The natural history and genotype-phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis.

TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.

Robotic assistance during cochlear implantation: the rationale for consistent, controlled speed of electrode array insertion.

Cochlear implants (CI) have revolutionized the treatment of patients with severe to profound sensory hearing loss by providing a method of bypassing normal hearing to directly stimulate the auditory nerve. A further advance in the field has been the introduction of "hearing preservation" surgery, whereby the CI electrode array (EA) is carefully inserted to spare damage to the delicate anatomy and function of the cochlea. Preserving residual function of the inner ear allows patients to receive maximal benefit from the CI and to combine CI electric stimulation with acoustic hearing, offering improved postoperative speech, hearing, and quality of life outcomes. However, under the current paradigm of implant surgery, where EAs are inserted by hand, the cochlea cannot be reliably spared from damage. Robotics-assisted EA insertion is an emerging technology that may overcome fundamental human kinetic limitations that prevent consistency in achieving steady and slow EA insertion. This review begins by describing the relationship between EA insertion speed and generation of intracochlear forces and pressures. The various mechanisms by which these intracochlear forces can damage the cochlea and lead to worsened postoperative outcomes are discussed. The constraints of manual insertion technique are compared to robotics-assisted methods, followed by an overview of the current and future state of robotics-assisted EA insertion.

Extraordinary Speech and Language Outcomes After Auditory Brainstem Implantation: Guidance From a Case Study.

PURPOSE: Large individual differences and poor speech recognition outcomes are routinely observed in most patients who have received auditory brainstem implants (ABIs). A case report of an ABI recipient with exceptionally good speech recognition outcomes presents an opportunity to better understand the core information processing mechanisms that underlie variability and individual differences in outcomes. METHOD: A case study is reported of an adult ABI recipient (ID-006) with postlingually acquired, Neurofibromatosis Type 2 (NF2)-related hearing loss who displayed exceptional postoperative speech recognition scores. A novel battery of assessment measures was used to evaluate ID-006's auditory, cognitive, and linguistic information processing skills. RESULTS: Seventeen years following ABI activation, ID-006 scored 77.6% correct on the AzBio Sentences in quiet. On auditory processing tasks, ID-006 scored higher on tasks with meaningful sentences and much lower on tasks that relied exclusively on audibility. ID-006 also demonstrated exceptionally strong abilities on several cognitive and linguistic information processing tasks. CONCLUSIONS: Results from a novel battery of information processing tests suggest that ID-006 relies extensively on top-down predictive processing and cognitive control strategies to efficiently encode and process auditory information provided by his ABI. Results suggest that current measures of outcomes and benefits should be expanded beyond conventional speech recognition measures to include more sensitive and robust measures of speech recognition as well as neurocognitive measures such as executive function, working memory, and lexical access.

Rationale for the Development of a Novel Clinical Grading Scale for Postoperative Facial Nerve Function: Results of a Multidisciplinary International Working Group.

OBJECTIVE: The objective of the current study was to present the results of an international working group survey identifying perceived limitations of existing facial nerve grading scales to inform the development of a novel grading scale for assessing early postoperative facial paralysis that incorporates regional scoring and is anchored in recovery prognosis and risk of associated complications. STUDY DESIGN: Survey. SETTING: A working group of 48 multidisciplinary clinicians with expertise in skull base, cerebellopontine angle, temporal bone, or parotid gland surgery. RESULTS: House-Brackmann grade is the most widely used system to assess facial nerve function among working group members (81%), although more than half (54%) agreed that the system they currently use does not adequately estimate the risk of associated complications, such as corneal injury, and confidence in interrater and intrarater reliability is generally low. Simplicity was ranked as the most important attribute of a novel postoperative facial nerve grading system to increase the likelihood of adoption, followed by reliability and accuracy. There was widespread consensus (91%) that the eye is the most critical facial region to focus on in the early postoperative setting. CONCLUSIONS: Members were invited to submit proposed grading systems in alignment with the objectives of the working group for subsequent validation. From these data, we plan to develop a simple, clinically anchored, and reproducible staging system with regional scoring for assessing early postoperative facial nerve function after surgery of the skull base, cerebellopontine angle, temporal bone, or parotid gland.

Selection of viral capsids and promoters affects the efficacy of rescue of Tmprss3-deficient cochlea.

Adeno-associated virus (AAV)-mediated gene transfer has shown promise in rescuing mouse models of genetic hearing loss, but how viral capsid and promoter selection affects efficacy is poorly characterized. Here, we tested combinations of AAVs and promoters to deliver Tmprss3, mutations in which are associated with hearing loss in humans. Tmprss3tm1/tm1 mice display severe cochlear hair cell degeneration, loss of auditory brainstem responses, and delayed loss of spiral ganglion neurons. Under the ubiquitous CAG promoter and AAV-KP1 capsid, Tmprss3 overexpression caused striking cytotoxicity in vitro and in vivo and failed to rescue degeneration or dysfunction of the Tmprss3tm1/tm1 cochlea. Reducing the dosage or using AAV-DJ-CAG-Tmprss3 diminished cytotoxicity without rescue of the Tmprss3tm1/tm1 cochlea. Finally, the combination of AAV-KP1 capsid and the EF1α promoter prevented cytotoxicity and reduced hair cell degeneration, loss of spiral ganglion neurons, and improved hearing thresholds in Tmprss3tm1/tm1 mice. Together, our study illustrates toxicity of exogenous genes and factors governing rescue efficiency, and suggests that cochlear gene therapy likely requires precisely targeted transgene expression.

Immediate CPAP Use after Skull Base Reconstruction with Hydroxyapatite Bone Cement.

OBJECTIVE: The timing for resuming continuous positive airway pressure (CPAP) postoperatively after skull base surgery remains controversial because of the risk of pneumocephalus. We determined the safety of immediate CPAP use after middle cranial fossa (MCF) spontaneous cerebrospinal fluid (sCSF) leak repair with bone cement. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary academic medical center. PATIENTS: Thirteen consecutive patients with CPAP-treated obstructive sleep apnea and temporal bone sCSF leaks who underwent skull base repair with hydroxyapatite bone cement between July 2021 and October 2022. INTERVENTIONS: CPAP use resumed on postoperative day 1 after the confirmation of skull base reconstruction with temporal bone computed tomography (CT). MAIN OUTCOME MEASURES: Postoperative skull base defects on CT, pneumocephalus, or intracranial complications. RESULTS: The average age was 55.5 ± 8.8 years (±standard deviation), and 69.2% were female with a BMI of 45.39 ± 15.1 kg/m 2 . Multiple tegmen defects were identified intraoperatively in 53.9% of patients with an average of 1.85 ± 0.99 defects and an average defect size on preoperative imaging of 6.57 ± 3.45 mm. All patients had an encephalocele identified intraoperatively. No residual skull base defects were observed on CT imaging on postoperative day 1. No postoperative complications occurred. One patient developed a contralateral sCSF leak 2 months after repair. There were no recurrent sCSF leaks 1 month postoperatively. CONCLUSION: Immediate postoperative CPAP use is safe in patients undergoing MCF sCSF leak repair with bone cement because of the robust skull base repair.

Facial Nerve Preservation With Inferior Long-Axis Dissection of Large Vestibular Schwannomas.

OBJECTIVE: To describe a tumor resection using the inferior long-axis (ILA) technique for cisternal facial nerve dissection in large vestibular schwannomas (VS). STUDY DESIGN: Retrospective case series from 2018 to 2021. SETTING: Tertiary academic medical center. PATIENTS: Patients who underwent surgical resection with ILA facial nerve dissection of VS (>2.0 cm measured parallel to the petrous ridge) and had at least 3-month follow-up. INTERVENTIONS: Cisternal facial nerve dissection during retrosigmoid or translabyrinthine approach using standardized ILA technique developed by author R.N. MAIN OUTCOME MEASURES: Immediate postoperative and last follow-up facial nerve function with House-Brackmann scores of I to II defined as "good" facial nerve function and House-Brackmann scores III to VI defined as "poor" function. Extent of resection was also assessed. RESULTS: A total of 48 patients underwent large VS resection with ILA dissection of tumor off of the facial nerve from 2018 to 2021. Mean (standard deviation) tumor size was 3.11 (0.76) cm. Mean (standard deviation) follow-up was 9.2 (9.0) months. Gross-total resection or near-total resection were achieved in 75% (radiographic estimate) to 83% (surgeon estimate) of cases. End-of-case facial nerve stimulation at 0.05 mAmp with a response of at least 240 mV was achieved in 80.4% of patients. Good facial nerve function was observed in 72% immediately postoperatively, 70% 1-month postoperatively, and 82% of patients at last follow-up. CONCLUSIONS: The ILA technique is now the method of choice of the senior surgeon (R.N.) when performing microsurgical dissection of the cisternal facial nerve, with which he has achieved high rates of total or near-total resection with excellent facial nerve preservation.

TMPRSS3 expression is limited in spiral ganglion neurons: implication for successful cochlear implantation.

BACKGROUND: It is well established that biallelic mutations in transmembrane protease, serine 3 (TMPRSS3) cause hearing loss. Currently, there is controversy regarding the audiological outcomes after cochlear implantation (CI) for TMPRSS3-associated hearing loss. This controversy creates confusion among healthcare providers regarding the best treatment options for individuals with TMPRSS3-related hearing loss. METHODS: A literature review was performed to identify all published cases of patients with TMPRSS3-associated hearing loss who received a CI. CI outcomes of this cohort were compared with published adult CI cohorts using postoperative consonant-nucleus-consonant (CNC) word performance. TMPRSS3 expression in mouse cochlea and human auditory nerves (HAN) was determined by using hybridisation chain reaction and single-cell RNA-sequencing analysis. RESULTS: In aggregate, 27 patients (30 total CI ears) with TMPRSS3-associated hearing loss treated with CI, and 85% of patients reported favourable outcomes. Postoperative CNC word scores in patients with TMPRSS3-associated hearing loss were not significantly different than those seen in adult CI cohorts (8 studies). Robust Tmprss3 expression occurs throughout the mouse organ of Corti, the spindle and root cells of the lateral wall and faint staining within <5% of the HAN, representing type II spiral ganglion neurons. Adult HAN express negligible levels of TMPRSS3. CONCLUSION: The clinical features after CI and physiological expression of TMPRSS3 suggest against a major role of TMPRSS3 in auditory neurons.

Cochlear Implant Electrode Misplacement: A Case Series and Contemporary Review.

OBJECTIVE: To determine root causes leading to misplaced cochlear implant (CI) electrode arrays and discuss their management using a case series and contemporary literature review. STUDY DESIGN: Retrospective case review and contemporary literature review. SETTING: Single tertiary-referral center. PATIENTS: Adult and pediatric patients who were diagnosed with a misplaced CI electrode array, excluding tip-foldover. Literature review was performed via a MEDLINE database PubMed query. All articles that described at least one case of extracochlear electrode array misplacement were included; partial insertions and extrusions were excluded. MAIN OUTCOME MEASURE: Extracochlear misplacement. RESULTS: A total of 61 cases were reviewed, including 4 new cases and 57 cases from 29 previously published articles. We discuss management of CI arrays in the carotid canal, the vestibule, and the modiolus. The rate of CI misplacement is estimated to be 0.49%. The most frequent location of misplacement CI was the vestibular system (50.8%) followed by the internal carotid canal (11.5%). Normal cochlear anatomy was noted on preoperative computer tomography (CT) in 59.0% of patients; abnormalities were noted in 27.9%. The most common technical issue was misidentification or poor visualization of the round window. CONCLUSION: CI electrode misplacement is rare but can cause postoperative complications and may result in permanently diminished CI performance and hearing outcomes, even after revision surgery. Failure to identify the round window is the most common reason for CI misplacement, despite most patients having normal cochlear anatomy. Surgical strategies to localize the round window and basal turn are imperative for proper electrode placement. LEVEL OF EVIDENCE: 4.

Speech Recognition Outcomes in Adults With Slim Straight and Slim Modiolar Cochlear Implant Electrode Arrays.

OBJECTIVE: To compare differences in audiologic outcomes between slim modiolar electrode (SME) CI532 and slim lateral wall electrode (SLW) CI522 cochlear implant recipients. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary academic hospital. METHODS: Comparison of postoperative AzBio sentence scores in quiet (percentage correct) in adult cochlear implant recipients with SME or SLW matched for preoperative AzBio sentence scores in quiet and aided and unaided pure tone average. RESULTS: Patients with SLW (n = 52) and patients with SME (n = 37) had a similar mean (SD) age (62.0 [18.2] vs 62.6 [14.6] years, respectively), mean preoperative aided pure tone average (55.9 [20.4] vs 58.1 [16.4] dB; P = .59), and mean AzBio score (percentage correct, 11.1% [13.3%] vs 8.0% [11.5%]; P = .25). At last follow-up (SLW vs SME, 9.0 [2.9] vs 9.9 [2.6] months), postoperative mean AzBio scores in quiet were not significantly different (percentage correct, 70.8% [21.3%] vs 65.6% [24.5%]; P = .29), and data log usage was similar (12.9 [4.0] vs 11.3 [4.1] hours; P = .07). In patients with preoperative AzBio <10% correct, the 6-month mean AzBio scores were significantly better with SLW than SME (percentage correct, 70.6% [22.9%] vs 53.9% [30.3%]; P = .02). The intraoperative tip rollover rate was 8% for SME and 0% for SLW. CONCLUSIONS: Cochlear implantation with SLW and SME provides comparable improvement in audiologic functioning. SME does not exhibit superior speech recognition outcomes when compared with SLW.

Centralized Otolaryngology Research Efforts: Stepping-stones to Innovation and Equity in Otolaryngology-Head and Neck Surgery.

The Centralized Otolaryngology Research Efforts (CORE) grant program coordinates research funding initiatives across the subspecialties of otolaryngology-head and neck surgery. Modeled after National Institutes of Health study sections, CORE grant review processes provide comprehensive reviews of scientific proposals. The organizational structure and grant review process support grant-writing skills, attention to study design, and other components of academic maturation toward securing external grants from the National Institutes of Health or other agencies. As a learning community and a catalyst for scientific advances, CORE evaluates clinical, translational, basic science, and health services research. Amid the societal reckoning around long-standing social injustices and health inequities, an important question is to what extent CORE engenders diversity, equity, and inclusion for the otolaryngology workforce. This commentary explores CORE's track record as a stepping-stone for promoting equity and innovation in the specialty. Such insights can help maximize opportunities for cultivating diverse leaders across the career continuum.

Pediatric intraosseous cranial myxoma: A case report and review of literature.

While intraosseous cranial myxoma is a rare pathology, it is important for providers to be aware of it, as early diagnosis and treatment is imperative for prognosis. Long-term follow-up is needed as high rates of recurrence have been documented.

Aerosol generation during cadaveric simulation of otologic surgery and live cochlear implantation.

OBJECTIVE: The risk of SARS-CoV-2 transmission to healthcare workers through airborne aerosolization during otologic surgery has not been characterized. The objective of this study was to describe and quantify the aerosol generation during common otologic procedures in both cadaveric surgical simulation and live patient surgery. METHODS: The number concentrations of generated aerosols in the particle size range of 0.30 to 10.0 µm were quantified using an optical particle sizer during both a cadaveric simulation of routine otologic procedures as well as cochlear implant surgery on live patients in the operating room. RESULTS: In the cadaveric simulation, temporalis fascia graft harvest using cold techniques (without electrocautery) (n = 4) did not generate aerosols above baseline concentrations. Tympanoplasty (n = 3) and mastoidectomy (n = 3) both produced statistically significant increases in concentrations of aerosols (P < 0.05), predominantly submicron particles (< 1.0 µm). High-speed, powered drilling of the temporal bone during mastoidectomy with a Multi Flute cutting burr resulted in higher peak concentrations and greater number of spikes in aerosols than with a diamond burr. In the operating room, spikes in aerosols occurred during both cochlear implant surgeries. CONCLUSION: In the cadaveric simulation, temporalis fascia graft harvest without electrocautery did not generate aerosol levels above baseline, while significant aerosol levels were generated during mastoidectomy and to a much less degree during tympanoplasty. Aerosol spikes were appreciated during cochlear implantation surgery in live patients. LEVEL OF EVIDENCE: 2.

Middle Cranial Fossa Repair of Temporal Bone Spontaneous CSF Leaks With Hydroxyapatite Bone Cement.

OBJECTIVES: To determine the safety and effectiveness of the middle cranial fossa (MCF) approach in repairing spontaneous cerebrospinal fluid (sCSF) leaks. STUDY DESIGN: Retrospective cohort study. METHODS: Patient with sCSF leaks repaired by MCF approach between January 1, 2014 and August 31, 2019 were included. Demographic information, clinical and surgical findings, and postoperative outcomes were recorded. RESULTS: The cohort (n = 45) included 24 tegmen repairs by multilayer reconstruction using hydroxyapatite cement and 21 cases of multilayer repair without hydroxyapatite cement. Ten MCF repairs were performed on patients ≥65 years old. Twenty (53%) ears had multiple tegmen defects (range, 1-9 tegmen defects) and 78% of patients had ≥1 encephaloceles. All sCSF leaks were resolved with one surgical intervention. There were no major intracranial complications. Transient expressive aphasia occurred in 2 patients. Medical complications occurred in four patients. There were no short-term postoperative CSF leaks with bone cement reconstruction and two postoperative leaks without bone cement. One resolved with lumbar drain (LD) and the other resolved without treatment. The average (SD) length of stay (LOS) with bone cement was shorter than in patients without bone cement (2.54 [0.83] days vs. 3.52 [1.99] days, P < .05). There have been no long-term CSF leak recurrences with an average (SD) follow-up of 13.5 (12.9) months (range 0.25-46 months). CONCLUSIONS: MCF approach for sCSF repairs demonstrate efficacious outcomes, particularly with tegmen reconstruction using hydroxyapatite cement. The approach exhibited no serious adverse events and few complications requiring intervention. Therefore, MCF is a safe and effective approach to resolve sCSF leaks. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:624-632, 2021.

Calvarium Thinning in Patients with Spontaneous Cerebrospinal Fluid Leaks of the Anterior Skull Base.

OBJECTIVES/HYPOTHESIS: Patients with spontaneous cerebrospinal fluid leaks (sCSF-L) of the temporal bone have isolated calvarial and skull base thinning that is independent of obesity. This study determines if anterior skull base (ASB) sCSF-L patients also have calvarial thinning. STUDY DESIGN: Retrospective Cohort Study. METHODS: This was a retrospective cohort study of ASB sCSF-L patients compared to nonobese (body mass index [BMI] < 30 kg/m2 ) and obese (BMI ≥ 30) control groups. Twenty-one patients in the ASB sCSF-L group and 25 patients in each control group were included. Calvarium and extracranial zygoma thicknesses were measured bilaterally with blinded, standardized, volumetric analysis. RESULTS: ASB sCSF-L patients had a mean (SD) age of 50.43 (10.19) years, an average (SD) BMI of 38.81 (8.92) kg/m2 , and most were female (85.71%). The calvarium in patients with ASB sCSF-L was significantly thinner than the nonobese (2.55 mm [0.77] vs. 2.97 [0.67] mm; P = .006; 95% confidence intervals [CI], 0.12-0.30; Cohen d, 0.58) and obese control groups (2.55 [0.77] vs. 2.92 [0.76] mm; P = .02; 95% CI, 0.05-0.34; Cohen d, 0.66). The calvarium thickness of the nonobese patients was not significantly different from the obese patient controls (2.97 [0.67] vs. 2.92 [0.76] mm, P = .9). The extracranial zygoma was not significantly different among the groups (analysis of variance, P = .33). CONCLUSIONS: ASB sCSF-L patients have isolated calvarial thinning that is independent of obesity. Like lateral skull base sCSF-L patients, these data suggest that the additional obesity-associated intracranial process contributes to skull thinning. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1271-1276, 2021.

Metastatic Disease of the Temporal Bone: A Contemporary Review.

OBJECTIVES: To identify the frequency and primary site of metastatic pathologies to the temporal bone and characterize the associated symptomatology. METHODS: The MEDLINE, Embase, and Web of Science databases were systematically reviewed according to the PRISMA guidelines to identify all cases of pathologically confirmed distant temporal bone metastases published with English translation until October 2019. Descriptive statistics were performed. RESULTS: Out of 576 full-length articles included for review, 109 met final criteria for data extraction providing 255 individual cases of distant temporal bone metastases. There was a male predominance (54.9%) with median age of 59.0 years (range 2-90). The most common locations of primary malignancy included the breasts (19.6%), lungs (16.1%), and prostate (8.6%). Most tumors were carcinomas of epithelial origin (75.3%) and predominantly adenocarcinoma (49.4%). The commonest metastatic sites encountered within the temporal bone were the petrous (72.0%) and mastoid (49.0%) portions. Bilateral temporal bone metastases occurred in 39.8% of patients. Patients were asymptomatic in 32.0% of cases. Symptomatic patients primarily reported hearing loss (44.3%), facial palsy (31.2%), and otalgia (16.6%) for a median duration of 1 month. Petrous lesions were associated with asymptomatic cases (P = .001) while mastoid lesions more often exhibited facial palsy (P = .026), otalgia (P < .001), and otorrhea (P < .001). Non-carcinomatous tumors were associated with petrosal metastasis (P = .025) and asymptomatic cases (P = .109). Carcinomatous metastases more often presented with otalgia (P = .003). CONCLUSIONS: Temporal bone metastasis is uncommon but should be considered in patients with subacute otologic symptoms or facial palsy and history of distant malignancy. Laryngoscope, 131:1101-1109, 2021.

The Effects of Age and Race on Calvarium, Tegmen, and Zygoma Thickness.

OBJECTIVE: Temporal bone spontaneous cerebrospinal fluid (sCSF) leaks are characterized by defects in the tegmen along with calvarial thinning without associated thinning of the extracranial zygoma. The authors sought to determine the effect of age and race on calvarial, tegmen, and zygoma thickness. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary Referral Center. PATIENTS: A total of 446 patients with high-resolution head computer tomography (CT) imaging from 2003 to 2018.Intervention(s): Calvarial, tegmen, and zygoma thicknesses were measured using 3D slicer.Main Outcome Measure(s): Effects of age and race on calvarium, tegmen, zygoma thickness. RESULTS: Among all patients, increased age was associated with increased thickness of the calvarium [95% CI, 0.0002 to 0.007 mm/year, P < 0.05] and tegmen [95% CI, 0.00039 to 0.0075 mm/year, P = 0.03], but decreased thickness of the zygoma [95% CI, -0.013 to -0.005 mm/year, P < 0.001]. When compared to white patients, black patients had thicker mean [SD] calvaria (2.63 [0.61] versus 3.30 [0.79] mm; difference, 0.67 mm; [95% CI, 0.57 to 0.77]; Cohen d, 1.02), tegmen (0.73 [0.34] versus 0.92 [0.36] mm; difference 0.19 mm; [95% CI, 0.101 to 0.279]; Cohen d, 0.533) and zygoma (4.89 [0.81] versus 5.55 [0.91] mm; difference, 0.66 mm; [95% CI, 0.53 to 0.79]; Cohen d, 0.78). CONCLUSIONS: Racial differences exist in calvarial and zygoma thickness. Aging generally leads to increased calvarium and tegmen thickness, suggesting that early onset of obesity and comorbid conditions known to thin the skull base may predispose patients to developing sCSF leaks by reversing the effects of age.

Progress in Modeling and Targeting Inner Ear Disorders with Pluripotent Stem Cells.

Sensorineural hearing loss and vestibular dysfunction are caused by damage to neurons and mechanosensitive hair cells, which do not regenerate to any clinically relevant extent in humans. Several protocols have been devised to direct pluripotent stem cells (PSCs) into inner ear hair cells and neurons, which display many properties of their native counterparts. The efficiency, reproducibility, and scalability of these protocols are enhanced by incorporating knowledge of inner ear development. Modeling human diseases in vitro through genetic manipulation of PSCs is already feasible, thereby permitting the elucidation of mechanistic understandings of a wide array of disease etiologies. Early studies on transplantation of PSC-derived otic progenitors have been successful in certain animal models, yet restoration of function and long-term cell survival remain unrealized. Through further research, PSC-based approaches will continue to revolutionize our understanding of inner ear biology and contribute to the development of therapeutic treatments for inner ear disorders.

The role of obesity, sleep apnea, and elevated intracranial pressure in spontaneous cerebrospinal fluid leaks.

PURPOSE OF REVIEW: Spontaneous cerebrospinal fluid (sCSF) leaks often occurs in middle age, obese females. Here we investigate the role of obesity, idiopathic intracranial hypertension (IIH), and obstructive sleep apnea (OSA) in the pathophysiology of sCSF leaks. RECENT FINDINGS: The association of obesity and sCSF leaks has been well established in many studies. It has now been revealed that sCSF leak patients have thinner calvariums along with the skull base. An intracranial process likely leads to calvarium and skull base thinning in sCSF leaks patients since this occurs independent of extracranial bone thinning and independent of obesity. OSA, which is known to cause spikes in intracranial pressure (ICP), has been found to be significantly prevalent in the sCSF population and has been shown to lead to both calvarial and skull base thinning. Chronically elevated ICP (IIH) has also been shown to impact calvarial and skull base thicknesses. SUMMARY: The incidence of sCSF leaks has increased in recent decades along with an increasing rate of obesity. OSA and IIH, which are obesity-related factors and cause transient and chronic elevations in ICP, have now been implicated as critical factors leading to calvarial and skull base thinning and resultant sCSF leaks.

Association of Obstructive Sleep Apnea With Calvarial and Skull Base Thinning.

Importance: Spontaneous cerebrospinal fluid leaks (sCSF-L) of the temporal bone are associated with obesity, calvarial thinning, and obstructive sleep apnea (OSA), and the incidence has doubled in the past decade. It is currently unknown if OSA is independently associated with skull thinning. Objective: To determine if patients with OSA have thinner skulls than patients without OSA. Design, Setting, and Participants: A retrospective cohort study of patients who underwent a level 1 polysomnogram (PSG) and also had high-resolution computed tomographic (CT) imaging of the head from January 2010 to March 2017 at Indiana University was carried out. Patients with moderate to severe OSA (apnea-hypopnea index [AHI]≥25/h) and without OSA (AHI<5/h) were matched for age and body mass index (BMI, calculated as weight in kilograms divided by height in meters squared). Interventions: Measurement of calvarial thickness, extracranial zygoma thickness, skull base height and tegmen dehiscence (>4 mm) when blinded to OSA status. Main Outcomes and Measures: Primary outcomes were calvarial, skull base, and zygoma thickness differences between patients with OSA vs those without OSA. Results: A total of 22 933 patients had a PSG and 1012 also had head CT imaging. Of the 1012 patients with both PSG and CT, the mean (SD) age was 50.8 (16.2) years and 624 (61.7%) were women. Those patients with moderate to severe OSA (56) and without OSA (58) were matched for mean (SD) age (50.3 [6.5] vs 49.8 [6.1] years]) and BMI (37.4 [8.1] vs 38.6 [6.8]). Patients with OSA had thinner mean (SD) calvaria (2.73 [0.67] vs 2.47 [0.52] mm; difference, -0.26 mm; 95% CI, -0.49 to -0.04; Cohen d, 0.44) and thinner skull bases (5.03 [1.40] vs 4.32 [1.28] mm; difference, -0.71; 95% CI, -1.23 to -0.19; Cohen d, 0.53). The mean (SD) extracranial zygoma thickness was the same (4.92 [0.87] vs 4.84 [0.84] mm; difference, -0.07 mm; 95% CI, -0.39 to 0.24). The tegmen mastoideum was dehiscent in nearly twice as many patients with OSA as those without (37% vs 20%; difference, 17%; 95% CI, 0.4-32). Conclusions and Relevance: Obstructive sleep apnea was independently associated with intracranial bone (calvaria and skull base) thinning and not with extracranial (zygoma) thinning. These findings support a possible role of OSA in the pathophysiologic development of sCSF-L.