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Objective: This report presents a case study of a patient who resumed bilateral hearing aid use after nearly four years of limited progress and subjective dissatisfaction with a hybrid cochlear implant device., Design: Case study., Study Sample: One patient., Results: The patient's post-operative objective and subjective abilities with bilateral hearing aids were better than with a hybrid cochlear implant and contralateral hearing aid., Conclusions: Although the benefits of combined acoustic and electric hearing have been well-documented, this report presents a solution for those with well-preserved hearing and poor hybrid cochlear implant performance: returning to bilateral hearing aid use.

Objective: Vestibular schwannomas (VSs) are benign nerve sheath tumors that result from mutation in the tumor suppressor gene NF2, with functional loss of the protein merlin. The authors have previously shown that c-Jun N-terminal kinase (JNK) is constitutively active in human VS cells and plays a central role in their survival by suppressing accumulation of mitochondrial superoxides, implicating JNK inhibitors as a potential systemic treatment for VS. Thus, the authors hypothesized that the adenosine 5'-triphosphate-competitive JNK inhibitor AS602801 would demonstrate antitumor activity in multiple VS models., Methods: Treatment with AS602801 was tested in primary human VS cultures, human VS xenografts, and a genetic mouse model of schwannoma (Postn-Cre;Nf2flox/flox). Primary human VS cell cultures were established from freshly obtained surgical tumor specimens; treatment group media was enriched with AS602801. VS xenograft tumors were established in male athymic nude mice from freshly collected human tumor. Four weeks postimplantation, a pretreatment MRI scan was obtained, followed by 65 days of AS602801 (n = 18) or vehicle control (n = 19) treatment. Posttreatment MRI scans were used to measure final tumor volume. Tumors were then harvested. Finally, Postn-Cre;Nf2flox/flox mice were treated with AS602801 (n = 10) or a vehicle (n = 13) for 65 days. Posttreatment auditory brainstem responses were obtained. Dorsal root ganglia from Postn-Cre;Nf2flox/flox mice were then harvested. In all models, schwannoma identity was confirmed with anti-S100 staining, cell proliferation was measured with the EdU assay, and cell death was measured with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. All protocols were approved by the local institutional review board and Institutional Animal Care and Use Committees., Results: Treatment with AS602801 decreased cell proliferation and increased apoptosis in primary human VS cultures. The systemic administration of AS602801 in mice with human VS xenografts reduced tumor volume and cell proliferation. Last, the AS602801-treated Postn-Cre;Nf2flox/flox mice demonstrated decreased cell proliferation in glial cells in the dorsal root ganglia. However, AS602801 did not significantly delay hearing loss in Postn-Cre;Nf2flox/flox mice up to 3 months posttreatment., Conclusions: The data suggest that JNK inhibition with AS602801 suppresses growth of sporadic and neurofibromatosis type 2-associated VSs. As such, AS602801 is a potential systemic therapy for VS and warrants further investigation.

Objective: Electrocochleography (ECochG) is increasingly being used during cochlear implant (CI) surgery to detect and mitigate insertion-related intracochlear trauma, where a drop in ECochG signal has been shown to correlate with a decline in hearing outcomes. In this study, an ECochG-guided robotics-assisted CI insertion system was developed and characterized that provides controlled and consistent electrode array insertions while monitoring and adapting to real-time ECochG signals., Study Design: Experimental research., Setting: A research laboratory and animal testing facility., Methods: A proof-of-concept benchtop study evaluated the ability of the system to detect simulated ECochG signal changes and robotically adapt the insertion. Additionally, the ECochG-guided insertion system was evaluated in a pilot in vivo sheep study to characterize the signal-to-noise ratio and amplitude of ECochG recordings during robotics-assisted insertions. The system comprises an electrode array insertion drive unit, an extracochlear recording electrode module, and a control console that interfaces with both components and the surgeon., Results: The system exhibited a microvolt signal resolution and a response time <100 milliseconds after signal change detection, indicating that the system can detect changes and respond faster than a human. Additionally, animal results demonstrated that the system was capable of recording ECochG signals with a high signal-to-noise ratio and sufficient amplitude., Conclusion: An ECochG-guided robotics-assisted CI insertion system can detect real-time drops in ECochG signals during electrode array insertions and immediately alter the insertion motion. The system may provide a surgeon the means to monitor and reduce CI insertion-related trauma beyond manual insertion techniques for improved CI hearing outcomes.

Understanding genetic causes of hearing loss can determine the pattern and course of a patient's hearing loss and may also predict outcomes after cochlear implantation. Our goal in this study was to evaluate genetic causes of hearing loss in a large cohort of adults and children with cochlear implants. We performed comprehensive genetic testing on all patients undergoing cochlear implantation. Of the 459 patients included in the study, 128 (28%) had positive genetic testing. In total, 44 genes were identified as causative. The top 5 genes implicated were GJB2 (20, 16%), TMPRSS3 (13, 10%), SLC26A4 (10, 8%), MYO7A (9, 7%), and MT-RNR1 (7, 5%). Pediatric patients had a higher diagnostic rate. This study lays the groundwork for future studies evaluating the relationship between genetic variation and cochlear implant performance.

Acoustic hearing can be preserved after cochlear implant (CI) surgery, allowing for combined electric-acoustic stimulation (EAS) and superior speech understanding compared to electric-only hearing. Among patients who initially retain useful acoustic hearing, 30-40 % experience a delayed hearing loss that occurs 3 or more months after CI activation. Increases in electrode impedances have been associated with delayed loss of residual acoustic hearing, suggesting a possible role of intracochlear inflammation/fibrosis as reported by Scheperle et al. (Hear Res 350:45-57, 2017) and Shaul et al. (Otol Neurotol 40(5):e518-e526, 2019). These studies measured only total impedance. Total impedance consists of a composite of access resistance, which reflects resistance of the intracochlear environment, and polarization impedance, which reflects resistive and capacitive properties of the electrode-electrolyte interface as described by Dymond (IEEE Trans Biomed Eng 23(4):274-280, 1976) and Tykocinski et al. (Otol Neurotol 26(5):948-956, 2005). To explore the role of access and polarization impedance components in loss of residual acoustic hearing, these measures were collected from Nucleus EAS CI users with stable acoustic hearing and subsequent precipitous loss of hearing. For the hearing loss group, total impedance and access resistance increased over time while polarization impedance remained stable. For the stable hearing group, total impedance and access resistance were stable while polarization impedance declined. Increased access resistance rather than polarization impedance appears to drive the increase in total impedances seen with loss of hearing. Moreover, access resistance has been correlated with intracochlear fibrosis/inflammation in animal studies as observed by Xu et al. (Hear Res 105(1-2):1-29, 1997) and Tykocinski et al. (Hear Res 159(1-2):53-68, 2001). These findings thus support intracochlear inflammation as one contributor to loss of acoustic hearing in our EAS CI population., (© 2021. Association for Research in Otolaryngology.)

Hypothesis: Application of photografted zwitterionic coatings to cochlear implant (CI) biomaterials will reduce friction and insertion forces., Background: Strategies to minimize intracochlear trauma during implantation of an electrode array are critical to optimize outcomes including preservation of residual hearing. To this end, advances in thin-film zwitterionic hydrogel coatings on relevant biomaterials may show promise, in addition to the potential of these materials for decreasing the intracochlear foreign body response., Methods: Using a recently designed one-step process, thin-film coatings derived from zwitterionic sulfobetaine methacrylate (SBMA) were photopolymerized and photografted to the surface of polydimethylsiloxane (PDMS, silastic) samples and also to CI arrays from two manufacturers. Fluorescein staining and scanning electron microscopy with energy-dispersive X-ray spectroscopy verified and characterized the coatings. Tribometry was used to measure the coefficient of friction between uncoated and coated PDMS and synthetic and biological tissues. Force transducer measurements were obtained during insertion of uncoated (n = 9) and coated (n = 9) CI electrode arrays into human cadaveric cochleae., Results: SBMA thin-film coating of PDMS resulted in >90% reduction in frictional coefficients with steel, ceramic, and dermal tissue from guinea pigs (p < 0.0001). We employed a novel method for applying covalently bonded, durable, and uniform coating in geographically selective areas at the electrode array portion of the implant. Image analysis confirmed uniform coating of PDMS systems and the CI electrode arrays with SBMA polymer films. During insertion of electrode arrays into human cadaveric cochleae, SBMA coatings reduced maximum force by ∼40% during insertion (p < 0.001), as well as decreasing force variability and the overall work of insertion., Conclusion: Thin-film SBMA photografted coatings on PDMS and electrode arrays significantly reduce frictional coefficients and insertional forces in cadaveric cochleae. These encouraging findings support that thin-film zwitterionic coating of CI electrode arrays may potentially reduce insertional trauma and thereby promote improved hearing and other long-term outcomes., (Copyright © 2021, Otology & Neurotology, Inc.)

Purpose of Review: Advancements in cochlear implant surgical approaches and electrode designs have enabled preservation of residual acoustic hearing. Preservation of low-frequency hearing allows cochlear implant users to benefit from electroacoustic stimulation, which improves performance in complex listening situations, such as music appreciation and speech understanding in noise. Despite the relative high rates of success of hearing preservation, postoperative acoustic hearing outcomes remain unpredictable., Recent Findings: Thin, flexible, lateral wall arrays are preferred for hearing preservation. Both shortened and thin, lateral wall arrays have shown success with hearing preservation and the optimal implant choice is an issue of ongoing investigation. Electrocochleography can monitor cochlear function during and after insertion of the electrode array. The pathophysiology of hearing loss acutely after cochlear implant may differ from that involved in delayed hearing loss following cochlear implant. Emerging innovations may reduce cochlear trauma and improve hearing preservation., Summary: Hearing preservation is possible using soft surgical techniques and electrode arrays designed to minimize cochlear trauma; however, a subset of patients suffer from partial to total loss of acoustic hearing months to years following surgery despite evidence of residual apical hair cell function. Early investigations in robotic-assisted insertion and dexamethasone-eluting implants show promise., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To report a case series of subjective and objective hearing function changes associated with teprotumumab treatment for thyroid eye disease., Observations: A 74-year-old female with a history of Graves' disease with thyroid eye disease was treated with teprotumumab. She had a history of bilateral tinnitus and noticed a subjective improvement in her tinnitus after the second infusion. Audiology testing obtained before, during, and after completion of infusions showed symmetric and rapidly progressive worsening of the patient's sensorineural hearing loss. In contrast, a 42-year-old male with a history of Grave's disease endorsed worsening intermittent tinnitus and low-pitched hearing loss after initiation of teprotumumab. Audiology testing before, during, and after completion of infusions showed stable and normal hearing function bilaterally., Conclusion and Importance: This case series highlights the importance of objective testing in patients prior to and after teprotumumab initiation as subjective hearing changes may not accurately reflect objective hearing function. In addition, this report suggests that teprotumumab may play a role in potentiating sensorineural hearing loss., Competing Interests: The following authors have financial disclosures: EMS is a consultant/advisor for Horizon Therapeutics. The following authors have no financial disclosures: CYY, TC, BAS, MRH., (© 2021 Published by Elsevier Inc.)

Zwitterionic polymer networks have shown promise in reducing the short- and long-term inflammatory foreign body response to implanted biomaterials by combining the antifouling properties of zwitterionic polymers with the mechanical stability provided by cross-linking. Cross-link density directly modulates mechanical properties (i.e., swelling behavior, resistance to stress and strain, and lubricity) but theoretically could reduce desirable biological properties (i.e., antifouling) of zwitterionic materials. This work examined the effect of varying poly(ethylene glycol) dimethacrylate cross-linker concentration on protein adsorption, cell adhesion, equilibrium swelling, compressive modulus, and lubricity of zwitterionic thin films. Furthermore, this work aimed to determine the appropriate balance among each of these mechanical and biologic properties to produce thin films that are strong, durable, and lubricious, yet also able to resist biofouling. The results demonstrated nearly a 20-fold reduction in fibrinogen adsorption on zwitterionic thin films photografted on polydimethylsiloxane (PDMS) across a wide range of cross-link densities. Interestingly, either at high or low cross-link densities, increased levels of protein adsorption were observed. In addition to fibrinogen, macrophage and fibroblast cell adhesion was reduced significantly on zwitterionic thin films, with a large range of cross-link densities, resulting in low cell counts. The macrophage count was reduced by 30-fold, while the fibroblast count was reduced nearly 10-fold on grafted zwitterionic films relative to uncoated films. Increasing degrees of cell adhesion were noted as the cross-linker concentration exceeded 50%. As expected, increased cross-link density resulted in a reduced swelling but greater compressive modulus. Notably, the coefficient of friction was dramatically reduced for zwitterionic thin films compared to uncoated PDMS across a broad range of cross-link densities, an attractive property for insertional implants. This work identified a broad range of cross-link densities that provide desirable antifouling effects while also maintaining the mechanical functionality of the thin films.

Changes in cochlear implant (CI) design and surgical techniques have enabled the preservation of residual acoustic hearing in the implanted ear. While most Nucleus Hybrid L24 CI users retain significant acoustic hearing years after surgery, 6-17 % experience a complete loss of acoustic hearing (Roland et al. Laryngoscope. 126(1):175-81. (2016), Laryngoscope. 128(8):1939-1945 (2018); Scheperle et al. Hear Res. 350:45-57 (2017)). Electrocochleography (ECoG) enables non-invasive monitoring of peripheral auditory function and may provide insight into the pathophysiology of hearing loss. The ECoG response is evoked using an acoustic stimulus and includes contributions from the hair cells (cochlear microphonic-CM) as well as the auditory nerve (auditory nerve neurophonic-ANN). Seven Hybrid L24 CI users with complete loss of residual hearing months after surgery underwent ECoG measures before and after loss of hearing. While significant reductions in CMs were evident after hearing loss, all participants had measurable CMs despite having no measurable acoustic hearing. None retained measurable ANNs. Given histological data suggesting stable hair cell and neural counts after hearing loss (e.g., Quesnel et al. Hear Res. 333:225-234. (2016)), the loss of ECoG and audiometric hearing may reflect reduced synaptic input. This is consistent with the theory that residual CM responses coupled with little to no ANN responses reflect a "disconnect" between hair cells and auditory nerve fibers (Fontenot et al. Ear Hear. 40(3):577-591. 2019). This "disconnection" may prevent proper encoding of auditory stimulation at higher auditory pathways, leading to a lack of audiometric responses, even in the presence of viable cochlear hair cells.

Due to its attractive mechanical properties and biocompatibility, poly(dimethyl)siloxane (PDMS) is widely used in the fabrication of biomedical materials. On the other hand, PDMS is also prone to adsorption of both proteins and bacteria, making PDMS implants susceptible to infection. Herein, we examine the use of durably cross-linked zwitterionic coatings for PDMS surfaces to mitigate bacterial adhesion. Using a single-step photografting technique, poly(sulfobetaine methacrylate) (pSBMA) and poly(carboxybetaine methacrylate) (pCBMA) thin films were covalently attached to PDMS substrates. The abilities of these coatings to resist the adhesion of Staphylococcus aureus and Staphylococcus epidermidis were tested in vitro under both wet and droplet conditions, as well as in subcutaneous and transcutaneous implantation models using Sprague-Dawley rats. Zwitterionic thin films effectively reduced bacterial adhesion in both in vitro and in vivo conditions. This was particularly true for pCBMA-coated materials, which exhibited significant reduction in bacterial adhesion and growth with respect to S. aureus and S. epidermidis for all in vitro conditions as well as the ability to resist bacterial growth on PDMS implants. The results of this study suggest that a simple and durable photografting process can be used to produce polymer thin films capable of preventing infection of implantable medical devices.

Importance: Cochlear implants are a treatment option for individuals with severe, profound, or moderate sloping to profound bilateral sensorineural hearing loss (SNHL) who receive little or no benefit from hearing aids; however, cochlear implantation in adults is still not routine., Objective: To develop consensus statements regarding the use of unilateral cochlear implants in adults with severe, profound, or moderate sloping to profound bilateral SNHL., Design, Setting, and Participants: This study was a modified Delphi consensus process that was informed by a systematic review of the literature and clinical expertise. Searches were conducted in the following databases: (1) MEDLINE In-Process & Other Non-Indexed Citations and Ovid MEDLINE, (2) Embase, and (3) the Cochrane Library. Consensus statements on cochlear implantation were developed using the evidence identified. This consensus process was relevant for the use of unilateral cochlear implantation in adults with severe, profound, or moderate sloping to profound bilateral SNHL. The literature searches were conducted on July 18, 2018, and the 3-step Delphi consensus method took place over the subsequent 9-month period up to March 30, 2019., Main Outcomes and Measures: A Delphi consensus panel of 30 international specialists voted on consensus statements about cochlear implantation, informed by an SR of the literature and clinical expertise. This vote resulted in 20 evidence-based consensus statements that are in line with clinical experience. A modified 3-step Delphi consensus method was used to vote on and refine the consensus statements. This method consisted of 2 rounds of email questionnaires and a face-to-face meeting of panel members at the final round. All consensus statements were reviewed, discussed, and finalized at the face-to-face meeting., Results: In total, 6492 articles were identified in the searches of the electronic databases. After removal of duplicate articles, 74 articles fulfilled all of the inclusion criteria and were used to create the 20 evidence-based consensus statements. These 20 consensus statements on the use of unilateral cochlear implantation in adults with SNHL were relevant to the following 7 key areas of interest: level of awareness of cochlear implantation (1 consensus statement); best practice clinical pathway from diagnosis to surgery (3 consensus statements); best practice guidelines for surgery (2 consensus statements); clinical effectiveness of cochlear implantation (4 consensus statements); factors associated with postimplantation outcomes (4 consensus statements); association between hearing loss and depression, cognition, and dementia (5 consensus statements); and cost implications of cochlear implantation (1 consensus statement)., Conclusions and Relevance: These consensus statements represent the first step toward the development of international guidelines on best practices for cochlear implantation in adults with SNHL. Further research to develop consensus statements for unilateral cochlear implantation in children, bilateral cochlear implantation, combined electric-acoustic stimulation, unilateral cochlear implantation for single-sided deafness, and asymmetrical hearing loss in children and adults may be beneficial for optimizing hearing and quality of life for these patients.

Objectives/hypothesis: The use of a short 10-mm/10-electrode cochlear implant to preserve low-frequency residual hearing was investigated. This report describes the 12-month outcomes of this multicenter clinical trial., Study Design: Single-subject design., Methods: Twenty-eight subjects with low-frequency hearing at or better than 60 dB HL at 500 Hz and severe high-frequency hearing loss were implanted with a Nucleus Hybrid S12 implant in their poorer ear. Speech perception in quiet using Consonant-Nucleus-Consonant (CNC) words and sentences in noise using AzBio sentences was collected pre- and postoperatively at 3, 6, and 12 months. Subjective reporting using the Speech, Spatial, and Qualities of Hearing Scale (SSQ) questionnaire was also collected pre- and postoperatively., Results: Functional hearing preservation was accomplished in 96% of subjects. At 3 and 6 months, 86% of the 28 subjects had maintained functional hearing. By 12 months, 23 out of 27 subjects (85%) had maintained functional hearing (one subject with functional hearing at 6 months withdrew from the study prior to the 12-month visit). Speech perception results demonstrated that 81% of the participants on CNC words and 77% with AzBio sentences in noise had significant improvements using their everyday listening condition at 12 months compared to preoperative performance with bilateral hearing aids. Furthermore, preoperative to 12 months postoperative subjective ratings showed significant improvements for the SSQ., Conclusions: This study demonstrates that a high degree of hearing preservation enabling acoustic-electric hearing and improvement in speech understanding in quiet and in noise can be accomplished using a short-electrode 10-mm cochlear implant., Level of Evidence: 2c Laryngoscope, 130:E548-E558, 2020., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Hypothesis: The objective was to evaluate the effect of cochlear implant (CI) insertion technique on electrode insertion forces and intracochlear trauma. We hypothesize that robotics-assisted insertions will reduce insertion forces and intracochlear trauma compared with manual insertions., Background: Variability in CI outcomes exists across patients, implant centers, surgeons, and electrode types. While surgical techniques that reduce electrode insertion trauma are well established, insertion trauma remains one contributing factor to variability in CI outcomes. Previous work demonstrates that micromechanically controlled insertion tools reduce both maximum insertion forces and insertion variability compared with manual insertions., Methods: CI electrode insertions were performed either by hand (n = 12) or utilizing a robotics-assisted tool (n = 12) in fresh frozen, human cadaveric cochleae using electrodes from four different CI manufacturers. Electrodes array insertion forces were additionally evaluated in benchtop cochlea models. Following cadaveric insertions, samples were imaged via high resolution x-ray microscopy to evaluate electrode position and intracochlear trauma events based on a modified Eshraghi scale., Results: Electrode array insertions performed by robotics-assisted system showed significantly lower insertion forces and variability. Manual electrode array insertions had a significantly higher overall trauma score of 3.1 ± 2.0 compared with 0.9 ± 1.0 for robotics-assisted insertions. Robotics-assisted insertions had higher rate of basilar membrane elevations while manual insertions showed higher rates of severe trauma events., Conclusions: The robotic-assisted insertion system reduced trauma events associated with CI electrode insertions in cadaveric cochleae compared with manual insertions. Surgical devices which help to precisely and more consistently insert electrodes may improve CI outcomes and hearing preservation.

Objectives: The rise in the use of cochlear implants (CIs) has continued to fuel research aimed at improving surgical approaches and the preservation of residual hearing. Current in vivo models involve small animals not suitable for evaluating full-sized CIs nor are prohibitively expensive nonhuman primates. The objective of this study was to develop and evaluate an in vivo model of cochlear implantation in sheep., Methods: Eight adult, female sheep were implanted with full-sized CIs from three manufacturers using a retrofacial approach to the round window. Partial electrode insertions were performed to a depth of 10 to 12 mm before closure. Round window electrocochleography (ECoG) and auditory brainstem responses (ABR) were conducted during and after surgery. Following a 30-day implantation, cochleae were explanted and imaged using both x-ray microscopy and histology., Results: The surgery was well tolerated although limited complications were observed in three of eight sheep. Electrode insertions were up to 12 mm before insertion resistance noted. ECoG and ABR responses were reduced postimplantation, reflecting changes in cochlear mechanics due to the presence of the implant, and/or insertion trauma. Histological and radiological image analysis showed the presence of intracochlear fibrosis as well as one instance of tip fold-over., Conclusions: The use of sheep presents a feasible live-animal model to study cochlear implantations. Full-sized implants as well as surgical techniques can be evaluated on functional outcomes such as ABR and ECoG as well as histological markers for residual hearing including intracochlear fibrosis. Use of this model and surgical approach has potential to evaluate CIs and surgical techniques in both the acute and chronic setting.

Cochlear implantation has become the standard-of-care for adults and children with severe to profound hearing loss. There is growing evidence that qualitative as well as quantitative deficits in the auditory nerve may affect cochlear implant (CI) outcomes. Auditory neuropathy spectrum disorder (ANSD) is characterized by dysfunctional transmission of sound from the cochlea to the brain due to defective synaptic function or neural conduction. In this review, we examine the precise mechanisms of genetic lesions causing ANSD and the effect of these lesions on CI outcomes. Reviewed data show that individuals with lesions that primarily affect the cochlear sensory system and the synapse, which are bypassed by the CI, have optimal CI outcomes. Individuals with lesions that affect the auditory nerve show poor performance with CIs, likely because neural transmission of the electrical signal from the CI is affected. We put forth a nuanced molecular classification of ANSD that has implications for preoperative counseling for patients with this disorder prior to cochlear implantation. We propose that description of ANSD patients should be based on the molecular site of lesion typically derived from genetic evaluation (synaptopathy vs. neuropathy) as this has implications for expected CI outcomes. Improvements in our understanding of genetic site of lesions and their effects on CI function should lead to better CI outcomes, not just for individuals with auditory neuropathy, but all individuals with hearing loss.

Hypothesis: Use of micro-mechanical control during cochlear implant (CI) electrode insertion will result in reduced number and magnitude of pressure transients when compared with standard insertion by hand., Introduction: With increasing focus on hearing preservation during CI surgery, atraumatic electrode insertion is of the utmost importance. It has been established that large intracochlear pressure spikes can be generated during the insertion of implant electrodes. Here, we examine the effect of using a micro-mechanical insertion control tool on pressure trauma exposures during implantation., Methods: Human cadaveric heads were surgically prepared with an extended facial recess. Electrodes from three manufacturers were placed both by using a micro-mechanical control tool and by hand. Insertions were performed at three different rates: 0.2 mm/s, 1.2 mm/s, and 2 mm/s (n = 20 each). Fiber-optic sensors measured pressures in scala vestibuli and tympani., Results: Electrode insertion produced pressure transients up to 174 dB SPL. ANOVA revealed that pressures were significantly lower when using the micro-mechanical control device compared with insertion by hand (p << 0.001). No difference was noted across electrode type or speed. Chi-square analysis showed a significantly lower proportion of insertions contained pressure spikes when the control system was used (p << 0.001)., Conclusion: Results confirm previous data that suggest CI electrode insertion can cause pressure transients with intensities similar to those elicited by high-level sounds. Results suggest that the use of a micro-mechanical insertion control system may mitigate trauma from pressure events, both by reducing the amplitude and the number of pressure spikes resulting from CI electrode insertion.

Central nervous system neurons become postmitotic when radial glia cells divide to form neuroblasts. Neuroblasts may migrate away from the ventricle radially along glia fibers, in various directions or even across the midline. We present four cases of unusual migration that are variably connected to either pathology or formation of new populations of neurons with new connectivities. One of the best-known cases of radial migration involves granule cells that migrate from the external granule cell layer along radial Bergman glia fibers to become mature internal granule cells. In various medulloblastoma cases this migration does not occur and transforms the external granule cell layer into a rapidly growing tumor. Among the ocular motor neurons is one unique population that undergoes a contralateral migration and uniquely innervates the superior rectus and levator palpebrae muscles. In humans, a mutation of a single gene ubiquitously expressed in all cells, induces innervation defects only in this unique motor neuron population, leading to inability to elevate eyes or upper eyelids. One of the best-known cases for longitudinal migration is the facial branchial motor (FBM) neurons and the overlapping inner ear efferent population. We describe here molecular cues that are needed for the caudal migration of FBM to segregate these motor neurons from the differently migrating inner ear efferent population. Finally, we describe unusual migration of inner ear spiral ganglion neurons that result in aberrant connections with disruption of frequency presentation. Combined, these data identify unique migratory properties of various neuronal populations that allow them to adopt new connections but also sets them up for unique pathologies.

Objective: Stereotactic radiation therapy is increasingly used to treat vestibular schwannomas (VSs) primarily and to treat tumor remnants following microsurgery. Little data are available regarding the effects of radiation on VS cells. Tyrosine nitrosylation is a marker of oxidative stress following radiation in malignant tumors. It is not known how long irradiated tissue remains under oxidative stress, and if such modifications occur in benign neoplasms such as VSs treated with significantly lower doses of radiation. We immunostained sections from previously radiated VSs with an antibody that recognizes nitrosylated tyrosine residues to assess for ongoing oxidative stress., Study Design: Immunohistochemical analysis., Methods: Four VSs, which recurred after excision, were treated with stereotactic radiation therapy. Ultimately each tumor required salvage reresection for regrowth. Histologic sections of each tumor before and after radiation were immunolabeled with a monoclonal antibody specific to nitrotyrosine and compared. Two VSs that underwent reresection of a growing tumor remnant without previous radiation therapy served as additional controls., Results: Irradiated tumors enlarged in volume by 3.16 to 8.62 mL following radiation. Preradiation sections demonstrated little to no nitrotyrosine immunostaining. Three of four of irradiated VSs demonstrated increased nitrotyrosine immunostaining in the postradiation sections compared with preradiation tumor sections. Nonirradiated VSs did not label with the antinitrotyrosine antibody., Conclusions: VSs exhibit oxidative stress up to 7 years after radiotherapy, yet these VSs continued to enlarge. Thus, VSs that grow following radiation appear to possess mechanisms for cell survival and proliferation despite radiation-induced oxidative stress.

Purpose of Review: Facial nerve paralysis is a debilitating condition. Bell's palsy and temporal bone trauma are common causes of acute facial palsy, with recurrent idiopathic paralysis and Melkersson-Rosenthal syndrome accounting for a smaller subset of cases. Properly selected patients may benefit from facial nerve decompression. This article will review the relevant literature on facial nerve decompression., Recent Findings: The middle cranial fossa approach provides access to the primary site of lesion in Bell's palsy while preserving hearing. Patients with complete facial paralysis secondary to Bell's palsy or temporal bone trauma, more than 90% degeneration on electroneurography testing, and absent voluntary electromyography within 14 days of onset may benefit from facial nerve decompression. Facial nerve decompression may prevent future occurrences of recurrent forms of facial nerve paralysis. The return of facial nerve function following decompression will occur over weeks to months., Summary: Appropriately selected patients with facial paralysis secondary to Bell's palsy or temporal bone trauma may benefit from facial nerve decompression. Patients should be counseled regarding the risks of decompression and that the return of maximal facial nerve function may be delayed up to 12 months.

Objective: To evaluate the association between signal changes during intraoperative audiologic monitoring and postoperative audiometric outcome in patients undergoing vestibular schwannoma (VS) resection via middle cranial fossa (MCF) approach., Study Design: Retrospective chart review., Setting: Academic tertiary referral center., Patients: One hundred twenty-six consecutive patients (mean age 48.6 yrs, range 16-67; mean tumor size 9.9 mm, range 1.8-18.9 mm) who underwent MCF VS resection., Interventions: Intraoperative audiologic monitoring using auditory brainstem response (ABR) and direct cochlear nerve action potential (CNAP)., Main Outcome Measures: Intraoperative ABR wave V and CNAP N1 amplitudes and postoperative pure-tone average (PTA) and word recognition score (WRS)., Results: On ABR, absent wave V amplitude was associated with an 81.1% increase and 82.3% decrease in postoperative PTA and WRS, respectively. On CNAP, decreased or absent N1 amplitude was associated with 47.3 and 100% increase, respectively, in postoperative PTA, and 45.3% and 100% decrease, respectively, in postoperative WRS. Receiver-operating curve analysis showed that ABR combined with CNAP using a Cueva electrode achieved the highest diagnostic accuracy in predicting postoperative hearing decline when measured by WRS class (sensitivity 83.3%, specificity 100%), and performed better compared with each modality alone., Conclusion: Intraoperative ABR wave V and CNAP amplitude changes are associated with changes in postoperative hearing, and dual modality monitoring was more diagnostic of postoperative hearing decline compared with each modality alone during MCF VS resection. Overall, intraoperative ABR and CNAP were more specific than sensitive for postoperative hearing decline.

Objective: To determine the association between radiographic cerebrospinal fluid (CSF) cap in the lateral internal auditory canal (IAC) and likelihood of successful hearing preservation in middle cranial fossa (MCF) vestibular schwannoma (VS) surgery., Study Design: Retrospective chart review., Setting: Academic tertiary referral center., Patients: One hundred thirty-eight consecutive patients (mean age/standard deviation, SD, 50/11 yr) who underwent MCF VS resection., Interventions: MCF VS excision., Main Outcome Measures: Size of fundal fluid cap on preoperative magnetic resonance imaging (MRI), pre- and postoperative pure-tone average (PTA), and word recognition score (WRS)., Results: Mean tumor and fundal fluid sizes were 9.7 mm (SD, 3.9 mm) and 2.8 mm (SD, 1.7 mm), respectively. On bivariate analysis, fundal fluid size was associated with larger tumor size (p = 0.005) but not changes in postoperative PTA (p = 0.45) or WRS (p = 0.17). When fundal fluid size was stratified as none (<1 mm), small (≥1 mm and <4 mm), and large (≥4 mm), no significant differences were seen in rates of hearing preservation. Using multivariate linear regression models adjusting for patient age, sex, tumor nerve of origin, neurofibromatosis type II status, and preoperative PTA and WRS, superior vestibular nerve tumor origin but not increasing fundal fluid size was associated with preserved postoperative PTA or WRS., Conclusions: Presence or size of CSF fluid cap may not be a reliable prognostic indicator for hearing preservation in MCF VS resection, with important implications for patient counseling.

Objective: Define the long-term audiometric outcomes of vestibular schwannomas treated using the middle cranial fossa (MCF) approach., Study Design: Retrospective records review., Setting: University-based tertiary referral center., Patients: Patients undergoing treatment of small vestibular schwannomas using the MCF approach., Intervention(s): MCF exposure and treatment of small vestibular schwannomas., Main Outcome Measure(s): Demographic and audiometric variables were assessed., Results: Thirteen subjects demonstrated audiometric data for review. The average time between surgery and the most recent audiometric testing was 14 years (range 10-18 yr). The mean baseline pure-tone average (PTA) was 36 dB HL and the most recent PTA was 59 dB HL in the operated ear. The mean baseline PTA was 16 dB HL and the most recent PTA was 37 dB HL in the nonoperated ear. The mean change from baseline to most recent follow-up was a threshold elevation of 22 and 19 dB HL in the operated and nonoperated ears, respectively. The mean baseline speech discrimination score (SDS) was 83% and the most recent SDS was 73% in the operated ear. The mean baseline SDS was 98% and the most recent SDS was 94% in the nonoperated ear. The mean changes from baseline to most recent follow-up were 10 and 0% SDS depression in the operated and nonoperated ears, respectively. The rates of changes in PTA and SDS were not statistically different between the operated and nonoperated ears., Conclusions: Surgically preserved hearing is maintained in the majority of patients more than 10 years following surgery. PTA and SDS changes were similar between the ipsilateral and contralateral ears.

Objective: To study the indications and outcomes of lateral sphenoidectomy as part of a combined skull base approach in the treatment of tumors involving Meckel's cave (MC) and cavernous sinus (CS)., Study Design: Retrospective patient series., Setting: Tertiary referral center., Patients: Twenty-two consecutive patients (mean age: 45 yr, range: 16-76) who underwent transzygomatic, extended middle fossa approaches for tumors involving MC and CS., Interventions: Surgical access to MC and CS was achieved via extended middle fossa, trans-clinoid approach. Lateral sphenoidectomy was defined as drill-out of the greater sphenoid wing lateral to foramen rotundum and ovale, decompression of superior orbital fissure, and removal of anterior clinoid process. Reconstruction was achieved using combination of autologous and synthetic materials. Eleven patients (50%) received adjuvant radiation., Main Outcome Measures and Results: Tumor pathologies included meningioma (16 patients), epidermoid cyst (2), trigeminal schwannoma (2), invasive pituitary adenoma (1), and chondrosarcoma (1). Mean (range) preoperative tumor size was 4.0 cm (1.3-9). Mean (range) length of follow-up was 4 years (range 0.1-10). Overall tumor control and gross total resection were achieved in 95 and 23% of patients, respectively. Lateral sphenoidectomy was performed in 16 patients (73%) for enhanced surgical access and/or tumor extension to the infratemporal fossa (6 patients). Postoperatively, cranial nerve deficits occurred in 12 (55%) patients (V-9 patients; III, IV, or VI-4; VII-2; VIII-2). Cerebrospinal fluid leak and hydrocephalus occurred in two and four patients, respectively., Conclusion: In combination with middle fossa-based approaches to tumors involving MC and CS, lateral sphenoidectomy may play a viable role in tumor access and control.

Hypothesis: Microtopographical patterns generated by photopolymerization of methacrylate polymer systems will direct growth of neurites from adult neurons, including spiral ganglion neurons (SGNs)., Background: Cochlear implants (CIs) provide hearing perception to patients with severe to profound hearing loss. However, their ability to encode complex auditory stimuli is limited due, in part, to poor spatial resolution caused by spread of the electrical currents in the inner ear. Directing the regrowth of SGN peripheral processes towards stimulating electrodes could help reduce current spread and improve spatial resolution provided by the CI. Previous work has demonstrated that micro- and nano-scale patterned surfaces precisely guide the growth of neurites from a variety of neonatal neurons including SGNs. Here, we sought to determine the extent to which adult neurons likewise respond to these topographical surface features., Methods: Photopolymerization was used to fabricate methacrylate polymer substrates with micropatterned surfaces of varying amplitudes and periodicities. Dissociated adult dorsal root ganglion neurons (DRGNs) and SGNs were cultured on these surfaces and the alignment of the neurite processes to the micropatterns was determined., Results: Neurites from both adult DRGNs and SGNs significantly aligned to the patterned surfaces similar to their neonatal counterparts. Further DRGN and SGN neurite alignment increased as the amplitude of the microfeatures increased. Decreased pattern periodicity also improved neurite alignment., Conclusion: Microscale surface topographic features direct the growth of adult SGN neurites. Topographical features could prove useful for guiding growth of SGN peripheral axons towards a CI electrode array.

The first successful in vitro experiments on the cochlea were conducted in 1928 by Honor Fell (Fell, Arch Exp Zellforsch 7(1):69-81, 1928). Since then, techniques for culture of this tissue have been refined, and dissociated primary culture of the spiral ganglion has become a widely accepted in vitro model for studying nerve damage and regeneration in the cochlea. Additionally, patterned substrates have been developed that facilitate and direct neural outgrowth. A number of automated and semi-automated methods for quantifying this neurite outgrowth have been utilized in recent years (Zhang et al., J Neurosci Methods 160(1):149-162, 2007; Tapias et al., Neurobiol Dis 54:158-168, 2013). Here, we describe a method to study the effect of topographical cues on spiral ganglion neurite and Schwann cell alignment. We discuss our microfabrication process, characterization of pattern features, cell culture techniques for both spiral ganglion neurons and spiral ganglion Schwann cells. In addition, we describe protocols for reducing fibroblast count, immunocytochemistry, and methods for quantifying neurite and Schwann cell alignment.

Cochlear implantation and cochlear implants (CIs) have a long history filled with innovations that have resulted in the high-performing device's currently available. Several promising technologies have been reviewed in this article, which hold the promise to drive performance even higher. Remote CI programming, totally implanted devices, improved neural health and survival through targeted drug therapy and delivery, intraneural electrode placement, electroacoustical stimulation and hybrid CIs, and methods to enhance the neural-prosthesis interface are evolving areas of innovation reviewed in this article., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Vestibular schwannomas (VSs) arise from Schwann cells (SCs) and result from the loss of function of merlin, the protein product of the NF2 tumor suppressor gene. In contrast to non-neoplastic SCs, VS cells survive long-term in the absence of axons. We find that p75(NTR) is overexpressed in VSs compared with normal nerves, both at the transcript and protein level, similar to the response of non-neoplastic SCs following axotomy. Despite elevated p75(NTR) expression, VS cells are resistant to apoptosis due to treatment with proNGF, a high affinity ligand for p75(NTR) . Furthermore, treatment with proNGF protects VS cells from apoptosis due to c-Jun N-terminal kinase (JNK) inhibition indicating that p75(NTR) promotes VS cell survival. Treatment of VS cells with proNGF activated NF-κB while inhibition of JNK with SP600125 or siRNA-mediated knockdown reduced NF-κB activity. Significantly, proNGF also activated NF-κB in cultures treated with JNK inhibitors. Thus, JNK activity appears to be required for basal levels of NF-κB activity but not for proNGF-induced NF-κB activity. To confirm that the increase in NF-κB activity contributes to the prosurvival effect of proNGF, we infected VS cultures with Ad.IκB.SerS32/36A virus, which inhibits NF-κB activation. Compared with control virus, Ad.IκB.SerS32/36A significantly increased apoptosis including in VS cells treated with proNGF. Thus, in contrast to non-neoplastic SCs, p75(NTR) signaling provides a prosurvival response in VS cells by activating NF-κB independent of JNK. Such differences may contribute to the ability of VS cells to survive long-term in the absence of axons., (© 2014 Wiley Periodicals, Inc.)

Ménière disease (MD) is a complex disorder of unknown etiology characterized by the symptom triad of vertigo, sensorineural hearing loss, and tinnitus. Its reported incidence is 1-2 per 1,000 in Caucasians and 0.03-0.37 per 1,000 in Japanese. Doi et al. [Doi et al. (2005); ORL J Otorhinolaryngol Relat Spec 67:289-293] recently reported that two single nucleotide polymorphisms (SNPs) in KCNE1 and KCNE3 are associated with MD in Japanese subjects. Consistent with this possibility, these two genes encode potassium channels that are expressed in the stria vascularis and endolymphatic sac, respectively, and their role in ion transport suggests that they may be important in inner ear homeostasis. To establish whether a similar association exists in the Caucasian MD population, we sequenced the coding regions and exon-intron boundaries of both genes in 180 Caucasian persons with MD and 180 matched Caucasian controls. Neither of the two reported SNPs was significantly associated with MD when compared to the Caucasian controls (KCNE1, P = 0.55; KCNE3, P = 0.870). Comparison of allele frequencies between the Japanese MD population and our study population revealed no significant difference between groups (KCNE1, P = 0.90; KCNE3, P = 0.862), suggesting that the significant differences reported in the Japanese study arose from their control population. Six additional SNPs in both KCNE1 and KCNE3 were genotyped and none was associated with MD. Population stratification within our MD and Caucasian control population was excluded. Our data show that SNPs in KCNE1 and KCNE3 are not associated with MD in Caucasians.

The effect of membrane electrical activity on spiral ganglion neuron (SGN) neurite growth remains unknown despite its relevance to cochlear implant technology. We demonstrate that membrane depolarization delays the initial formation and inhibits the subsequent extension of cultured SGN neurites. This inhibition depends directly on the level of depolarization with higher levels of depolarization causing retraction of existing neurites. Cultured SGNs express subunits for L-type, N-type, and P/Q type voltage-gated calcium channels (VGCCs) and removal of extracellular Ca(2+) or treatment with a combination of L-type, N-type, and P/Q-type VGCC antagonists rescues SGN neurite growth under depolarizing conditions. By measuring the fluorescence intensity of SGNs loaded with the fluorogenic calpain substrate t-butoxy carbonyl-Leu-Met-chloromethylaminocoumarin (20 microM), we demonstrate that depolarization activates calpains. Calpeptin (15 microM), a calpain inhibitor, prevents calpain activation by depolarization and rescues neurite growth in depolarized SGNs suggesting that calpain activation contributes to the inhibition of neurite growth by depolarization.

Hypothesis: ErbB2 resides in lipid rafts (regions of receptor regulation) in vestibular schwannoma (VS) cells., Background: ErbB2 is a growth factor receptor critical for Schwann cell (SC) proliferation and development. ErbB2 localization and activity may be regulated by merlin, an adaptor protein deficient in VS. Lipid rafts are microdomains in the plasma membrane that amplify and regulate receptor signaling. Persistence of erbB2 in lipid rafts in VS due to merlin deficiency may explain increased VS cell growth., Methods: Protein extracts from VS or rat sciatic nerve (proximal or distal to a crush injury) were isolated into lipid raft and nonraft fractions and immunoblotted for erbB2, phosphorylated erbB2, and merlin (for sciatic nerve). Cultured VS cells were probed with anti-erbB2 antibody and a lipid raft marker, cholera toxin B (CTB)., Results: ErbB2 moves to lipid rafts in proliferating SCs and is persistently localized to lipid rafts in VS cells. ErbB2 is phosphorylated (activated) in lipid rafts. ErbB2 colocalized with CTB in cultured VS cells, confirming raft targeting. Merlin also persistently localized to lipid rafts in SCs, and its relative phosphorylation increased in proliferating cells., Conclusion: Lipid raft localization of erbB2 in proliferating SCs and in VS cells supports a critical role for lipid rafts in amplifying/regulating erbB2 signaling. Merlin resides in lipid rafts in SCs, and its phosphorylation increases in proliferating SCs, suggesting it regulates cell proliferation within lipid rafts. The absence of merlin in VS may therefore lead to persistent erbB2 localization to lipid rafts and increased cell proliferation.

Objectives: After axotomy, Schwann cells (SCs), required for successful nerve regeneration, undergo a number of cellular changes including dedifferentiation, proliferation, expression of molecules that support axon growth, and apoptosis. This study investigated the role of p75, sortilin, and proneurotrophins in SC survival after facial nerve (FN) axotomy., Study Design: Preliminary animal study., Methods: With use of FN SCs, expression of p75 and its coreceptor sortilin were quantified by immunofluorescence on days 12, 22, and 52 after axotomy in vivo and by Western blot in vitro. Contralateral FNs served as a control. SC apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). To verify a causative role for p75 in FN SC death, cultured FN SCs were treated with pro-nerve growth factor (NGF), and apoptosis was determined by TUNEL., Results: Expression of p75 and sortilin increased in FN SCs distal (P < .05) to the axotomy compared with the contralateral controls for all time points. SC apoptosis also significantly increased in the distal segment compared with the contralateral and proximal portions (P < .05). ProNGF, a p75 ligand, increased apoptosis and p75 expression in primary FN SC cultures., Conclusion: FN axotomy increases p75 and sortilin expression in SCs, which correlates with increased apoptosis. These findings suggest roles for p75 and sortilin in SC loss after FN injury. Sortilin is a novel target in promoting FN healing after injury.

Spiral ganglion neurons (SGNs) provide afferent innervation to the cochlea and rely on contact with hair cells (HCs) for their survival. Following deafferentation due to hair cell loss, SGNs gradually die. In a rat culture model, we explored the ability of prosurvival members of the Bcl-2 family of proteins to support the survival and neurite outgrowth of SGNs. We found that overexpression of either Bcl-2 or Bcl-xL significantly increases SGN survival in the absence of neurotrophic factors, establishing that the Bcl-2 pathway is sufficient for SGN cell survival and that SGN deprived of trophic support die by an apoptotic mechanism. However, in contrast to observations in central neurons and PC12 cells where Bcl-2 appears to promote neurite growth, both Bcl-2 and Bcl-xL overexpression dramatically inhibit neurite outgrowth in SGNs. This inhibition of neurite growth by Bcl-2 occurs in nearly all SGNs even in the presence of multiple neurotrophic factors implying that Bcl-2 directly inhibits neurite growth rather than simply rescuing a subpopulation of neurons incapable of extending neurites without additional stimuli. Thus, although overexpression of prosurvival members of the Bcl-2 family prevents SGN loss following trophic factor deprivation, the inhibition of neurite growth by these molecules may limit their efficacy for support of auditory nerve maintenance or regeneration following hair cell loss., ((c) 2007 Wiley Periodicals, Inc.)

Objective: To report a unique presentation of disseminated histoplasmosis., Study Design: Case report., Setting: University hospital, tertiary referral center., Patient: Our patient presented with vertigo, tinnitus, and unilateral hearing loss, and was initially found to have a 5-mm enhancing left internal auditory canal mass, as revealed by a magnetic resonance imaging (MRI) scan. Subsequently, the patient developed multiple focal neurologic deficits., Interventions: Magnetic resonance imaging and treatment with intravenously administered amphotericin B, with subsequent oral administration of itraconazole., Main Outcome Measures: Clinical presentation and imaging findings of Histoplasmosis involving the cranial nerve VIII., Results: A subsequent MRI scan revealed enlargement of the initial lesion and multiple parenchymal lesions. Further workup revealed a pulmonary lesion; the diagnosis of disseminated histoplasmosis was made on the basis of bronchoalveolar lavage culture., Conclusion: Infectious processes, including disseminated histoplasmosis, should be considered in the differential of internal auditory canal masses, especially in the setting of rapid progression of symptoms.

The Coxsackievirus and Adenovirus Receptor (CAR) is an essential regulator of cell growth and adhesion during development. The gene for CAR, CXADR, is located within the genomic locus for Usher syndrome type 1E (USH1E). Based on this and a physical interaction with harmonin, the protein responsible for USH1C, we hypothesized that CAR may be involved in cochlear development and that mutations in CXADR may be responsible for USH1E. The expression of CAR in the cochlea was determined by PCR and immunofluorescence microscopy. We found that CAR expression is highly regulated during development. In neonatal mice, CAR is localized to the junctions of most cochlear cell types but is restricted to the supporting and strial cells in adult cochlea. A screen of two populations consisting of non-syndromic deaf and Usher 1 patients for mutations in CXADR revealed one haploid mutation (P356S). Cell surface expression, viral receptor activity, and localization of the mutant form of CAR were indistinguishable from wild-type CAR. Although we were unable to confirm a role for CAR in autosomal recessive, non-syndromic deafness, or Usher syndrome type 1, based on its regulation, localization, and molecular interactions, CAR remains an attractive candidate for genetic deafness.

Vestibular schwannomas (VSs) are benign tumors that arise from the Schwann cells (SCs) lining the vestibular nerve. VS cells survive and proliferate far from neurons and axonally derived growth factors. We have previously shown that VSs produce the glial growth factor, neuregulin-1 (NRG1), and its receptors, ErbB2 and ErbB3. In the present work, we explore the contribution of constitutive NRG1:ErbB signaling to human VS cell proliferation. We confirm that human VSs, which express markers of immature and denervated SCs, also express endogenous NRG1 and activated ErbB2. We find that a blocking anti-NRG1 antibody and trastuzumab (Herceptin, HCN), a humanized anti-ErbB2 inhibitory monoclonal antibody, effectively inhibit NRG1 induced SC proliferation. Treatment of primary VS cultures with anti-NRG1 or HCN reduces cell proliferation in the absence of exogenous NRG1. Furthermore, conditioned medium from VS cell cultures contains NRG1 and stimulates SC proliferation in SC cultures, an effect that is inhibited by anti-NRG1 and HCN. These data suggest an autocrine pathway of VS growth stimulation involving NRG and ErbB receptors. Inhibition of constitutive NRG:ErbB signaling reduces VS cell proliferation in vitro and may have therapeutic potential for patients with VSs.

Objective: Evaluate factors affecting outcomes of small acoustic neuroma (AN) removal via a middle cranial fossa (MCF) approach, and compare results to published data on observation and radiation therapy., Study Design: Retrospective chart review., Setting: Academic tertiary referral center., Methods: 162 consecutive patients (ages 19-70) with unilateral AN (0.2-2.5 cm in largest dimension) removed through a MCF approach were reviewed focusing on preservation of hearing, facial nerve function and complications. One hundred thirteen patients had pre-operative word recognition scores (WRS)>70%., Results: Both tumor size and pre-operative WRS were related to post-operative WRS (p<0.01). Overall, at least some hearing was preserved in 94 (60%) of the 156 patients who had hearing before surgery. If the WRS was also >70% (N=113), 56 (50%) maintained WRS>70%. Importantly, WRS for 12 others improved to >70% after surgery. When the patients were stratified by tumor size, the patients with small tumors (2-10 mm) faired better than the overall group. At least some hearing was preserved in 65 (72%) of the 90 patients. If the WRS was also >70% (N=66), 39 (59%) maintained WRS>70%. WRS for eight others improved to >70% after surgery. When the tumor was 1.1-1.4 cm (N=34), the chance of preserving some hearing decreased to 42% (14/33). If the WRS was also >70% (N=23), 9 (39%) maintained WRS>70%. WRS for three others improved to >70% after surgery. When the tumor reached 1.5-2.5 cm (N=35), the hearing preservation rate was 43%. If the WRS was also >70% (N=24), only eight (33%) maintained WRS of 70%, and one other improved to >70%. The addition of intra-operative whole eighth nerve near field monitoring improved results during small tumor (70% WRS in 76% (22/29) of those with >70% pre-operative WRS. Good facial nerve function (HB I-II) was achieved in 97% (86% HB I). When tumor size was

A 7-year-old boy was found to have hearing loss on the left side on school screening. On otolaryngology examination he was noted to have a vascular mass behind the tympanic membrane, located inferiorly. Computerized tomography (CT) scan and magnetic resonance imaging (MRI) revealed a dehiscent high jugular bulb. He underwent surgical decompression of the jugular bulb. Two weeks after surgery, he complained of headache and diplopia and was noted to have papilledema and a sixth nerve palsy without visual loss. Cranial MRI scan revealed thrombosis of the left internal jugular vein, transverse and sigmoid sinus. There was no cerebral venous infarct. He was treated with oral acetazolamide and anticoagulation. Two months later he was symptomatically better, neurologically intact with resolved sixth nerve palsy and markedly improved optic disc edema. To our knowledge this is the first reported case of venous thrombosis following jugular bulb surgery in the English language ophthalmologic literature.

Objectives: This study was designed to evaluate the authors' experience with canal wall reconstruction (CWR) tympanomastoidectomy with mastoid obliteration in the treatment of chronic otitis media with cholesteatoma., Study Design: Institutional review board approved retrospective case review., Methods: Retrospective review was performed of all patients undergoing CWR tympanomastoidectomy with mastoid obliteration from 1997 to 2004. Data included pre- and postoperative audiometry, findings at second look surgery with ossiculoplasty, and postoperative complications including wound infection and canal wall displacement., Results: One hundred thirty ears in 127 adults and children underwent the procedure. Mean time postoperative was 48 (range 2-94) months. A second look ossiculoplasty was performed in 102 (78%). Percentage of ears that remain safe without evidence of recurrence was 98.5. The postoperative infection rate decreased from an initial rate of 14.3% to 4.5% for the last 88 ears after protocol modification. Recurrence occurred in two (1.5%) patients, requiring conversion to a canal wall down mastoidectomy., Conclusions: A CWR technique can provide improved intraoperative exposure of the middle ear and mastoid without creating a mastoid bowl and reduces the incidence of recurrent disease. A single procedure is used for all patients with acquired cholesteatoma, including children.

Purpose of Review: Degeneration of spiral ganglion neurons following hair cell loss carries critical implications for efforts to rehabilitate severe cases of hearing loss with cochlear implants or hair cell regeneration. This review considers recently identified neurotrophic factors and therapeutic strategies which promote spiral ganglion neuron survival and neurite growth. Replacement of these factors may help preserve or regenerate the auditory nerve in patients with extensive hair cell loss., Recent Findings: Spiral ganglion neurons depend on neurotrophic factors supplied by hair cells and other targets for their development and continued survival. Loss of this trophic support leads to spiral ganglion neuron death via apoptosis. Hair cells support spiral ganglion neuron survival by producing several peptide neurotrophic factors such as neurotrophin-3 and glial derived neurotrophic factor. In addition, neurotransmitter release from the hair cells drives membrane electrical activity in spiral ganglion neurons which also supports their survival. In animal models, replacement of peptide neurotrophic factors or electrical stimulation with an implanted electrode attenuates spiral ganglion neuron degeneration following deafferentation. Cell death inhibitors can also preserve spiral ganglion neuron populations. Preliminary studies show that transfer of stem cells or neurons from other ganglia are two potential strategies to replace lost spiral ganglion neurons. Inducing the regrowth of spiral ganglion neuron peripheral processes to approximate or contact cochlear implant electrodes may help optimize signaling from a diminished population of neurons., Summary: Recent studies of spiral ganglion neuron development and survival have identified several trophic and neuritogenic factors which protect these specialized cells from degeneration following hair cell loss. While still preliminary, such strategies show promise for future clinical applications.

Objective: To determine the surgical outcomes in patients with endolymphatic sac tumors (ELSTs)., Study Design: Retrospective review of patients at a referral-based otology-neurotology practice., Methods: A review of the records from the House Ear Clinic revealed 16 patients treated for ELSTs from 1971 to 2002. This article reports the treatment outcomes for the 14 patients for whom clinical data were available., Results: Sensorineural hearing loss, tinnitus, and dizziness were the most common presenting signs and symptoms. Six patients presented with facial weakness, and three patients had symptoms characteristic of Menière's syndrome. One patient suffered from Von Hippel-Lindau disease. Patients underwent microsurgical removal and were followed for an average of 59.6 months. Patients that presented with normal facial function maintained excellent postoperative function, and hearing was preserved in two patients with small tumors. Two patients suffered persistent, progressive disease despite multiple attempts at microsurgical removal and radiotherapy. Both had incomplete resections of their initial tumors. A third patient developed a small recurrent tumor that was successfully managed by a second attempt at microsurgical removal., Conclusions: Taken together with other reports, these results suggest that ELSTs are best managed by complete surgical resection. This can generally be accomplished with minimal additional morbidity.

Hypothesis: We sought to determine whether vestibular schwannomas are capable of producing and responding to the glial growth factor neuregulin., Background: Neuregulin is a neuronally derived trophic factor that interacts with erbB2 and erbB3 receptors on Schwann cells and is required for normal Schwann cell proliferation, survival, and development. Vestibular schwannomas grow several millimeters or even centimeters away from adjacent axons, suggesting that vestibular schwannomas do not depend critically on axons for their proliferation or survival. This raises the possibility that vestibular schwannomas themselves produce and respond to trophic factors in an autocrine fashion., Methods: Pathologic specimens from eight patients undergoing microsurgical removal of vestibular schwannomas and one patient undergoing vestibular nerve section were immunostained with anti-neuregulin, anti-erbB2, anti-erbB3, and anti-phosphorylated-erbB2 antibodies. Three patients had received previous gamma knife radiation therapy and two patients had neurofibromatosis Type 2., Results: The Scarpa ganglion neurons express neuregulin, and normal vestibular Schwann cells express erbB2 and erbB3. Vestibular schwannomas from all eight patients demonstrated neuregulin, erbB2, and erbB3 immunoreactivity. In addition, all vestibular schwannomas demonstrated immunoreactivity to anti-phosphorylated-erbB2 antibody that only recognizes erbB2 when it is phosphorylated, or activated., Conclusion: These results demonstrate that vestibular schwannomas express neuregulin and its receptors, erbB2 and erbB3. Because erbB2 exists in an activated state, as evidenced by phosphorylated-erbB2 immunoreactivity, it likely responds to the locally produced neuregulin. This suggests the possibility that vestibular schwannomas produce and respond to neuregulin in an autocrine fashion.

Sarcomas of the skull base occurring in the field of prior radiotherapy are rare; only a few have been reported in the English literature. We report a fatal osteosarcoma of the skull base arising in a patient with McCune-Albright syndrome and severe fibrous dysplasia of the skull base 22 years after radiation therapy for a pituitary adenoma. This malignancy fulfills Cahan's criteria for a radiation-induced tumor in that it arose in the radiation field of a pituitary adenoma with a latency of 22 years. The literature on radiation-induced sarcomas of the skull base is reviewed, and the predisposition of patients with isolated fibrous dysplasia or McCune-Albright syndrome to develop radiation-induced tumors is discussed. Although the risk of radiation-induced malignancy is low in the general population, special consideration should be given when contemplating the use of radiotherapy for benign disease in patients with McCune-Albright syndrome or isolated fibrous dysplasia.

Spiral ganglion neuron (SGN) survival in vitro can be maintained by neurotrophins, permeant cAMP analogs, and depolarization in an additive manner, with depolarization being the most efficacious. Therefore, we used cultured SGNs to determine the mechanism by which depolarization promotes neuronal survival. Our data implicate Ca(2+)/calmodulin-dependent protein kinase (CaMK) activity by showing that it is induced by depolarization, that CaMK activity is necessary for at least part of the survival-promoting effect of depolarization, and that CaMKII or CamKIV activity suffices to support neuronal survival in the absence of other trophic stimuli. First, that depolarization of SGNs activates CaMKs is evidenced by observation of increased CaMKII phosphorylation and of CaMK-dependent CREB phosphorylation. Second, the requirement for CaMKs is shown by a reduction of SGN survival under depolarizing conditions in the presence of CaMK inhibitors. Third, transfection of COOH-terminal-truncated (lacking regulatory domain), constitutively active CaMKII or CaMKIV, but not of normal, full-length CAMKs, promotes SGN survival in the absence of other trophic stimuli, indicating that CaMK activity is sufficient to promote survival. The survival-promoting effect of truncated CaMKs is additive with that of depolarization, neurotrophins, or cyclic AMP. Although both CaMKII and CaMKIV activities converge in promoting survival, their actions on axon growth are markedly different: Transfection of truncated CaMKII, but not of truncated CaMKIV, into SGNs prevents axon outgrowth., (Copyright 2003 Wiley-Liss, Inc.)

Objective/hypothesis: To compare the effectiveness and long-term stability of hearing results between stapedectomy and small fenestra stapedotomy in patients with conductive hearing loss due to otosclerosis., Study Design: Retrospective review of prospectively collected audiometric data., Methods: The hearing results and complication rates of 209 ears with long-term follow-up that underwent either stapedectomy or stapedotomy by the senior author (h.p.h.) between 1961 and 1989 were compared. Forty-two patients underwent stapedectomy in one ear and stapedotomy in the opposite ear, permitting a paired case review of the results in these patients. The techniques were compared with respect to initial and late hearing results and change of the results over time., Results: Patients undergoing stapedectomy and stapedotomy were followed for an average of 11.5 and 6.0 years, respectively. There were no statistically significant differences in initial or late postoperative pure-tone average (PTA), PTA air-bone gap, speech discrimination scores, or incidence of sensorineural hearing loss between the two groups. Ears treated by stapedotomy showed statistically better initial and late postoperative 4-kHz air-conduction threshold and initial 4-kHz air-bone gap, but the gap difference was not significant with late follow-up. There was no significant difference in the percentage of patients with air-bone gap closure within 10 dB for any frequency other than 4 kHz at the initial postoperative test. Importantly, the successful outcomes in both groups were stable over long-term follow-up. Results were the same when comparing the two procedures in patients having undergone both., Conclusion: These results show that, in the hands of an experienced surgeon, either technique provides satisfactory and stable long-term results.