Regulation of PCDH15 function in mechanosensory hair cells by alternative splicing of the cytoplasmic domain.

Protocadherin 15 (PCDH15) is expressed in hair cells of the inner ear and in photoreceptors of the retina. Mutations in PCDH15 cause Usher Syndrome (deaf-blindness) and recessive deafness. In developing hair cells, PCDH15 localizes to extracellular linkages that connect the stereocilia and kinocilium into a bundle and regulate its morphogenesis. In mature hair cells, PCDH15 is a component of tip links, which gate mechanotransduction channels. PCDH15 is expressed in several isoforms differing in their cytoplasmic domains, suggesting that alternative splicing regulates PCDH15 function in hair cells. To test this model, we generated three mouse lines, each of which lacks one out of three prominent PCDH15 isoforms (CD1, CD2 and CD3). Surprisingly, mice lacking PCDH15-CD1 and PCDH15-CD3 form normal hair bundles and tip links and maintain hearing function. Tip links are also present in mice lacking PCDH15-CD2. However, PCDH15-CD2-deficient mice are deaf, lack kinociliary links and have abnormally polarized hair bundles. Planar cell polarity (PCP) proteins are distributed normally in the sensory epithelia of the mutants, suggesting that PCDH15-CD2 acts downstream of PCP components to control polarity. Despite the absence of kinociliary links, vestibular function is surprisingly intact in the PCDH15-CD2 mutants. Our findings reveal an essential role for PCDH15-CD2 in the formation of kinociliary links and hair bundle polarization, and show that several PCDH15 isoforms can function redundantly at tip links.

Longitudinal Auditory Benefit for Elderly Patients After Cochlear Implant for Bilateral Hearing Loss, Including Those Meeting Expanded Centers for Medicare & Medicaid Services Criteria.

OBJECTIVE: To examine the effect of patient age on longitudinal speech understanding outcomes after cochlear implantation (CI) in bilateral hearing loss. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary academic center. PATIENTS: One thousand one hundred five adult patients with bilateral hearing loss receiving a unilateral CI between 1987 and 2022InterventionsNone. MAIN OUTCOME MEASURES: Postoperative speech recognition outcomes, including AzBio sentences, consonant-nucleus-consonant word, and Hearing in Noise Test in quiet were analyzed at short-term (<2 yr), medium-term (2-8 y), and long-term (>8 yr) term postoperative intervals. RESULTS: Eighty-six very elderly (>80 yr), 409 elderly (65-80 yr), and 709 nonelderly (18-65 yr) patients were included. Short-term postoperative AzBio scores demonstrated similar magnitude of improvement relative to preoperative scores in the very elderly (47.6, 95% confidence interval [CI], 28.9-66.4), elderly (49.0; 95% CI, 39.2-58.8), and nonelderly (47.9; 95% CI, 35.4-60.4). Scores for those older than 80 years remained stable after 2 years after implant, but in those 80 years or younger, scores continued to improve for up to 8 years (elderly: 6.2 [95% CI, 1.5-12.4]; nonelderly: 9.9 [95% CI, 2.1-17.7]) after implantation. Similar patterns were observed for consonant-nucleus-consonant word scores. Across all age cohorts, patients with preoperative Hearing in Noise Test scores between 40 and 60% had similar scores to those with preoperative scores of less than 40%, at short-term (82.4, 78.9; 95% CI, -23.1 to 10.0), medium-term (77.2, 83.9; 95% CI, -15.4 to 8.2), or long-term (73.4, 71.2; 95% CI, -18.2 to 12.2) follow-up. CONCLUSIONS: Patients older than 80 years gain significant and sustained auditory benefit after CI, including those meeting expanded Centers for Medicare & Medicaid Service criteria for implantation. Patients younger than 80 years demonstrated continued improvement over longer periods than older patients, suggesting a role of central plasticity in mediating CI outcomes as a function of age.

Polymorphisms in KCNE1 or KCNE3 are not associated with Ménière disease in the Caucasian population.

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.

Surgical Complications from Superior Canal Dehiscence Syndrome Repair: Two Decades of Experience.

Objective To determine the incidence of surgical complications associated with superior canal dehiscence syndrome (SCDS) repair and identify the demographic, medical, and intraoperative risk factors that are associated with SCDS complications. Study Design Cases series with chart review, including patients who underwent SCDS repair between 1996 and 2015. Setting A tertiary care academic medical center. Subjects and Methods Data were collected from 220 patients, including demographic information, medical comorbidities, prior otologic surgical history, surgical approach, intraoperative findings, and postoperative complications. Relative risk analysis and multivariable logistic regression evaluated the associations between perioperative risk factors and SCDS complications. Results A total of 242 consecutive cases were performed: 95.5% middle fossa and 4.5% transmastoid approach (mean age: 47.8 ± 10.6 years; 54.5% female). Surgical complications were reported in 27 (11.2%) cases; 20 (8.3%) had Clavien-Dindo grade I complications, most commonly benign paroxysmal positional vertigo (n = 11, 4.5%) and profound sensorineural hearing loss (n = 6, 2.5%). Two cases (0.8%) had grade II; 4 cases (1.7%), grade III; and 1 case (0.4%), grade IV complications. In the analysis of comorbidities, only preoperative coagulopathy was significantly associated with increased risk of complications (relative risk = 6.4, P < .01). Following multivariate logistic regression adjusting for demographic covariates, coagulopathy was still associated with increased odds of complications (odds ratio = 15.7, P = .03). There were no significant associations between other risk factors and complications. Conclusion SCDS repair has low rates of adverse events. We observed an incidence of 11.2% complications, most commonly postoperative benign paroxysmal positional vertigo. The risk of nonotologic intracranial complications (1.7%) is low.

Superior canal dehiscence is not due to cephalic displacement of the labyrinth.

Superior semicircular canal dehiscence syndrome may have a congenital basis. CT scans of 44 control and 21 dehiscent superior canals were examined to determine if dehiscent canals were more cephalically placed or vertically oriented than control canals. Results showed that neither was the case. Instead, the defect may be in the process of ossification above the superior canal.

Silent sinus syndrome: an acquired condition.

We present the case of a 30-year-old man with silent sinus syndrome. A CT scan obtained 10 years earlier showed completely normal maxillary sinuses. This case illustrates the acquired nature of this disorder.

Search-coil head-thrust and caloric tests in Ménière's disease.

CONCLUSIONS: Our findings suggest that canal function is substantially preserved in subjects with active vertigo attacks as a result of Ménière's disease (MD). In these subjects, the head-thrust test (HTT) may not be as sensitive to canal dysfunction as traditional caloric testing. MD may differentially affect the low-frequency sensitivity of the canals. OBJECTIVE: Caloric tests have traditionally been used to characterize semicircular canal function in vestibular disorders, including MD. The quantitative HTT provides an objective measurement of semicircular canal function in the frequency and velocity ranges of normal head movements. The aim of this study was to compare the findings of caloric and HTTs in subjects with unilateral MD. MATERIAL AND METHODS: The study population consisted of 38 candidates for gentamicin treatment due to a high frequency of vertiginous attacks (25 males, 13 females; mean age 52.9 years; range 30-70 years). The duration of symptoms was 1-30 years (mean 5.3 years). Horizontal canal function was characterized with bithermal aqueous caloric tests and recordings of the angular vestibulo-ocular reflexes (aVORs) using the scleral search-coil technique during HTTs. The main outcomes were unilateral weakness (UW) on caloric testing and aVOR gain asymmetry (GA) during HTTs. A caloric response asymmetry of >20% was considered to be indicative of pathologic UW. A difference in GA during HTTs of >5.8% was considered significant. RESULTS: Twenty subjects (52.6%) showed abnormal results on one or both tests. Pathologic UW was present in 16 subjects (42.1%). During HTTs, 11 subjects (28.9%) showed pathologic GA. Seven subjects (18.4%) showed abnormal results on both tests. A significant correlation was found between UW and GA. However, pathologic GA during HTTs in subjects with unilateral MD was less frequent and the values smaller than those published for vestibular neuritis patients. Two subjects with unilateral MD had 100% UW, but none had >30% asymmetry on HTTs.