Search

The purpose of this study is to retrospectively evaluate the clinical and surgical outcomes of a large surgical series of vestibular schwannoma from North America over 20 years.After institutional review board approval a retrospective review of the senior author's personal case logs to identify patients who had operations for vestibular schwannoma was performed. The clinical notes, operative record, preoperative and postoperative imagings, and long-term clinical follow-up notes were evaluated.A total of 415 patients who underwent 420 surgeries were identified from the years 1998-2021. The average length of follow-up was 3 years and 9 months. Overall, at last follow-up the rate of "good" facial nerve outcomes (House-Brackmann [HB] score I and II) was 86% and "poor" facial nerve outcomes (HB III-VI) was 14%. The amount of cerebellopontine angle extension (P = 0.023), tumor volume (P = 0.015), facial nerve consistency (P0.001), preoperative HB score (P0.001), and FN stimulation threshold at the end of the procedure (P0.001) were correlated to facial nerve function at the last follow-up.This study represents one of the largest recently reported surgical series of vestibular schwannoma in North American literature with available long term follow-up. Facial nerve outcomes correlated with cerebellopontine angle extension, tumor volume, facial nerve stimulation threshold, facial nerve consistency, preoperative facial nerve function, and history of a prior resection. Tumor recurrence remains significantly higher after subtotal resection. We believe the data supports a continuation of a strategy of general intent of gross total resection, greatly modifiable by intraoperative findings and judgment.

Neurofibromatosis type 2 (NF2) is a nervous system tumor disorder caused by inactivation of the merlin tumor suppressor encoded by the NF2 gene. Bilateral vestibular schwannomas are a diagnostic hallmark of NF2. Mainstream treatment options for NF2-associated tumors have been limited to surgery and radiotherapy; however, off-label uses of targeted molecular therapies are becoming increasingly common. Here, we investigated drugs targeting two kinases activated in NF2-associated schwannomas, c-Met and Src. We demonstrated that merlin-deficient mouse Schwann cells (MD-MSC) treated with the c-Met inhibitor, cabozantinib, or the Src kinase inhibitors, dasatinib and saracatinib, underwent a G1 cell-cycle arrest. However, when MD-MSCs were treated with a combination of cabozantinib and saracatinib, they exhibited caspase-dependent apoptosis. The combination therapy also significantly reduced growth of MD-MSCs in an orthotopic allograft mouse model by greater than 80% of vehicle. Moreover, human vestibular schwannoma cells with NF2 mutations had a 40% decrease in cell viability when treated with cabozantinib and saracatinib together compared with the vehicle control. This study demonstrates that simultaneous inhibition of c-Met and Src signaling in MD-MSCs triggers apoptosis and reveals vulnerable pathways that could be exploited to develop NF2 therapies. Mol Cancer Ther; 16(11); 2387–98. ©2017 AACR.

All supplementary data - four figures and supplementary methods

HYPOTHESIS: Vestibular Schwannoma (VS) can avoid cell death following radiation injury by entering cell cycle arrest and activating RAD51-related DNA repair. BACKGROUND: Although the radiobiology of various cancers is well-studied, the radiobiological effects in VS are poorly understood. In this study, we describe how VS cells enter cell cycle arrest (through p21 expression), activate DNA repair (through RAD51 upregulation), and avoid cell death after radiation-induced double-stranded breaks (DSB) in DNA (as measured by γ-H2AX). METHODS: Primary human VS cells were cultured on 96-well plates and 16-well culture slides at 10,000 cells/well and exposed to either 0 or 18 Gray of radiation. Viability assays were performed at 96 hours in vitro. Immunofluorescence for γ-H2AX, RAD51, and p21 was performed at 6 hours. RESULTS: Radiation (18 Gy) induced the expression of γ-H2AX, p21, and RAD51 in 6 cultured VS, suggesting that irradiated VS acquire DSBs, enter cell cycle arrest, and initiate RAD51 DNA repair to evade cell death. However, viability studies demonstrate variable responses in individual VS cells with 3 of 6 VS showing radiation resistance to 18 Gy. On further analyses, radiation-resistant VS cells expressed significantly more p21 than radiation-responsive tumors. CONCLUSIONS: In response to radiation-induced DNA damage, primary VS cells can enter cell cycle arrest and express RAD51 DNA repair mechanisms to avoid cell death. Radioresistant VS cells may mount a more robust p21 response to ensure sufficient time for DNA repair. Further investigation into DNA repair proteins and cell cycle checkpoints may provide important insight on the radiobiology of VS and mechanisms for resistance.

Papaverine, a vasodilator approved for use by the U.S. Food and Drug Administration, has shown efficacy in treating vasospasm in cardiology, urology, and nephrology. The vasodilatory effect of papaverine is also hoped to protect the facial nerve from ischemic damage and nerve manipulation during vestibular schwannoma surgery. Our institution uses intracisternal papaverine irrigation during vestibular schwannoma resection to protect the facial nerve in patients with neuromonitoring changes. Our objective was to investigate the safety and facial nerve outcomes of intracisternal papaverine irrigation during vestibular schwannoma resection.We retrospectively reviewed patients who underwent resection of vestibular schwannoma at our institution between 2008 and 2021. Patients received papaverine if the intraoperative facial nerve stimulation threshold increased above 0.05 mA. Postoperative outcomes were compared with control patients who did not receive papaverine.A total of 283 cases were included in our analysis. Patients who received papaverine (n = 60) had lower immediate postoperative House-Brackmann (HB) grades than did control individuals (mean, 1.54 vs. 1.95; P = 0.029) and a lower likelihood of immediate postoperative HB grade1 (odds ratio, 0.514; P = 0.039). At long-term follow-up, there was no significant difference in HB grade. Papaverine use was not associated with increased rates of perioperative complications (P = 0.24).The off-label use of intracisternal papaverine irrigation during vestibular schwannoma resection can certainly be used safely for select cases. It is associated with improved immediate postoperative facial nerve outcomes, similar long-term facial nerve outcomes, and no significant increase in complications.

To evaluate the utility of intracochlear electrocochleography (ECochG) monitoring during cochlear implant (CI) surgery on postoperative hearing preservation.Prospective, randomized clinical trial.Ten high-volume, tertiary care CI centers.Adult patients with sensorineural hearing loss meeting the CI criteria who selected an Advanced Bionics CI.Patients were randomized to CI surgery either with audible ECochG monitoring available to the surgeon during electrode insertion or without ECochG monitoring. Hearing preservation was determined by comparing preoperative unaided low-frequency (125-, 250-, and 500-Hz) pure-tone average (LF-PTA) to postoperative LF-PTA at CI activation. Pre- and post-CI computed tomography was used to determine electrode scalar location and electrode translocation.Eighty-five adult CI candidates were enrolled. The mean (standard deviation [SD]) unaided preoperative LF-PTA across the sample was 54 (17) dB HL. For the whole sample, hearing preservation was "good" (i.e., LF-PTA change 0-15 dB) in 34.5%, "fair" (i.e., LF-PTA change15-29 dB) in 22.5%, and "poor" (i.e., LF-PTA change ≥30 dB) in 43%. For patients randomized to ECochG "on," mean (SD) LF-PTA change was 27 (20) dB compared with 27 (23) dB for patients randomized to ECochG "off" ( p = 0.89). Seven percent of patients, all of whom were randomized to ECochG off, showed electrode translocation from the scala tympani into the scala vestibuli.Although intracochlear ECochG during CI surgery has important prognostic utility, our data did not show significantly better hearing preservation in patients randomized to ECochG "on" compared with ECochG "off."

BACKGROUND: Vestibular schwannoma (VS) are intracranial tumors caused by merlin deficiency. Sodium fluorescein (SF) is a fluorescent compound that accumulates in various intracranial tumors, causing tumors to emit green fluorescence after blue light excitation. HYPOTHESIS: Intravenous SF preferentially deposits in VS, helping surgeons differentiate tumor from surrounding tissue. METHODS: Merlin-deficient Schwann cells were grafted onto cochleovestibular nerves of immunodeficient rats. Rats were randomized to receive SF (7.5 mg/kg; n=5) or saline (n=3). Tissues were harvested at 1 hour and photographed in white and blue light. Sixteen surgeons identified and marked the tumor-tissue interfaces on images. Fluorescence was measured on tissue specimens using the IVIS® imaging system and on tissue cross-sections obtained with confocal microscopy. Western blot was performed to measure levels of organic anion transporting polypeptide (OATP), a drug transporter specific for SF. RESULTS: Under blue light, tumors from SF rats demonstrated bright green fluorescence under direct visualization, higher fluorescence measurements on tissue specimens (p

Objectives Vestibular schwannomas (VS) are intracranial tumors, which are caused by NF2 gene mutations that lead to loss of merlin protein. A treatment for VS is stereotactic radiosurgery, a form of radiation. To better understand the radiobiology of VS and radiation toxicity to adjacent structures, our main objectives were (1) investigate effects of single fraction (SF) radiation on viability, cytotoxicity, and apoptosis in normal Schwann cells (SCs) and merlin-deficient Schwann cells (MD-SCs) in vitro, and (2) analyze expression of double strand DNA breaks (γ-H2AX) and DNA repair protein Rad51 following irradiation. Study Design This is a basic science study. Setting This study is conducted in a research laboratory. Participants Patients did not participate in this study. Main Outcome Measures In irradiated normal SCs and MD-SCs (0–18 Gy), we measured (1) viability, cytotoxicity, and apoptosis using cell-based assays, and (2) percentage of cells with γ-H2AX and Rad51 on immunofluorescence. Results A high percentage of irradiated MD-SCs expressed γ-H2AX, which may explain the dose-dependent losses in viability in rodent and human cell lines. In comparison, the viabilities of normal SCs were only compromised at higher doses of radiation (>12 Gy, human SCs), which may be related to less Rad51 repair. There were no further reductions in viability in human MD-SCs beyond 9 Gy, suggesting that Conclusion The MD-SCs are more susceptible to radiation than normal SCs, in part through differential expression of γ-H2AX and Rad51. Understanding the radiobiology of MD-SCs and normal SCs is important for optimizing radiation protocols to maximize tumor control while limiting radiation toxicity in VS patients.

Background Congenital hearing loss is remarkably heterogeneous, with over 130 deafness genes and thousands of variants, making for innumerable genotype/phenotype combinations. Understanding both the pathophysiology of hearing loss and molecular site of lesion along the auditory pathway permits for significantly individualized counseling. Electrophysiologic techniques such as electrocochleography (ECochG) and electrically-evoked compound action potentials (eCAP) are being studied to localize pathology and estimate residual cochlear vs. neural health. This review describes the expanding roles of genetic and electrophysiologic evaluation in the precision medicine of congenital hearing loss. The basics of genetic mutations in hearing loss and electrophysiologic testing (ECochG and eCAP) are reviewed, and how they complement each other in the diagnostics and prognostication of hearing outcomes. Used together, these measures improve the understanding of insults to the auditory system, allowing for individualized counseling for CI candidacy/outcomes or other habilitation strategies. Conclusion Despite tremendous discovery in deafness genes, the effects of individual genes on neural function remain poorly understood. Bridging the understanding between molecular genotype and neural and functional phenotype is paramount to interpreting genetic results in clinical practice. The future hearing healthcare provider must consolidate an ever-increasing amount of genetic and phenotypic information in the precision medicine of hearing loss.

This combined American Neurotology Society, American Otological Society, and American Academy of Otolaryngology - Head and Neck Surgery Foundation document aims to provide guidance during the coronavirus disease of 2019 (COVID-19) on 1) "priority" of care for otologic and neurotologic patients in the office and operating room, and 2) optimal utilization of personal protective equipment. Given the paucity of evidence to inform otologic and neurotologic best practices during COVID-19, the recommendations herein are based on relevant peer-reviewed articles, the Centers for Disease Control and Prevention COVID-19 guidelines, United States and international hospital policies, and expert opinion. The suggestions presented here are not meant to be definitive, and best practices will undoubtedly change with increasing knowledge and high-quality data related to COVID-19. Interpretation of this guidance document is dependent on local factors including prevalence of COVID-19 in the surgeons' local community. This is not intended to set a standard of care, and should not supersede the clinician's best judgement when managing specific clinical concerns and/or regional conditions.Access to otologic and neurotologic care during and after the COVID-19 pandemic is dependent upon adequate protection of physicians, audiologists, and ancillary support staff. Otolaryngologists and associated staff are at high risk for COVID-19 disease transmission based on close contact with mucosal surfaces of the upper aerodigestive tract during diagnostic evaluation and therapeutic procedures. While many otologic and neurotologic conditions are not imminently life threatening, they have a major impact on communication, daily functioning, and quality of life. In addition, progression of disease and delay in treatment can result in cranial nerve deficits, intracranial and life-threatening complications, and/or irreversible consequences. In this regard, many otologic and neurotologic conditions should rightfully be considered "urgent," and almost all require timely attention to permit optimal outcomes. It is reasonable to proceed with otologic and neurotologic clinic visits and operative cases based on input from expert opinion of otologic care providers, clinic/hospital administration, infection prevention and control specialists, and local and state public health leaders. Significant regional variations in COVID-19 prevalence exist; therefore, physicians working with local municipalities are best suited to make determinations on the appropriateness and timing of otologic and neurotologic care.

In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.

Objective (1) Characterize the distribution of M1 and M2 macrophages in vestibular schwannomas by hearing status. (2) Develop assays to assess monocyte migration and macrophage polarization in cocultures with vestibular schwannoma cells. Study Design Basic and translational science. Setting Tertiary care center. Methods A retrospective chart review of 30 patients with vestibular schwannoma (VS) was performed. Patients were stratified into serviceable and unserviceable hearing groups. Immunohistochemistry for CD80 + M1 and CD163 + M2 macrophages was conducted. Primary VS cultures (n = 4) were developed and cocultured with monocytes. Immunohistochemistry for macrophage markers was performed to assess monocyte migration and macrophage polarization. Results Although tumors associated with unserviceable hearing had higher levels of CD80 and CD163 than those with serviceable hearing, the relationship was only significant with CD163 ( P = .0161). However, CD163 level did not remain a significant predictor variable associated with unserviceable hearing on multivariate analysis when adjusted for other variables. In vitro assays show that VS cells induced monocyte migration and polarization toward CD80 + M1 or CD163 + M2 macrophage phenotypes, with qualitative differences in CD163 + macrophage morphologies between serviceable and unserviceable hearing groups. Conclusion Vestibular schwannomas express varying degrees of CD80 + M1 and CD163 + M2 macrophages. We present evidence that higher expression of CD163 + may contribute to poorer hearing outcomes in patients with VS. We also describe in vitro assays in a proof-of-concept investigation that VS cells can initiate monocyte migration and macrophage polarization. Future investigations are warranted to explore the relationships between tumor, macrophages, secreted cytokines, and hearing outcomes in patients with VS.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive, neuromodulating technique for brain hyperexcitability disorders. The objective of this paper is to discuss the mechanism of action of rTMS as well as to investigate the literature involving the application of rTMS in the treatment of tinnitus. The reviewed aspects of the protocols included baseline evaluation, the total number of sessions, frequency and the total number of stimuli, the location of treatment, and the outcome measures. Even with heterogeneous protocols, most studies utilized validated tinnitus questionnaires as baseline and outcome measures. Low frequency (1 Hz) stimulation throughout 10 consecutive sessions was the most widely used frequency and treatment duration; however, there was no consensus on the total number of stimuli necessary to achieve significant results. The auditory cortex (AC) was the most targeted location, with most studies supporting changes in neural activity with multi-site stimulation to areas in the frontal cortex (FC), particularly the dorsolateral prefrontal cortex (DLPFC). The overall efficacy across most of the reviewed trials reveals positive statistically significant results. Though rTMS has proven to impact neuroplasticity at the microscopic and clinical level, further studies are warranted to demonstrate and support the clinical use of rTMS in tinnitus treatment with a standardized protocol.

Simple Summary Vestibular schwannomas (VS) are intracranial tumors that originate from the Schwann cells of the vestibulocochlear nerve and cause hearing loss and dizziness. Although radiation therapy is a common treatment for VS, some irradiated tumors do not respond well and continue to grow, requiring additional therapies such as surgery. Little is known about the molecular mechanisms behind the normal response of VS to radiation therapy and why some VS are resistant to radiation. Thus, we aimed to review the current understanding of radiation response and resistance in VS through an in-depth summary of the DNA damage and cell cycle response to ionizing radiation. A better understanding of the radiobiology of VS can help guide future investigations looking at optimal radiation dosing strategies, unique targets for intervention, and novel therapies to improve patient outcomes. Abstract Vestibular schwannomas (VS) are benign tumors arising from cranial nerve VIII that account for 8–10% of all intracranial tumors and are the most common tumors of the cerebellopontine angle. These tumors are typically managed with observation, radiation therapy, or microsurgical resection. Of the VS that are irradiated, there is a subset of tumors that are radioresistant and continue to grow; the mechanisms behind this phenomenon are not fully understood. In this review, the authors summarize how radiation causes cellular and DNA injury that can activate (1) checkpoints in the cell cycle to initiate cell cycle arrest and DNA repair and (2) key events that lead to cell death. In addition, we discuss the current knowledge of VS radiobiology and how it may contribute to clinical outcomes. A better understanding of VS radiobiology can help optimize existing treatment protocols and lead to new therapies to overcome radioresistance.

Hypothesis Application of localized, mild therapeutic hypothermia during cochlear implantation (CI) surgery is feasible for residual hearing preservation. Background CI surgery often results in a loss of residual hearing. In preclinical studies, local application of controlled, mild therapeutic hypothermia has shown promising results as a hearing preservation strategy. This study investigated a suitable surgical approach to deliver local hypothermia in patients utilizing anatomical and radiologic measurements and experimental measurements from cadaveric human temporal bones. Methods Ten human cadaveric temporal bones were scanned with micro-computed tomography and anatomical features and measurements predicting round window (RW) visibility were characterized. For each bone, the standard facial recess and myringotomy approaches for delivery of hypothermia were developed. The St. Thomas Hospital (STH) classification was used to record degree of RW visibility with and without placement of custom hypothermia probe. Therapeutic hypothermia was delivered through both approaches and temperatures recorded at the RW, RW niche, over the lateral semicircular canal and the supero-lateral mastoid edge. Results The average facial recess area was 13.87 ± 5.52 mm. The introduction of the cooling probe through either approach did not impede visualization of the RW or cochleostomy as determined by STH grading. The average temperatures at RW using the FR approach reduced by 4.57 ± 1.68 °C for RW, while using the myringotomy approach reduced by 4.11 ± 0.98 °C for RW. Conclusion Local application of therapeutic hypothermia is clinically feasible both through the facial recess and myringotomy approaches without limiting optimal surgical visualization.

Objectives To review the current state of knowledge about the influence of specific genetic mutations that cause sensorineural hearing loss (SNHL) on cochlear implant (CI) functional outcomes, and how this knowledge may be integrated into clinical practice. A multistep and sequential population-based genetic algorithm suitable for the identification of congenital SNHL mutations before CI placement is also examined. Data sources, study selection A review was performed of the English literature from 2000 to 2019 using PubMed regarding the influence of specific mutations on CI outcomes and the use of next-generation sequencing for genetic screening of CI patients. Conclusion CI is an effective habilitation option for patients with severe-profound congenital SNHL. However, it is well known that CI outcomes show substantial inter-patient variation. Recent advances in genetic studies have improved our understanding of genotype-phenotype relationships for many of the mutations underlying congenital SNHL, and have explored how these relationships may account for some of the variance seen in CI performance outcomes. A sequential genetic screening strategy utilizing next-generation sequencing-based population-specific gene panels may allow for more efficient mutation identification before CI placement. Understanding the relationships between specific mutations and CI outcomes along with integrating routine comprehensive genetic testing into pre-CI evaluations will allow for more effective patient counseling and open the door for the development of mutation-specific treatment strategies.

The SARS-CoV-2 virus and resulting COVID-19 pandemic have significantly impacted surgical procedures of the skull base.In particular, aerosol-generating procedures (AGP) confer a greater risk of surgeons contracting the disease1. AGPs includethe use of electrocautery, open suctioning, and drilling. Temporal bone drilling aerosolizes bone, blood, and mucosa. Thelining of the eustachian tube, middle ear, and mastoid air cells has been shown to harbor multiple respiratory viruses.Incidents of combined neurootology and neurosurgical procedures resulting in infections of surgeons and trainees havebeen reported. Intraoperative exposures may occur even when patients test negative for COVID-19 preoperatively, despiteproper personal protective equipment (PPE). We describe the use of a protective tent to reduce the number of aerosolizedparticles within the operating room. Using a standard c-arm drape ([ Fig. 1 ]), a sterile tent can be created between theoperating field and microscope. The drape is cut in the middle between the two arms. One side has a circumferential rubberband that goes around the patient and irrigation bag, where it is then secured with clamps. Suction tubing and drill wiresare passed beneath this with additional tenting support from a Leyla's retractor on the contralateral side ([ Fig. 2 ]).Surgeons may attach suctions to the integrated smoke evacuator of the Neptune 3 Waste Management System. Thesurgeon accesses the operative site by two small slits that accommodate the forearms, while still allowing access to themicroscope handles ([ Fig. 3 ]). The surgical technician can pass instruments by going beneath the drape, through smallslits, or by the creation of a flap that is closed and secured when the surgeon is actively working. During temporal bonedrilling it has been clear that the generation of smoke, fluids, and other particles is substantial ([ Fig. 4 ]). With consistentuse, we have found that both the surgeon and assistants quickly accommodate to the new set-up. In addition to proper PPE(eye protection and N95 surgical mask), a protective tent that limits the spread of particles during AGPs in skull basesurgery may help decrease transmission of COVID-19 to health care workers.

Objectives: To determine the impact of age, electrode array, and time on impedance patterns in cochlear implant (CI) patients. Methods: A retrospective case review was performed on 98 patients implanted with the CI24RE perimodiolar (PM) and CI422 lateral wall (LW) arrays between 2010 and 2014 to assess impedances at the 1 week and 3-6 month visit after initial stimulation (IS). Results: With respect to age, impedances were higher in young patients compared to older patients in the middle and apical turns. With time, there were significant reductions in impedances across most electrodes. Electrode array type also had a significant impact on impedance measurements with PM and LW arrays having higher impedances in the basal turn and apical turns, respectively. Furthermore, PM arrays demonstrated significantly lower impedances in the middle and apical turn with time, when compared to LW arrays. Conclusions: Age, electrode array, and time can independently affect CI impedances. Moreover, we show that PM arrays may be advantageous to LW arrays, due to demonstrated lower impedances in the middle and apical turns long term. Understanding the impact of impedance on speech discrimination and determining the intracochlear processes that contribute to differences in impedance are future research directions.

Objectives In this review, we discuss current knowledge about the genetics and epigenetics of vestibular schwannoma (VS) in relation to hearing loss. A multistep and sequential genetic algorithm suitable for the identification of Neurofibromatosis Type 2 (NF2) constitutional and somatic mutations is discussed. Data sources, study selection A review was performed of the English literature from 1990 to 2019 using PubMed regarding genetics and epigenetics of vestibular schwannoma and NF2. Conclusion NF2 is a genetic disorder characterized by NF2 mutations that affect the function of a tumor suppressor called merlin. In particular, individuals with NF2 develop bilateral VS that can lead to hearing loss and even deafness. Recent advances in genetic and epigenetic studies have improved our understanding of the genotype-phenotype relationships that affect hearing in NF2 patients. Specific constitutional NF2 mutations including particular truncating, deletion, and missense mutations have been associated with poorer hearing outcomes and more severe clinical manifestations. Epigenetic events, such as DNA methylation and histone modifications, also contribute to the development and progression of hearing loss in NF2 patients. Furthermore, the accumulation of multiple NF2 and non-NF2 genetic and epigenetic abnormalities at the level of the tumor may contribute to worse hearing outcomes. Understanding genetic and epigenetic signatures in individual NF2 patients and particularly in each VS will allow us to develop novel gene therapies and precision medicine algorithms to preserve hearing in NF2 individuals.

Objective. To describe coronavirus disease 2019 (COVID-19) patient presentations requiring otolaryngology consultation and provide recommendations for protective measures based on the experience of ear, nose, and throat (ENT) departments in 4 Chinese hospitals during the COVID-19 pandemic. Study Design. Retrospective case series. Setting. Multicenter. Subjects and Methods. Twenty hospitalized COVID-19 patients requiring ENT consultation from 3 designated COVID-19 hospitals in Wuhan, Shanghai, and Shenzhen were identified. Data on demographics, comorbidities, COVID-19 symptoms and severity, consult reason, treatment, and personal protective equipment (PPE) use were collected and analyzed. Infection control strategies implemented for ENT outpatients and emergency room visits at the Eye and ENT Hospital of Fudan University were reported. Results. Median age was 63 years, 55% were male, and 95% were in severe or critical condition. Six tracheotomies were performed. Posttracheotomy outcomes were mixed (2 deaths, 2 patients comatose, all living patients still hospitalized). Other consults included epistaxis, pharyngitis, nasal congestion, hyposmia, rhinitis, otitis externa, dizziness, and tinnitus. At all hospitals, powered air-supply filter respirators (PAPRs) were used for tracheotomy or bleeding control. PAPR or N95-equivalent masks plus full protective clothing were used for other complaints. No inpatient ENT providers were infected. After implementation of infection control strategies for outpatient clinics, emergency visits, and surgeries, no providers were infected at the Eye and ENT Hospital of Fudan University. Conclusions and Relevance. COVID-19 patients require ENT consultation for many reasons, including tracheotomy. Otolaryngologists play an indispensable role in the treatment of COVID-19 patients but, due to their work, are at high risk of exposure. Appropriate protective strategies can prevent infection of otolaryngologists.

More than half of COVID-19 patients are afebrile early in the disease course, yet mildly ill or asymptomatic patients can still spread SARS-CoV-2 with high efficiency. Atypically presenting patients may be seen in noninfectious disease settings such as otolaryngology, which is a specialty prone to occupational exposure. Otolaryngologists have been infected with COVID-19 at higher rates than other specialties in China and other countries. Otolaryngology providers should maintain high clinical suspicion for mild and asymptomatic COVID-19 patients. Protective strategies should be implemented including preappointment screening, triaging, restriction of nonurgent visits and surgeries, telemedicine, and appropriate personal protective equipment use.

Hypothesis Merlin-deficient Schwann cells (MD-SC) and primary human vestibular schwannoma (VS) cells exhibit selective uptake of sodium-fluorescein (SF), allowing for fluorescent detection and improved visualization of tumor cells, when compared with Schwann cells (SC). Background SF is a fluorescent compound used for fluorescence-guided resection of gliomas. The utility of SF for VS surgery has not been assessed. Methods Mouse MD-SCs and rat SCs were cultured on 96-well plates at different cell densities and treated with SF at several drug concentrations and durations. Relative fluorescence units (RFU) were measured using a fluorometer to determine optimal treatment parameters in vitro. Subsequently, a four-point Likert scale for fluorescence visualization of pelleted cells was created and validated. Blinded observers rated SF-treated primary human VS and SC cultures, which were developed from deidentified specimens obtained from live and cadaveric donors, respectively. Results In contrast to SCs that showed low levels of fluorescence, MD-SCs demonstrated dose-dependent increases in RFUs when treated with incremental dosages of SF as well as longer treatment and fluorescent excitation times. In addition, RFUs were higher at greater MD-SC densities. The Likert scale for fluorescence visualization was validated using nine blinded observers and there were excellent inter- and intrarater reliabilities (intraclass coefficients of 0.989 and >0.858, respectively). Using the Likert scale, human VS treated with SF received higher scores than human SCs (p Conclusion Mouse MD-SC and human VS cells demonstrate preferential uptake of SF when compared with normal primary SCs. Observers detected differences in fluorescence using the validated Likert scale. Further investigations into the utility of SF-guidance in VS surgery are warranted.

Objectives Cochlear implantation surgery has been shown to result in trauma to inner ear sensory structures, resulting in loss of residual hearing. Localized therapeutic hypothermia has been shown in clinical care to be a neuroprotective intervention. Previously, we have shown in an experimental model that localized hypothermia protects cochlear hair cells and residual hearing function against surgical and cochlear implantation trauma. Using experimental temperature measurements carried out in human cadaver temporal bones and a finite element model of the inner ear, the present study examined the temperature distribution of a custom-designed hypothermia delivery system in the human inner ear organs. Design The efficacy of the hypothermia probe and resulting heat distribution across human cochlea and surrounding tissues were modeled in three-dimensional in COMSOL. The geometry and dimensions of inner ear and temporal bones were derived from computed tomographic and magnetic resonance imaging images. Model predictions were compared with experimental observations from five human temporal bones. Results In both the modeling and experimental studies, the cochlear temperature was lowered by 4 to 6 °C on the round window from a baseline of 37 °C within 16 to 18 minutes. The model simulations showed uniformly distributed cooling across the cochlea. This study provides insight for design, operation, and protocols for efficacious delivery of mild therapeutic hypothermia to the human cochlea that may significantly benefit patients undergoing surgical cochlear implantation by preserving residual hearing. Conclusion There was a close correlation between the results of the numerical simulations and experimental observations in this study. Our custom-designed system is capable of effectively providing mild therapeutic hypothermia locally to the human cochlea. When combined with results from in vivo animal experiments, the present study suggests that the application of localized therapeutic hypothermia may hold potential for patients with an aim to preserve residual hearing after cochlear implantation.

Diagnosis and treatment of advanced otosclerosis can be controversial. In 1961, House and Sheehy defined advanced otosclerosis as hearing loss in air conduction threshold by 85 dB with nonmeasurable bone conduction. Recently, the definition of advanced otosclerosis is mostly based on the decrease of speech recognition. There are some treatment modalities: stapes surgery and hearing aids, cochlear implantation, or direct acoustic cochlear implant. The authors propose a new algorithm for treatment. If the patient is treated with cochlear implantation, the surgeon should be cautious for facial nerve stimulation after surgery because it is the most prevalent complication.

Objective: To demonstrate the safety and effectiveness of the MED-EL Electric-Acoustic Stimulation (EAS) System, for adults with residual low-frequency hearing and severe-to-profound hearing loss in the mid to high frequencies. Study Design: Prospective, repeated measures. Setting: Multicenter, hospital. Patients: Seventy-three subjects implanted with PULSAR or SONATA cochlear implants with FLEX24 electrode arrays. Intervention: Subjects were fit postoperatively with an audio processor, combining electric stimulation and acoustic amplification. Main Outcome Measures: Unaided thresholds were measured preoperatively and at 3, 6, and 12 months postactivation. Speech perception was assessed at these intervals using City University of New York sentences in noise and consonant–nucleus–consonant words in quiet. Subjective benefit was assessed at these intervals via the Abbreviated Profile of Hearing Aid Benefit and Hearing Device Satisfaction Scale questionnaires. Results: Sixty-seven of 73 subjects (92%) completed outcome measures for all study intervals. Of those 67 subjects, 79% experienced less than a 30 dB HL low-frequency pure-tone average (250–1000 Hz) shift, and 97% were able to use the acoustic unit at 12 months postactivation. In the EAS condition, 94% of subjects performed similarly to or better than their preoperative performance on City University of New York sentences in noise at 12 months postactivation, with 85% demonstrating improvement. Ninety-seven percent of subjects performed similarly or better on consonant–nucleus–consonant words in quiet, with 84% demonstrating improvement. Conclusion: The MED-EL EAS System is a safe and effective treatment option for adults with normal hearing to moderate sensorineural hearing loss in the low frequencies and severe-to-profound sensorineural hearing loss in the high frequencies who do not benefit from traditional amplification.

// Alejandra M. Petrilli 1 , Jeanine Garcia 1 , Marga Bott 1 , Stephani Klingeman Plati 1 , Christine T. Dinh 2 , Olena R. Bracho 2 , Denise Yan 2 , Bing Zou 2 , Rahul Mittal 2 , Fred F. Telischi 2 , Xue-Zhong Liu 2 , Long-Sheng Chang 3 , D. Bradley Welling 3, 4 , Alicja J. Copik 1 and Cristina Fernandez-Valle 1 1 Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Lake Nona-Orlando, FL 32827, USA 2 University of Miami Miller School of Medicine, Department of Otolaryngology, Miami, FL 33136, USA 3 Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children’s Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43205, USA 4 Current Affiliation: Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital and Harvard University, Boston, MA 02114, USA Correspondence to: Cristina Fernandez-Valle, email: cfv@ucf.edu Keywords: neurofibromatosis type 2, schwannoma, PDGFR, SRC, STAT3 Received: August 17, 2016 Accepted: February 20, 2017 Published: March 06, 2017 ABSTRACT Neurofibromatosis type 2 (NF2) is a genetic syndrome that predisposes individuals to multiple benign tumors of the central and peripheral nervous systems, including vestibular schwannomas. Currently, there are no FDA approved drug therapies for NF2. Loss of function of merlin encoded by the NF2 tumor suppressor gene leads to activation of multiple mitogenic signaling cascades, including platelet-derived growth factor receptor (PDGFR) and SRC in Schwann cells. The goal of this study was to determine whether ponatinib, an FDA-approved ABL/SRC inhibitor, reduced proliferation and/or survival of merlin-deficient human Schwann cells (HSC). Merlin-deficient HSC had higher levels of phosphorylated PDGFRα/β, and SRC than merlin-expressing HSC. A similar phosphorylation pattern was observed in phospho-protein arrays of human vestibular schwannoma samples compared to normal HSC. Ponatinib reduced merlin-deficient HSC viability in a dose-dependent manner by decreasing phosphorylation of PDGFRα/β, AKT, p70S6K, MEK1/2, ERK1/2 and STAT3. These changes were associated with decreased cyclin D1 and increased p27 Kip1 levels, leading to a G 1 cell-cycle arrest as assessed by Western blotting and flow cytometry. Ponatinib did not modulate ABL, SRC, focal adhesion kinase (FAK), or paxillin phosphorylation levels. These results suggest that ponatinib is a potential therapeutic agent for NF2-associated schwannomas and warrants further in vivo investigation.

Stereotactic radiosurgery for lateral skull base tumors can cause hearing loss when the cochleae are exposed to high doses of single-fraction radiation. Currently, there are no known nondosimetric preventative treatments for radiation-induced ototoxicity.Intratympanic (IT) dexamethasone (DXM), a synthetic steroid, protects against radiation-induced auditory hair cell (HC) and hearing losses in rats in vivo.Seven rats received radiation (12 Gy) to both cochleae. In irradiated rats and six nonirradiated rats, IT DXM was randomized to one ear, while tympanic puncture without DXM was performed on the contralateral ear. Baseline and 4-week postradiation auditory-evoked potential tests were performed. The cochleae were processed for HC viability.Cochleae exposed to radiation demonstrated more outer HC (OHC) loss in all turns than nonirradiated ears (p 0.05). OHCs were more susceptible to radiation injury than inner HCs in the middle and basal turns (p 0.05). In irradiated cochleae, there was a nonsignificant trend for less OHC loss with IT DXM in the basal turn when compared with placebo. IT DXM did not improve radiation-induced hearing threshold shifts; however, a high rate of tympanic membrane perforations occurred with irradiated ears which may contribute to this finding.Radiation induced loss of OHCs in all turns of the cochlea. IT DXM reduced OHC loss in the basal turn of irradiated ears; however, this finding did not achieve statistical significance. Although IT DXM did not affect radiation-induced hearing threshold shifts in adult rats in vivo, this may be due to a high rate of tympanic membrane perforations.

Background Neurofibromatosis type 2 (NF2) is a genetic tumor-predisposition disorder caused by NF2/merlin tumor suppressor gene inactivation. The hallmark of NF2 is formation of bilateral vestibular schwannomas (VS). Because merlin modulates activity of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, we investigated repurposing drugs targeting MEK1 and/or MEK2 as a treatment for NF2-associated schwannomas. Methods Mouse and human merlin-deficient Schwann cell lines (MD-MSC/HSC) were screened against 6 MEK1/2 inhibitors. Efficacious drugs were tested in orthotopic allograft and NF2 transgenic mouse models. Pathway and proteome analyses were conducted. Drug efficacy was examined in primary human VS cells with NF2 mutations and correlated with DNA methylation patterns. Results Trametinib, PD0325901, and cobimetinib were most effective in reducing MD-MSC/HSC viability. Each decreased phosphorylated pERK1/2 and cyclin D1, increased p27, and induced caspase-3 cleavage in MD-MSCs. Proteomic analysis confirmed cell cycle arrest and activation of pro-apoptotic pathways in trametinib-treated MD-MSCs. The 3 inhibitors slowed allograft growth; however, decreased pERK1/2, cyclin D1, and Ki-67 levels were observed only in PD0325901 and cobimetinib-treated grafts. Tumor burden and average tumor size were reduced in trametinib-treated NF2 transgenic mice; however, tumors did not exhibit reduced pERK1/2 levels. Trametinib and PD0325901 modestly reduced viability of several primary human VS cell cultures with NF2 mutations. DNA methylation analysis of PD0325901-resistant versus -susceptible VS identified genes that could contribute to drug resistance. Conclusion MEK inhibitors exhibited differences in antitumor efficacy resistance in schwannoma models with possible emergence of trametinib resistance. The results support further investigation of MEK inhibitors in combination with other targeted drugs for NF2 schwannomas.

This study recommends using soft surgical principal and round window insertion to protect residual hearing with favorable anatomical exposure. Further studies are needed to evaluate the impact of the electrical stimulation on the organ of corti and hearing.The objective of this study is to analyze various factors that impact on preservation of residual hearing post-implantation.A retrospective study was performed to analyze loss of residual hearing in a cohort of 225 patients implanted in a large academic center. Sixty-four patients met the inclusion criteria. The impact of age at implantation, gender, etiology of hearing loss, cochleostomy vs round window insertion, partial vs full insertion, and effect of initial stimulation were analyzed using appropriate statistical analysis.The overall hearing preservation rate for all implanted patients was 64%. Loss of residual hearing was significantly more observed in cases of cochleostomy and/or non-soft surgical techniques. No correlation was observed with age at implantation, gender, side of implant, device manufacturer, and presence of pre-lingual deafness vs post-lingual, full or partial electrode insertion. In addition, there was a small but significant decrease in hearing between pre-stimulation and post-stimulation audiograms at 6000 Hz.

Transcranial attenuation (TA) of bone-conducted sound has a high degree of variability by frequency and subject, which may play a role in the objective benefit of individuals with single-sided deafness (SSD) treated with a bone-anchored implant (BAI). This study sought to determine whether TA is predictive of benefit in individuals with SSD who receive a BAI. Adult, English-speaking patients with unilateral profound sensorineural hearing loss who underwent a BAI evaluation were included for study. Absolute TA values were consistent with previously published reports. Regression analysis indicated no correlation between TA values and aided speech-in-noise performance for any combined or individual frequencies. Measures of TA do not provide predictive value in determining behavioral outcomes in the SSD population. Specifically, low TA does not suggest improved outcomes with a BAI.

Hypothesis The retrofacial approach is a feasible approach to the round window niche and that the Round window-Sigmoid sinus line will help determine the feasibility of retrofacial approach for cochlear implantation unless there is a very high jugular bulb. Background When the round window cannot be visualized by facial recess approach during cochlear implantation, other conservative techniques can be used to improve visualization such as the retrofacial approach. Methods Thirteen adult dry cadaveric temporal bones were studied. Computed tomography (CT) scan was obtained on all temporal bones. An imaginary Round window-Sigmoid sinus line was drawn on the axial images. We assessed whether this line is anterior (including intersection) or posterior to the facial nerve (FN). The following closest distances were measured on CT scans: 1) posterior semicircular canal (PSC)-FN, 2) PSC-Stapedius muscle, 3) PSC-Jugular bulb, 4) lateral semicircular canal (LSC)-Jugular bulb, 5) sigmoid sinus-FN. A canal wall-up mastoidectomy, facial recess, and retrofacial approach were performed in all specimens. We have noted whether we need a standard or an extended mastoidectomy. Results The Round window-Sigmoid sinus line was posterior to the FN in all specimens. The retrofacial approach was feasible and the round window was visualized in all specimens. Extended mastoidectomy was required in seven specimens and the PSC-FN was ≤ 3 mm in five of them. Conclusion Retrofacial approach is feasible in cochlear implantation when the Round window-Sigmoid sinus line is posterior to the FN and the jugular bulb is not obstructing the round window.

HYPOTHESIS: Microsurgical implantation of mouse merlin-deficient Schwann cells (MD-SC) into the cerebellopontine angle of immunodeficient rats will initiate tumor formation, hearing loss, and vestibular dysfunction. BACKGROUND: The progress in identifying effective drug therapies for treatment of Neurofibromatosis type II (NF2) is limited by the availability of animal models of VS that develop hearing loss and imbalance. METHODS: A microsurgical technique for implanting MD-SCs onto the cochleovestibular nerve of rats was developed. Ten Rowett Nude rats were implanted with either ~10(5) MD-SCs expressing luciferase (N=5) or vehicle (N=5). Rats received bioluminescence imaging, auditory brainstem response testing, and were observed for head tilt every two weeks after surgery, for a total of 6 weeks. Tumors were harvested and processed with hematoxylin & eosin staining and immunohistochemistry was performed for S100. RESULTS: Rats implanted with MD-SCs developed significantly higher tumor bioluminescence measurements and hearing threshold shifts at multiple frequencies by the 4(th) and 6(th) weeks post-implantation, compared to control rats. Rats implanted with MD-SCs also developed gross tumor. The tumor volume was significantly greater than nerve volumes obtained from rats in the control group. All rats with tumors developed a head tilt, while control rats had no signs of vestibular dysfunction. Tumors demonstrated histological features of schwannoma and express S100. CONCLUSION: Using this microsurgical technique, this xenograft rat model of VS develops tumors involving the cochleovestibular nerve, shifts in hearing thresholds, and vestibular dysfunction. This animal model can be utilized to investigate tumor-mediated hearing loss and perform preclinical drug studies for NF2.

Diagnosis and treatment of advanced otosclerosis can be controversial. In 1961, House and Sheehy defined advanced otosclerosis as hearing loss in air conduction threshold by 85 dB with nonmeasurable bone conduction. Recently, the definition of advanced otosclerosis is mostly based on the decrease of speech recognition. There are some treatment modalities: stapes surgery and hearing aids, cochlear implantation, or direct acoustic cochlear implant. The authors propose a new algorithm for treatment. If the patient is treated with cochlear implantation, the surgeon should be cautious for facial nerve stimulation after surgery because it is the most prevalent complication.

Background: Precise techniques to find the facial nerve (FN) and recess are lacking. Objectives: We aimed to define incus-spine and incus-FN angles which can be used to localize the FN and recess during mastoidectomy. Material and methods: Thirty adult cadaveric temporal bones were studied. Canal-wall up mastoidectomy with a facial recess approach was performed. The temporal bones and microscope were positioned differently to change the visual angle. The following distances were measured: (1) Short process of the incus (SPI)-FN; (2) Body of the incus-FN. Photographs were taken. Three lines were drawn on the photographs between the SPI, FN, and the spine of Henle. The angles were created and measured. Results: Three of the temporal bones were excluded due to the absence of the spine of Henle and two of them due to the displacement of the SPI. The mean of the incus-spine angle in 25 temporal bones was 90.12 degrees and the mean of the Incus-FN angle was 135.96 degrees. The mean distances of the SPI-FN and body of incus-FN were 4.85 and 9.26 mm, respectively. Conclusions and significance: The incus-spine and the incus-FN angles along with the distances can help localize the FN and recess.

Hypothesis: Dexamethasone (DXM) protects against radiation-induced loss of auditory hair cells (HCs) in rat organ of Corti (OC) explants by reducing levels of oxidative stress and apoptosis. Background: Radiation-induced sensorineural hearing loss (HL) is progressive, dose-dependent, and irreversible. Currently, there are no preventative therapeutic modalities for radiation-induced HL. DXM is a synthetic steroid that can potentially target many of the pathways involved in radiation-induced ototoxicity. Methods: Whole OC explants were dissected from 3-day-old rat cochleae exposed to specific dosages of single-fraction radiation (0, 2, 5, 10, or 20 Gy), were either untreated or treated with DXM (75, 150, 300 μg/mL), and then cultured for 48 or 96 hours. Confocal microscopy for oxidative stress (CellRox, 48 h) and apoptosis (TUNEL assay, 96 h) and fluorescent microscopy for viable HC counts (fluorescein isothiocyanate-phalloidin, 96 h) were performed. Analysis of variance and Tukey post hoc testing were used for statistical analysis. Results: Radiation exposure initiated dose-dependent losses of inner and outer HCs, predominantly in the basal turns of the OC explants. DXM protected against radiation-induced HC losses in a dose-dependent manner. DXM significantly reduced levels of oxidative stress and apoptosis in radiation-injured OC explants (p Conclusions: Radiation-initiated HC losses were dose-dependent in OC explants. DXM treatment protected explant HCs against radiation-initiated losses by decreasing the levels of oxidative stress and apoptosis. DXM may potentially be a therapeutic modality for preventing radiation-induced HL; further in vivo studies are necessary.

Otitis media (OM) is an inflammation of the middle ear associated with infection. Despite appropriate therapy, acute OM (AOM) can progress to chronic suppurative OM (CSOM) associated with ear drum perforation and purulent discharge. The effusion prevents the middle ear ossicles from properly relaying sound vibrations from the ear drum to the oval window of the inner ear, causing conductive hearing loss. In addition, the inflammatory mediators generated during CSOM can penetrate into the inner ear through the round window. This can cause the loss of hair cells in the cochlea, leading to sensorineural hearing loss. Pseudomonas aeruginosa and Staphylococcus aureus are the most predominant pathogens that cause CSOM. Although the pathogenesis of AOM is well studied, very limited research is available in relation to CSOM. With the emergence of antibiotic resistance as well as the ototoxicity of antibiotics and the potential risks of surgery, there is an urgent need to develop effective therapeutic strategies against CSOM. This warrants understanding the role of host immunity in CSOM and how the bacteria evade these potent immune responses. Understanding the molecular mechanisms leading to CSOM will help in designing novel treatment modalities against the disease and hence preventing the hearing loss.