Temporal Swelling Following Cochlear Implantation: Frequency, Treatment, and Outcomes.

OBJECTIVE: To investigate the frequency, treatment, and outcomes of postoperative delayed-onset swelling around cochlear implants. STUDY DESIGN: Retrospective, observational, nonrandomized group study. SETTING: Academic medical center. PATIENTS/INTERVENTIONS: Among 354 patients (516 ears) who underwent cochlear implantation (CI) at our hospital between May 2009 and October 2022, 329 (472 ears: 138 children [246 ears] and 191 adults [226 ears]) with a follow-up period of >3 months were included. MAIN OUTCOME MEASURES: Physical examination and computed tomography of the head were performed. RESULTS: In total, 5.5% (26/472 ears) had a history of delayed-onset swelling around the implant. This complication occurred in 9.8% (24/246 ears) of children and 0.9% (2/226 ears) of adults. The mean time to onset of swelling was 50 (range, 5.5-147) months following CI. In 60% (21/35) of the cases, the cause was unknown, whereas in 25.7% (9/35) and 11.5% (4/35) of cases, it was head trauma and acute inflammation, respectively. Conservative treatment (observation, antibiotics, and/or strong magnetic compression) was adapted in 91.4% (32/35) of cases. After conservative treatment, revision CI surgery was performed in one ear. Additionally, recurrent swelling was observed in 23.1% (6/26 ears) of swelling cases. CONCLUSIONS: The results suggest that delayed-onset swelling around implants occurs more frequently in children than in adults because of the higher incidence rates of head trauma and acute otitis media in children. In most cases, conservative treatment was adequate; however, careful follow-up is necessary. Our findings can serve as a reference for optimizing care and intervention options after CI.

Epidemiology, aetiology and diagnosis of congenital hearing loss via hearing screening of 153 913 newborns.

BACKGROUND: Congenital hearing loss (HL), one of the most common paediatric chronic conditions, significantly affects speech and language development. Its early diagnosis and medical intervention can be achieved via newborn hearing screening. However, data on the prevalence and aetiology of congenital HL in infants who fail newborn hearing screening are limited. METHODS: The sample population included 153 913 infants who underwent newborn hearing screening, and the prevalence of congenital HL, defined as moderate to profound bilateral HL (BHL) or unilateral HL (UHL) (≥40 dB HL), in one prefecture of Japan was measured to minimize the loss-to-follow-up rate, a common factor affecting the screening procedure. Comprehensive aetiological investigation, including physiology, imaging, genetic tests, and congenital cytomegalovirus screening, was performed on children diagnosed with congenital HL. RESULTS: The calculated prevalence of congenital HL was 1.62 per 1000 newborns (bilateral, 0.84; unilateral, 0.77). More than half of the cases with congenital bilateral or severe to profound UHL showed genetic aetiology or cochlear nerve deficiency (CND), respectively. Approximately 4% and 6% of the cases of congenital BHL and UHL were associated with congenital cytomegalovirus infection and auditory neuropathy spectrum disorder, respectively. CONCLUSIONS: This is an epidemiological and comprehensive aetiological study of congenital HL, as determined via newborn hearing screening according to its severity and laterality, in a large-scale general population of a developed country. Our findings can serve as a reference for optimizing care and intervention options for children with HL and their families.

Cause, severity, and efficacy of treatment for hearing loss in children with Trisomy 18: A single institution-based retrospective study.

Trisomy 18 is a common chromosomal aberration syndrome, characterized by variable clinical manifestations, including cardiovascular, pulmonary, genitourinary, and musculoskeletal findings, leading to a shorter survival and severe developmental delay in survivors. However, recently, intensive therapeutic intervention has allowed for prolonging survival. In terms of otological complications, only a limited number of relevant reports have been published. To demonstrate the characteristic of hearing loss (HL) in children with Trisomy 18, we retrospectively evaluated 22 patients (44 ears) by comprehensive auditory evaluation with the auditory steady-state response (ASSR) test and temporal bone computed tomography (CT). ASSR revealed that 20 patients (91%) had bilateral moderate to profound HL, more frequent and severe than that in Trisomy 21; among 42 ears having HL, 12 ears (29%) had conductive HL, and 26 ears (62%) had mixed HL. CT scans of 38 ears revealed that 34 ears (89%) had an external and middle ear malformation. Hearing aids (HA) were fitted in 17 patients (air and bone-conduction HAs). The threshold hearing with HA was improved in all of them. Accurate otological evaluation using ASSR and CT and intervention by HAs could be a feasible choice for children with Trisomy 18.

Treatment following Triple-AAV Delivery in Mature Murine Model of Human CDH23-Associated Hearing Loss.

This study aimed to investigate the transduction efficiency of triple adeno-associated virus (AAV) vectors in the cochleae of adult mice, focusing on large-gene-associated hearing loss (HL). Additionally, we sought to evaluate the feasibility of cochlear gene therapy in a mouse model of human CDH23-mediated HL using the triple AAV approach. To create a reporter protein, we fused EGFP to mCherry, which was then divided into three parts, each packaged in a separate AAV2/2 vector. Four weeks after co-injecting the triple AAV vectors into 4-5-week-old mice, we assessed transduction efficiency. We found that up to 5.9% of inner hair cells were positive for both EGFP and mCherry. Subsequently, we developed triple Cdh23 AAV vectors for therapeutic purposes. After administering these vectors to 4- to 5-week-old C57/BL6 mice, we conducted auditory tests and immunohistochemistry studies over a period of 60 weeks. Co-injecting triple Cdh23-AAVs did not alter auditory function or lead to hair cell degeneration. In conclusion, this study confirms the feasibility of the triple-AAV approach for cochlear gene delivery. While this strategy did not produce any treatment effects, our findings suggest that large deafness genes could be potential future targets for cochlear gene therapy.

Determining optimal cochlear implant electrode array with OTOPLAN.

BACKGROUND: To achieve better speech performance following cochlear implantation (CI), measuring the patient's cochlear duct length (CDL) and determining the appropriate length of the CI array are important. OBJECTIVE: To investigate the CDL in CI patients after using the OTOPLAN software preoperatively and compare the results of angular insertion depth (AID) estimation by OTOPLAN and postoperative radiography. MATERIALS AND METHODS: The study included 105 Japanese CI patients with normal cochleae. We measured the CDL using OTOPLAN and the position of the tip channel of the electrode for each selected electrode array, and estimated the AID using the software. RESULTS: The mean CDL was 35.1 ± 1.6 mm. Preoperatively, the mean estimated AID was 580.3 ± 57.8°. Postoperative radiography revealed a mean AID of 583.0 ± 56.7°, demonstrating a strong linear correlation between the two measurements (R2 = 0.635). CONCLUSION AND SIGNIFICANCE: Our findings revealed that CDL varies widely, which is consistent with previous studies. To achieve better speech perception, surgeons should select the appropriate length of CI electrode array based on the individual's CDL. Preoperative measurement of each CDL by OTOPLAN, which is clinically feasible and comparable to postoperative evaluation, can be used to ensure selection of the appropriate electrode array length.

Enhanced Cochlear Transduction by AAV9 with High-Concentration Sucrose.

The inner ear is a primary lesion in sensorineural hearing loss and has been a target in gene therapy. The efficacy of gene therapy depends on achieving sufficient levels of transduction at a safe vector dose. Vectors derived from various adeno-associated viruses (AAVs) are predominantly used to deliver therapeutic genes to inner ear cells. AAV9 and its variants vector are attractive candidates for clinical applications since they can cross the mesothelial cell layer and transduce inner hair cells (IHCs), although this requires relatively high doses. In this study, we investigated the effects of sucrose on the transduction of a variant of the AAV9 vector for gene transfer in the inner ear. We found that high concentrations of sucrose increased gene transduction in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells in vitro. In addition, we demonstrated that simultaneous administration of sucrose enhanced the transduction of mouse IHCs and spiral ligament cells using an AAV9 variant vector. The procedure did not increase the thresholds in the auditory brainstem response, suggesting that sucrose had no adverse effect on auditory function. This versatile method may be valuable in the development of novel gene therapies for adult-onset sensorineural hearing loss.

Single-cell RNA-sequencing of stria vascularis cells in the adult Slc26a4-/- mouse.

BACKGROUND: The primary pathological alterations of Pendred syndrome are endolymphatic pH acidification and luminal enlargement of the inner ear. However, the molecular contributions of specific cell types remain poorly characterized. Therefore, we aimed to identify pH regulators in pendrin-expressing cells that may contribute to the homeostasis of endolymph pH and define the cellular pathogenic mechanisms that contribute to the dysregulation of cochlear endolymph pH in Slc26a4-/- mice. METHODS: We used single-cell RNA sequencing to identify both Slc26a4-expressing cells and Kcnj10-expressing cells in wild-type (WT, Slc26a4+/+) and Slc26a4-/- mice. Bioinformatic analysis of expression data confirmed marker genes defining the different cell types of the stria vascularis. In addition, specific findings were confirmed at the protein level by immunofluorescence. RESULTS: We found that spindle cells, which express pendrin, contain extrinsic cellular components, a factor that enables cell-to-cell communication. In addition, the gene expression profile informed the pH of the spindle cells. Compared to WT, the transcriptional profiles in Slc26a4-/- mice showed downregulation of extracellular exosome-related genes in spindle cells. Immunofluorescence studies in spindle cells of Slc26a4-/- mice validated the increased expression of the exosome-related protein, annexin A1, and the clathrin-mediated endocytosis-related protein, adaptor protein 2. CONCLUSION: Overall, cell isolation of stria vascularis from WT and Slc26a4-/- samples combined with cell type-specific transcriptomic analyses revealed pH-dependent alternations in spindle cells and intermediate cells, inspiring further studies into the dysfunctional role of stria vascularis cells in SLC26A4-related hearing loss.

A case of hematohidrosis successfully treated with a beta-blocker.

Hematohidrosis is a rare disorder characterized by bloody sweating on the skin without trauma. The ear, nose, and other facial areas are the most commonly affected sites. This study shows usefulness of beta-blockers in the treatment of hematohidrosis.

Feasibility and limitations of head MRI in patients with cochlear implants.

OBJECTIVE: Cochlear implants (CIs) were noncompatible with magnetic resonance imaging (MRI) initially; however, recently, implants have become available that are compatible with MRI without the need for magnet removal or bandage fixation. The images produced by MRI scans are sometimes deteriorated by artifacts and are not clinically useful. In this study, we discussed the size differences of such artifacts with respect to the imaging modality and sequences with their clinical validity. METHODS: We performed a head MRI, using a head bandage and without magnet removal in five patients who underwent cochlear implantation at our department and analyzed the MRI findings. RESULTS: Without magnet removal, diffusion-weighted images and T2 star-weighted images had larger artifacts and less useful images. T1-weighted images, T2-weighted images (T2WIs), T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) images, and heavy T2WIs could evaluate the unimplanted side and middle of the head but had limited applicability on the CI side. CONCLUSION: The characteristic features of MRI scan images vary with the method used as well as with the sequence, suggesting that the choice of MRI is largely determined on the basis of clinical feasibility and the requirement. Accordingly, we need to judge well in advance of imaging whether the images would be clinically relevant.

The relationship between preoperative factors and the pattern of longitudinal improvement in speech perception following cochlear implantation.

BACKGROUND: Many studies have discussed the factors influencing hearing outcomes after cochlear implantation, but few have addressed improvements in speech perception for these patients over time. OBJECTIVE: To investigate the relationship between preoperative factors and the pattern of longitudinal improvement in speech perception following cochlear implantation (CI). MATERIALS AND METHODS: This study enrolled 83 patients (96 ears) who underwent CI at Shinshu University Hospital. The patients were assessed up to 12 months after CI by a monosyllable test, and showed either delayed improvement (DI), early improvement (EI), or stable improvement (SI) when compared with their preoperative score. Eight preoperative variables were also examined for their effects on speech perception over time. RESULTS: The DI, EI, SI groups comprised 35.4%, 43.8%, and 20.8% of all patients, respectively. Patients in the DI group were older at surgery than those in the EI and SI groups, and their onset age were also older than that in the SI group. No other preoperative variables showed significant differences across the three groups. CONCLUSIONS AND SIGNIFICANCE: Our findings revealed that age at implantation and age at onset of hearing loss significantly affected the improvement pattern of speech perception. Age may be useful in predicting recovery of speech perception after CI.

Mutation-agnostic RNA interference with engineered replacement rescues Tmc1-related hearing loss.

Hearing loss is the most common sensory deficit, of which genetic etiologies are a frequent cause. Dominant and recessive mutations in TMC1, a gene encoding the pore-forming subunit of the hair cell mechanotransduction channel, cause DFNA36 and DFNB7/11, respectively, accounting for ∼2% of genetic hearing loss. Previous work has established the efficacy of mutation-targeted RNAi in treatment of murine models of autosomal dominant non-syndromic deafness. However, application of such approaches is limited by the infeasibility of development and validation of novel constructs for each variant. We developed an allele-non-specific approach consisting of mutation-agnostic RNAi suppression of both mutant and WT alleles, co-delivered with a knockdown-resistant engineered WT allele with or without the use of woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) to augment transgene expression. This therapeutic construct was delivered into the mature murine model of DFNA36 with an AAV vector and achieved robust hair cell and auditory brainstem response preservation. However, WPRE-enhanced Tmc1 expression resulted in inferior outcomes, suggesting a role for gene dosage optimization in future TMC1 gene therapy development.

Clinical and molecular features of patients with COL1-related disorders: Implications for the wider spectrum and the risk of vascular complications.

Abnormalities in type I procollagen genes (COL1A1 and COL1A2) are responsible for hereditary connective tissue disorders including osteogenesis imperfecta (OI), specific types of Ehlers-Danlos syndrome (EDS), and COL1-related overlapping disorder (C1ROD). C1ROD is a recently proposed disorder characterized by predominant EDS symptoms of joint and skin laxity and mild OI symptoms of bone fragility and blue sclera. Patients with C1ROD do not carry specific variants for COL1-related EDS, including classical, vascular, cardiac-valvular, and arthrochalasia types. We describe clinical and molecular findings of 23 Japanese patients with pathogenic or likely pathogenic variants of COL1A1 or COL1A2, who had either OI-like or EDS-like phenotypes. The final diagnoses were OI in 17 patients, classical EDS in one, and C1ROD in five. The OI group predominantly experienced recurrent bone fractures, and the EDS group primarily showed joint hypermobility and skin hyperextensibility, though various clinical and molecular overlaps between OI, COL1-related EDS, and C1ROD as well as intrafamilial phenotypic variabilities were present. Notably, life-threatening vascular complications (vascular dissections, arterial aneurysms, subarachnoidal hemorrhages) occurred in seven patients (41% of those aged >20 years) with OI or C1ROD. Careful lifelong surveillance and intervention regarding bone and vascular fragility could be required.

Audiological Features in 63 Patients With Cochlear Nerve Deficiency.

OBJECTIVE: We aimed to investigate the clinical features of cochlear nerve deficiency (CND), and in particular, the long-term course of hearing disability and audiogram shapes. STUDY DESIGN: Retrospective observational nonrandomized group study. SETTING: Academic medical center. PATIENTS/INTERVENTIONS: The subjects were 63 children with congenital hearing loss who visited our hospital between 2009 and 2019 and underwent MRI, based on which they were diagnosed with CND. There were 61 cases of unilateral CND and two cases of bilateral CND. MAIN OUTCOME MEASURES: Imaging tests by MRI and CT and audiometric assessments by pure-tone audiometry and distortion product otoacoustic emission were performed. RESULTS: Among the cases of CND diagnosed by assessing the cochlear nerve on MRI, approximately 20% of the bony cochlear nerve canals that could be assessed on CT were normal. Of the 61 cases diagnosed with unilateral CND, 55 cases had cochlear nerve aplasia (90.2%), and six had cochlear nerve hypoplasia (9.8%), with a mean hearing ability of 92.2 and 94.6 dB HL, respectively. Thus, the majority of cases had severe-to-profound hearing loss. The overall audiometric patterns were 78.7% flat, 9.8% cookie-bite, and 9.8% high-frequency. Six of 61 cases (9.8%) had a distortion product otoacoustic emission (DPOAE) response based on the affected side, and none of the cases lost the response during follow-up. CONCLUSIONS: Herein, we report the largest study on CND and performed CND image and audiometric assessments. Accurately in diagnosing CND requires not only CT but also MRI assessment. Hearing loss is often severe to profound; however, various audiometric patterns have been observed. CND includes a small number of cases that respond to DPOAE, indicating that some CND cases are clinically diagnosed with auditory neuropathy spectrum disorder (ANSD). A sustained DPOAE response might help in differentiating CND from other ANSDs. Children with congenital deafness who have passed the newborn hearing screening by DPOAE should be examined by MRI to rule out CND.

Detailed clinical features and genotype-phenotype correlation in an OTOF-related hearing loss cohort in Japan.

Mutations in the OTOF gene are a common cause of hereditary hearing loss and the main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype-phenotype correlation in patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype-phenotype correlation. Detailed clinical information was available for 64 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.6%) showed a "typical" phenotype; prelingual and severe-to-profound hearing loss. Forty-seven patients (73.4%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85-90% of the patients showed a hearing level of 20-39 dB with cochlear implant and a Categories of Auditory Performance (CAP) scale level 6 or better. Although truncating mutations and p.Arg1939Gln were clearly related to severe phenotype, almost half of the patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.His513Arg, p.Ile1573Thr and p.Glu1910Lys showed "true" auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype-phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype-phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients.

Frequency and natural course of congenital cytomegalovirus-associated hearing loss in children.

BACKGROUND: Congenital cytomegalovirus-associated hearing loss (cCMV-associated HL) is a common cause of congenital or early-onset deafness. Although cCMV infection has been reported to lead to various types of HL, the natural course of cCMV-associated HL over a long period is not yet known. OBJECTIVES: To investigate the clinical phenotype of cCMV-associated HL in the largest study to date. METHODS: Thirty-one CMV-positive children, diagnosed by examining CMV DNA extracted from their dried umbilical cords retrospectively, were divided into unilateral and bilateral HL groups, and their hearing ability was evaluated using pure-tone audiometry and auditory steady-state response over time. RESULTS: Thirteen patients (41.9%) had unilateral HL and 18 (58.1%) had bilateral HL. In most cases of unilateral cCMV-associated HL, the ear with better hearing maintained a normal hearing threshold. Notably, in most cases of both unilateral and bilateral HL, the ear with worse hearing ultimately showed severe to profound HL. CONCLUSION: Our findings revealed that the natural course of cCMV-associated HL was different between the cases of unilateral and bilateral HL, as well as between the ears with better or worse hearing in all cases. These findings indicate that accurate diagnosis could enable proper follow-up and management of cCMV-associated HL in children.

Milestones toward cochlear gene therapy for patients with hereditary hearing loss.

A number of genes are reportedly responsible for hereditary hearing loss, which accounts for over 50% of all congenital hearing loss cases. Recent advances in genetic testing have enabled the identification of pathogenic variants in many cases, and systems have been developed to provide personalized treatment based on etiology. Gene therapy is expected to become an unprecedented curative treatment. Several reports have demonstrated the successful use of cochlear gene therapy to restore auditory function in mouse models of genetic deafness; however, many hurdles remain to its clinical application in humans. Herein, we focus on the frequency of deafness genes in patients with congenital and late-onset progressive hearing loss and discuss the following points regarding which genes need to be targeted to efficiently proceed with clinical application: (a) which cells' genes are expressed within the cochlea, (b) whether gene transfer to the targeted cells is possible using vectors such as adeno-associated virus, (c) what phenotype of hearing loss in patients is exhibited, and (d) whether mouse models exist to verify the effectiveness of treatment. Moreover, at the start of clinical application, gene therapy in combination with cochlear implantation may be useful for cases of progressive hearing loss.

Vibrant soundbridge implantation prior to auricular reconstruction with unilateral microtia-atresia.

We presented the first successful application of VSB implantation prior to auriculoplasty, which can provide hearing improvement in safe conditions and open new strategies for earlier hearing rehabilitation in unilateral microtia-atresia children.

A nationwide epidemiologic, clinical, genetic study of Usher syndrome in Japan.

BACKGROUND: Usher syndrome (USH) typically leads to deaf-blindness, requiring the provision of extensive education and rehabilitation services. Therefore, investigating the prevalence is crucial to requests for proper government support for USH patients. OBJECTIVE: The aim was to perform a nationwide epidemiologic survey of USH in Japan to estimate the prevalence of USH and reveal the relative frequency and characteristics of the three USH subtypes. METHODS: To estimate the number of USH patients visiting hospitals over a 1-year period, 1,628 hospitals were randomly selected from all Departments of Otorhinolaryngology and Ophthalmology in Japan. Subsequently, we collected data regarding the clinical characteristics of each patient treated and the results of genetic testing, if performed. RESULTS: We found that the prevalence of USH was at least 0.4 per 100,000 population. The frequency of clinical subtypes and causal genes for USH were consistent with previous reports. Also, we demonstrated the feasibility of genetic counseling for USH patients based on the results of genetic testing. CONCLUSION: USH is a rare disease, but requires social support due to the severity of symptoms. To minimize these issues, understanding the clinical characteristics and performing comprehensive genetic testing could allow early and accurate diagnosis as well as medical intervention.

Electric-acoustic stimulation with longer electrodes for potential deterioration in low-frequency hearing.

Background: Electric-acoustic stimulation (EAS) has emerged as a standard treatment for patients with high-frequency hearing loss. EAS is usually performed with shorter electrodes of 16-24 mm in length. As most EAS recipients gradually lose residual acoustic hearing in the implanted ear over time, EAS with longer electrodes without causing significant intra-cochlear damage might be ideal.Objective: The aim of this study was to investigate hearing preservation (HP) results after EAS surgery with longer electrodes.Methods: Ten patients (11 ears) with partial deafness that met the indications for EAS with a MED-EL FLEX28 electrode were included in this study. Auditory thresholds before and at 6 months after activation were examined.Results: In 100% of cases, HP was comfortably achieved, indicating that all patients could utilize acoustic amplification combined with electric stimulation.Conclusion: EAS with longer electrodes can offer broader cochlear coverage, resulting in natural frequency matching in comparison with shorter electrodes, even in EAS cases. The combination of advanced surgical techniques and flexible, long, straight electrodes permits deep insertion that reaches the apical region with little or no insertion trauma.