Amplitude Parameters Are Predictive of Hearing Preservation in a Randomized Controlled Trial of Intracochlear Electrocochleography During Cochlear Implant Surgery.

OBJECTIVE: To prospectively evaluate the association between hearing preservation after cochlear implantation (CI) and intracochlear electrocochleography (ECochG) amplitude parameters. STUDY DESIGN: Multi-institutional, prospective randomized clinical trial. SETTING: Ten high-volume, tertiary care CI centers. PATIENTS: Adults (n = 87) with sensorineural hearing loss meeting CI criteria (2018-2021) with audiometric thresholds of ≤80 dB HL at 500 Hz. METHODS: Participants were randomized to CI surgery with or without audible ECochG monitoring. Electrode arrays were inserted to the full-depth marker. Hearing preservation was determined by comparing pre-CI, unaided low-frequency (125-, 250-, and 500-Hz) pure-tone average (LF-PTA) to LF-PTA at CI activation. Three ECochG amplitude parameters were analyzed: 1) insertion track patterns, 2) magnitude of ECochG amplitude change, and 3) total number of ECochG amplitude drops. RESULTS: The Type CC insertion track pattern, representing corrected drops in ECochG amplitude, was seen in 76% of cases with ECochG "on," compared with 24% of cases with ECochG "off" ( p = 0.003). The magnitude of ECochG signal drop was significantly correlated with the amount of LF-PTA change pre-CI and post-CI ( p < 0.05). The mean number of amplitude drops during electrode insertion was significantly correlated with change in LF-PTA at activation and 3 months post-CI ( p ≤ 0.01). CONCLUSIONS: ECochG amplitude parameters during CI surgery have important prognostic utility. Higher incidence of Type CC in ECochG "on" suggests that monitoring may be useful for surgeons in order to recover the ECochG signal and preventing potentially traumatic electrode-cochlear interactions.

Single Fraction and Hypofractionated Radiation Cause Cochlear Damage, Hearing Loss, and Reduced Viability of Merlin-Deficient Schwann Cells.

BACKGROUND: Vestibular schwannomas (VS) are benign intracranial tumors caused by loss of function of the merlin tumor suppressor. We tested three hypotheses related to radiation, hearing loss (HL), and VS cell survival: (1) radiation causes HL by injuring auditory hair cells (AHC), (2) fractionation reduces radiation-induced HL, and (3) single fraction and equivalent appropriately dosed multi-fractions are equally effective at controlling VS growth. We investigated the effects of single fraction and hypofractionated radiation on hearing thresholds in rats, cell death pathways in rat cochleae, and viability of human merlin-deficient Schwann cells (MD-SC). METHODS: Adult rats received cochlear irradiation with single fraction (0 to 18 Gray [Gy]) or hypofractionated radiation. Auditory brainstem response (ABR) testing was performed for 24 weeks. AHC viabilities were determined using immunohistochemistry. Neonatal rat cochleae were harvested after irradiation, and gene- and cell-based assays were conducted. MD-SCs were irradiated, and viability assays and immunofluorescence for DNA damage and cell cycle markers were performed. RESULTS: Radiation caused dose-dependent and progressive HL in rats and AHC losses by promoting expression of apoptosis-associated genes and proteins. When compared to 12 Gy single fraction, hypofractionation caused smaller ABR threshold and pure tone average shifts and was more effective at reducing MD-SC viability. CONCLUSIONS: Investigations into the mechanisms of radiation ototoxicity and VS radiobiology will help determine optimal radiation regimens and identify potential therapies to mitigate radiation-induced HL and improve VS tumor control.

Can Electrocochleography Help Preserve Hearing After Cochlear Implantation With Full Electrode Insertion?

OBJECTIVES: To evaluate the utility of intracochlear electrocochleography (ECochG) monitoring during cochlear implant (CI) surgery on postoperative hearing preservation. STUDY DESIGN: Prospective, randomized clinical trial. SETTING: Ten high-volume, tertiary care CI centers. PATIENTS: Adult patients with sensorineural hearing loss meeting the CI criteria who selected an Advanced Bionics CI. METHODS: 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. RESULTS: 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 change >15-29 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. CONCLUSIONS: 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."

Effect of Bone Marrow-Derived Mesenchymal Stem Cells on Cochlear Function in an Experimental Rat Model.

Mesenchymal stem cell (MSC) therapy is an emerging treatment modality for various human diseases. Although induced pluripotent stem cells have been explored for the restoration of hearing, the potential of MSCs as a therapeutic strategy for various cochlear insults is not precisely known. MSCs possess anti-inflammatory, anti-apoptotic and neuroprotective properties, making them an attractive target for the treatment of inner ear disorders such as hair cell damage in response to inflammation. Most of the previous studies have used immunosuppression or the complex surgical techniques to deliver stem cells into the cochlea. However, no information is available regarding the biocompatibility and safety of MSCs in the inner ear in immunocompetent cochlea. The aim of the present study was to determine the effect of non-surgical administration of rodent bone marrow derived MSCs (BM-MSCs) through transtympanic delivery on the cochlear function and to assess any adverse effects on the auditory system employing a rat model without immunosuppression. We observed that the transtympanic administration of BM-MSCs has no significant effect on the hearing thresholds as determined by auditory brainstem response and distortion product otoacoustic emissions. Histopathological examination revealed no recruitment of inflammatory leukocytes and edema in the cochlea of BM-MSCs administrated rats. The results of this study suggest that transtympanic administration of BM-MSCs is safe and can be explored in providing otoprotection against cochlear insults. Anat Rec, 303:487-493, 2020. © 2019 American Association for Anatomy.

Otoprotection to Implanted Cochlea Exposed to Noise Trauma With Dexamethasone Eluting Electrode.

Cochlear implantation (CI) is now widely used to provide auditory rehabilitation to individuals having severe to profound sensorineural hearing loss (SNHL). However, CI can lead to electrode insertion trauma (EIT) that can cause damage to sensory cells in the inner ear resulting in loss of residual hearing. Even with soft surgical techniques where there is minimal macroscopic damage, we can still observe the generation of molecular events that may initiate programmed cell death via various mechanisms such as oxidative stress, the release of pro-inflammatory cytokines, and activation of the caspase pathway. In addition, individuals with CI may be exposed to noise trauma (NT) due to occupation and leisure activities that may affect their hearing ability. Recently, there has been an increased interest in the auditory community to determine the efficacy of drug-eluting electrodes for the protection of residual hearing. The objective of this study is to determine the effect of NT on implanted cochlea as well as the otoprotective efficacy of dexamethasone eluting electrode to implanted cochlea exposed to NT in a guinea pig model of CI. Animals were divided into five groups: EIT with dexamethasone eluting electrode exposed to NT; EIT exposed to NT; NT only; EIT only and naïve animals (control group). The hearing thresholds were determined by auditory brainstem recordings (ABRs). The cochlea was harvested and analyzed for transcript levels of inflammation, apoptosis and fibrosis genes. We observed that threshold shifts were significantly higher in EIT, NT or EIT + NT groups compared to naive animals at all the tested frequencies. The dexamethasone eluting electrode led to a significant decrease in hearing threshold shifts in implanted animals exposed to NT. Proapoptotic tumor necrosis factor-α [TNF-α, TNF-α receptor 1a (TNFαR1a)] and pro-fibrotic transforming growth factor ß1 (TGFß) genes were more than two-fold up-regulated following EIT and EIT + NT compared to the control group. The use of dexamethasone releasing electrode significantly decreased the transcript levels of pro-apoptotic and pro-fibrotic genes. The dexamethasone releasing electrode has shown promising results for hearing protection in implanted animals exposed to NT. The results of this study suggest that dexamethasone releasing electrode holds great potential in developing effective treatment modalities for NT in the implanted cochlea.

Caracterización de los pacientes con diagnóstico presuntivo de síndrome coronario agudo sin elevación del segmento ST que asisten a un servicio de urgencias / Profile of patients with non-ST elevation acute coronary syndrome that attend an Emergency Department

Resumen El dolor torácico es uno de los principales motivos de consulta al sistema de urgencias, y este es secundario a condiciones como el síndrome coronario agudo entre otras. Para su diagnóstico se requiere no sólo el resultado de la troponina, sino una evaluación clínica completa en la que se tengan en cuenta factores de riesgo cardiovascular, características del dolor y hallazgos electrocardiográficos. La interpretación inadecuada de las troponinas ultrasensibles lleva a que se someta al paciente a riesgos innecesarios a causa de estudios como el cateterismo cardiaco. Se llevó a cabo un estudio de corte trasversal en un hospital de Bogotá, en el que la causa principal de consulta en el servicio de urgencias fue el dolor torácico, y la primera causa de hospitalización en Cardiología el síndrome coronario agudo. Se recolectaron datos de 411 pacientes a quienes se les realizó arteriografía coronaria, la mayoría hombres con factores de riesgo como hipertensión arterial, tabaquismo y un evento coronario previo. Dentro de los estudios paraclínicos, la fracción de eyección promedio estuvo cercana al 50% y sólo en 201 pacientes se encontraron lesiones epicárdicas significativas.De la muestra analizada, el 13% tenía creatinina mayor de 1,5 mg/dl como causa alterna de elevación del biomarcador y 28% tenía disfunción ventricular izquierda de algún grado. La mayoría de los pacientes en quienes no se documentaron lesiones angiográficamente significativas en el cateterismo cardiaco, la troponina no cumplía criterios de positividad con base en el aumento del 20% respecto al valor inicial si este era positivo o de 50% en caso de que el primer valor fuese negativo. Adicionalmente, del grupo de pacientes con enfermedad coronaria angiográficamente significativa fue más frecuente la combinación de tres o más factores de riesgo cardiovascular en presencia de biomarcador positivo.

Abstract Chest pain is one of the main reasons for consulting the Emergency Department, and it is secondary to conditions, such as acute coronary syndrome. For its diagnosis, it not only requires a Troponin result, but also a full clinical evaluation, in which factors like cardiovascular risk have to be taken into account, as well as characteristics of the pain and the findings on the electrocardiogram. The poor interpretation of the ultrasensitive Troponins leads to the patient being subjected to unnecessary risks due to studies such as cardiac catheterisation. A cross-sectional study was conducted in a hospital in Bogota, in which chest pain was the main reason for consulting the Emergency Department, and acute coronary syndrome the first cause of admission to Cardiology. The study included a total of 411 patients on whom a coronary angiography was performed. The majority were males with risk factors such as arterial hypertension, smokers, and with a previous coronary event. Among the para-clinical studies, the mean ejection fraction was around 50%, and significant epicardial lesions were found in only 201 patients.Of the sample analysed, 13% had a creatinine greater than 1.5 mg/dl as an alternative cause of the elevation of the biomarker, and 28% had some degree of left ventricular function. the majority of patients that did not have significant angiographic lesions in the cardiac catheterisation documented, the Troponin did not meet the criteria for being positive, based on an increase of 20% as regards the initial value if this was positive or 50% in the case where the first value was negative. Furthermore, of the patient group with significant angiographic coronary disease, the combination of three or more cardiovascular risk factors was the most frequent in the presence of a positive biomarker.

Molecular mechanisms involved in cochlear implantation trauma and the protection of hearing and auditory sensory cells by inhibition of c-Jun-N-terminal kinase signaling.

OBJECTIVES/HYPOTHESIS: To investigate the molecular mechanisms involved in electrode insertion trauma (EIT) and to test the otoprotective effect of locally delivered AM-111. STUDY DESIGN: An animal model of cochlear implantation. METHODS: Guinea pigs' hearing thresholds were measured by auditory brainstem response (ABR) before and after cochlear implantation in four groups: EIT; pretreated with hyaluronate gel 30 minutes before EIT (EIT+Gel); pretreated with hyaluronate gel/AM-111 30 minutes before EIT (EIT+AM-111); and unoperated contralateral ears as controls. Neurofilament, synapsin, and fluorescein isothiocyanate (FITC)-phalloidin staining for hair cell counts were performed at 90 days post-EIT. Immunostaining for 4-hydroxy-2-nonenal (HNE), activated caspase-3, CellROX, and phospho-c-Jun were performed at 24 hours post-EIT. RESULTS: ABR thresholds increased post-EIT in the cochleae of EIT only and EIT+Gel treated animals. There was no significant increase in hearing thresholds in cochleae from either EIT+AM-111 treated or unoperated control ears. AM-111 protection of organ of Corti sensory elements (i.e., hair cells [HCs], supporting cells [SCs], nerve fibers, and synapses) was documented at 3 months post-EIT. Immunostaining of 24-hour post-EIT specimens demonstrated increased levels of HNE in HCs and SCs; increased levels of CellROX and activation of caspase-3 was observed only in SCs, and phosphorylation of c-Jun occurred only in HCs of the EIT-only and EIT+Gel specimens. There was no immunostaining for either HNE, CellROX, caspase-3, or phospho-c-Jun in the organ of Corti specimens from AM-111 treated cochleae. CONCLUSIONS: Molecular mechanisms involved in programmed cell death of HCs are different than the ones involved in programmed cell death of SCs. Local delivery of AM-111 provided a significant level of protection against EIT-induced hearing losses, HC losses, and damage to neural elements.

Preventing hearing damage using topical dexamethasone during reversible cochlear ischemia: an animal model.

HYPOTHESIS: Local application of dexamethasone to the round window (RW) niche prevents cochlear damage caused by local reversible ischemia. BACKGROUND: Cochlear ischemia induced by internal auditory artery (IAA) compression/stretching is thought to cause postoperative sensory hearing loss after attempted hearing preservation removal of acoustic neuroma tumors. Dexamethasone administered to the RW niche traveling through the membrane to the cochlear fluids may prevent ischemic damage. MATERIALS AND METHODS: Ten young albino rabbits were used for this study. Ischemic episodes were induced by compressing the IAA. Laser Doppler cochlear blood flow was measured using a probe positioned at the RW niche. Transtympanic electrocochleography was measured at 4, 8, and 12 kHz. In 5 test ears, dexamethasone was administered topically at the RW for approximately 50 minutes before the IAA compressions, whereas in 5 control ears, saline was applied in the same way. Each ear underwent one 10-minute IAA compression with a 60-minute postischemic period of transtympanic electrocochleography monitoring. RESULTS: In both control- and dexamethasone-treated ears, ischemic episodes measured by Laser Doppler cochlear blood flow were comparable. Fifty minutes after IAA decompression, in dexamethasone-pretreated ears, cochlear microphonic and compound action potential amplitudes at all test frequencies were 10 to 15% less reduced than those in control ears. Compound action potential latencies in dexamethasone-pretreated ears resulted in shorter latency delay than in control ears. CONCLUSION: The RW seems to be an efficacious route for the administration of dexamethasone into the inner ear. Dexamethasone showed a protective effect on cochlear function after local ischemia. Transtympanic electrocochleography was found to be a sufficient and effective tool in monitoring hearing.

Intraoperative monitoring of hearing during cerebellopontine angle tumor surgery using transtympanic electrocochleography.

OBJECTIVE: To investigate the use of transtympanic electrocochleography (TT-ECochG) analyzed on-line by a detector strategy software that made possible automatic extraction of TT-ECochG components intraoperatively in real-time domain. PATIENTS: Fifteen patients with cerebellopontine angle tumor among 50 patients were included in this study. INTERVENTION: All subjects were operated on via middle fossa or retrosigmoid approach. Pure-tone average (PTA) was measured at 0.5, 1.0, and 2.0 kHz, and calculations were performed before and after surgery. Auditory function was monitored intraoperatively via TT-ECochG, and analyzed data were displayed on-line. MAIN OUTCOME MEASURES: TT-ECochG changes in morphology were described. Postoperative PTA elevation level correlated with TT-ECochG morphology changes occurring intraoperatively. RESULTS: Analyzed on-line, TT-ECochG data were displayed as first negative peak of compound action potential amplitude and latency in time domain every 3 to 5 seconds. A good correlation between postoperative PTA elevation and TT-ECochG morphology changes was showed (Spearman rank test, R = +0.93; t(N-2) = 9.00; p < 0.0001). CONCLUSION: TT-EcochG seemed to effectively mirror even minimal changes in auditory function during intraoperative monitoring in real-time domain. Developed strategy of on-line analysis makes the intraoperative hearing status assessment faster and easier.

Neuromonitoring of cochlea and auditory nerve with multiple extracted parameters during induced hypoxia and nerve manipulation.

A system capable of comprehensive and detailed monitoring of the cochlea and the auditory nerve during intraoperative surgery was developed. The cochlear blood flow (CBF) and the electrocochleogram (ECochGm) were recorded at the round window (RW) niche using a specially designed otic probe. The ECochGm was further processed to obtain cochlear microphonics (CM) and compound action potentials (CAP). The amplitude and phase of the CM were used to quantify the activity of outer hair cells (OHC); CAP amplitude and latency were used to describe the auditory nerve and the synaptic activity of the inner hair cells (IHC). In addition, concurrent monitoring with a second electrophysiological channel was achieved by recording compound nerve action potential (CNAP) obtained directly from the auditory nerve. Stimulation paradigms, instrumentation and signal processing methods were developed to extract and differentiate the activity of the OHC and the IHC in response to three different frequencies. Narrow band acoustical stimuli elicited CM signals indicating mainly nonlinear operation of the mechano-electrical transduction of the OHCs. Special envelope detectors were developed and applied to the ECochGm to extract the CM fundamental component and its harmonics in real time. The system was extensively validated in experimental animal surgeries by performing nerve compressions and manipulations.