Surgically-Relevant Anatomy of the External Auditory Canal Bulge and Scutum Hypothesis: Anatomic study of the external auditory canal's (EAC) anterior bulge, scutum, and ossicular chain will generate knowledge applicable to safe ear surgery and instrument design. Background: The EAC contains two structures that obscure view of the middle ear: the anterior bulge and the scutum. The dimensions of these structures and their relationships to the ossicular chain have not been previously described. Methods: Cadaveric temporal bones underwent computed tomography scanning, and three-dimensional reconstructions were created. Dimensions and angles of the EAC, its anterior bulge and scutum were measured. Distances to ossicular landmarks and the facial nerve were examined. Results: The anterior EAC had a swan-neck shape. The thinnest portion was located medially and correlated with the canal thickness at the anterior bulge. However the thickness of the anterior bulge was not correlated with its angulation. The scutum averaged 3.8 mm long with a base thickness of 2.3 mm and a mean tip angle of 33 degrees. The short process of the incus was significantly closer to the scutum than other ossicular landmarks. Conclusion: Prominent anterior canal bulges are formed by posterior temporomandibular joints, not thicker bone. The scutum has asymmetric distances to various portions of the ossicles with the incus short process sometimes as close as 0.2 mm, placing it at risk of injury. Address correspondence and reprint requests to Arnaldo L. Rivera, M.D., Department of Otolaryngology—MA 314, One Hospital Drive, Columbia, MO 65212; E-mail: riveraal@health.missouri.edu The scutum portion of this paper was presented at the American Academy of Otolaryngology Head and Neck Surgery Annual Meeting 2018. The authors have no competing interests to disclose. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Is Asymmetric Hearing Loss a Risk Factor for Vestibular Dysfunction? Lesson From Big Data Analysis Based on the Korean National Health and Nutrition Survey Objective: The purpose of this study was to investigate whether asymmetric hearing loss affects vestibular function. Study Design: Retrospective cross-sectional study. Patients: Data from the 2010 Korean National Health and Nutrition Survey for adults aged 40 years or more were used. Interventions: The modified Romberg test and pure-tone audiometry were performed. Data were analyzed using a complex sample χ2 test of independence and complex sample logistic regression analysis. Main Outcome Measures: Vestibular dysfunction and hearing thresholds. Results: The overall prevalence of vestibular dysfunction was 3.3% (95% confidence interval [CI], 2.5–4.3%). In adults more than 40 years of age, multivariate linear regression analyses showed that the odds ratio (OR) of vestibular dysfunction was 3.067 times higher than the reference for a 30-dB difference in hearing thresholds between both ears (CI, 1.481–6.351; p = 0.007) after adjusting for factors associated with vestibular dysfunction. Among these individuals, the risk of equilibrium disturbance was higher in the presence of low-frequency asymmetric hearing loss (OR, 2.148; CI, 1.216–3.793; p = 0.009); on the other hand, high-frequency asymmetry did not lead to a higher risk. Conclusions: As low-frequency asymmetric hearing thresholds tend to coexist with vestibular dysfunction in adults, those with asymmetric hearing loss should be closely monitored. Address correspondence and reprint requests to Sung Huhn Kim, M.D., Ph.D., Department of Otorhinolaryngology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea; E-mail: fledermaus@yuhs.ac This work was supported by a research grant from Jeju National University Hospital in 2018. The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Commercial Quinolone Ear Drops Cause Perforations in Intact Rat Tympanic Membranes Hypothesis: Commercial quinolone ear drops may promote the development of perforations (TMPs) in intact tympanic membrane (TMs). Background: Quinolone ear drops have been associated with TMPs after myringotomy +/- tube placement in a drug-specific manner and potentiation by steroids. Methods: Rats were randomized to six groups (10/group), with one ear receiving otic instillation of dexamethasone, ofloxacin, ciprofloxacin, ofloxacin + dexamethasone, ciprofloxacin + dexamethasone, or neomycin + polymyxin + hydrocortisone—all commercial formulations and at standard clinical concentrations—and the contralateral ear receiving saline, twice daily for 10 days. TMs were assessed over 42 days. Results: No TMPs were seen in ears treated with saline, dexamethasone, or neomycin. At day 10, TMPs were seen in one of 10 ofloxacin- and three of 10 ciprofloxacin + dexamethasone-treated ears (p = 0.038). At day 14, the ofloxacin TMP healed. In contrast, the three ciprofloxacin + dexamethasone TMPs remained and one new TMP developed in this group. A ciprofloxacin and an ofloxacin + dexamethasone-treated ears also had TMPs (p = 0.023). By day 21, the ofloxacin + dexamethasone TMP and two of four of the ciprofloxacin + dexamethasone TMPs healed but two new TMPs were seen in ciprofloxacin + dexamethasone ears (p = 0.0006). At day 28, 1 of 10 ciprofloxacin and 4 of 10 ciprofloxacin + dexamethasone-treated ears had TMPs (p = 0.0006). By day 35, only one ciprofloxacin + dexamethasone had TMP (p = 0.42). All TMPS were healed at day 42. Conclusions: Application of commercial quinolone ear drops can cause TMPs in intact TMs. This effect appears to be drug-specific and potentiated by steroids. Address correspondence and reprint requests to Carolyn O. Dirain, Ph.D., Department of Otolaryngology, University of Florida, Box 100264, 1345 Center Drive MSB M2-228, Gainesville, FL 32610-0264; E-mail: ojanoc@ent.ufl.edu None of these commercial entities was involved in the design and conduct of the study or in the interpretation of the data and preparation of the manuscript. Financial support for this study was provided solely by the University of Florida. Dr. Antonelli discloses research support from Alcon Laboratories, Edison Pharmaceuticals, Otonomy, Next Science, and Medtronic ENT; service on Otonomy and Metarmor advisory boards; and speaker sponsorship by Alkem Laboratories and Vindico Medical Education. Dr. Dirain discloses research support from Next Science and Medtronic ENT. Mr. Karnani has no relevant conflicts to disclose. 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 (http://journals.lww.com/otology-neurotology). Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Cochlear MRI Signal Change Following Vestibular Schwannoma Resection Depends on Surgical Approach Objective: Information on cochlear MRI signal change following vestibular schwannoma (VS) surgery by the retrolabyrinthine approach (RLA) is nonexisting, and information using the translabyrinthine approach (TLA) is scarce. We aimed to evaluate cochlear MRI fluid signal in patients with a unilateral VS, before and after surgery by the RLA or the TLA, that can have clinical importance for subsequent cochlear implantation feasibility. Study Design: Retrospective cohort study. Setting: University hospital. Patients: One hundred one patients with a unilateral VS. Intervention: VS resection by the TLA or the RLA. Pre- and postoperative T2-weighted MRI. Main Outcome Measure: Cochlear signal change using a semiquantitative system for grading cochlear asymmetry, with grades ranging from 1 (normal fluid signal both sides) to 4 (no fluid signal one side). Results: Seventy-four patients were operated by the TLA and 27 by the RLA. The number of cochleas with grade 3 and 4 asymmetries postoperative was significantly higher than preoperative. The postoperative proportions of grade 1 (TLA 20%, RLA 56%) and grade 2–4 asymmetry (TLA 80%, RLA 44%) were significantly different between the two groups. In the TLA group, 46 patients (62%) demonstrated an increased asymmetry postoperatively, as compared with three patients (11%) in the RLA group. Conclusions: Postoperative decrease of cochlear MRI fluid signal is more likely to occur after translabyrinthine surgery (occurring in 62%), as compared with retrolabyrinthine surgery (occurring in 11%). The decrease of cochlear signal may be due to compromised vascularity or fibrosis. Address correspondence and reprint requests to Niels West, M.D., Department of Otorhinolaryngology Head and Neck Surgery and Audiology, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. E-mail: westniels@gmail.com Parts of the data were presented at the EAONO conference, June 2018, Copenhagen. The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Open Mastoid Cavity Obliteration With a High-Porosity Hydroxyapatite Ceramic Leads to High Rate of Revision Surgery and Insufficient Cavity Obliteration Objective: To assess long-term results and present experience with a high-porosity hydroxyapatite ceramic for obliterating large open mastoid cavities. Study-Design: Cross-sectional cohort study. Setting: Tertiary academic referral center. Patients: All patients who underwent tympanomastoid surgery for chronic middle ear disease or revision surgery with reduction of an open mastoid cavity using a highly porous hydroxyapatite matrix material (HMM) between May 2005 and June 2013 were assessed for eligibility. Twenty three patients (56.9 ± 18.3 yr) were included. Intervention: Primary middle ear surgery or revision surgery using a HMM. Main Outcome Measures: Pure-tone average, computed tomography (CT), and magnetic resonance imaging (MRI) to investigate osseoinduction, osseointegration and presence of cholesteatoma, current quality of life assessed by Zurich Chronic Middle Ear Inventory and change in quality of life post-intervention assessed by the Glasgow Benefit Inventory. Results: Patients were reexamined after a mean follow-up period of 88.3 months (SD 21.4 mo) after obliteration of the open mastoid cavity with HMM. Compared with visit 1, patients showed a significantly reduced ABG at visit 2 (29.22 dB ± 2.71 dB versus 12.77 dB ± 3.46 dB). CT scan was carried out in 21 patients (91%) patients and 17 patients (74%) underwent MRI. Revision surgery was required in a total of 17 cases (74%). In four patients recurrent cholesteatoma was found at follow up. Conclusions: Poor cavity obliteration, a high rate of revision surgery and difficult differentiation between recurrent cholesteatoma and granulation tissue in CT scan was observed. Address correspondence and reprint requests to Nora M. Weiss, Department of Oto-Rhino-Laryngology, Head and Neck Surgery “Otto Körner”, Rostock University Medical Center, Doberaner Strasse 137-139, D-18057 Rostock, Germany; E-mail: nora-magdalena.weiss@med.uni-rostock.de The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Musical Ear Syndrome and Cochlear Explantation: Case Report and Proposal for a Theoretical Framework Objective: To report an unusual case of musical ear syndrome, and to present a theoretical framework for this condition, merging information from the presented case and from former case reports. Patient: A 67-year-old semi-professional musician, who underwent bilateral cochlear implantation and experienced musical ear syndrome, i.e., hearing music, where none was present. Interventions: Cochlear implantation with a bilateral cochlear implant, and cochlear explantation 17 months later. Main Outcome Measure: Report of presence or absence of musical ear syndrome by the patient. Results: Musical ear syndrome started 1 day after implantation. It ceased immediately after cochlear explantation, but reappeared 3 months later. Conclusions: Several types of factors seem to determine whether a musical ear syndrome is present or not. We propose to differentiate between triggers, modifiers, and conditions, which determine a base vulnerability. Vulnerability seems to be increased by auditory deprivation and by habitual retrieval of music from memory. Cochlear implantation or explantation seems to act as triggers. The proposed framework may help to stimulate reporting of more potentially relevant factors in future case reports on musical ear syndrome, and ultimately to help to understand this condition better. Address correspondence and reprint requests to Martin Kompis, M.D., Ph.D., Department of ENT, Head and Neck Surgery, Inselspital, University of Berne, CH—3010 Bern, Switzerland; E-mail: martin.kompis@insel.ch The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

High Altitude Alternobaric Facial Palsy: Case Series and Systematic Review of the Literature Background: Alternobaric facial palsy (AFP) is a rare phenomenon which occurs in patients with Eustachian tube dysfunction, a dehiscent facial canal, and subsequent compression induced ischemic neuropraxia of the facial nerve upon exposure to atmospheric pressure changes. There are few documented cases of AFP and most relate to underwater diving. There is limited understanding in the literature of AFP in the setting of high altitude, leading to a potential for misdiagnosis and inappropriate management. Objective: We present two cases of transient, recurrent, unilateral facial palsy at high altitude and perform a systematic review of the available literature. Data Sources: Full-text articles indexed to Medline, EMBase, and PubMed, and associated reference lists. Data Extraction: Data was extracted into standardized data extraction forms. Data Synthesis: Binomial proportions and Fischer's exact test were used to analyze sex distribution and relationship between sex and side of palsy, and number of episodes experienced. Methods: Systematic review using PRISMA guidelines with meta-analysis. Results: We identified 19 cases in the literature relating to AFP in patients at high altitude and present two new cases. Conclusion: AFP is an uncommon but important diagnosis. We present two cases and systematically review the literature to discuss the diagnosis and management of AFP. Address correspondence and reprint requests to Benjamin Cumming, M.D., Otolaryngology, Head and Neck Surgery Research Group, Department of Otolaryngology, Head and Neck Surgery, Prince of Wales Hospital, Barker St, Randwick NSW 2031, Australia; E-mail: bencumming@me.com The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

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