Distinct microRNA profiles in the perilymph and serum of patients with Menière\u27s disease

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

Successful treatment of noise-induced hearing loss by mesenchymal stromal cells: An RNAseq analysis of protective/repair pathways

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\u27s 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

Rescue of auditory function by a single Administration of AAV-TMPRSS3 Gene Therapy in Aged Mice of Human Recessive Deafness DFNB8

Patients with mutations in the TMPRSS3 gene suffer from recessive deafness DFNB8/DFNB10. For these patients, cochlear implantation is the only treatment option. Poor cochlear implantation outcomes are seen in some patients. To develop biological treatment for TMPRSS3 patients, we generated a knockin mouse model with a frequent human DFNB8 TMPRSS3 mutation. The Tmprss3A306T/A306T homozygous mice display delayed onset progressive hearing loss similar to human DFNB8 patients. Using AAV2 as a vector to carry a human TMPRSS3 gene, AAV2-hTMPRSS3 injection in the adult knockin mouse inner ear results in TMPRSS3 expression in the hair cells and the spiral ganglion neurons. A single AAV2-hTMPRSS3 injection in Tmprss3A306T/A306T mice of an average age of 18.5 months leads to sustained rescue of the auditory function to a level similar to wild-type mice. AAV2-hTMPRSS3 delivery rescues the hair cells and the spiral ganglions neurons. This study demonstrates successful gene therapy in an aged mouse model of human genetic deafness. It lays the foundation to develop AAV2-hTMPRSS3 gene therapy to treat DFNB8 patients, as a standalone therapy or in combination with cochlear implantation

Detection of BDNF-Related Proteins in Human Perilymph in Patients With Hearing Loss

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

Suitable Electrode Choice for Robotic-Assisted Cochlear Implant Surgery: A Systematic Literature Review of Manual Electrode Insertion Adverse Events

BACKGROUND AND OBJECTIVE: The cochlear implant (CI) electrode insertion process is a key step in CI surgery. One of the aims of advances in robotic-assisted CI surgery (RACIS) is to realize better cochlear structure preservation and to precisely control insertion. The aim of this literature review is to gain insight into electrode selection for RACIS by acquiring a thorough knowledge of electrode insertion and related complications from classic CI surgery involving a manual electrode insertion process. METHODS: A systematic electronic search of the literature was carried out using PubMed, Scopus, Cochrane, and Web of Science to find relevant literature on electrode tip fold over (ETFO), electrode scalar deviation (ESD), and electrode migration (EM) from both pre-shaped and straight electrode types. RESULTS: A total of 82 studies that include 8,603 ears implanted with a CI, i.e., pre-shaped (4,869) and straight electrodes (3,734), were evaluated. The rate of ETFO (25 studies, 2,335 ears), ESD (39 studies, 3,073 ears), and EM (18 studies, 3,195 ears) was determined. An incidence rate (±95% CI) of 5.38% (4.4–6.6%) of ETFO, 28.6% (26.6–30.6%) of ESD, and 0.53% (0.2–1.1%) of EM is associated with pre-shaped electrodes, whereas with straight electrodes it was 0.51% (0.1–1.3%), 11% (9.2–13.0%), and 3.2% (2.5–3.95%), respectively. The differences between the pre-shaped and straight electrode types are highly significant (p < 0.001). Laboratory experiments show evidence that robotic insertions of electrodes are less traumatic than manual insertions. The influence of round window (RW) vs. cochleostomy (Coch) was not assessed. CONCLUSION: Considering the current electrode designs available and the reported incidence of insertion complications, the use of straight electrodes in RACIS and conventional CI surgery (and manual insertion) appears to be less traumatic to intracochlear structures compared with pre-shaped electrodes. However, EM of straight electrodes should be anticipated. RACIS has the potential to reduce these complications

Steroid perfusion of the inner ear for sudden sensorineural hearing loss after failure of conventional therapy: a pilot study.

peer reviewedThe aim of this study was to determine if high-dose delivery of methylprednisolone to the round window can improve hearing after the failure of conventional treatment for sudden sensorineural hearing loss (SSHL). In 6 patients with SSHL an Intraear microcatheter was placed in the round window niche and methylprednisolone (62.5 mg/ml) was infused at a rate of 10 microl/h for 8-10 days. Audiometric assessments (including measurement of speech discrimination) were made at presentation, either every day or every other day during treatment and 5 days after the completion of perfusion. Perfusion of methylprednisolone was beneficial for all 6 patients, with a 16.25-25 dB improvement in hearing threshold. A dramatic improvement in speech discrimination was also noted in all patients. In conclusion, methylprednisolone perfused at the level of the round window membrane resulted in significant recovery of hearing function after the failure of standard treatment of SSHL

Ipsilateral acoustic electric pitch matching: A case study of cochlear implantation in an up-sloping hearing loss with preserved hearing across multiple frequencies

Objectives Determine ipsilateral acoustic electric pitch place match in a patient with preserved residual hearing across a broad frequency range. Methods Case report. Patient with up-sloping sensorineural hearing loss underwent implantation with a 680° insertion angle with preserved residual hearing. Pitch matching with variance of pulse rate was carried out. Results Electrical pitch percepts closely approximated the Greenwood map when compared to the acoustical pitch percepts and electrode position as determined by post-operative computed tomographic scan. The pitch matching results achieved from the deeply inserted electrodes, in the apical portion of the cochlea, suggest that the electrical stimulation may activate the dendritic extensions from the ganglion cell bodies that radiate from the terminal bulb. Stimulation rate influenced pitch perception in the apical turn but not in the mid- and basilar regions. Discussion Frequency to pitch allocation can potentially be improved by cochlear implants that access the apical third of the spiral ganglion. The ultimate goal of stimulating the apical third of the cochlea is to provide the maximum amount of spectral information to the user. We had the unique opportunity to work with a patient who presented with a severe sensorineural hearing loss rising to within normal limits and poor speech discrimination scores. Data from this study may aid our ability to give patients a broader spectrum of sound perception

Topical steroid therapy using the Silverstein Microwick in sudden sensorineural hearing loss after failure of conventional treatment.

CONCLUSIONS: Local administration of steroids to the inner ear through the round window route improves hearing in patients after failure of conventional therapy. OBJECTIVES: To determine if delivery of methylprednisolone to the round window can improve hearing after failure of conventional treatment for sudden sensorineural hearing loss (SSHL) administered for 10 days after the onset of the hearing loss. PATIENTS AND METHODS: A Silverstein microwick was placed in the round window niche under local anesthesia and endoscopic control, allowing self-administration of methylprednisolone twice a day for 3 weeks. Treated patients were compared to a control group composed of similar patients, treated with the same systemic regimen but who did not receive local therapy. RESULTS: Of the 12 patients enrolled in this nonrandomized prospective study, 8 patients showed an improvement of the pure tone average (PTA) and 4 remain stable. Of those who responded to perfusion, eight patients demonstrated a significant mean 24.5 +/- 12 dB improvement in PTA, and seven patients had a mean 17.5 +/- 18% improvement in discrimination, with five patients reaching 100% speech discrimination score (SDS). Patients in the control group did not show any improvement of the PTA

Partial Deafness Cochlear Implantation at the University of Kansas: Techniques and Outcomes

One of the most significant recent advances in cochlear implantation is the implantation of patients with residual hearing. These patients have a downsloping sensorineural hearing loss with poor speech discrimination and perform poorly with standard amplification. Studies using a variety of different electrode designs have demonstrated that it is possible to implant an inner ear and preserve residual hearing. Initial studies have demonstrated that a combination of residual acoustic hearing in the low frequencies with electrical stimulation in the mid- to high frequencies resulted in superior hearing performance in background noise. The objective of this study was to determine the effect of electrode insertion depth on hearing preservation. Eighteen patients with mild to severe hearing loss in the low frequencies combined with poor word recognition were recruited for the study. Cochlear implantation. Pre- and postoperative hearing test, Hearing in Noise Test, and consonant-nucleus-consonant testing. Data analysis was performed with Kruskal Wallis and Mann-Whitney testing. In our study of 18 patients implanted with a Med-El PulsarCI100 we demonstrated the ability to preserve residual hearing with implant insertion depths ranging from 20 to 28 mm, giving us the possibility of near complete cochlear frequency coverage with an implant array while preserving residual hearing. These patients performed well both in quiet and in 10 dB signal-to-noise ratio conditions. Hearing preservation was achievable even with deep implant insertion. Patients performed well in combined acoustic and electric conditions