Cochlear Implantation in the Poorer-Hearing Ear Is a Reasonable Choice.

Choosing the optimal side for cochlear implantation (CI) remains a major challenge because of the lack of evidence. We investigated the choice of the surgery side for CI (i.e., the better- or poorer-hearing ear) in patients with asymmetric hearing. Audiological records of 74 adults with a unilateral hearing aid who had undergone surgery at Okayama University Hospital were reviewed. The definition of 'better-hearing ear' was the aided ear, and the unaided ear was considered the poorer-hearing ear. We performed a multiple regression analysis to identify potential predictors of speech recognition performance after unilateral CI in the patients. Fifty-two patients underwent CI in the poorer-hearing ear. The post-Ci bimodal hearing rate was far higher in the poorer-ear group (77.8% vs. 22.2%). A multivariate analysis revealed that prelingual hearing loss and the patient's age at CI significantly affected the speech recognition outcome (beta coefficients: 24.6 and -0.33, 95% confidence intervals [11.75-37.45] and [-0.58 to -0.09], respectively), but the CI surgery side did not (-6.76, [-14.92-1.39]). Unilateral CI in the poorer-hearing ear may therefore be a reasonable choice for adult patients with postlingual severe hearing loss, providing a greater opportunity for postoperative bimodal hearing.

Revision cochlear implant surgery in adults and children is a safe and effective technique: a retrospective single faculty study in Okayama University Hospital, Japan.

BACKGROUND: Cochlear implant (CI) surgery is a safe surgical technique, although some patients require revision CI surgery. AIMS/OBJECTIVES: This study investigated the cause and underlying reason of revision CI surgery as well as hearing outcomes in a single institution. PATIENTS AND METHODS: This retrospective study evaluated patients who underwent CI surgery between April 2006 to March 2022 (n = 351). Sex, aetiology of hearing loss (HL), age and period from initial CI surgery to reimplantation, cause of revision, and related factors were examined. RESULTS: Twelve patients (8 males, 4 females) received CI reimplantation. The revision surgery rate was 2.59% (3.15% children, 1.69% adults); the period from initial surgery to reoperation was 8.60 ± 6.56 years for 9 children with congenital HL and 15.27 ± 5.72 years for 3 adults with progressive HL. Device failure was the most common cause (n = 8), followed by infections (n = 2), advanced facial irritation symptoms (n = 1), and electrode slip-out (n = 1). Mean preoperative and postoperative CI thresholds were 44.0 ± 9.46 dBnHL and 39.19 ± 8.89 dBnHL (p < .068), respectively. CONCLUSION AND SIGNIFICANCE: Caregiver education, surgical technique advances, flap design, and extensive antibiotic use may decrease the revision surgery rate. The lack of post-revision deterioration of the hearing threshold contributed to well-being in patients with CI.

Endolymphatic Hydrops on Magnetic Resonance Imaging May Be an Independent Finding on Aging in Neurotologic Patients.

OBJECTIVE: To clarify whether age impacts the development of endolymphatic hydrops (ELH) in neurotologic patients. Documentation of ELH in living patients on magnetic resonance imaging (MRI) allows analysis of patient age and formation of ELH, which is impossible by means of postmortem temporal bone pathology. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Fifty patients (100 ears) with top 3 diagnoses of definite Menière's disease, delayed ELH, or probable Menière's disease. INTERVENTIONS: Endolymph MRI after intravenous gadolinium injection and pure-tone audiometry. MAIN OUTCOME MEASURES: Cochlear and vestibular ELH confirmed by MRI. RESULTS: The prevalences of ears showing both cochlear and vestibular ELH were similar among age groups <30 years (30%), 30-59 years (25.9%), and ≥60 years (34.4%; p > 0.05; χ2 test). Using logistic regression modeling, mean hearing level at the six frequencies was positively associated with a higher risk of cochlear ELH (odds ratio, 1.3; 95% confidence interval, 1.1-1.5 per 10-dB increment). In the same regression model, age did not impact the outcome of cochlear ELH (odds ratio, 1.0; 95%confidence interval, 0.7-1.4 per 10-year increment). Age did not differ among ears with no ELH (mean ± standard deviation age, 48.6 ± 14.4 yr), ears with only cochlear ELH (59.3 ± 10.7 yr), ears with only vestibular ELH (50.4 ± 16.9 yr), or ears with both cochlear and vestibular ELH (51.5 ± 18.4 yr; p > 0.05, analysis of variance). CONCLUSION: Chronological age was not associated with the formation of ELH. Aging per se may not be associated with the development of ELH in neurotologic patients.

15-year follow-up for steroid-responsive, fluctuating hearing loss in the ear with endolymphatic hydrops confirmed by magnetic resonance imaging.

Autoimmune mechanisms may play crucial roles in the etiology of endolymphatic hydrops (ELH), which was previously regarded as a postmortem finding in the temporal bone. Recently, ELH has been visualized using 3-T MR imaging in living patients. A 47-year-old woman with deafness in the left ear since adolescence developed right-sided steroid-responsive sensorineural hearing loss in the low frequencies. During over 15 years of follow-up at our otolaryngology clinic, acute deteriorations of hearing in the only hearing ear repeatedly recovered with administration of intravenous and oral steroids. Hearing in the only hearing ear at 62 years old was preserved and comparable to that at 47 years old. At 61 years old, cochlear ELH was documented bilaterally on MR imaging, appearing more severe in the deafened ear than in the hearing ear. This case provides new evidence of the potential steroid-responsiveness of hearing loss due to contralateral-type delayed ELH distinctly visualized on MR imaging.

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.

The voltage-gated Ca2+ channel subunit α2δ-4 regulates locomotor behavior and sensorimotor gating in mice.

Voltage-gated Ca2+ channels are critical for the development and mature function of the nervous system. Variants in the CACNA2D4 gene encoding the α2δ-4 auxiliary subunit of these channels are associated with neuropsychiatric and neurodevelopmental disorders. α2δ-4 is prominently expressed in the retina and is crucial for vision, but extra-retinal functions of α2δ-4 have not been investigated. Here, we sought to fill this gap by analyzing the behavioral phenotypes of α2δ-4 knockout (KO) mice. α2δ-4 KO mice (both males and females) exhibited significant impairments in prepulse inhibition that were unlikely to result from the modestly elevated auditory brainstem response thresholds. Whereas α2δ-4 KO mice of both sexes were hyperactive in various assays, only females showed impaired motor coordination in the rotarod assay. α2δ-4 KO mice exhibited anxiolytic and anti-depressive behaviors in the elevated plus maze and tail suspension tests, respectively. Our results reveal an unexpected role for α2δ-4 in sensorimotor gating and motor function and identify α2δ-4 KO mice as a novel model for studying the pathophysiology associated with CACNA2D4 variants.

Upregulation of a nuclear factor-kappa B-interacting immune gene network in mice cochleae with age-related hearing loss.

Epidemiological data suggest that inflammation and innate immunity play significant roles in the pathogenesis of age-related hearing loss (ARHL) in humans. In this mouse study, real-time RT-PCR array targeting 84 immune-related genes revealed that the expressions of 40 genes (47.6%) were differentially regulated with greater than a twofold change in 12-month-old cochleae with ARHL relative to young control mice, 33 (39.3%) of which were upregulated. These differentially regulated genes (DEGs) were involved in functional pathways for cytokine-cytokine receptor interaction, chemokine signaling, TNF signaling, and Toll-like receptor signaling. An NF-κB subunit, Nfkb1, was upregulated in aged cochleae, and bioinformatic analyses predicted that NF-κB would interact with the genomic regulatory regions of eight upregulated DEGs, including Tnf and Ptgs2. In aging cochleae, major proinflammatory molecules, IL1B and IL18rap, were upregulated by 6 months of age and thereafter. Remarkable upregulations of seven immune-related genes (Casp1, IL18r1, IL1B, Card9, Clec4e, Ifit1, and Tlr9) occurred at an advanced stage (between 9 and 12 months of age) of ARHL. Immunohistochemistry analysis of cochlear sections from the 12-month-old mice indicated that IL-18r1 and IL-1B were localized to the spiral ligament, spiral limbus, and organ of Corti. The two NF-κB-interacting inflammatory molecules, TNFα and PTGS2, immunolocalized ubiquitously in cochlear structures, including the lateral wall (the stria vascularis and spiral ligament), in the histological sections of aged cochleae. IBA1-positive macrophages were observed in the stria vascularis and spiral ligament in aged mice. Therefore, inflammatory and immune reactions are modulated in aged cochlear tissues with ARHL.

Effects of Protective Measures against COVID-19 on Auditory Communication for People with Hearing Loss.

WHO has recommended various measures to combat the COVID-19 pandemic, including mask-wearing and physical distancing. However, these changes impair communication for individuals with hearing loss. We investigated the changes in auditory communication associated with COVID-19 measures in 269 patients (male: 45.7%, female: 54.3%, median age: 54 y.o.). Most patients with hearing loss had difficulty engaging in auditory communication with people wearing masks, especially in noisy surroundings or with physical distanc-ing. These difficulties were noticeable in patients with severe hearing loss. Developing communication support strategies for people with hearing loss is an urgent need while COVID-19 measures are in place.

Effect of Prostaglandin D2 on mRNA Expression of Three Isoforms of Hyaluronic Acid Synthase in Nasal Polyp Fibroblasts.

BACKGROUND: Hyaluronan is one of the major extracellular matrixes in chronic rhinosinusitis (CRS) associated with tissue remodeling. Prostaglandin D2 (PGD2) is also associated with the pathogenesis of CRS. However, little is known about whether PGD2 regulates hyaluronan production by human airway fibroblasts. OBJECTIVE: We sought to determine the effect of PGD2 on the mRNA expression of three isoforms of membrane-bound hyaluronic acid synthase (HAS1, HAS2 and HAS3) in fibroblasts, the major source of hyaluronan production, derived from CRS patients. METHODS: Nasal polyp-derived fibroblasts (NPDF) and uncinate tissue-derived fibroblasts (UTDF) were established from CRS patients with nasal polyps and those without, respectively. These fibroblasts were stimulated with PGD2 or PGD2 receptor (DP/CRTH2)-selective agonists in the presence or absence of receptor-selective antagonists. mRNA levels for HAS1, HAS2 and HAS3 were determined by real-time quantitative PCR. RESULTS: PGD2 (1 µM) significantly enhanced HAS1 but not HAS2 or HAS3 mRNA expression by NPDF. Enhanced HAS1 mRNA expression was also obtained by stimulation with a DP receptor-selective agonist, but not with a CRTH2 receptor-selective agonist. In addition, PGD2-induced HAS1 mRNA expression was significantly inhibited by pre-treatment with DP receptor-selective antagonists. Similar induction of PGD2-induced HAS1 mRNA expression was seen in UTDF. CONCLUSION: PGD2 selectively stimulates HAS1 mRNA expression in local fibroblasts in CRS via DP, but not CRTH2, receptors.

Hair Cell Transduction Efficiency of Single- and Dual-AAV Serotypes in Adult Murine Cochleae.

Gene delivery is a key component for the treatment of genetic hearing loss. To date, a myriad of adeno-associated virus (AAV) serotypes and surgical approaches have been employed to deliver transgenes to cochlear hair cells, but the efficacy of dual transduction remains unclear. Herein, we investigated cellular tropism of single injections of AAV serotype 1 (AAV1), AAV2, AAV8, AAV9, and Anc80L65, and quantitated dual-vector co-transduction rates following co-injection of AAV2 and AAV9 vectors in adult murine cochlea. We used the combined round window membrane and canal fenestration (RWM+CF) injection technique for vector delivery. Single AAV2 injections were most robust and transduced 96.7% ± 1.1% of inner hair cells (IHCs) and 83.9% ± 2.0% of outer hair cells (OHCs) throughout the cochlea without causing hearing impairment or hair cell loss. Dual AAV2 injection co-transduced 96.9% ± 1.7% of IHCs and 65.6% ± 8.95% of OHCs. Together, RWM+CF-injected single or dual AAV2 provides the highest auditory hair cell transduction efficiency of the AAV serotypes we studied. These findings broaden the application of cochlear gene therapy targeting hair cells.

Gene therapy for hearing loss.

Sensorineural hearing loss (SNHL) is the most common sensory disorder. Its underlying etiologies include a broad spectrum of genetic and environmental factors that can lead to hearing loss that is congenital or late onset, stable or progressive, drug related, noise induced, age related, traumatic or post-infectious. Habilitation options typically focus on amplification using wearable or implantable devices; however exciting new gene-therapy-based strategies to restore and prevent SNHL are actively under investigation. Recent proof-of-principle studies demonstrate the potential therapeutic potential of molecular agents delivered to the inner ear to ameliorate different types of SNHL. Correcting or preventing underlying genetic forms of hearing loss is poised to become a reality. Herein, we review molecular therapies for hearing loss such as gene replacement, antisense oligonucleotides, RNA interference and CRISPR-based gene editing. We discuss delivery methods, techniques and viral vectors employed for inner ear gene therapy and the advancements in this field that are paving the way for basic science research discoveries to transition to clinical trials.

Targeted PCR Array Analysis of Genes in Innate Immunity and Glucocorticoid Signaling Pathways in Mice Cochleae Following Acoustic Trauma.

AIM: To comprehensively analyze cochlear gene expressions related to innate immunity and glucocorticoid signaling at onset of acute noise-induced hearing loss (NIHL). BACKGROUND: Recent studies suggested innate immunity is involved in the cochlear pathology of NIHL. Glucocorticoids may modulate immune actions in cochleae. METHODS: Mice were exposed to 120 dB-octave band noise for 2 hours. Twelve hours later, a targeted PCR array analyzed cochlear expressions of 84 key genes in inflammation and immune pathways and 84 genes in the glucocorticoid signaling pathway. Real-time RT-PCR was used to analyze expression of two immune-related genes, Ccl12 and Glycam1, in noise-exposed cochleae with or without dexamethasone. RESULT: In inflammatory and immune gene pathways, 31.0% (26/84 genes) were significantly upregulated (>2-fold change) or downregulated (<0.5-fold change) (p < 0.05) in noise-exposed cochleae compared with controls. Sixteen of these differentially expressed genes (DEGs) encoded chemokines. DEGs included Ccl12, Ccl2, Ccl4, Ccl7, Cxcl1, Cxcl10, and Ptgs2 (upregulated genes), and Ccr7, Cxcr2, Kng1, Ltb, and Tnfsf14 (downregulated genes). In the glucocorticoid signaling pathway, 92.9% (78/84 genes) were unchanged in noise-exposed cochleae without dexamethasone administration. Cochlear expressions of Ccl12 and Glycam1 were significantly upregulated by noise and downregulated by dexamethasone. CONCLUSION: The targeted PCR array demonstrated that several dozen genes involved in innate immunity are actively regulated in cochleae with NIHL. The glucocorticoid signaling pathway was not endogenously regulated at 12 hours post-noise trauma. Systemic dexamethasone downregulated Ccl12 and Glycam1, which are upregulated in noise-exposed cochleae. These data may provide a basis for genomic medicine treatment of acute sensorineural hearing loss.

Transcanal endoscopic ear surgery for perilymphatic fistula after electric acoustic stimulation.

Transcanal endoscopic ear surgery (TEES) will become a very useful therapeutic option. A perilymphatic fistula (PLF) is defined as sudden sensorineural hearing loss and/or vertigo caused by leakage of the perilymph through a fistula from the oval window and/or round window. We report a case of PLF after electric acoustic stimulation (EAS), a kind of cochlear implant, successfully treated by TEES. A 38-year-old man presented to our hospital with vertigo and hearing loss (HL). His vertigo was induced by Valsalva maneuvers. Eight months ago, he underwent EAS for his right ear for congenital sensorineural HL. Although he maintained his hearing level after EAS, his pure tone audiogram this time showed deterioration of hearing at low frequencies in his right ear. A diagnosis of right PLF was made. After confirming the non-effectiveness of oral prednisolone treatment, PLF repair surgery to patch the oval and round windows by TEES was performed. His vertigo did not recur after the surgery. To the best of our knowledge, this is the first report of PLF repair surgery by TEES without a microscope. The wide-field view of the middle ear by TEES was useful to prevent electrode damage in a PLF patient with a cochlear implant.

Evaluation of a new and simple classification for endoscopic sinus surgery.

OBJECTIVE: In 2013, the Japanese Rhinologic Society proposed a simple classification for endoscopic sinus surgery (ESS). This classification consists of five procedures (type I, fenestration of the ostiomeatal complex, with uncinectomy and widening of the natural ostium; type II, single-sinus procedure, with manipulating the inside of the sinus; type III, polysinus procedure; type IV, pansinus procedure; type V, extended procedure beyond the sinus wall). The clinical relevance of this classification in chronic rhinosinusitis (CRS) and paranasal sinus cyst was evaluated. STUDY DESIGN: A retrospective validation study. METHODS: A total of 122 patients (195 sinuses) who underwent ESS in Okayama University Hospital in 2012 were enrolled. The relationships between the ESS classification and the clinical course, including the operation time, bleeding amounts during surgery and postoperative changes of olfaction, the computed tomography (CT) score, and nasal airway resistance were analyzed. RESULTS: A total of 195 ESS procedures were classified into type I (n = 3), type II (n = 17), type III (n = 91), type IV (n = 82), and type V (n = 2). The major phenotypes of type II, III, and IV ESS were paranasal sinus cyst (68%), CRS without nasal polyps (77%), and CRS with nasal polyps (55%), respectively, and the difference was significant. The degree of ESS based on this classification was positively and significantly correlated with the operation time and bleeding amounts. As a whole, olfaction, CT score, and nasal airway resistance were significantly improved after surgery. The degree of improvement was similar between type III and type IV ESS. CONCLUSION: This simple classification for ESS reflected the perioperative burden of the disease.

Cochlear Transcriptome Following Acoustic Trauma and Dexamethasone Administration Identified by a Combination of RNA-seq and DNA Microarray.

AIM: To elucidate molecular mechanisms of noise-induced hearing loss (NIHL) and glucocorticoid therapy in the cochlea. BACKGROUND: Glucocorticoids are used to treat many forms of acute sensorineural hearing loss, but their molecular action in the cochlea remains poorly understood. METHODS: Dexamethasone was administered intraperitoneally immediately following acoustic overstimulation at 120 dB SPL for 2 hours to mice. The whole cochlear transcriptome was analyzed 12 and 24 hours following noise trauma and dexamethasone administration by both next-generation sequencing (RNA-seq) and DNA microarray. Differentially expressed genes (DEGs) with more than 2-fold changes after noise trauma and dexamethasone administration were identified. The functions of these DEGs were analyzed by David Bioinformatics Resources and a literature search. RESULTS: Twelve hours after acoustic overstimulation, immune-related gene pathways such as "chemokine signaling activity," "cytokine-cytokine receptor interaction," and "cell adhesion molecules (CAMs) in the immune system" were significantly changed compared with the baseline level without noise. These DEGs were involved in immune and defense responses in the cochlea. Dexamethasone was administered to this NIHL model, and it modulated gene pathways of "cytokine-cytokine receptor interaction" and "cell adhesion molecules (CAMs) in the immune system" at 12 hours, compared with saline-injected control. Dexamethasone-dependent DEGs were also involved in immune and defense responses. A literature search showed that 10 other genes associated with hearing functions were regulated by dexamethasone both at 12 and 24 hours post-administration. CONCLUSION: Dexamethasone modulates the immune reaction in the traumatized cochlea following acoustic overstimulation. Dexamethasone may also regulate cochlear functions other than immunity.

Genetic Counseling of a Hearing-impaired Patient with Multiple Genetic Mutations.

Since April 2012, genetic testing for congenital hearing loss is covered by the public health insurance in Japan. Recent (since August 2015) developments in next-generation sequencing technology have enabled the detection of 154 mutations in 19 genes. Genetic testing provides valuable information on hearing phenotype, prognosis, and prediction of associated symptoms. We report a hearing-impaired patient in whom multiple genetic mutations were detected. This patient carries two missense mutations in GJB2 (p.G45E, p.Y136X), as well as a mitochondrial mutation (7445A>G). Since the number of genes detectable by genetic testing has increased, the diagnosis of hearing loss can be made with greater accuracy. However, it is often difficult to clinically understand and interpret the genotype information, especially when multiple gene variants are detected in one patient or family. Genetic counseling plays an important part in the intervention for or follow-up of such patients. Genotypic and phenotypic information of other family members is necessary, so that both the patient and the family can understand and accept the results of genetic testing.

Effect of prostaglandin D2 on VEGF release by nasal polyp fibroblasts.

BACKGROUND: Vascular endothelial growth factor (VEGF) is known to be associated with the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). VEGF is produced by a variety of cells including fibroblasts. It was recently reported that prostaglandin (PG) E2 induces VEGF release by nasal polyp fibroblasts. However, little is known regarding possible regulation of VEGF by other PGs. We have reported that molecules that regulate PGD2 metabolism play roles in the pathogenesis of CRS including in local eosinophilia and type 2 cytokine production. In the present study, we sought to determine whether PGD2 regulates VEGF release by nasal polyp fibroblasts. METHODS: Nasal polyp fibroblasts were established from nasal polyps. These fibroblasts were stimulated with serial dilutions of PGD2 or PGD2 receptor (DP/CRTH2)-selective agonists in the presence or absence of receptor-selective antagonists. The concentration of VEGF in the culture supernatants was determined using ELISA. RESULTS: 5 µM of PGD2 significantly induced VEGF release by nasal polyp fibroblasts. VEGF release was also obtained by stimulation with a DP receptor-selective, but not with a CRTH2 receptor-selective agonist. In addition, PGD2-induced VEGF release was significantly inhibited by pre-treatment with DP receptor-selective antagonists. In contrast, pre-treatment with a CRTH2 receptor-selective antagonist significantly enhanced PGD2-induced VEGF release. CONCLUSIONS: PGD2 stimulates VEGF production via DP but not CRTH2 receptors in nasal polyp fibroblasts.