IGF-1 Mediated Neuroprotective Effects of Olfactory-Derived Mesenchymal Stem Cells on Auditory Hair Cells.

IMPORTANCE: Mesenchymal stem cells (MSCs) have the capability of providing ongoing paracrine support to degenerating tissues. Since MSCs can be extracted from a broad range of tissues, their specific surface marker profiles and growth factor secretions can be different. We hypothesized that MSCs derived from different sources might also have different neuroprotective potential. OBJECTIVE: In this study, we extracted MSCs from rodent olfactory mucosa and compared their neuroprotective effects on auditory hair cell survival with MSCs extracted from rodent adipose tissue. METHODS: Organ of Corti explants were dissected from 41 cochlea and incubated with olfactory mesenchymal stem cells (OMSCs) and adipose mesenchymal stem cells (AMSCs). After 72 hours, Corti explants were fixed, stained, and hair cells counted. Growth factor concentrations were determined in the supernatant and cell lysate using Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: Co-culturing of organ of Corti explants with OMSCs resulted in a significant increase in inner and outer hair cell stereocilia survival, compared to control. Comparisons between both stem cell lines, showed that co-culturing with OMSCs resulted in superior inner and outer hair cell stereocilia survival rates over co-culturing with AMSCs. Assessment of growth factor secretions revealed that the OMSCs secrete significant amounts of insulin-like growth factor 1 (IGF-1). Co-culturing OMSCs with organ of Corti explants resulted in a 10-fold increase in IGF-1 level compared to control, and their secretion was 2 to 3 times higher compared to the AMSCs. CONCLUSIONS: This study has shown that OMSCs may mitigate auditory hair cell stereocilia degeneration. Their neuroprotective effects may, at least partially, be ascribed to their enhanced IGF-1 secretory abilities compared to AMSCs.

Canal-wall up cholesteatoma surgery with mastoid obliteration leads to lower rates of disease recurrence without affecting hearing outcomes.

Objectives: The primary objective was to determine whether obliteration of the epitympanic area and mastoid cavity during canal wall up (CWU) cholesteatoma surgery reduces the rate of recurrent and residual cholesteatoma compared to not obliterating the same area. The secondary objective was to compare postoperative hearing outcomes between both techniques. Methods: A retrospective cohort study was conducted in a tertiary referral center. One-hundred-fourty-three ears were included of patients (≥18y) who underwent a CWU tympanomastoidectomy for cholesteatoma with or without bony obliteration between January 2015 and March 2020 in the University Medical Center Utrecht. The median follow-up was respectively 1.4 (IQR 1.1-2.2) vs. 2.0 years (IQR 1.2-3.1) (p = 0.013). Interventions: All patients underwent CWU tympanomastoidectomy for cholesteatoma. For 73 ears bone dust, Bonalive® or a combination was used for obliteration of the mastoid and epitympanic area, the rest of the ears (n = 70) were not obliterated. In accordance with the Dutch protocol, included patients are planned to undergo an MRI scan with diffusion-weighted imaging (DWI) one, three and five years after surgery to detect recurrent or residual cholesteatoma. Main outcome measures: The primary outcome measure was recurrent and residual cholesteatoma as evaluated by MRI-DWI and/or micro-otoscopy and confirmed by micro-otoscopy and/or revision surgery. The secondary outcome measure was the postoperative hearing. Results: In this cohort, the group treated with canal wall up tympanomastoidectomy with subsequent bony obliteration (73 ears, 51.0%) had significantly lower recurrent (4.1%) and residual (6.8%) cholesteatoma rates than the group without obliteration (70 ears, 25.7% and 20.0%, respectively; p < 0.001). There was no significant difference between both groups in postoperative bone conduction thresholds (mean difference 2.7 dB, p = 0.221) as well as the mean air-bone gap closure 6 weeks after surgery (2.3 dB in the non-obliteration and 1.5 dB in the obliteration group, p = 0.903). Conclusions: Based on our results, a canal wall up tympanomastoidectomy with bony obliteration is the treatment of choice, since the recurrent and residual disease rate is lower compared to the group without obliteration. The bony obliteration technique does not seem to affect the perceptive or conductive hearing results, as these are similar between both groups.

Long-term survival of LGR5 expressing supporting cells after severe ototoxic trauma in the adult mouse cochlea.

Introduction: The leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is a tissue resident stem cell marker, which it is expressed in supporting cells (SCs) in the organ of Corti in the mammalian inner ear. These LGR5+ SCs can be used as an endogenous source of progenitor cells for regeneration of hair cells (HCs) to treat hearing loss and deafness. We have recently reported that LGR5+ SCs survive 1 week after ototoxic trauma. Here, we evaluated Lgr5 expression in the adult cochlea and long-term survival of LGR5+ SCs following severe hearing loss. Methods: Lgr5GFP transgenic mice and wild type mice aged postnatal day 30 (P30) and P200 were used. P30 animals were deafened with a single dose of furosemide and kanamycin. Seven and 28 days after deafening, auditory brainstem responses (ABRs) were recorded. Cochleas were harvested to characterize mature HCs and LGR5+ SCs by immunofluorescence microscopy and quantitative reverse transcription PCR (q-RT-PCR). Results: There were no significant age-related changes in Lgr5 expression when comparing normal-hearing (NH) mice aged P200 with P30. Seven and 28 days after ototoxic trauma, there was severe outer HC loss and LGR5 was expressed in the third row of Deiters' cells and in inner pillar cells. Seven days after induction of ototoxic trauma there was an up-regulation of the mRNA expression of Lgr5 compared to the NH condition; 28 days after ototoxic trauma Lgr5 expression was similar to NH levels. Discussion: The presence of LGR5+ SCs in the adult mouse cochlea, which persists after severe HC loss, suggests potential regenerative capacity of endogenous cochlear progenitor cells in adulthood. To our knowledge, this is the first study showing not only long-term survival of LGR5+ SCs in the normal and ototoxically damaged cochlea, but also increased Lgr5 expression in the adult mouse cochlea after deafening, suggesting long-term availability of potential target cells for future regenerative therapies.

Health Economic Cost Analysis for Percutaneous Bone Conduction Devices: The Minimally Invasive Ponto Surgery Versus Linear Incision Technique with Tissue Preservation.

OBJECTIVES: To identify differences in mean cost per patient between the Minimally Invasive Ponto Surgery (MIPS) and the linear incision technique with tissue preservation (LITT-P). STUDY DESIGN: Health economic cost analysis. SETTING: The analysis was performed in a randomized multicenter controlled trial cohort. PATIENTS: Adult patients eligible for unilateral bone conduction device surgery. INTERVENTIONS: MIPS versus LITT-P surgery for bone conduction device implantation. MAIN OUTCOME MEASURES: Perioperative and postoperative costs were identified and compared. RESULTS: The difference in mean cost per patient between both techniques was €77.83 in favor of the MIPS after 22 months follow-up. The mean costs per patient were lower in the MIPS cohort for surgery (€145.68), outpatient visits (€24.27), systemic antibiotic therapy with amoxicillin/clavulanic acid (€0.30) or clindamycin (€0.40), abutment change (€0.36), and abutment removal (€0.18). The mean costs per patient were higher for implant and abutment set (€18.00), topical treatment with hydrocortison/oxytetracycline/polymyxine B (€0.43), systemic therapy with azithromycin (€0.09) or erythromycin (€1.15), local revision surgery (€1.45), elective explantation (€1.82), and implant extrusion (€70.42). Additional analysis of scenarios in which all patients were operated under general or local anesthesia or with recalculation when using current implant survival rates showed that differences in mean cost per patient were also in favor of the MIPS. CONCLUSION: The difference between the MIPS and the LITT-P in mean cost per patient was €77.83 in favor of the MIPS after 22 months of follow-up. The MIPS is an economically responsible technique and could be promising for the future.

Regeneration of Hair Cells from Endogenous Otic Progenitors in the Adult Mammalian Cochlea: Understanding Its Origins and Future Directions.

Sensorineural hearing loss is caused by damage to sensory hair cells and/or spiral ganglion neurons. In non-mammalian species, hair cell regeneration after damage is observed, even in adulthood. Although the neonatal mammalian cochlea carries regenerative potential, the adult cochlea cannot regenerate lost hair cells. The survival of supporting cells with regenerative potential after cochlear trauma in adults is promising for promoting hair cell regeneration through therapeutic approaches. Targeting these cells by manipulating key signaling pathways that control mammalian cochlear development and non-mammalian hair cell regeneration could lead to regeneration of hair cells in the mammalian cochlea. This review discusses the pathways involved in the development of the cochlea and the impact that trauma has on the regenerative capacity of the endogenous progenitor cells. Furthermore, it discusses the effects of manipulating key signaling pathways targeting supporting cells with progenitor potential to promote hair cell regeneration and translates these findings to the human situation. To improve hearing recovery after hearing loss in adults, we propose a combined approach targeting (1) the endogenous progenitor cells by manipulating signaling pathways (Wnt, Notch, Shh, FGF and BMP/TGFß signaling pathways), (2) by manipulating epigenetic control, and (3) by applying neurotrophic treatments to promote reinnervation.

Management and Outcomes of Necrotizing Otitis Externa: A Retrospective Cohort Study in a Tertiary Referral Center.

Objectives: Necrotizing otitis externa (NOE) is a rare infection of the ear that causes osteomyelitis. We aimed to evaluate treatment outcomes and the role of imaging in diagnosing and monitoring disease resolution in a single-center study of patients with NOE. Methods: In this retrospective cohort study, patients with NOE who were diagnosed and treated in a tertiary otology center in Utrecht, The Netherlands, between January 1, 2013 and August 1, 2022, were included. Data were retrieved from the medical records on demographics, symptoms, physical and diagnostic findings, type and duration of treatment, and course of disease. Results: A total of 24 cases were included. Patients were often elderly (mean age = 75 years) and diabetic (88%). Pseudomonas aeruginosa was the most commonly found microorganism (63%). Twenty-two cases (92%) received intravenous antibiotic treatment, and 7 cases (29%) received additional systemic antifungal treatment. The mean duration of systemic treatment was 29 weeks. In 20 out of 22 cases (91%), imaging was used to determine the end point of treatment. None of the cases with a total resolution of disease activity (n = 5) on 18F-fluorodeoxyglucose-positron emission tomography-computed tomography imaging at the time of cessation of therapy showed clinical relapse, compared with 1 out of 4 cases on gallium single-photon emission computerized tomography. Conclusion: Based on the experience from our center, we demonstrated that patients with NOE can successfully be treated with prolonged systemic treatment. Molecular imaging is reasonably successful for disease evaluation and decision-making on the eradication of disease.

Ex vivo Evaluation of a New Drill System for Placement of Percutaneous Bone Conduction Devices.

The procedure for installation of a percutaneous bone-conducting device has undergone significant improvements since its introduction 40 years ago. Today, the linear incision technique with tissue preservation (LITT-P) and the minimally invasive procedure (MIPS) are the most commonly used approaches. In both these techniques, a gradual increase of the osteotomy using a three-step drilling sequence is utilized, as this approach can allow a stepwise deepening and widening of the osteotomy in the mastoid and can prevent bone overheating. A new minimally invasive procedure (MONO) has been developed that allows an osteotomy to be performed and enables complete removal of the bone volume in one single drill step for a 4 mm implant using a novel parabolic twist drill. Here, the feasibility of the MONO procedure was qualitatively and quantitatively evaluated in terms of the dura response to drill trauma in comparison with the outcomes achieved with guide drills used for the LITT-P and MIPS techniques. Fresh frozen temporal bone from a human cadaver was subjected to penetration by three drills beyond the base of the mastoid bone to different depths. The sites were evaluated, and the damage to and possible penetration of the dura were determined. The results showed that for a drill depth exceeding mastoid bone thickness by not more than 1 mm, damage to the dura was limited or nonexistent, whereas for a drill depth exceeding bone thickness by 2 mm, damage increased, or the dura was penetrated. There was a trend toward more damage and penetration for both the round burr and MIPS guide drill compared with the MONO drill bit. From this experimental ex vivo study, it can be concluded that if the dura is encountered, the MONO system is not more inclined to penetrate the dura than the conventional LITT-P and MIPS systems.

Labyrinthine fistulas: Surgical outcomes and an additional diagnostic strategy.

PURPOSE: To evaluate perioperative findings and audiological and vestibular outcomes in patients operated for cholesteatoma with labyrinthine fistulas. Also to assess radiological fistula size. MATERIALS AND METHODS: Patients who underwent surgery for a labyrinthine fistula caused by a cholesteatoma between 2015 and 2020 in a tertiary referral center were retrospectively investigated. Fistula size was determined on preoperative CT scan. Bone and air conduction pure tone average thresholds were obtained pre- and postoperatively. Clinical outcomes, such as vertigo and otorrea were also evaluated. Main purpose was to determine whether there is a correlation between fistula size and postoperative hearing. Furthermore, perioperative findings and vestibular outcomes are evaluated. RESULTS: 21 patients (22 cases) with a labyrinthine fistula were included. There was no significant change after surgery in bone conduction pure tone average (preoperatively 27.6 dB ± 26.7; postoperatively 30.3 dB ± 34.3; p = 0.628) or air conduction pure tone average (preoperatively 58.7 dB ± 24.3; postoperatively 60.2 dB ± 28.3; p = 0.816). Fistula size was not correlated to postoperative hearing outcome. There were two patients with membranous labyrinth invasion: one patient was deaf preoperatively, the other acquired total sensorineural hearing loss after surgery. CONCLUSIONS: Sensorineural hearing loss after cholesteatoma surgery with labyrinthine fistula is rare. Fistula size and postoperative hearing loss are not correlated, however, membranous labyrinthine invasion seems to be related to poor postoperative hearing outcomes. Therefore, additional preoperative radiological work up, by MRI scan, in selected cases is advocated to guide the surgeon to optimize preoperative counselling.

LGR5-Positive Supporting Cells Survive Ototoxic Trauma in the Adult Mouse Cochlea.

Sensorineural hearing loss is mainly caused by irreversible damage to sensory hair cells (HCs). A subgroup of supporting cells (SCs) in the cochlea express leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), a marker for tissue-resident stem cells. LGR5+ SCs could be used as an endogenous source of stem cells for regeneration of HCs to treat hearing loss. Here, we report long-term presence of LGR5+ SCs in the mature adult cochlea and survival of LGR5+ SCs after severe ototoxic trauma characterized by partial loss of inner HCs and complete loss of outer HCs. Surviving LGR5+ SCs (confirmed by GFP expression) were located in the third row of Deiters' cells. We observed a change in the intracellular localization of GFP, from the nucleus in normal-hearing to cytoplasm and membrane in deafened mice. These data suggests that the adult mammalian cochlea possesses properties essential for regeneration even after severe ototoxic trauma.

Long-Term Outcomes of the Minimally Invasive Ponto Surgery vs. Linear Incision Technique With Soft Tissue Preservation for Installation of Percutaneous Bone Conduction Devices.

Objective: Comparing the surgical outcomes of the Minimally Invasive Ponto Surgery (MIPS) technique with the linear incision technique with soft tissue preservation (LITT-P) for bone conduction devices after a follow-up of 22 months. Methods: In this multicenter randomized controlled trial, there was the inclusion of 64 adult patients eligible for unilateral surgery. There was 1:1 randomization to the MIPS (test) or the LITT-P (control) group. The primary outcome was an (adverse) soft tissue reaction. Secondary outcomes were pain, loss of sensibility, soft tissue height/overgrowth, skin sagging, implant loss, Implant Stability Quotient measurements, cosmetic scores, and quality of life questionnaires. Results: Sixty-three subjects were analyzed in the intention-to-treat population. No differences were found in the presence of (adverse) soft tissue reactions during complete follow-up. Also, there were no differences in pain, wound dehiscence, skin level, soft tissue overgrowth, and overall quality of life. Loss of sensibility (until 3-month post-surgery), cosmetic scores, and skin sagging outcomes were better in the MIPS group. The Implant Stability Quotient was higher after the LITT-P for different abutment lengths at various points of follow-up. Implant extrusion was nonsignificantly higher after the MIPS (15.2%) compared with LITT-P (3.3%). Conclusion: The long-term results show favorable outcomes for both techniques. The MIPS is a promising technique with some benefits over the LITT-P. Concerns regarding nonsignificantly higher implant loss may be overcome with future developments and research. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02438618.

Management and Outcomes of Spontaneous Cerebrospinal Fluid Otorrhoea.

Objective: A cohort of patients with spontaneous cerebrospinal fluid (sCSF) otorrhoea. To report surgical outcome and discuss a treatment protocol. Materials and Methods: Between 2012 and 2018 all patients presenting with sCSF were collected and data assessment was performed including clinical symptoms (hearing loss, aural fullness, meningitis, recurrent otitis media), preoperative audiometry, CT and MRI scanning. According to the site and size of the dural defect, different surgical approaches were applied. Results: A total of 12 patients (14 operations) were included. Four of these had a history of meningitis. All beta-trace protein testings were positive. These patients were treated with different surgical approaches: middle fossa approach (MCF, seven patients), transmastoid approach (TMA) with bony obliteration of the cavity (three patients), and four patients underwent a subtotal petrosectomy (STP) procedure. Three cases underwent revision surgery (MCF or STP) due to residual disease (CFS leakage). After follow up duration of 13 months (6.5 months SD), no recurrence was observed. No severe adverse events such as cerebrovascular injury, meningitis, wound infection, or headache was observed in the postoperative course. Conclusion: Spontaneous aural cerebrospinal fluid leakage is a rare but manageable pathology with potential severe complications. Appropriate diagnosis, laboratory testing, and imaging is primordial to obtain optimal patient outcome.

Current insights in noise-induced hearing loss: a literature review of the underlying mechanism, pathophysiology, asymmetry, and management options.

BACKGROUND: Noise-induced hearing loss is one of the most common forms of sensorineural hearing loss, is a major health problem, is largely preventable and is probably more widespread than revealed by conventional pure tone threshold testing. Noise-induced damage to the cochlea is traditionally considered to be associated with symmetrical mild to moderate hearing loss with associated tinnitus; however, there is a significant number of patients with asymmetrical thresholds and, depending on the exposure, severe to profound hearing loss as well. MAIN BODY: Recent epidemiology and animal studies have provided further insight into the pathophysiology, clinical findings, social and economic impacts of noise-induced hearing loss. Furthermore, it is recently shown that acoustic trauma is associated with vestibular dysfunction, with associated dizziness that is not always measurable with current techniques. Deliberation of the prevalence, treatment and prevention of noise-induced hearing loss is important and timely. Currently, prevention and protection are the first lines of defence, although promising protective effects are emerging from multiple different pharmaceutical agents, such as steroids, antioxidants and neurotrophins. CONCLUSION: This review provides a comprehensive update on the pathophysiology, investigations, prevalence of asymmetry, associated symptoms, and current strategies on the prevention and treatment of noise-induced hearing loss.

Temporal Cortex Activation to Audiovisual Speech in Normal-Hearing and Cochlear Implant Users Measured with Functional Near-Infrared Spectroscopy.

BACKGROUND: Speech understanding may rely not only on auditory, but also on visual information. Non-invasive functional neuroimaging techniques can expose the neural processes underlying the integration of multisensory processes required for speech understanding in humans. Nevertheless, noise (from functional MRI, fMRI) limits the usefulness in auditory experiments, and electromagnetic artifacts caused by electronic implants worn by subjects can severely distort the scans (EEG, fMRI). Therefore, we assessed audio-visual activation of temporal cortex with a silent, optical neuroimaging technique: functional near-infrared spectroscopy (fNIRS). METHODS: We studied temporal cortical activation as represented by concentration changes of oxy- and deoxy-hemoglobin in four, easy-to-apply fNIRS optical channels of 33 normal-hearing adult subjects and five post-lingually deaf cochlear implant (CI) users in response to supra-threshold unisensory auditory and visual, as well as to congruent auditory-visual speech stimuli. RESULTS: Activation effects were not visible from single fNIRS channels. However, by discounting physiological noise through reference channel subtraction (RCS), auditory, visual and audiovisual (AV) speech stimuli evoked concentration changes for all sensory modalities in both cohorts (p < 0.001). Auditory stimulation evoked larger concentration changes than visual stimuli (p < 0.001). A saturation effect was observed for the AV condition. CONCLUSIONS: Physiological, systemic noise can be removed from fNIRS signals by RCS. The observed multisensory enhancement of an auditory cortical channel can be plausibly described by a simple addition of the auditory and visual signals with saturation.

Cochlear implantation in late-implanted prelingually deafened adults: changes in quality of life.

BACKGROUND: With expanding inclusion criteria for cochlear implantation, the number of prelingually deafened persons who are implanted as adults increases. Compared with postlingually deafened adults, this group shows limited improvement in speech recognition. In this study, the changes in health-related quality of life in late-implanted prelingually deafened adults are evaluated and related to speech recognition. METHODS: Quality of life was measured before implantation and 1 year after implantation in a group of 28 prelingually deafened adults, who had residual hearing and who used primarily oral communication. Patients completed 3 questionnaires (Nijmegen Cochlear Implant Questionnaire, Glasgow Benefit Inventory, and Health Utility Index 3). Postoperative scores were compared with preoperative scores. Additionally, phoneme recognition scores were obtained preimplantation and 1 year postimplantation. RESULTS: Quality of life improved after implantation: scores on the Nijmegen Cochlear Implant Questionnaire improved significantly in all subdomains (basic speech perception, advanced speech perception, speech production, self-esteem, activity, and social interaction), the total Glasgow Benefit Inventory score improved significantly, and the Health Utility Index 3 showed a significant improvement in the utility score and in the subdomains "hearing" and "emotion." Additionally, a significant improvement in speech recognition scores was found. No significant correlations were found between gain in quality of life and speech perception scores. CONCLUSION: The results suggest that quality of life and speech recognition in prelingually deafened adults significantly improved as a result of cochlear implantation. Lack of correlation between quality of life and speech recognition suggests that in evaluating performance after implantation in prelingually deafened adults, measures of both speech recognition and quality of life should be used.