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ZusammenfassungAuch wenn die einzelnen Krankheitsbilder selten sind, stellen seltene Erkrankungen der Cochlea in ihrer Gänze eine doch gehäufte Entität dar, die zu Hörstörungen führt. Ein/Das Ziel des vorliegenden Referates war es, unter Berücksichtigung der Embryonalentwicklung der Hörschnecke und einer systematischen Zusammenfassung eine übersichtliche Darstellung der seltenen cochleären Erkrankungen zu ermöglichen. Auch wenn rapide biotechnologische und bioinformatische Fortschritte die Diagnose einer seltenen Erkrankung erleichtern, so kann oft nur im interdisziplinären Austausch der Verdacht einer seltenen Erkrankung erhoben werden. Trotz gleicher zugrunde liegender Mutationen kann der Phänotyp nicht nur bei den genetisch bedingten Hörstörungen sondern auch bei den syndromalen Erkrankungen stark variieren. Schließlich wird deutlich, dass der Phänotyp der einzelnen seltenen Erkrankungen nicht ausschließlich durch die klassische Genetik bestimmt werden kann.

Objectives There are no approved pharmacologic therapies for chronic sensorineural hearing loss (SNHL). The combination of CHIR99021+valproic acid (CV, FX-322) has been shown to regenerate mammalian cochlear hair cells ex vivo. The objectives were to characterize the cochlear pharmacokinetic profile of CV in guinea pigs, then measure FX-322 in human perilymph samples, and finally assess safety and audiometric effects of FX-322 in humans with chronic SNHL. Study designs Middle ear residence, cochlear distribution, and elimination profiles of FX-322 were assessed in guinea pigs. Human perilymph sampling following intratympanic FX-322 dosing was performed in an open-label study in cochlear implant subjects. Unilateral intratympanic FX-322 was assessed in a Phase 1b prospective, randomized, double-blinded, placebo-controlled clinical trial. Setting Three private otolaryngology practices in the US. Patients Individuals diagnosed with mild to moderately severe chronic SNHL (≤70 dB standard pure-tone average) in one or both ears that was stable for ≥6 months, medical histories consistent with noise-induced or idiopathic sudden SNHL, and no significant vestibular symptoms. Interventions Intratympanic FX-322. Main outcome measures Pharmacokinetics of FX-322 in perilymph and safety and audiometric effects. Results After intratympanic delivery in guinea pigs and humans, FX-322 levels in the cochlear extended high-frequency region were observed and projected to be pharmacologically active in humans. A single dose of FX-322 in SNHL subjects was well tolerated with mild, transient treatment-related adverse events (n = 15 FX-322 vs 8 placebo). Of the six patients treated with FX-322 who had baseline word recognition in quiet scores below 90%, four showed clinically meaningful improvements (absolute word recognition improved 18-42%, exceeding the 95% confidence interval determined by previously published criteria). No significant changes in placebo-injected ears were observed. At the group level, FX-322 subjects outperformed placebo group in word recognition in quiet when averaged across all time points, with a mean improvement from baseline of 18.9% (p = 0.029). For words in noise, the treated group showed a mean 1.3 dB signal-to-noise ratio improvement (p = 0.012) relative to their baseline scores while placebo-treated subjects did not (-0.21 dB, p = 0.71). Conclusions Delivery of FX-322 to the extended high-frequency region of the cochlea is well tolerated and enhances speech recognition performance in multiple subjects with stable chronic hearing loss.

Subjective tinnitus is the conscious perception of sound in the absence of any acoustic source. The literature suggests various tinnitus mechanisms, most of which invoke changes in spontaneous firing rates of central auditory neurons resulting from modification of neural gain. Here, we present an alternative model based on evidence that tinnitus is: (1) rare in people who are congenitally deaf, (2) common in people with acquired deafness, and (3) potentially suppressed by active cochlear implants used for hearing restoration. We propose that tinnitus can only develop after fast auditory fiber activity has stimulated the synapse formation between fast-spiking parvalbumin positive (PV1) interneurons and projecting neurons in the ascending auditory path and coactivated frontostriatal networks after hearing onset. Thereafter, fast auditory fiber activity promotes feedforward and feedback inhibition mediated by PV1 interneuron activity in auditory-specific circuits. This inhibitory network enables enhanced stimulus resolution, attention-driven contrast improvement, and augmentation of auditory responses in central auditory pathways (neural gain) after damage of slow auditory fibers. When fast auditory fiber activity is lost, tonic PV1 interneuron activity is diminished, resulting in the prolonged response latencies, sudden hyperexcitability, enhanced cortical synchrony, elevated spontaneous c oscillations, and impaired attention/stress-control that have been described in previous tinnitus models. Moreover, because fast processing is gained through sensory experience, tinnitus would not exist in congenital deafness. Electrical cochlear stimulation may have the potential to reestablish tonic inhibitory networks and thus suppress tinnitus. The proposed framework unites many ideas of tinnitus pathophysiology and may catalyze cooperative efforts to develop tinnitus therapies.

Diagnosis and treatment of Ménière's disease remains a significant challenge because of our inability to understand what is occurring on a molecular level. MicroRNA (miRNA) perilymph profiling is a safe methodology and may serve as a "liquid biopsy" equivalent. We used machine learning (ML) to evaluate miRNA expression profiles of various inner ear pathologies to predict diagnosis of Ménière's disease.Prospective cohort study.Tertiary academic hospital.Perilymph was collected during labyrinthectomy (Ménière's disease, n = 5), stapedotomy (otosclerosis, n = 5), and cochlear implantation (sensorineural hearing loss [SNHL], n = 9). miRNA was isolated and analyzed with the Affymetrix miRNA 4.0 array. Various ML classification models were evaluated with an 80/20 train/test split and cross-validation. Permutation feature importance was performed to understand miRNAs that were critical to the classification models.In terms of miRNA profiles for conductive hearing loss versus Ménière's, 4 models were able to differentiate and identify the 2 disease classes with 100% accuracy. The top-performing models used the same miRNAs in their decision classification model but with different weighted values. All candidate models for SNHL versus Ménière's performed significantly worse, with the best models achieving 66% accuracy. Ménière's models showed unique features distinct from SNHL.We can use ML to build Ménière's-specific prediction models using miRNA profile alone. However, ML models were less accurate in predicting SNHL from Ménière's, likely from overlap of miRNA biomarkers. The power of this technique is that it identifies biomarkers without knowledge of the pathophysiology, potentially leading to identification of novel biomarkers and diagnostic tests.

ObjectiveThe diagnostic value of exploratory tympanotomy in sudden sensorineural hearing loss remains controversial. This study and review were performed to identify the incidence of perilymphatic fistula in patients with sudden sensorineural hearing loss. The effectiveness of tympanotomy for sealing of the cochlear windows in cases with perilymphatic fistula was evaluated.MethodsA search in common databases was performed. Overall, 5034 studies were retrieved. Further, a retrospective analysis on 90 patients was performed.ResultsEight publications dealing with tympanotomy in patients with sudden sensorineural hearing loss were identified. In 90 patients diagnosed with sudden sensorineural hearing loss and undergoing exploratory tympanotomy, 10 patients (11 per cent) were identified with a perilymphatic fistula, and this corresponds to the results obtained from our review (13.6 per cent).ConclusionThere was no significant improvement after exploratory tympanotomy and sealing of the membranes for patients with a definite perilymphatic fistula.

Introduction: Although sensorineural hearing loss (SNHL) is the most common neurodegenerative disease in humans, no approved pharmaceutical interventions are currently available. The progre...

OBJECTIVE To correlate the CT imaging findings of the visibility and size of the vestibular aqueduct (VA) with the degree of the cochlear hydrops determined in MRI late imaging of the hydrops. Study Design: Retrospective study. Setting: Tertiary referral center. Patients: A total of 127 patients (62 women, 65 men, average age 55.6 yrs): 86 of these were diagnosed with Meniere's disease (American Academy of Otolaryngology-Head and Neck Surgery [AAO-HNS] criteria; 67 unilateral, 19 bilateral). INTERVENTIONS Temporal bone CT and hydrops MRI were performed in all patients. MAIN OUTCOME MEASURES Visibility/width of the VA in temporal bone CT and grade of cochlear hydrops evaluated by MRI. RESULTS The width of the VA is significantly smaller in patients diagnosed with Meniere's disease (30% non-visible VA), compared with the patients who did not fulfill the diagnostic criteria of Meniere's disease (12% non-visible VA) (double sided Spearman correlation, p

Mesenchymal stromal cells (MSCs) are an adult derived stem cell-like population that has been shown to mediate repair in a wide range of degenerative disorders. The protective effects of MSCs are mainly mediated by the release of growth factors and cytokines thereby modulating the diseased environment and the immune system. Within the inner ear, MSCs have been shown protective against tissue damage induced by sound and a variety of ototoxins. To better understand the mechanism of action of MSCs in the inner ear, mice were exposed to narrow band noise. After exposure, MSCs derived from human umbilical cord Wharton’s jelly were injected into the perilymph. Controls consisted of mice exposed to sound trauma only. Forty-eight hours post-cell delivery, total RNA was extracted from the cochlea and RNAseq performed to evaluate the gene expression induced by the cell therapy. Changes in gene expression were grouped together based on gene ontology classification. A separate cohort of animals was treated in a similar fashion and allowed to survive for 2 weeks post-cell therapy and hearing outcomes determined. Treatment with MSCs after severe sound trauma induced a moderate hearing protective effect. MSC treatment resulted in an up-regulation of genes related to immune modulation, hypoxia response, mitochondrial function and regulation of apoptosis. There was a down-regulation of genes related to synaptic remodeling, calcium homeostasis and the extracellular matrix. Application of MSCs may provide a novel approach to treating sound trauma induced hearing loss and may aid in the identification of novel strategies to protect hearing.

Human cochlear anatomy is highly variable. The phenomenon has been first described qualitatively, followed by a quantitative variability assessment with detailed anatomical models of the human cochlea. However, all previous work focused on lateral cochlear wall. Few information is available on the variability of the modiolar wall. Modiolar variability, likely determined by variability in the spiral ganglion, provides key information on when during ontogenesis the individual cochlear morphology is established: before and/or after neuronal structures are formed. In the present study we analyzed 108 corrosion casts, 95 clinical cone beam computer tomographies and 15 µCTs of human cochleae and observed modiolar variability of similar and larger extent than the lateral wall variability. Lateral wall measures correlated with modiolar wall measures significantly. ~49% of the variability has a common cause, very likely established already during the time when the spiral ganglion is formed. Proximity of other neuronal and vascular structures, defining the remaining variability in scalar spaces, are determined later in ontogenesis, when the scalae are formed. The present data further allows implications for perimodiolar cochlear implants and their tip fold-overs. In particular, the data demonstrate that tip fold-overs of preformed implants likely result from the morphology of the modiolus (with radius changing from base to apex), and that optimal cochlear implantation of perimodiolar arrays cannot be guaranteed without an individualized surgical technique.

Hypothesis: Menière's disease microRNA (miRNA) profiles are unique and are reflected in the perilymph and serum of patients.Background: Development of effective biomarkers for Menière's disease are needed. miRNAs are small RNA sequences that downregulate mRNA translation and play a significant role in a variety of disease states, ultimately making them a promising biomarker. miRNAs can be readily isolated from human inner ear perilymph and serum, and may exhibit disease-specific profiles.Methods: Perilymph sampling was performed in 10 patients undergoing surgery; 5 patients with Meniere's disease and 5 patients with otosclerosis serving as controls. miRNAs were isolated from the serum of 5 patients with bilateral Menière's disease and compared to 5 healthy age-matched controls. For evaluation of miRNAs an Agilent miRNA gene chip was used. Analysis of miRNA expression was carried out using Qlucore and Ingenuitey Pathway Analysis software. Promising miRNAs biomarkers were validated using qPCR.Results: In the perilymph of patients with Menière's disease, we identified 16 differentially expressed miRNAs that are predicted to regulate over 220 different cochlear genes. Six miRNAs are postulated to regulate aquaporin expression and twelve miRNAs are postulated to regulate a variety of inflammatory and autoimmune pathways. When comparing perilymph with serum samples, miRNA-1299 and−1270 were differentially expressed in both the perilymph and serum of Ménière's patients compared to controls. Further analysis using qPCR confirmed miRNA-1299 is downregulated over 3-fold in Meniere's disease serum samples compared to controls.Conclusions: Patients with Ménière's disease exhibit distinct miRNA expression profiles within both the perilymph and serum. The altered perilymph miRNAs identified can be linked to postulated Ménière's disease pathways and may serve as biomarkers. miRNA-1299 was validated to be downregulated in both the serum and perilymph of Menière's patients.

Extracellular vesicles (EVs) derived from the secretome of human mesenchymal stromal cells (MSC) contain numerous factors that are known to exert anti‐inflammatory effects. MSC‐EVs may serve as promising cell‐based therapeutics for the inner ear to attenuate inflammation‐based side effects from cochlear implantation which represents an unmet clinical need. In an individual treatment performed on a ‘named patient basis’, we intraoperatively applied allogeneic umbilical cord‐derived MSC‐EVs (UC‐MSC‐EVs) produced according to good manufacturing practice. A 55‐year‐old patient suffering from Menière's disease was treated with intracochlear delivery of EVs prior to the insertion of a cochlear implant. This first‐in‐human use of UC‐MSC‐EVs demonstrates the feasibility of this novel adjuvant therapeutic approach. The safety and efficacy of intracochlear EV‐application to attenuate side effects of cochlea implants have to be determined in controlled clinical trials.

Hypothesis MicroRNAs predicted to regulate neurotrophin signaling can be found in human perilymph. Background Animal and human temporal bone studies suggest that spiral ganglion health can affect cochlear implant (CI) outcomes. Neurotrophins have been identified as a key factor in the maintenance of spiral ganglion health. Changes in miRNAs may regulate neurotrophin signaling and may reflect neurotrophin expression levels. Methods Perilymph sampling was carried out in 18 patients undergoing cochlear implantation or stapedotomy. Expression of miRNAs in perilymph was evaluated using an Agilent miRNA gene chip. Using ingenuity pathway analysis (IPA) software, miRNAs targeting neurotrophin signaling pathway genes present in a cochlear cDNA library were annotated. Expression levels of miRNAs in perilymph were correlated to the patients' preoperative pure-tone average. Results Expression of mRNAs coding for neurotrophins and their receptors were identified in tissue obtained from normal human cochlea during skull base surgery. We identified miRNAs predicted to regulate these signaling cascades, including miR-1207-5p, miR-4651, miR-103-3p, miR-100-5p, miR-221-3p, miR-200-3p. There was a correlation between poor preoperative hearing and lower expression of miR-1207 (predicted to regulate NTR3) and miR-4651 (predicted to regulate NTR2). Additionally, miR-3960, miR-4481, and miR-675 showed significant differences in expression level when comparing mild and profound hearing loss patients. Conclusions Expression of some miRNAs that are predicted to regulate neurotrophin signaling in the perilymph of cochlear implant patients vary with the patient's level of residual hearing. These miRNAs may serve as biomarkers for changes in neurotrophin signaling.

Background In the field of hearing research a variety of imaging techniques are available to study molecular and cellular structures of the cochlea. Most of them are based on decalcifying, embedding, and cutting of the cochlea. By means of scanning laser optical tomography (SLOT), the complete cochlea can be visualized without cutting. The Cav1.3-/- mice have already been extensively characterized and show structural changes in the inner ear. Therefore, they were used in this study as a model to investigate whether SLOT can detect structural differences in the murine cochlea. Materials and methods Whole undissected cochleae from Cav1.3-/- and wildtype mice of various postnatal stages were immunostained and analyzed by SLOT. The results were compared to cochlea preparations that were immunostained and analyzed by fluorescence microscopy. In addition, cochlea preparations were stained with osmium tetraoxide. Results Visualization by SLOT showed that the staining of nerve fibers at P27 in Cav1.3-/- mice was almost absent compared to wildtype mice and earlier timepoints (P9). The analysis of cochlea preparations confirmed a reduction of the radial nerve fibers. In addition, a significantly reduced number of ribbon synapses per inner hair cell (IHC) at P20 and P27 in the apical part of the cochlea of Cav1.3-/- mice was detected. Conclusion The visualization of whole non-dissected cochleae by SLOT is a suitable tool for the analysis of gross phenotypic changes, as demonstrated by means of the Cav1.3-/- mouse model. For the analysis of finer structures of the cochlea, however, further methods must be used.

Increasing numbers of cochlear implant patients have residual hearing. Despite surgical and pharmacological efforts to preserve residual hearing, a significant number of these patients suffer a late, unexplained loss of residual hearing. Surgical trauma can be excluded as the cause. To investigate this phenomenon and because cells in their native environment react differently to stimuli (such as electrical current) than isolated cells, whole-organ explants from cochleae may be a better model. For early detection of synaptic changes in the organ of Corti, a high-resolution microscopic technique such as stimulated emission depletion (StED) can be used. The aim of this study was establishment of a qualitative and quantitative technique to determinate changes in the organ of Corti and its synapses after electrical stimulation. Explanted organs of Corti from postnatal rats (P2-4) were cultured on a coverslip for 24 h and subsequently exposed to biphasic pulsed electrical stimulation (amplitude 0.44-2.0 mA, pulse width 400 μs, interpulse delay 120 μs, repetition 1 kHz) for another 24 h. For visualization, the cytoskeleton and the ribbon synapses were stained immunocytochemically. For an early detectable response to electrical stimulation, the number of synapses was quantified. Organs of Corti without electrical stimulation served as a reference. Initial research has shown that electrical stimulation can cause changes in ribbon synapses and that StED can detect these alterations. The herein established model could be of great importance for identification of molecular changes in the organ of Corti in response to electrical or other stimuli.

OBJECTIVE To evaluate effect of prednisolone on the impedances after cochlear implantation. STUDY DESIGN Retrospective case series. SETTING Tertiary referral center. PATIENTS AND INTERVENTION A total of 130 patients underwent cochlear implantation with a Med-El Flex28 synchrony device between 2012 and 2016 and met the inclusion criteria. Only patients with full datasets regarding impedance measurements perioperatively, at first fitting (before and after chronic electric stimulation) and at 3 and 12 months appointments afterward were included. Patients (n = 101) received a single intravenous administration of at least 200 mg prednisolone intraoperatively and control patients (n = 29) did not receive any steroids at all. Patients receiving low dose steroids during surgery were excluded. MAIN OUTCOME MEASURES Mean values for impedances were calculated over all electrode contacts and separately for basal, medial, and apical regions. RESULTS Impedances increased significantly from perioperative measures to first fitting in both groups. Mainly at the basal region of the electrode array, impedances were slightly lower in the steroid group compared with controls. However, the majority of the patients showed increased impedances whether they received steroid treatment or not. CONCLUSION The present study shows a slight but statistically significant reduction of the mean value of postoperative impedances at the basal electrode contacts in patients receiving a single systemic high dose application of prednisolone. Less than half of the patients showed a decrease in impedances and whether this decrease is clinically relevant remains to be elucidated.

Evaluation of hearing loss patients using clinical audiometry has been unable to give a definitive cellular or molecular diagnosis, hampering the development of treatments of sensorineural hearing loss. However, biopsy of inner ear tissue without losing residual hearing function for pathologic diagnosis is extremely challenging. In a clinical setting, perilymph can be accessed, so alternative methods for molecular characterization of the inner ear may be developed. Recent approaches to improving inner ear diagnostics have been focusing on the evaluation of the proteomic or miRNA profiles of perilymph. Inspired by recent characterization and classification of many neurodegenerative diseases using exosomes which not only are produced in locally in diseased tissue but are transported beyond the blood brain barrier, we demonstrate the isolation of human inner ear specific exosomes using a novel ultrasensitive immunomagnetic nano pom-poms capture-release approach. Using perilymph samples harvested from surgical procedures, we were able to isolate exosomes from sensorineural hearing loss patients in only 2-5 μL of perilymph. By isolating sensory hair cell derived exosomes through their expression level of myosin VII, we for the first time sample material from hair cells in the living human inner ear. This work sets up the first demonstration of immunomagnetic capture-release nano pom-pom isolated exosomes for liquid biopsy diagnosis of sensorineural hearing loss. With the ability to isolate exosomes derived from different cell types for molecular characterization, this method also can be developed for analyzing exosomal biomarkers from more accessible patient tissue fluids such as plasma.

Objective Cochlear implants are the gold standard for patients with severe sensorineural hearing loss. A focused electrical stimulation of individual spiral ganglion neurons has not been achieved yet because the scala tympani is a fluid-filled compartment and does not offer a matrix for neuritic outgrowth. Coating of the electrode contacts with swelling hydrogels could fill that gap between the electrode array and the medial wall of the cochlea. Therefore, the exact position of the electrode array within the scala tympani has to be known. Study design Retrospective analysis of patient data sets. Setting Tertiary referral center. A total of 95 patients with cochlear implants from one manufacturer were included in this study. The lateral wall, the modiolar wall, and the cochlear implant electrode were segmented using OsiriX MD. For repositioning and reconstructing the respective contours and measuring distances, files were analyzed in MATLAB. The distances from the edge of each electrode contact to the cochlear walls showed no significant differences. But between the different contacts within each patient, there were significant differences. Around 180 degree insertion, electrodes start to get in contact with the lateral wall. The tip of the electrode array was always facing toward the modiolar wall independent of the length of the electrode. We established a method to analyze the position of electrodes within the cochlea.

OBJECTIVE To evaluate a possible correlation between impedance values and speech perception after cochlear implantation. STUDY DESIGN Retrospective chart review. SETTING Tertiary referral center. PATIENTS AND INTERVENTION All patients implanted with a MedEl Flex28 device in our department with complete audiometric data (Freiburger monosyllabic testing at 65 dB, Hochmaier-Schulz-Moser testing in quiet and in 10 dB noise) and impedance measurements at the 1-year refitting appointment were enrolled in this study. Further inclusion criteria were age > 17 years, native speakers, and no use of electric-acoustic-stimulation. MAIN OUTCOME MEASURES Mean values for impedances were calculated over all electrode contacts and separately for basal, medial, and apical regions. These data were correlated statistically (Pearson's correlation) with speech testing results. Furthermore, groups of patients with extreme values were built and compared against each other and against the rest of the collective. RESULTS Impedance values did not correlate significantly with speech performance in any of the audiometric tests neither for all electrode contacts nor for specific clusters of contacts. Patients with the lowest impedances did not perform statistically different than patients with the highest impedances in any condition. CONCLUSION To our knowledge, this is the first data on a possible correlation between impedances and speech perception. The extent of the impedances as a benchmark for a good performance in speech discrimination tests could not be verified. Further prospective studies, possibly with more precise diagnostic tools, should be carried out to define the value of impedance measurements for cochlear implantation provision.

Administration of low-dose steroids via a catheter inserted into the cochlea to apply pharmaceuticals to more apical regions was previously shown not to be sufficient for long-term reduction of electrode impedances. The aim of the present study was to investigate the effect of intra-cochlear high-dose triamcinolone application on impedances in cochlear implant recipients. Patients received low-dose (4 mg/ml; n = 5) or high-dose (20 mg/ml; n = 5) triamcinolone via a cochlear catheter just prior to the insertion of a Med-El Flex28 electrode. Impedances were measured at defined time points from intra-operatively up to 12 months after first fitting and retrospectively compared with a control group (no steroid application). Patients who received a high-dose application of crystalloid triamcinolone showed significantly reduced impedances in the first fitting measurements compared to the control group. This effect was no longer detectable in patients of the low-dose group at that time. Looking at the different regions of the electrode, the impedance values were lowered significantly only at the basal and medial contacts. At later time points, there were no significant differences between any of the groups. This is the first study to demonstrate a dose-dependent reduction of impedances by deep intra-cochlear injection of triamcinolone in cochlear implant patients. With a high-dose, single application of triamcinolone using a cochlear catheter prior to insertion of a Flex28 electrode, the impedances can be significantly reduced up to and including the first fitting. Although the effect was longer lasting than when compared to low-dose triamcinolone, it was also not permanent.

Background Chronic rhinosinusitis may be associated with nasal polyposis. Recurrence of disease is often observed and may be due to an intolerance of acetylsalicylic acid. Sex hormones are known to modulate allergic reactions and inflammation. Whether they may be involved in the development and progression of nasal polyposis has not been investigated yet. Aim Examine the relationship between levels of sex hormones and nasal polyposis. Methods Hormonal levels (estradiol, testosterone and progesterone) in patients with nasal polyposis (n = 26) with or without acetylsalicylic acid-intolerance were determined and compared to hormonal levels in patients with septal deviation (n = 35). Cone-beam computed tomography scans were analysed by using scores as defined by Lund and Mackay and by Kennedy. Results Our results show a 5 times greater odds (p = 0.01) for developing nasal polyposis in the presence of lowered estradiol plasma levels than in the presence of normal / elevated levels. When analyzing females and males separately, a 6 times greater odds for females to develop nasal polyposis in the presence of lowered estradiol plasma levels was calculated (p = 0.02). Thus, females are more likely to develop nasal polyposis when they have lowered estradiol levels than males. In addition, female patients showed an increased risk for developing ASA intolerance (p = 0.01). Conclusion Variation of sex hormones may be involved in nasal polyposis. Further studies including more patients to validate the presented results are required. Significance Retrospective clinical investigation suggesting a correlation between varying sex hormones and nasal polyposis.

Transplantation of mesenchymal stromal cells (MSC) presents a promising approach not only for the replacement of lost or degenerated cells in diseased organs but also for local drug delivery. It can potentially be used to enhance the safety and efficacy of inner ear surgeries such as cochlear implantation. Options for enhancing the effects of MSC therapy include modulating cell behaviour with customized bio-matrixes or modulating their behaviour by ex vivo transfection of the cells with a variety of genes. In this study, we demonstrate that MSC delivered to the inner ear of guinea pigs or to decellularized cochleae preferentially bind to areas of high heparin concentration. This presents an opportunity for modulating cell behaviour ex vivo. We evaluated the effect of carboxymethylglucose sulfate (Cacicol®), a heparan sulfate analogue on spiral ganglion cells and MSC and demonstrated support of neuronal survival and support of stem cell proliferation.

Hearing loss is common and caused by a wide range of molecular and cellular pathologies. Current diagnosis of hearing loss depends on a combination of physiologic testing, patient history, and in some cases genetic testing. Currently, no biopsy or equivalent procedure exists to diagnose inner ear disorders. MicroRNAs (miRNA) are short ribonucleic acids that regulate a variety of cellular processes. They have been found to be reliable markers for a variety of disease processes. In particular, a variety of miRNAs that are markers for neurodegenerative disease have been identified in cerebrospinal fluid. The aim of this study was to determine whether miRNAs could be identified in human perilymph potentially leading to the development of biomarkers for inner ear disease. Prospective sampling of human perilymph and its analysis were carried out. Patients undergoing surgery in which the inner ear is opened as part of the procedure (cochlear implantation, stapedectomy, labyrinthectomy) were recruited. A total of 2-5 μl of perilymph was collected and analyzed using Affymetrix GeneChip miRNA 4.0 microarrays. MiRNA common to all sampling approaches were selected. Analysis of miRNAs was carried out by evaluating miRNA targets in a cochlear transcriptome library using the Ingenuity Pathway Analysis software package. MiRNAs could be isolated from the perilymph of all patients. Evaluation of miRNAs shows the presence of miRNA populations that are predicted to interact with genes expressed in the inner ear. Additional analysis of miRNA populations shows that perilymph miRNAs could be linked to pathways associated with hearing disorders. Sampling of human perilymph is feasible and can potentially identify miRNAs associated with hearing disorders.

Genetic contribution to progressive hearing loss in adults is underestimated. Established machine learning-based software could offer a rapid supportive tool to stratify patients with progressive hearing loss. A retrospective longitudinal analysis of 141 adult patients presenting with hearing loss was performed. Hearing threshold was measured at least twice 18 months or more apart. Based on the baseline audiogram, hearing thresholds and age were uploaded to AudioGene v4® (Center for Bioinformatics and Computational Biology at The University of Iowa City, IA, USA) to predict the underlying genetic cause of hearing loss and the likely progression of hearing loss. The progression of hearing loss was validated by comparison with the most recent audiogram data of the patients. The most frequently predicted loci were DFNA2B, DFNA9 and DFNA2A. The frequency of loci/genes predicted by AudioGene remains consistent when using the initial or the final audiogram of the patients. In conclusion, machine learning-based software analysis of clinical data might be a useful tool to identify patients at risk for having autosomal dominant hearing loss. With this approach, patients with suspected progressive hearing loss could be subjected to close audiological followup, genetic testing and improved patient counselling.

Suppression of foreign body reaction, improvement of electrode-nerve interaction, and preservation of residual hearing are essential research topics in cochlear implantation. Intracochlear pharmaco- or cell-based therapies can open new horizons in this field. Local drug delivery strategies are desirable as higher local concentrations of agents can be realized and side effects can be minimized compared to systemic administrations. When administered locally at accessible, basal parts of the cochlea, drugs reach apical regions later and in much lower concentrations due to poor diffusion patterns in cochlear fluids. Therefore, new devices are needed to warrant rapid distribution of agents into all parts of the cochlea. Five patients received a deep intracochlear injection of triamcinolone with a specifically designed cochlear catheter during cochlear implantation right before inserting a cochlear implant electrode. As a measure for formation of fibrous tissue around the electrode, electrical impedances were measured in the operation room and over 4 months thereafter. No adverse events were observed peri- and postoperatively. The handling of the device was easy. Severe damage to the microstructure of the cochlea was excluded as far as possible by cone beam computed tomography and vestibular testing. A delayed rise of the impedances was seen in the catheter group compared to controls over all regions of the cochlea. A statistical significance, however, was only obtained at the midregion of the cochlea. Consequently, the cochlear catheter is a safe and feasible device for local drug delivery of pharmaceutical agents into deeper regions of the cochlea.

Objective Biomarkers reflecting the etiology and pathophysiology of inner ear diseases are limited. Evaluation of proteins in the perilymph may improve our understanding of inner ear disease. Heat shock proteins (HSP) belong to a superfamily of stress proteins and promote refolding of denatured proteins. The aim of the study was to analyze HSP in human perilymph and to identify possible correlation with audiological and etiologic data. Methods Sampling of the perilymph was performed during cochlear implantation and vestibular schwannoma removal. Individual proteins were identified by a shot-gun proteomics approach by orbitrap mass spectrometry. Expression of HSP genes was determined in human cochlear tissue that was obtained during transcochlear surgeries. Results Ten subgroups of HSP were identified in human perilymph samples. Increased levels of HSP were detected in a higher percentage in the perilymph of patients with residual hearing when compared with patients with no residual hearing in cochlear implantation. In patients with complete preservation of residual hearing, HSP 90 is identified in a lower percentage whereas HSP 70 1A/1B and 6 was identified in all the samples. Constitutive expression of HSP family members was verified in normal cochlear tissue. Conclusion The 10 HSP variants are not identified in all the perilymph samples, but in a higher proportion in patients with residual hearing compared with patients with no residual hearing. In-depth proteome analysis of perilymph samples in correlation to patients' audiogram data shows an increased concentration of HSP in patients with residual hearing. An increase in specific HSP in patients with loss of residual hearing after cochlear implantation was not observed.

Mehrere Millionen Menschen weltweit leiden an Horverlust. Derzeitige Therapien fur Patienten mit hochgradigem Horverlust beschranken sich auf die Versorgung mit einem Cochleaimplantat. Sofern der Hornerv intakt ist, profitieren die behandelten Personen enorm, und ein Sprachverstehen ist wieder moglich. Allerdings gibt es nach wie vor Einschrankungen, die aus technologischer Sicht nicht angegangen werden. Neuartige Ansatze, basierend auf Zelltransplantation und Gentherapie, entwickeln sich rapide, zumindest im experimentellen Sektor. Klinische Translationsansatze indes sind, verglichen mit der Fulle an Grundlagenforschung auf diesem Gebiet, eher rudimentar. Die vorliegende Ubersichtsarbeit konzentriert sich daher zum einen auf translationsfahige Ansatze und die zu uberkommenden Hindernisse bei der Translation, zum anderen auf erste klinische Ansatze biologischer Therapien bei hochgradiger Schwerhorigkeit, insbesondere in Verbindung mit einer Cochleaimplantation.

Objectives To determine the levels of endogenous α1-antitrypsin in the perilymph of patients undergoing cochlear implant (CI), and its reverse association with the severity of hearing loss. Study design Retrospective study. Setting Tertiary care university hospital. Participants The study includes 38 patients undergoing CI surgery, 11 patients diagnosed with congenital deafness and 27 non-congenital deafness, eight patients diagnosed with moderate hearing loss (N = 8; PTA = 70 dB), severe hearing loss (N = 11; PTA 70-90 dB) and profound hearing loss (N = 19; PTA > 90 dB). Main outcome and measure 1 to 12 μL perilymphatic fluids were collected by micropipette. α1-antitrypsin levels were determined, and current and historic audiological parameters were obtained. Results The congenital and non-congenital group exhibited AAT concentrations of 2.5 ± 1.9 × 106 LFQ and 3.2 ± 1.2 × 106 LFQ, respectively (mean ± SD; P = .38). Mean levels of α1-antitrypsin in the perilymph fluid within the moderate group was 3.64 × 106 ± 2.1 × 106 LFQ vs 3.5 × 106 ± 1.2 × 106 in severe hearing loss (P = .81) and 2.4 × 106 ± 1.1 × 106 LFQ in the profound hearings loss group (P = .06). The difference in levels of AAT in samples from the severe hearings loss group vs the profound hearings loss group reached statistical significance (P = .04). Conclusion Insufficiency in α1-antitrypsin levels in the perilymph fluid of the inner ear appears to display a relationship with the severity of hearing loss. The prospect of introducing clinical-grade plasma-purified α1-antitrypsin directly onto the site of cochlear injury deserves thorough investigation.

Background: The aim of the study was to investigate the extent of MRI artefacts due to the magnet of selected auditory implants.Study design: Artefacts of the Synchrony cochlear implant at 1.5 T as...

The molecular pathomechanisms in the majority of patients suffering from acute or progressive sensorineural hearing loss cannot be determined yet. The size and the complex architecture of the cochlea make biopsy and in-depth histological analyses impossible without severe damage of the organ. Thus, histopathology correlated to inner disease is only possible after death. The establishment of a technique for perilymph sampling during cochlear implantation may enable a liquid biopsy and characterization of the cochlear microenvironment. Inflammatory processes may not only participate in disease onset and progression in the inner ear, but may also control performance of the implant. However, little is known about cytokines and chemokines in the human inner ear as predictive markers for cochlear implant performance. First attempts to use multiplex protein arrays for inflammatory markers were successful for the identification of cytokines, chemokines, and endothelial markers present in the human perilymph. Moreover, unsupervised cluster and principal component analyses were used to group patients by lead cytokines and to correlate certain proteins to clinical data. Endothelial and epithelial factors were detected at higher concentrations than typical pro-inflammatory cytokines such as TNF-a or IL-6. Significant differences in VEGF family members have been observed comparing patients with deafness to patients with residual hearing with significantly reduced VEGF-D levels in patients with deafness. In addition, there is a trend toward higher IGFBP-1 levels in these patients. Hence, endothelial and epithelial factors in combination with cytokines may present robust biomarker candidates and will be investigated in future studies in more detail. Thus, multiplex protein arrays are feasible in very small perilymph samples allowing a qualitative and quantitative analysis of inflammatory markers. More results are required to advance this method for elucidating the development and course of specific inner ear diseases or for perioperative characterization of cochlear implant patients.

International audience; OBJECTIVE: To provide an overview of biotechnology and pharmaceutical companies active in the field of inner ear and central hearing disorders and their therapeutic approaches.METHODS: Scientific and grey literature was searched using broad search terms to identify companies and their hearing-related therapeutic approaches. For each approach its lead indication, product, therapeutic modality, target, mechanism of action and current phase of clinical development was collated.RESULTS: A total of 43 biotechnology and pharmaceutical companies have been identified that are developing therapeutics for inner ear and central hearing disorders. Their therapeutics include drug-, cell- and gene-based approaches to prevent hearing loss or its progression, restore hearing, and regenerate the inner ear. Their therapeutic targets and specific mechanisms of action are wide-ranging, reflecting the complexity of the hearing pathways and the diversity of mechanisms underlying inner ear disorders. While none of the novel products under investigation have yet made it to the clinical market, and a large proportion are still at preclinical phase, many therapeutics have already entered clinical testing with more expected to do so in the next few years.CONCLUSION: A wide range of novel therapeutics targeting different hearing, balance and tinnitus pathways, and patient populations are approaching the clinical domain. It is important that clinicians involved in the care of patients with hearing loss prepare for what may become a radically different approach to the management of hearing disorders, and develop a true understanding of the new therapies' mechanisms of action, applications, and indications.

In the field of hearing research a variety of imaging techniques are available to study molecular and cellular structures of the cochlea. Most of them are based on decalcifying, embedding, and cutting of the cochlea. By means of scanning laser optical tomography (SLOT), the complete cochlea can be visualized without cutting. The Cav1.3−/− mice have already been extensively characterized and show structural changes in the inner ear. Therefore, they were used in this study as a model to investigate whether SLOT can detect structural differences in the murine cochlea. Whole undissected cochleae from Cav1.3−/− and wild-type mice of various postnatal stages were immunostained and analyzed by SLOT. The results were compared to cochlea preparations that were immunostained and analyzed by fluorescence microscopy. In addition, cochlea preparations were stained with osmium tetraoxide. Visualization by SLOT showed that the staining of nerve fibers at P27 in Cav1.3−/− mice was almost absent compared to wild-type mice and earlier timepoints (P9). The analysis of cochlea preparations confirmed a reduction of the radial nerve fibers. In addition, a significantly reduced number of ribbon synapses per inner hair cell (IHC) at P20 and P27 in the apical part of the cochlea of Cav1.3−/− mice was detected. The visualization of whole non-dissected cochleae by SLOT is a suitable tool for the analysis of gross phenotypic changes, as demonstrated by means of the Cav1.3−/− mouse model. For the analysis of finer structures of the cochlea, however, further methods must be used.

The outcome of cochlear implantation depends on multiple variables including the underlying health of the cochlea. Brain derived neurotrophic factor (BDNF) has been shown to support spiral ganglion neurons and to improve implant function in animal models. Whether endogenous BDNF or BDNF-regulated proteins can be used as biomarkers to predict cochlear health and implant outcome has not been investigated yet. Gene expression of BDNF and downstream signaling molecules were identified in tissue of human cochleae obtained from normal hearing patients (n = 3) during skull base surgeries. Based on the gene expression data, bioinformatic analysis was utilized to predict the regulation of proteins by BDNF. The presence of proteins corresponding to these genes was investigated in perilymph (n = 41) obtained from hearing-impaired patients (n = 38) during cochlear implantation or skull base surgery for removal of vestibular schwannoma by nanoscale liquid chromatography coupled to tandem mass spectrometry (nano LC-MS/MS). Analyzed by mass spectrometry were 41 perilymph samples despite three patients undergoing bilateral cochlear implantation. These particular BDNF regulated proteins were not detectable in any of the perilymph samples. Subsequently, targeted analysis of the perilymph proteome data with Ingenuity Pathway Analysis (IPA) identified further proteins in human perilymph that could be regulated by BDNF. These BDNF regulated proteins were correlated to the presence of residual hearing (RH) prior to implantation and to the performance data with the cochlear implant after 1 year. There was overall a decreased level of expression of BDNF-regulated proteins in profoundly hearing-impaired patients compared to patients with some RH. Phospholipid transfer protein was positively correlated to the preoperative hearing level of the patients. Our data show that combination of gene expression arrays and bioinformatic analysis can aid in the prediction of downstream signaling proteins related to the BDNF pathway. Proteomic analysis of perilymph may help to identify the presence or absence of these molecules in the diseased organ. The impact of such prediction algorithms on diagnosis and treatment needs to be established in further studies.

Key Clinical Message Concurrent hyperbaric oxygen therapy (HBOT) and intratympanic steroid application (ITS) are beneficial as salvage therapy for therapy‐refractory sudden sensorineural hearing loss (SSNHL). The findings encourage further research on the treatment of noise‐induced and idiopathic SSNHL with concurrent use of HBOT and ITS respecting also patients with long‐term or therapy‐refractory SSNHL.

Hearing loss is present in millions of people worldwide. Current treatment for patients with severe to profound hearing loss consists of cochlear implantation. Providing the cochlear nerve is intact, patients generally benefit greatly from this intervention, frequently achieving significant improvements in speech comprehension. There are, however, some cases where current technology does not provide patients with adequate benefit. Ongoing research in cell transplantation and gene therapy promises to lead to new developments that will improve the function of cochlear implants. Translation of these experimental approaches is presently at an early stage. This review focuses on the application of biological therapies in severe hearing loss and discusses some of the barriers to translating basic scientific research into clinical reality. We emphasize the application of these novel therapies to cochlear implantation.

Objectives: Contact endoscopy is a noninvasive tool that allows in vivo and in situ examination of superficial mucosa. Its use for early diagnosis of cancerous lesions of the oropharynx and larynx has not been evaluated. The aim of the study was to validate contact endoscopy for the examination of pharyngeal and laryngeal mucosa. Study Design: Prospective clinical study. Methods: Superficial cells of the mucosa were stained with methylene blue and examined with contact endoscopes. The documented images were assessed by a cytopathologist and by an otolaryngologist independently for each patient. Biopsies for histopathological examination of the area were performed and correlated with contact endoscopic findings of both examiners. Results: Of the 42 examined specimen, 32 (76.2%) showed benign changes in the histological analysis. Squamous cell carcinoma was revealed in 10 specimen (23.8%). Using contact endoscopy, the cytopathologist accurately identified 90.6% of the benign findings (29 of 32); however, only seven of 10 (70%) carcinomas were correctly categorized. In comparison, the otolaryngologist made a correct diagnosis in 93.75% (30 of 32) of the benign and in 90% (nine of 10) of the malignant cases. Thus, a sensitivity of 90% and a specificity of 93.75% can be achieved by contact endoscopy. Conclusions: Contact endoscopy offers valuable support for the evaluation of oropharyngeal, hypopharyngeal, and laryngeal mucosa. Contact endoscopy can be a useful contribution to rapid intraoperative evaluation of mucosal alterations for early diagnosis of tumors and might reduce diagnostic biopsy sampling. Even so, it does not replace biopsy sampling. Laryngoscope, 2010