severe to profound hearing loss after false discovery rate correction. Pathway analysis of biofunctions revealed higher activation scores in the severe/profound hearing loss group of leukocyte migration, viral infection, and migration of cells in PL. Upregulation of CFHR2 and activation of these pathways indicate chronic inflammation in the cochlea of vestibular schwannoma patients with severe to profound hearing loss compared with patients with normal hearing or mild hearing loss.

Exploring Inner Ear and Brain Connectivity through Perilymph Sampling for Early Detection of Neurological Diseases: A Provocative Proposal.

Recent evidence shows that it is possible to identify the elements responsible for sensorineural hearing loss, such as pro-inflammatory cytokines and macrophages, by performing perilymph sampling. However, current studies have only focused on the diagnosis of such as otologic conditions. Hearing loss is a feature of certain neuroinflammatory disorders such as multiple sclerosis, and sensorineural hearing loss (SNHL) is widely detected in Alzheimer's disease. Although the environment of the inner ear is highly regulated, there are several communication pathways between the perilymph of the inner ear and cerebrospinal fluid (CSF). Thus, examination of the perilymph may help understand the mechanism behind the hearing loss observed in certain neuroinflammatory and neurodegenerative diseases. Herein, we review the constituents of CSF and perilymph, the anatomy of the inner ear and its connection with the brain. Then, we discuss the relevance of perilymph sampling in neurology. Currently, perilymph sampling is only performed during surgical procedures, but we hypothesize a simplified and low-invasive technique that could allow sampling in a clinical setting with the same ease as performing an intratympanic injection under direct visual check. The use of this modified technique could allow for perilymph sampling in people with hearing loss and neuroinflammatory/neurodegenerative disorders and clarify the relationship between these conditions; in fact, by measuring the concentration of neuroinflammatory and/or neurodegenerative biomarkers and those typically expressed in the inner ear in aging SNHL, it could be possible to understand if SNHL is caused by aging or neuroinflammation.

Correlation of endolymphatic hydrops and perilymphatic enhancement with the clinical features of Ménière's disease.

OBJECTIVES: To use three-dimensional real inversion recovery (3D-real IR) MRI to investigate correlations between endolymphatic hydrops (EH) grades or the degree of perilymphatic enhancement (PE) and clinical features of Ménière's disease (MD), as previous findings have been inconsistent. METHODS: A total of 273 consecutive patients with definite unilateral MD were retrospectively enrolled from September 2020 to October 2021. All patients underwent 3D-real IR and 3D-T2WI 6 h after intravenous gadolinium injection. MD-related symptom duration and vertigo frequency were recorded. EH grades were evaluated, the signal intensity ratio (SIR) was measured, and correlations between clinical features and EH, PE were assessed respectively. RESULTS: The study included 123 males and 150 females, with a mean age of 53.0 years. A longer duration of vertigo was associated with higher cochlear EH grades, whereas the opposite was true for the duration of aural fullness. A longer time since vertigo onset was associated with higher vestibular EH grades; the opposite was true for the duration of individual vertigo attacks. The multiple regression analysis revealed that age, tinnitus duration, and vestibular EH were risk factors for SIR. Furthermore, the low-frequency hearing threshold (HT) was a risk factor for cochlear and vestibular EH, and the SIR. CONCLUSION: The EH grade and SIR (an indicator for the quantitative evaluation of PE) were correlated with clinical features and HT of MD; thus, imaging can be a valuable tool in planning individualised treatment. CLINICAL RELEVANCE STATEMENT: This study revealed that the grade of endolymphatic hydrops and degree of perilymphatic enhancement positively correlates with the length of time since onset of clinical symptoms and hearing thresholds in patients with Ménière's disease, facilitating the tailored treatment. KEY POINTS: • Relationships between 3-dimensional real inversion recovery features and clinical symptoms in Ménière's disease are unknown. • Symptom duration and hearing thresholds correlated with endolymphatic hydrops grades and degree of perilymphatic enhancement. • MRI features correlate with MD severity; thus, imaging is valuable for planning tailored treatment.

Suspicion and Treatment of Perilymphatic Fistula: A Prospective Clinical Study.

Background: Since the discovery of the perilymphatic fistula (PLF), the diagnosis and treatment remain controversial. If successfully recognized, the PLF is surgically repairable with an obliteration of the fistula site. Successful treatment has a major impact on patient's quality of life with an improvement in their audiological and vestibular symptoms. Objective: To prospectively investigate patients' clinical and audiological evolution with PLF suspicion after middle ear exploration and obliteration of the round and oval window. Study Design: Prospective comparative study. Setting: Tertiary care center. Methods: Patients were divided into two groups: Group I consisted of patients where no PLF had been identified intraoperatively at the oval and/or at the round window, and Group II consisted of patients where a fistula had been visualized. Patient assessment was a combination of past medical history, the presence of any risk factors, cochlear and vestibular symptoms, a physical examination, temporal bone imaging, audiograms, and a videonystagmogram (VNG). Results: A total of 98 patients were divided into two groups: 62 in Group I and 36 in Group II. A statistically significant difference regarding gender was observed in Group II (83.3% of males vs. 16.7% of females, p = 0.008). A total of 14 cases (4 and 10 in Groups I and II, respectively) were operated for a recurrent PLF. Fat graft material was used in the majority of their previous surgery; however, no difference was found when comparing fat to other materials. In addition, no statistically significant difference was noted between Groups I and II concerning predisposing factors, imaging, VNG, symptom evolution, or a physical exam before the surgery and at 12 months post-operative. However, both groups showed statistically significant hearing and vestibular improvement. On the other hand, the air conduction (AC) and bone conduction (BC) at each frequency were not statistically different between the two groups before surgery but showed statistically significant improvement at 12 months post-operatively, especially for the BC at the frequencies 250 (p = 0.02), 500 (p = 0.0008), and 1000 Hz (p = 0.04). Conclusions: Whenever you suspect a perilymphatic fistula, do not hesitate to explore middle ear and do window obliterations using a tragal perichondrium material. Our data showed that cochlear and vestibular symptoms improved whether a fistula had been identified or not.

Pathogenic mechanism analysis of cochlear key structural lesion and phonosensitive hearing loss.

Due to ethical issues and the very fine and complex structure of the cochlea, it is difficult to directly perform experimental measurement on the human cochlea. Therefore, the finite element method has become an effective and replaceable new research means. Accurate numerical analysis on human ear using finite element method can provide better understanding of sound transmission and can be used to assess the influence of diseases on hearing and to treat hearing loss. In this research, a three-dimensional (3D) finite element model (FEM) of the human ear of cochlea was presented to investigate the destruction of basilar membrane (BM), round window (RW) sclerosis and perilymph fistula, the key structures of the cochlea, and analyze the effects of these abnormal pathological states in the cochlea on cochlear hearing, resulting in the changes in cochlear sense structure biomechanical behavior and quantitative prediction of the degree and harm of the disorder to the decline of human hearing. Therefore, this paper can deepen reader's understanding of the cochlear biomechanical mechanism and provide a theoretical foundation for clinical otology.

Characteristic findings in the human fetus vestibule: A human temporal bone study.

OBJECTIVE: The "collapse," a highly flexed, dented, or caved membrane between the endo- and peri-lymph of the saccule and utricle in adults, is considered as a morphological aspect of Ménière's syndrome. Likewise, when mesh-like tissues in the perilymphatic space are damaged or lost, the endothelium loses mechanical support and causes nerve irritation. However, these morphologies were not examined in fetuses. METHODS: By using histological sections from 25 human fetuses (crown-rump length[CRL] 82-372 mm; approximately 12-40 weeks), morphologies of the perilymphatic-endolymphatic border membrane and the mesh-like tissue around the endothelium were examined. RESULTS: The highly flexed or caved membrane between the endo- and peri-lymphatic spaces was usually seen in the growing saccule and utricle of fetuses, especially at junctions between the utricle and ampulla at midterm. Likewise, the perilymphatic space around the saccule, utricle and semicircular ducts often lost the mesh-like tissues. The residual mesh-like tissue supported the veins, especially in the semicircular canal. CONCLUSION: Within a cartilaginous or bony room showing a limited growth in size but containing increased perilymph, the growing endothelium appeared to become wavy. Owing to a difference in growth rates between the utricle and semicircular duct, the dentation tended to be more frequently seen at junctions than at free margins of the utricle. The difference in site and gestational age suggested that the deformity was not "pathological" but occurred due to unbalanced growth of the border membrane. Nevertheless, the possibility that the deformed membrane in fetuses was an artifact caused by delayed fixation is not deniable.

Sonoporation of the Round Window Membrane on a Sheep Model: A Safety Study.

Sonoporation using microbubble-assisted ultrasound increases the permeability of a biological barrier to therapeutic molecules. Application of this method to the round window membrane could improve the delivery of therapeutics to the inner ear. The aim of this study was to assess the safety of sonoporation of the round window membrane in a sheep model. To achieve this objective, we assessed auditory function and cochlear heating, and analysed the metabolomics profiles of perilymph collected after sonoporation, comparing them with those of the control ear in the same animal. Six normal-hearing ewes were studied, with one sonoporation ear and one control ear for each. A mastoidectomy was performed on both ears. On the sonoporation side, Vevo MicroMarker® microbubbles (MBs; VisualSonics-Fujifilm, Amsterdam, The Netherlands) at a concentration of 2 × 108 MB/mL were locally injected into the middle ear and exposed to 1.1 MHz sinusoidal ultrasonic waves at 0.3 MPa negative peak pressure with 40% duty cycle and 100 µs interpulse period for 1 min; this was repeated three times with 1 min between applications. The sonoporation protocol did not induce any hearing impairment or toxic overheating compared with the control condition. The metabolomic analysis did not reveal any significant metabolic difference between perilymph samples from the sonoporation and control ears. The results suggest that sonoporation of the round window membrane does not cause damage to the inner ear in a sheep model.

Dual viscosity mixture vehicle for intratympanic steroid treatment modifies the ROS and inflammation related proteomes.

Until recently, the most standard treatment for sensorineural or sudden hearing loss, which is caused by inner ear damage or deterioration, has been systemic oral steroid administration. In recent, intratympanic steroid injections such as dexamethasone have been used for the treatment of sudden hearing loss as well. It is injected into the tympanic cavity through its membrane and is expected to diffuse over the round window located between the tympanic cavity and the inner ear. However, in clinical situations, the delivery time of steroids to the inner ear is shorter than 24 h, which does not allow for a sufficient therapeutic effect. Therefore, we applied a previously invented dual viscosity mixture vehicle (DVV) for intratympanic dexamethasone to a guinea pig model, which could reduce the side effects of systemic steroid administration with sufficient dwelling time for the treatment of hearing loss, and we investigated the physiological changes with a global proteomic approach. In this study, we extracted perilymph in three different conditions from guinea pigs treated with dexamethasone-embedded DVV, dexamethasone mixed in saline, and control groups to compare proteomic changes using tandem mass spectrometry analysis. After liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) analysis, we first identified 46 differentially expressed proteins (DEPs) that were statistically significant after one-way ANOVA multiple-sample test. We also performed pairwise comparisons among each group to identify DEPs closely related to the treatment response of dexamethasone-embedded DVV. Gene ontology enrichment analysis showed that these DEPs were mostly related to inflammation, immune, actin remodeling, and antioxidant-related processes. As a result, the proteome changes in the DVV-treated groups revealed that most upregulated proteins activate the cell proliferation process, and downregulated proteins inhibit apoptosis and inflammatory reactions. Moreover, the reactive oxygen process was also regulated by DEPs after DVV treatment.

Intratympanic steroid treatment can reduce ROS and immune response in human perilymph investigated by in-depth proteome analysis.

Intratympanic (IT) steroid treatment is one of the most widely used and effective treatments for inner ear disorders such as sudden sensorineural hearing loss (SNHL). However, a clear mechanism of IT steroids in inner ear recovery has not yet been revealed. Therefore, we investigated proteome changes in extracted human perilymph after steroid treatment. In this study, we applied a tandem mass spectrometry (MS/MS)-based proteomics approach to discover global proteome changes by comparing human perilymph after steroid treatment with non-treated perilymph group. Using liquid chromatography-MS/MS analysis, we selected 156 differentially expressed proteins (DEPs) that were statistically significant according to Student's t-test. Functional annotation analysis showed that upregulated proteins after steroid treatment are related to apoptosis signaling, as well as reactive oxygen species (ROS) and immune responses. The protein-protein interaction (PPI) clusters the proteins associated with these processes and attempts to observe signaling circuitry, which mediates cellular response after IT steroid treatments. Moreover, we also considered the interactome analysis of DEPs and observed that those with high interaction scores were categorized as having equivalent molecular functions (MFs). Collectively, we suggest that DEPs and interacting proteins in human perilymph after steroid treatment would inhibit the apoptotic and adaptive immune processes that may lead to anti-inflammatory effects.

In Silico Localization of Perilymph Proteins Enriched in Menier̀e Disease Using Mammalian Cochlear Single-cell Transcriptomics.

Hypothesis: Proteins enriched in the perilymph proteome of Menier̀e disease (MD) patients may identify affected cell types. Utilizing single-cell transcriptome datasets from the mammalian cochlea, we hypothesize that these enriched perilymph proteins can be localized to specific cochlear cell types. Background: The limited understanding of human inner ear pathologies and their associated biomolecular variations hinder efforts to develop disease-specific diagnostics and therapeutics. Perilymph sampling and analysis is now enabling further characterization of the cochlear microenvironment. Recently, enriched inner ear protein expression has been demonstrated in patients with MD compared to patients with other inner ear diseases. Localizing expression of these proteins to cochlear cell types can further our knowledge of potential disease pathways and subsequent development of targeted therapeutics. Methods: We compiled previously published data regarding differential perilymph proteome profiles amongst patients with MD, otosclerosis, enlarged vestibular aqueduct, sudden hearing loss, and hearing loss of undefined etiology (controls). Enriched proteins in MD were cross-referenced against published single-cell/single-nucleus RNA-sequencing datasets to localize gene expression to specific cochlear cell types. Results: In silico analysis of single-cell transcriptomic datasets demonstrates enrichment of a unique group of perilymph proteins associated with MD in a variety of intracochlear cells, and some exogeneous hematologic and immune effector cells. This suggests that these cell types may play an important role in the pathology associated with late MD, suggesting potential future areas of investigation for MD pathophysiology and treatment. Conclusions: Perilymph proteins enriched in MD are expressed by specific cochlear cell types based on in silico localization, potentially facilitating development of disease-specific diagnostic markers and therapeutics.

Evaluation of prednisolone and prednisolone sodium succinate concentrations in human plasma and inner ear perilymph during cochlear implantation 24 h after intratympanic injection.

BACKGROUND: The use of intratympanic (IT) steroids has drastically increased over the past 10-15 years to manage many otological pathologies. OBJECTIVES: This study aimed to compare the concentrations of prednisolone and prednisolone sodium succinate (SS) in the plasma and inner ear perilymph of participants who underwent cochlear implantation 24 h after IT injection. MATERIALS AND METHODS: It was a prospective comparative randomized study. Twenty participants received an IT injection of prednisolone SS ∼24 h before the cochlear implantation. The other five participants received an IT saline injection and represented the control group. Perilymph and blood were sampled during the cochlear implantation surgery. RESULTS: Both prednisolone and prednisolone SS were still present in perilymph ∼24 h after the IT administration. Only prednisolone was present in the blood plasma of seven participants (35%). CONCLUSION: IT injection of prednisolone SS resulted in high perilymph concentrations of prednisolone and prednisolone SS, which could stay in the perilymph for at least 24 h. Using a mini-endoscope during the IT injection may effectively detect barriers infront of the round window membrane, increasing the drug concentration in the inner ear. SIGNIFICANCE: IT injection is an effective method for delivering prednisolone to the inner ear.

[Relationship between imaging features and intraoperative perilymph gusher in patients with Mondini inner ear malformation].

Objective:To investigate the relationship between imaging characteristics and intraoperative perilymph gusher in patients with Mondini inner ear malformation in cochlear implantation, in order to provide basis and clinical guidance for predicting of intraoperative perilymph gusher before cochlear implantation. Methods:According to Sennaroglu's classification method, children with severe sensorineural hearing loss screened from January 2020 to December 2021 were divided into Mondini group, simple enlarged vestibular aqueduct group and normal inner ear group according to inclusion criteria strictly. The images of temporal bone HRCT and inner ear MRI were post-processed, some relative indicators were measured, including cochlear height and width of vestibular aqueduct, etc., and the gusher situation during cochlear implantation was recorded. The mean value of each indicator among the three groups were compared respectively, and the differences of each indicator between the gusher group and the non-gusher group were analyzed. Results:There were statistically significant differences in cochlear height, length of cochlear bottom turn, width of cochlear aperture, vestibular length and vestibular width among the Mondini group（24 cases）, simple EVA group（15 cases） and normal inner ear group（28 cases）. The incidence of gusher of Mondini group in cochlear implantation was 30.77%（8/26）. The outer diameter of the VA（[3.10±0.74]mm） and the middle width of the VA（[1.90±0.68] mm） in the gusher group were wider than those in the non-gusher group, and the difference was statistically significant. The incidence of intraoperative gusher in patients with EVA was 20.00%（3/15）, and there was statistically significant difference in the length of endolymph sac between gusher group and non-gusher group（P<0.05）. Conclusion:The causes of intraoperative perilymph gusher in patients with Mondini inner ear malformation are complex. The enlarged vestibular aqueduct may be one of the anatomical basis. Whether it can be used to guide the preoperative assessment of the risk of intraoperative perilymph gusher need to be further confirmed by a large sample of clinical research from multiple centers in the future.

17O-labeled water distribution in the human inner ear: Insights into lymphatic dynamics and vestibular function.

We evaluated the inner ear distribution of 17O-labeled saline administered to the human tympanic cavity. Magnetic resonance imaging was performed after intratympanic administration in five healthy volunteers and one patient with cochlear endolymphatic hydrops. In all volunteers, 17O-labeled water permeated the cochlear basal turn and vestibule at 30 min and disappeared gradually within 2-4 h. All participants experienced positional vertigo lasting a few hours to a few days. Visualization of 17O-labeled water distribution in the endolymphatic space of the posterior ampulla showed indistinct separation of endolymph and perilymph in the cochlea and most of the vestibule in all participants. Intralabyrinthine distribution of 17O-labeled water differed from that in previous reports of intratympanically administered gadolinium-based contrast agent. 17O-labeled water in the endolymphatic space may cause heavier endolymph and positional vertigo. These results of this study may add new insights for investigating the distribution and the effects of molecules in the inner ear after the intratympanic administration in living humans.

Immediate-Early Modifications to the Metabolomic Profile of the Perilymph Following an Acoustic Trauma in a Sheep Model.

The pathophysiological mechanisms of noise-induced hearing loss remain unknown. Identifying biomarkers of noise-induced hearing loss may increase the understanding of pathophysiological mechanisms of deafness, allow for a more precise diagnosis, and inform personalized treatment. Emerging techniques such as metabolomics can help to identify these biomarkers. The objective of the present study was to investigate immediate-early changes in the perilymph metabolome following acoustic trauma. Metabolomic analysis was performed using liquid chromatography coupled to mass spectrophotometry to analyze metabolic changes in perilymph associated with noise-induced hearing loss. Sheep (n = 6) were exposed to a noise designed to induce substantial hearing loss. Perilymph was collected before and after acoustic trauma. Data were analyzed using univariate analysis and a supervised multivariate analysis based on partial least squares discriminant analysis. A metabolomic analysis showed an abundance of 213 metabolites. Four metabolites were significantly changed following acoustic trauma (Urocanate (p = 0.004, FC = 0.48), S-(5'-Adenosyl)-L-Homocysteine (p = 0.06, FC = 2.32), Trigonelline (p = 0.06, FC = 0.46) and N-Acetyl-L-Leucine (p = 0.09, FC = 2.02)). The approach allowed for the identification of new metabolites and metabolic pathways involved with acoustic trauma that were associated with auditory impairment (nerve damage, mechanical destruction, and oxidative stress). The results suggest that metabolomics provides a powerful approach to characterize inner ear metabolites which may lead to identification of new therapies and therapeutic targets.

Relationship between Signal Intensity of the Labyrinth and Cochleovestibular Testing and Morphologic Features of Vestibular Schwannoma.

Objectives The aim of this article was to evaluate the relationship between signal intensity of the labyrinth and vestibulocochlear function and morphologic features of vestibular schwannoma (VS). Design Cross-sectional Study. Setting Tertiary referral center. Participants Fifty-four patients with sporadic, untreated VS. Main Outcome Measure Signal intensity of the cochlea and vestibule (SIRc and SIRv: signal intensity of cochlea/vestibule compared with cerebellar signal intensity; AURc and AURv: SIRc/SIRv of the affected side compared with the unaffected side) in 1.5T T2-weighted images was correlated with size (Hannover classification), cystic status, distance from the fundus of the internal auditory canal, video head impulse test (vHIT), and audiometry. Results Signal intensity of the vestibule was higher than that of the cochlea ( p < 0.01). Large tumors had lower SIRc than smaller tumors ( p = 0.03); Hannover T1 tumors had higher SIRc ( p < 0.01), SIRv ( p < 0.01), AURc ( p < 0.01) and AURv ( p < 0.01) than the rest; heterogenous and cystic tumors had higher SIRv than solid large tumors ( p = 0.02); superior vestibular nerve pattern on vHIT had higher SIRv and AURv than inferior vestibular nerve and mixed patterns ( p = 0.03 and 0.004, respectively); and there was a weak correlation between AURv and speech discrimination ( r = 0.33, p = 0.04). Conclusion A more abnormal signal intensity of the labyrinth is associated with larger size and solid status of VS. There was a positive relationship between signal intensity of the labyrinth and speech discrimination scores on audiogram.

Bioinformatic Analysis of the Perilymph Proteome to Generate a Human Protein Atlas.

The high complexity of the cellular architecture of the human inner ear and the inaccessibility for tissue biopsy hampers cellular and molecular analysis of inner ear disease. Sampling and analysis of perilymph may present an opportunity for improved diagnostics and understanding of human inner ear pathology. Analysis of the perilymph proteome from patients undergoing cochlear implantation was carried out revealing a multitude of proteins and patterns of protein composition that may enable characterisation of patients into subgroups. Based on existing data and databases, single proteins that are not present in the blood circulation were related to cells within the cochlea to allow prediction of which cells contribute to the individual perilymph proteome of the patients. Based on the results, we propose a human atlas of the cochlea. Finally, druggable targets within the perilymph proteome were identified. Understanding and modulating the human perilymph proteome will enable novel avenues to improve diagnosis and treatment of inner ear diseases.

Metabolomic Studies in Inner Ear Pathologies.

Sensorineural hearing loss is the most common sensory deficit. The etiologies of sensorineural hearing loss have been described and can be congenital or acquired. For congenital non-syndromic hearing loss, mutations that are related to sites of cochlear damage have been discovered (e.g., connexin proteins, mitochondrial genes, etc.). For cytomegalovirus infection or auditory neuropathies, mechanisms are also well known and well researched. Although the etiologies of sensorineural hearing loss may be evident for some patients, the damaged sites and pathological mechanisms remain unclear for patients with progressive post-lingual hearing loss. Metabolomics is an emerging technique in which all metabolites present in a sample at a given time are analyzed, reflecting a physiological state. The objective of this study was to review the literature on the use of metabolomics in hearing loss. The findings of this review suggest that metabolomic studies may help to develop objective tests for diagnosis and personalized treatment.

Comparison between 3D SPACE FLAIR and 3D TSE FLAIR in Menière's disease.

PURPOSE: Heavily T2-weighted 3D FLAIR (hT2w-3D-FLAIR) sequence with constant flip angle (CFA) has been reported as being more sensitive to low concentrations of gadolinium (Gd) enabling endolymphatic hydrops (EH) visualization. The purpose of this study was to compare signal-to-noise (SNR) ratio, detection rate of EH, and increased perilymphatic enhancement (PE) as well as diagnostic accuracy in diagnosing definite Menière's disease (MD), using 3D-SPACE FLAIR versus conventional 3D-TSE FLAIR. METHODS: This retrospective study included 29 definite MD patients who underwent a 4-h delayed intravenous (IV) Gd-enhanced 3D-TSE FLAIR and 3D-SPACE FLAIR MRI between February 2019 and February 2020. MR images were qualitatively and quantitatively analyzed twice by 2 experienced head and neck radiologists. Qualitative assessment included grading of cochlear and vestibular EH and visual comparison of PE. Quantitative assessment of PE was performed by placing a region of interest (ROI) and ratio calculation in the basal turn of the cochlea and the brainstem. RESULTS: The intra- and inter-reader reliability for grading of EH and PE was excellent (0.7 < kappa < 0.9) for 3D-SPACE FLAIR and exceeded the values for 3D-TSE FLAIR (0.5 < kappa < 0.9) The combination of EH and visual assessment of PE has the highest diagnostic accuracy in diagnosing definite MD on 3D-SPACE FLAIR with a sensitivity of 0.91 and a specificity of 0.98 resulting in a sensitivity raise of 6% compared to 3D-TSE FLAIR. CONCLUSION: Four-hour delayed IV Gd-enhanced 3D-SPACE FLAIR sequence has a higher sensitivity and reproducibility than 3D-TSE FLAIR for the visualization of EH and increased PE in definite MD patients.

Perilymph metabolomic and proteomic MALDI-ToF profiling with porous silicon chips: A proof-of-concept study.

INTRODUCTION: Sensorineural hearing losses (SNHLs) are a significant public health issue, and the hearing loss field is desperately in need of effective therapy. Pathophysiological mechanisms are not yet clearly understood in the absence of validated methods to assess the inner ear content. Proteomic and metabolomic analysis of perilymph is opening new research perspectives for SNHLs. We aimed to demonstrate the feasibility of an innovative mass spectrometry (MS) strategy using porous silicon chips (PSCs) to investigate the low molecular weight (LMW) protein and metabolite content of human perilymph. Our second objective was to stratify perilymph samples according to their MS profiles and compare these results with clinical data. MATERIAL AND METHODS: Perilymph samples obtained during cochlear implant surgery from patients with SNHLs were retrieved from a validated biobank. To focus on LMW entities, we used a PSC enrichment protocol before MALDI-ToF MS analysis. PSCs were used as a LMW molecular preanalytical stabilizer and amplifier. Patients' clinical data and SNHL characteristics were retrieved retrospectively from medical charts. RESULTS: We successfully acquired and compared 59 exploitable MS profiles out of 71 perilymph samples. There was a good correlation between duplicates. Comparing both ears from the same patient, we found good reproducibility even when there was a one-year interval between samplings. We identified three distinct groups when comparing the samples' metabolomic profiles and four homogeneous groups comparing their LMW proteome profiles. Clinical data analysis suggested that some groups shared clinical or preanalytical characteristics. CONCLUSION: This proof-of-concept study confirms that LMW proteome and metabolome content of perilymph can be analyzed with PSCs. Based on protein profiles, we managed to stratify perilymp samples according to their molecular composition. These results must be confirmed with a larger population, and sampling methods require improvement, but this approach seems promising. In the future, this approach may pave the way for companion test strategies to precisely diagnose and define potential molecular targets for audioprotective therapies.