Toll-like Receptor 4 Signaling and Downstream Neutrophilic Inflammation Mediate Endotoxemia-Enhanced Blood–Labyrinth Barrier Trafficking Hypothesis: Both toll-like receptor 4 (TLR4) and downstream neutrophil activity are required for endotoxemia-enhanced blood–labyrinth barrier (BLB) trafficking. Background: Aminoglycoside and cisplatin are valuable clinical therapies; however, these drugs often cause life-long hearing loss. Endotoxemia enhances the ototoxicity of aminoglycosides and cisplatin in a TLR4 dependent mechanism for which downstream proinflammatory signaling orchestrates effector immune cells including neutrophils. Neutrophil-mediated vascular injury (NMVI) can enhance molecular trafficking across endothelial barriers and may contribute to endotoxemia-enhanced drug-induced ototoxicity. Methods: Lipopolysaccharide (LPS) hypo-responsive TLR4-KO mice and congenitally neutropenic granulocyte colony-stimulating factor (GCSF) GCSF-KO mice were studied to investigate the relative contributions of TLR4 signaling and downstream neutrophil activity to endotoxemia-enhanced BLB trafficking. C57Bl/6 wild-type mice were used as a positive control. Mice were treated with LPS and 24 hours later cochleae were analyzed for gene transcription of innate inflammatory cytokine/chemokine signaling molecules, neutrophil recruitment, and vascular trafficking of the paracellular tracer biocytin-TMR. Results: Cochlear transcription of innate proinflammatory cytokines/chemokines was increased in endotoxemic C57Bl/6 and GCSF-KO, but not in TLR4-KO mice. More neutrophils were recruited to endotoxemic C57Bl/6 cochleae compared with both TLR4 and GCSF-KO cochleae. Endotoxemia enhanced BLB trafficking of biocytin-TMR in endotoxemic C57Bl/6 cochleae and this was attenuated in both TLR4 and GCSF-KO mice. Conclusion: Together these results suggest that TLR4-mediated innate immunity cytokine/chemokine signaling alone is not sufficient for endotoxemia-enhanced trafficking of biocytin-TMR and that downstream neutrophil activity is required to enhance BLB trafficking. Clinically, targeting neutrophilic inflammation could protect hearing during aminoglycoside, cisplatin, or other ototoxic drug therapies. Address correspondence and reprint requests to Edward A. Neuwelt, M.D., Blood-Brain Barrier Program, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, L603, Portland, OR 97239; E-mail: neuwelte@ohsu.edu Equal contributors: Jessica L. Bills, David Y. Cahana. The authors thank Jason Shohet for our colony founding G-csf-KO mice; Leonard Rybak, Peter Barr-Gillespie, and Daniel Marks for critical reading and editing of this manuscript; Peter Steyger for his role in help in developing the concepts motivating this study and for sponsoring the affiliated F30 and American Otological Society fellowships; Oregon Health and Science University's Advanced Light Microscopy Core for guidance and resources for confocal microscopy data analysis. This study received funding from NIH/NIDCD F30DC014229-01A1 (Z.D.U.), American Otological Society Fellowship (Z.D.U.); NINDS P30 NS061800 imaging core grant (Sue Aicher); and National Cancer Institute Grant CA199111 to E.A.N. The authors disclose no conflicts of interest. Supplemental digital content is available in the text. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.jcraniofacialsurgery.com). Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Outcomes Following Transcanal Endoscopic Lateral Graft Tympanoplasty Outcome Objectives: Demonstrate feasibility of performing endoscopic transcanal lateral graft tympanoplasty. Compare audiometric and clinical outcomes of transcanal endoscopic lateral graft with previously reported outcomes of microscopic post-auricular lateral graft tympanoplasty. Methods: A retrospective review of sequential pediatric and adult endoscopic transcanal lateral graft tympanoplasties (type I) performed between May 2014 and August 2015 at a single institution by two experienced otologists. Rate of perforation closure and audiometric outcomes (pure-tone average [PTA] and word recognition scores [WRS]) were obtained and compared with previous published outcomes of post-auricular microscopic lateral grafts. Results: Twenty patients, five right and 15 left ears, met criteria. Ninety percent of patients had successful closure of their perforation. One patient had a residual central perforation; active acute otitis media was noted intraoperatively in this case. One patient had graft lateralization. Mean follow up was 10.5 months (standard deviation [SD] = 141 d). Mean operative time was 160 (SD = 26.1) minutes. Mean improvement in PTA was 18 dB (SD = 10.3). Two patients had worsening of audiometric outcomes with <15 dB decreases in PTA and unchanged WRS; all other patients showed improvement or no change in audiometric outcomes. These results are similar to previously published outcomes for post-auricular microscopic approaches. Conclusion: Transcanal endoscopic lateral graft tympanoplasty is a novel technique for closure of anterior and subtotal perforations that avoids a postauricular incision. Outcomes in this cohort were similar to historical results for post-auricular microscopic approaches. Prospective studies with larger cohorts will be crucial to understanding the advantages and limitations of this new surgical approach. Address correspondence and reprint requests to Francis X. Creighton, Jr, M.D., 901 N. Caroline St. 6th Floor Department of Otolaryngology, Baltimore, MD 21287; E-mail: francis.creighton@jhmi.edu The authors have no conflicts of interest relevant to this work. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Predicting Development of Bilateral Menière's Disease Based on cVEMP Threshold and Tuning Objective: To investigate if the cervical vestibular evoked myogenic potential (cVEMP) is predictive for developing bilateral Menière's disease (MD). Study Design: Retrospective cohort study. Setting: Tertiary care center. Patients: Records of 71 patients previously diagnosed with unilateral MD at our institution who underwent cVEMP testing between 2002 and 2011 were screened. Intervention: Patients were contacted to answer a questionnaire to identify which patients had developed bilateral disease. Based on questionnaires and medical charts, 49 patients with a follow-up time of at least 5 years were included. The 49 originally asymptomatic ears are referred to as “study ears.” Previously reported cVEMP criteria (original criteria) applied to study-ear cVEMPs separated them into Menière-like and normal-like groups. Main Outcome Measure: The main purpose was to determine if previously obtained cVEMP thresholds and tuning ratios of unilateral MD patients could predict who develops bilateral disease. Results: From the 49 included patients, 12 developed bilateral disease (24.5%). The study ears characterized by original cVEMP criteria as Menière-like were significantly more likely to develop bilateral disease compared with the normal-like study ears. The original criteria predicted development of bilateral disease with a positive predictive value (PPV) and negative predictive value (NPV) of 58.3% and 86.5% respectively. ROC curves were used to revise cVEMP criteria for predicting the progression to bilateral disease. A revised criterion combining three cVEMP metrics, reached a PPV and NPV of 85.7% and 93.7%. Conclusion: cVEMP threshold and tuning in unilateral MD patients are predictive of which patients will develop bilateral disease. Address correspondence and reprint requests to Steven D. Rauch, M.D., 243 Charles Street, Boston, MA 02114; E-mail: Steven_Rauch@meei.harvard.edu This study was approved by the Human Studies Committee of the Massachusetts Eye and Ear Infirmary. Protocol number: 13-097H. Principal Investigator: S.D.R. The authors disclose no conflicts of interest. Supplemental digital content is available in the text. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.jcraniofacialsurgery.com). Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

The Relation Between Tinnitus and a Neurovascular Conflict of the Cochleovestibular Nerve on Magnetic Resonance Imaging Introduction: Magnetic resonance (MR) imaging is often used in diagnostic evaluation of tinnitus patients. Incidental findings like a neurovascular conflict (NVC) in the cerebellopontine angle are often found; however, the diagnostic value of this finding remains unclear. The aim of this study is to investigate whether the type or degree of compression of the vestibulocochlear nerve is of diagnostic value in patients with a NVC. Methods: A retrospective study was performed in 111 tinnitus patients with available MR imaging between 2013 and 2015. Clinical and audiometric variables were gathered and MR imaging was reevaluated by two neuroradiologists. NVCs were analyzed using a grading system based on previous research by Sirikci et al. Results: In total, 220 ears were available for assessment. In patients with unilateral tinnitus a loop compression and an indentation of the cochleovestibular nerve were more frequent than in patients with bilateral tinnitus. However, there was no significant difference in distribution of the type of compression between tinnitus and nontinnitus ears. Patient with unilateral tinnitus had a significantly higher degree of hearing loss in the symptomatic ear, compared with the asymptomatic ear and with the bilateral tinnitus group. Also, it was found that the degree of hearing loss did not differ between the various types of compression. Conclusion: This study did not find a diagnostic value of specific types of compression in patients with a NVC. Although the distribution of NVC classification was different in patients with unilateral and bilateral tinnitus, there was no definite relation between the type of NVC and the presence of ipsilateral tinnitus. Also, the degree of hearing loss was not related to specific types of NVC. Address correspondence and reprint requests to Minke J.C. van den Berge, M.D., Department of Otolaryngology, BB20, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands; E-mail: m.j.c.van.den.berge@umcg.nl The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Extraluminal Sigmoid Sinus Angioplasty: A Pertinent Reconstructive Surgical Method Targeting Dural Sinus Hemodynamics to Resolve Pulsatile Tinnitus Objectives: 1) To provide information on the treatment of pulsatile tinnitus (PT) with transtemporal extraluminal sigmoid sinus angioplasty (ESSA); and 2) to discuss the current clinical management of PT. Study Design: This was a retrospective study. Settings: Multi-institutional tertiary university medical centers. Patients: Fifty-four PT patients with transverse–sigmoid sinus enlargement and prominent transverse–sigmoid junction with or without sigmoid sinus wall anomalies or transverse sinus anomalies. Intervention: All patients underwent ESSA under local anesthesia. Main Outcome Measures: Intraoperative discoveries and surgical resolution of PT, morphology, and computational fluid dynamics. Results: Fifty-three of the 54 (98%) patients experienced a significant reduction in, or complete resolution of, PT after ESSA. No major surgical complications occurred, except for one case where we observed a full collapse of the sinus wall. On average, this surgery reduced the cross-sectional area at the transverse–sigmoid junction by 61.5%. Our intraoperative discoveries suggest that sigmoid sinus wall anomalies may not be a definitive cause of PT. The transverse–sigmoid sinus system was significantly larger (in term of both cross-sectional area and volume) on the ipsilesional side compared with the contralesional side. Following ESSA, the vascular wall pressure and vortex flow at the transverse–sigmoid junction decreased considerably, and the flow velocity and wall shear stress increased significantly. Conclusion: ESSA is a highly effective surgical technique for PT patients with transverse–sigmoid sinus enlargement and prominent transverse–sigmoid junction, regardless of whether they also have sigmoid sinus wall or transverse sinus anomalies. A large transverse–sigmoid system with prominent transverse–sigmoid junction is a predisposing factor for PT, and only by improving patients’ intrasinus hemodynamics could PT be resolved efficiently. In cases without complete obstruction of venous return, ESSA is safe. No postoperative complications related to neurological disorders were observed. Address correspondence and reprint requests to Wuqing Wang, Ph.D., Department of Otology and Skull Base Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai 200031, China; E-mail: wwuqing@189.cn This work was supported by NSFC no. 84670933 to W.W. The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Assessment of a Novel 3T MRI Compatible Cochlear Implant Magnet: Torque, Forces, Demagnetization, and Imaging Hypothesis: A novel cochlea implant (CI) device magnet providing alignment to the static field of a magnetic resonance imaging (MRI) will lead to reduced torque, longitudinal forces, and demagnetization effects. The image void and distortion will be comparable to those obtained with standard CI magnets. Background: MRI investigations of CI users pose several challenges such as magnet dislocation, demagnetization, and may cause pain. The presence of a CI magnet within MRI field causes image distortions and may diminish the diagnostic value of an MRI procedure. Objective of this work is to evaluate magnetic forces and imaging properties of the novel CI magnet within 1.5 and 3T MRI. Methods: Forces and torque of the novel CI magnet were measured in both 1.5 and 3T MRI and compared with the standard magnet in 1.5T. One cadaver head was implanted with the CI devices containing the novel and standard magnets in different configurations reflecting clinical scenarios and imaging properties were assessed and compared. Results: In particular the torque has been reduced with the novel CI magnet in comparison to the standard one. Both CI magnets have not shown any signs of demagnetization. The image void and distortion was comparable between the two magnets for the main MRI clinical scanning protocols in 1.5T MRI. Conclusions: The novel CI magnet is safe to use for MRI investigations of CI users in 3T MRI without a need for bandaging and has acceptable level of image artefacts. Address correspondence and reprint requests to Dzemal Gazibegovic, Biomed. Eng., AB GmbH, European Research Centre ERC, Feodor-Lynenstr. 35, 30625 Hannover, Germany; E-mail: Dzemal.gazibegovic@advancedbionics.com Advanced Bionics has provided the cochlear implant devices and the test equipment for all force measurements and supported the radiology service. D.G. is an employee of Advanced Bionics’ research department. J.R.T. is a paid consultant of Advanced Bionics. The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Long-term Implant Usage and Quality-of-Life in Sequential Bilateral Pediatric Cochlear Implantation Objectives: Our primary objective was to investigate the long-term usage of cochlear implants (CIs) in children who underwent sequential bilateral CI (SeqBCI), and to study factors that impact usage. Our secondary objective was to understand the difference in subjective benefit and educational/employment status, between users and non-users of the second CI (CI2). Study Design: Prospective case series. Setting: Tertiary academic centers. Patients: Sixty-eight young adults who underwent SeqBCI as children. Interventions: Pediatric SeqBCI. Main Outcome Measures: The main outcome measures were the current usage of the first CI (CI1) and CI2, factors that determine usage, current perceptions of their CIs, educational/employment status, and Speech, Spatial and Qualities of Hearing scale (SSQ12) scores. Results: Sixty five (95.6%) participants were using CI1 for over 8 h/d and the rest were using CI1 for 4 to 8 h/d. Fourty four (64.7%) participants used CI2 for at least 4 h/d, 10 (15%) indicated that they rarely used CI2 (<4 h/d) and 14 (21%) were not using CI2 at all. On multivariate analysis, the only independent predictor of long-term usage of CI2 was the inter-implant interval (odds ratio [OR] 0.78, standard deviation [SD] 0.65–0.91, p = 0.002). There was no significant difference in the SSQ12 scores of users and non-users of CI2. Conclusion: The finding of increasing rates of non-usage of CI2 with lengthening inter-implant interval is clinically relevant and critical to health-economic assessment. From a usage point of view, the evidence is sufficiently robust to recommend that in children with bilateral deafness, bilateral CI should be done simultaneously, and if not, soon after the first CI. In the context of a longer inter-implant interval, clinicians should weigh the marginal benefits of CI2 against the surgical risks vis-a-vis non-usage and bilateral vestibular hypofunction. Address correspondence and reprint requests to David Low, M.B.B.S., M.R.C.S., M.Med., Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Room M1.102, Toronto, ON, M4N 3M5, Canada; E-mail: yongming@singnet.com.sg Funding: None. The authors disclose no conflicts of interest. Supplemental digital content is available in the text. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.jcraniofacialsurgery.com). Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Intraoperative Monitoring of Auditory Function During Lateral Skull Base Surgery Objective: We present a unique case of a patient with a jugular foramen tumor with serviceable hearing. This study discusses the audiometric results and intraoperative electrocochleographic (ECochG) findings recorded during tumor removal to illustrate the potential utility of this technique in skull base surgery. Patients: A 22-year-old female patient presented with a jugular foramen schwannoma and associated symptoms of right-sided otalgia, mild hearing loss, and blurry vision. Interventions: Intraoperative ECochG responses during an infratemporal fossa approach: click and tone burst (1, 2, 4 kHz) stimuli were used and presented at 90 dB nHL. Main Outcome Measures: Intraoperative ECochG testing using frequency-specific tone bursts and clicks before and after tumor resection. Results: The compound action potential magnitudes, cochlear microphonic, and summation potential were recorded pre- and post-tumor removal. For statistical analysis, a paired t test with significance set at p < 0.05 was used. The compound action potential magnitudes increased at all test frequencies (p < 0.01) while the summation potential and cochlear microphonic remained relatively stable (p > 0.05). Audiometric testing demonstrated an improvement of the preoperative mild right-sided hearing loss after tumor resection (pure-tone average for 0.5, 1, 2, and 4 kHz of 30 dB HL preoperation and 7.5 dB HL after tumor resection). Conclusions: Intraoperative ECochG may allow for real-time monitoring during complex skull base surgery. Address correspondence and reprint requests to Eleonora M.C. Trecca, M.D., Division of Otology, Neurotology, and Cranial Base Surgery, 915 Olentangy River Road, Suite 4000, Columbus, OH 43212; E-mail: eleonoramc.trecca@gmail.com, eleonora.trecca@osumc.edu. Oliver F. Adunka, M.D., F.A.C.S., Professor and Vice Chairman for Clinical Operations, Director, Otology, Neurotology, and Cranial Base Surgery, 915 Olentangy River Road, Suite 4000, Columbus, OH 43212; E-mail: oliver.adunka@osumc.edu D.P. is consultant for Stryker, Medtronic and Integra. D.P. has royalties (KLS-Martin and Mizuho), and honorarium (Mizuho). O.F.A. is consultant for Advanced Bionics Corp, Med-El Corp, Cochlear Corporation, Spiral Therapeutics, and Advanced Genetics Technologies Corporation. O.F.A. has an ownership interest in Advanced Cochlear Diagnostics, LLC. The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Concurrent Treatment With Intratympanic Dexamethasone for Moderate-Severe Through Severe Bell's Palsy Objective: To determine whether early intervention with intratympanic steroid injection, known as concurrent intratympanic steroid therapy, is effective as a supplement to systemic steroid therapy for treating moderate-severe to severe Bell's palsy. Design: An open-label historical control trial. Setting: Tertiary referral center. Participants: A total of 35 Bell's palsy patients presenting with House–Brackmann grade IV or higher were treated with intratympanic steroid therapy concurrent with standard systemic treatment and compared with 108 patients treated with standard systemic therapy alone started within 7 days of onset. Interventions: In the concurrent intratympanic steroid therapy group, patients received both 410 mg of prednisolone (standard dose) and 1.65 mg of intratympanic dexamethasone for 10 consecutive days. Patients in the control group received the standard dose, or more, of systemic prednisolone. Both groups were additionally treated with valacyclovir. Main Outcomes and Measures: The primary outcome measure was restoration of a House–Brackmann score of grade I. Results: The rate of recovery to House–Brackmann Grade I was higher for the concurrent intratympanic steroid therapy group than for the control group (94% vs 73%, p = 0.008). The adjusted odds ratio was 5.47 (95% confidence interval: 1.18–25.21, p = 0.029). Conclusions: The recovery rate was higher for concurrent intratympanic steroid therapy treatment than for standard-of-care control treatment, regardless of whether steroid with lower or equivalent glucocorticoid action was administered. This result suggests that concurrent treatment with intratympanic steroid therapy is a potentially beneficial supplement to systemic steroid administration. Address correspondence and reprint requests to Akira Inagaki, M.D., Ph.D., 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya City, Aichi 467-8601, Japan; E-mail: ainagaki@med.nagoya-cu.ac.jp Akira Inagaki: ORCID ID: 0000-0001-5560-9321. Disclosure of funding received: Japan Society for the Promotion for Science (Nos. 15H04990, 16K15724 to A.I. and 16K11188 to S.M.). The authors disclose no conflicts of interest. Supplemental digital content is available in the text. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.jcraniofacialsurgery.com). Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Triphasic Pulses in Cochlear Implant Patients With Facial Nerve Stimulation Objective: Evaluation of triphasic pulse stimulation in comparison to the traditional biphasic pulse stimulation in cochlear implant (CI) patients with unintended facial nerve costimulation. Study Design: Retrospective case review. Setting: Cochlear Implant Center of a University Department of Otolaryngology, Head and Neck Surgery. Patients: Fifteen CI patients (MED-EL, Innsbruck, Austria) received a triphasic fitting map instead of a biphasic fitting map due to a previous diagnosis of facial nerve stimulation or stimulus induced pain during the years 2014 to 2017. Intervention(s): Application of a triphasic stimulation strategy. Main Outcome Measure(s): Reduction of facial nerve costimulation and speech understanding. Biphasic and triphasic fitting maps were compared to accurately assess the effects of the switch, and hearing tests (monosyllables and sentences in noise tests) were analyzed. Results: Triphasic pulse stimulation showed a significant reduction of unintended side effects and resulted in an observed improved quality of life in most cases. Although there was no significant change in the understanding of speech with CI in all test situations, in many cases, improvement was observed. Conclusions: Triphasic pulse stimulation had a beneficial effect for CI patients with severe, unintended costimulation and should be considered a valuable tool during CI fitting. Address correspondence and reprint requests to Katharina Braun, M.D./Dr. med., University Department of Otolaryngology, Head and Neck Surgery, Elfriede-Aulhorn-Straße 5, 72076 Tübingen, Germany; E-mail: Katharina.Braun@med.uni-tuebingen.de The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company