Prognostic significance vestibular examination results in patients with vestibular migraine.

Introduction: Vestibular migraine (VM) is a newly defined clinical condition. Several vestibular abnormalities have been reported in patients with VM. However, to date, no specific vestibular examinations are used to define VM. Therefore, the utility of vestibular examinations is limited. Currently, the role of vestibular examination has not been clearly defined. We speculated that the results of vestibular examinations could predict the prognosis of VM. We investigated the relationship between the vestibular examination results and clinical outcomes in patients with VM. Methods: This study included 25 patients with VM. Vestibular examinations, including the video head impulse test (V-HIT), cervical and ocular vestibular evoked myogenic potential (c-VEMP and o-VEMP), posturography, and several questionnaires, including the Dizziness Handicap Inventory (DHI), were conducted at the initial evaluation. Lifestyle modifications for VM and conventional pharmacological prophylactic treatments, including lomerizine, amitriptyline, and valproic acid, were performed. After 4 weeks of treatment, clinical improvements were evaluated using the Clinical Global Improvement Scale (CGI-s). The relationships among the CGI-S score, several clinical variables, and the results of several vestibular examinations were evaluated. Each patient was further classified into two subgroups according to treatment outcomes concerning vertigo and headache: CGI-S score from 0 to 2 (good response [GR]) and CGI-S score > 3 (poor response [PR]). Results: Overall, after treatment, most of the patients had improved dizziness and headache, and the CGI-s was 2.7 ± 1.3. There were 12 GRs, and 13 had PRs. Thus, neither V-HIT nor posturography predicted the prognosis. For c-VEMP, patients with GRs had significantly small AR concerning PR (19.2 ± 12.8 and 62.5 ± 42.5, respectively, [p < 0.01]). There were five normal, six unilateral, and 14 bilateral no response in 500hz o-VEMP. CGI-s of normal, unilateral, and bilateral no response was 1.4 ± 0.5, 2.8 ± 1.3, and 3.1 ± 1.2, respectively. There was a statistically significant difference between the normal and bilateral non-response o-VEMP groups (p < 0.05). Conclusion: Patients with VM had improvements in both headache and vertigo through a combination of lifestyle changes and prophylactic medications. Vestibular examinations, especially o- or c-VEMP, are beneficial for predicting the treatment outcomes of VM. The pathophysiology of VM is closely related to vestibular abnormalities, particularly the otolith-related pathways.

Functional Studies of Deafness-Associated Pendrin and Prestin Variants.

Pendrin and prestin are evolutionary-conserved membrane proteins that are essential for normal hearing. Dysfunction of these proteins results in hearing loss in humans, and numerous deafness-associated pendrin and prestin variants have been identified in patients. However, the pathogenic impacts of many of these variants are ambiguous. Here, we report results from our ongoing efforts to experimentally characterize pendrin and prestin variants using in vitro functional assays. With previously established fluorometric anion transport assays, we determined that many of the pendrin variants identified on transmembrane (TM) 10, which contains the essential anion binding site, and on the neighboring TM9 within the core domain resulted in impaired anion transport activity. We also determined the range of functional impairment in three deafness-associated prestin variants by measuring nonlinear capacitance (NLC), a proxy for motor function. Using the results from our functional analyses, we also evaluated the performance of AlphaMissense (AM), a computational tool for predicting the pathogenicity of missense variants. AM prediction scores correlated well with our experimental results; however, some variants were misclassified, underscoring the necessity of experimentally assessing the effects of variants. Together, our experimental efforts provide invaluable information regarding the pathogenicity of deafness-associated pendrin and prestin variants.

Functional studies of deafness-associated pendrin and prestin variants.

Pendrin and prestin are evolutionary conserved membrane proteins that are essential for normal hearing. Pendrin is an anion transporter required for normal development and maintenance of ion homeostasis in the inner ear, while prestin is a voltage-dependent motor responsible for cochlear amplification essential for high sensitivity and frequency selectivity of mammalian hearing. Dysfunction of these proteins result in hearing loss in humans, and numerous deafness-associated pendrin and prestin variants have been identified in patients. However, the pathogenic impacts of many of these variants are ambiguous. Here we report results from our ongoing efforts in experimentally characterizing pendrin and prestin variants using in vitro functional assays, providing invaluable information regarding their pathogenicity.

Prevalence of perilymphatic fistula in patients with sudden-onset sensorineural hearing loss as diagnosed by Cochlin-tomoprotein (CTP) biomarker detection: its association with age, hearing severity, and treatment outcomes.

PURPOSE: To determine the prevalence of perilymphatic fistula (PLF) in sudden-onset sensorineural hearing loss (SSNHL) patients by employing the Cochlin-tomoprotein (CTP) detection test, a specific diagnostic marker for perilymph. We also analyzed the clinical characteristics associated with hearing outcomes in this cohort. METHODS: A total of 74 eligible patients were prospectively enrolled. Following myringotomy, middle ear lavage (MEL) samples underwent the CTP test to identify perilymph leakage. Intratympanic dexamethasone (IT-DEX) therapy was administered, and hearing outcomes were assessed. Control groups comprised patients with chronic otitis media (n = 40) and non-inflammatory middle ears (n = 51) with concurrent MEL sample collection. RESULTS: CTP was positive in 16 (22%) patients. No control samples showed positive results. Multiple regression analysis indicated that age and pre-treatment hearing levels significantly contributed to the CTP value. We found a positive correlation between CTP values, age, and pre-treatment pure-tone averages. Notably, CTP values in SSNHL cases aged 60 and above were significantly higher than in those below 60 years. Patients with positive CTP had significantly worse recovery rates after IT-DEX treatment. CONCLUSION: This study is the first prospective investigation demonstrating a positive relationship between CTP values, age, and hearing severity in SSNHL, indicating that PLF might be the essential cause of SSNHL, particularly in the elderly. Our findings suggest that IT-DEX may be less effective for PLF-associated SSNHL. Future research could reveal that PLF repair surgery is a viable treatment strategy for SSNHL. This study was registered under the UMIN Clinical Trials Registry (UMIN000010837) on 30/May/2013.

Novel approach of prophylactic radiation to reduce toxicities comparing 2-step40 with 56-Gy simultaneous integrated boost intensity-modulated radiation therapy for locally advanced squamous cell carcinoma of the head and neck, an intergroup phase III trial (JCOG1912, NEW BRIDGE).

BACKGROUND: Chemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, CRT is associated with increased severe late adverse events, including swallowing dysfunction, xerostomia, ototoxicity, and hypothyroidism. Few strategies aimed at less invasive CRT without compromising treatment outcomes have been successful. The purpose of this study is to confirm the non-inferiority of reduced dose prophylactic radiation with 40 Gy compared to standard dose prophylactic radiation with 56 Gy in terms of the time to treatment failure (TTF) among patients with clinical stage III-IVB LA-SCCHN. METHODS: This study is a multicenter, two-arm, open-label, randomized phase III trial. Patients with LA-SCCHN excluding p16 positive oropharynx cancer are randomized to the standard arm or experimental arm. A total dose of 70 Gy for tumors with concurrent cisplatin at 100 mg/m2 are administered in both arms. For prophylactic field, patients in the standard arm receive a total dose of 56 Gy in 35 fractions for 7 weeks using simultaneous integrated boost (SIB56) and those in the experimental arm receive 40 Gy in 20 fractions using two-step methods for 4 weeks (2-step40). A total of 400 patients will be enrolled from 52 Japanese institutions within 5 years. The primary endpoint is TTF, and the secondary endpoints are overall survival, complete response rate, progression-free survival, locoregional relapse-free survival, acute and late adverse events, quality of life score, and swallowing function score. DISCUSSION: If the experimental arm is non-inferior to the standard arm in terms of TTF and superior on the safety endpoints, the 2-step40 procedure is the more useful treatment than SIB56 for definitive CRT. TRIAL REGISTRATION: This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031210100 ( https://jrct.niph.go.jp/latest-detail/jRCTs031210100 ). Date of Registration: May 2021.

Characteristics of pure tone audiogram in patients with untreated sporadic vestibular schwannoma: Analysis of audiometric shape and interaural differences stratified by age and mode of onset.

OBJECTIVE: Asymmetric sensorineural hearing loss (ASHL) is the most common symptom of sporadic vestibular schwannoma (VS). However, there is still no universally accepted MRI protocol for diagnosing VS. This study identified the characteristics of pure tone audiogram (PTA) in patients with VS. METHODS: We conducted a retrospective chart review of patients diagnosed with sporadic unilateral VS. In the analysis, we focused on the shape and interaural differences of PTA, stratified by the mode of onset and patient age. RESULTS: In total, 390 patients met the inclusion criteria. The U-shaped audiogram showed the highest proportion in patients with the onset of sudden sensorineural hearing loss (SSNHL). In patients with SSNHL, U-shaped audiograms were younger than other audiograms, and 86.7 % of patients under 40 had U-shaped audiograms. Patients with VS were more likely to have interaural differences at higher frequencies than at lower frequencies. Patients with SSNHL had a significantly higher percentage of interaural differences at 500-4000 Hz than those with onset other than SSNHL (non-SSNHL patients). In addition, non-SSNHL patients had a significant trend toward a higher percentage of interaural differences at all frequencies with increasing age. CONCLUSION: MRI screening can be considered in patients with SSNHL with U-shaped audiograms under 40 years of age. In ASHL, not SSNHL, MRI screening can be considered for older patients with interaural differences at wider continuous frequencies. Patients with interaural differences at high frequencies had a higher priority than those with interaural differences at low frequencies as indications for MRI screening for VS.

Correlation between genotype and phenotype with special attention to hearing in 14 Japanese cases of NF2-related schwannomatosis.

NF2-related schwannomatosis (NF2) is an autosomal dominant genetic disorder caused by variants in the NF2 gene. Approximately 50% of NF2 patients inherit pathogenic variants, and the remainder acquire de novo variants. NF2 is characterized by development of bilateral vestibular schwannomas. The genetic background of Japanese NF2 cases has not been fully investigated, and the present report performed a genetic analysis of 14 Japanese NF2 cases and examined genotype-phenotype correlations. DNA samples collected from peripheral blood were analyzed by next-generation sequencing, multiplex ligation-dependent probe amplification analysis, and in vitro electrophoresis. Ten cases had pathogenic or likely pathogenic variants in the NF2 gene, with seven truncating variants and three non-truncating variants. The age of onset in all seven cases with truncating variants was < 20 years. The age of onset significantly differed among cases with truncating NF2 variants, non-truncating NF2 variants, and no NF2 variants. However, the clinical course of tumor growth and hearing deterioration were not predicted only by germline pathogenic NF2 variants. The rate of truncating variants was higher in the present study than that of previous reports. Genotype-phenotype correlations in the age of onset were present in the analyzed Japanese NF2 cases.

Pathophysiological Roles of the cGAS-STING Inflammatory Pathway.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) inflammatory pathway is a component of the innate immune system that recognizes cytosolic nucleic acids. The pathway has been implicated in several processes including aging, autoinflammatory conditions, cancer, and metabolic diseases. The cGAS-STING pathway represents a promising therapeutic target in a variety of chronic inflammatory diseases.

Association between atherosclerosis, hearing recovery, and hearing in the healthy ear in idiopathic sudden sensorineural hearing loss: a retrospective chart analysis.

Atherosclerosis is reported to be a risk factor for the severity of idiopathic sudden sensorineural hearing loss (ISSNHL). We evaluated the hypothesis that atherosclerosis affects the hearing thresholds of both the affected and healthy sides of ISSNHL patients. We conducted multivariate analyses on retrospectively collected data of patients with ISSNHL (N = 762) to evaluate the relationship between known factors linked to atherosclerosis and hearing thresholds on affected and healthy sides and whether these factors are prognostic for hearing recovery. Older ages, vertigo or dizziness, diabetes mellitus, and congestive heart failure were significantly related to higher hearing thresholds on the affected side. Older ages, male, and vascular disease were significantly related to higher hearing thresholds on the healthy side. Vertigo or dizziness, severe hearing loss and hearing loss at high frequencies on the affected side, higher hearing thresholds on the healthy side, regular anticoagulant medication, and delayed steroid treatment were significantly related to lack of recovery. Since several atherosclerosis-related factors are associated with higher hearing thresholds on both affected and healthy sides in ISSNHL and higher hearing thresholds on the healthy side predict poorer prognosis, diagnosis, and predicting prognosis of ISSNHL may benefit from rigorous evaluation of patients' cardiovascular comorbidities and hearing levels on both the healthy and affected sides.

Prevalence of Hearing Impairment by Age: 2nd to 10th Decades of Life.

Background: Accurate data on the prevalence of hearing impairment and severity across age and gender are paramount to formulate hearing health policies. Here, we sought to analyze audiometric data from a large group of age-diverse people in Japan, which has not been previously described in detail. Methods: We analyzed retrospective hearing threshold data of 23,860 participants (10−99 years; left-right hearing threshold difference <15 dB; air-bone gap ≤10 dB) at 500, 1000, 2000, and 4000 Hz, and then classified them for hearing impairment severity according to the WHO Classification. Findings: There was a significant gender difference in median hearing thresholds, starting in 20-year-olds up to early 80-year-olds. Twenty-five percent of men in their late 50s had some level of HI, ~50% in their late 60s, and ~75% in their late 70s. For women, 25% had some level of HI in their early 60s, ~50% in their early 70s, and ~75% in their late 70s. For participants in their early 80s, 50% of either gender had moderate or more severe HI. Interpretation: Our results, derived from a large number of participants, provide basic information about the prevalence of hearing loss by age decade. Since people can expect to live longer than those in previous generations, our detailed data can inform national social systems responsible for hearing screening in making decisions about hearing-aid qualification, which may reduce barriers to older people's independence, productivity, and quality of life.

Tone Enhancement Electro-Fiberscope Combined with Strobe Light Source and Re-analysis Past Images-Tone Enhancement Dynamic Stroboscope.

Tone enhancement electro fiberscope combined with strobe light source is benefit for dynamic observation of vocal fold vibration, mucosal waves and voice, it also may be effective for early detection of cases of glottal cancer rather than ordinate stroboscopic examination or simple NBI observation. Laryngoscope, 132:2206-2208, 2022.

Understanding the Molecular Mechanism of Vestibular Schwannoma for Hearing Preservation Surgery: Otologists' Perspective from Bedside to Bench.

Vestibular schwannoma is a clinically benign schwannoma that arises from the vestibulocochlear nerve that causes sensorineural hearing loss. This tumor is clinically and oncologically regarded as a benign tumor as it does not metastasize or invade surrounding tissues. Despite being a benign tumor, its management is difficult and controversial due to the potential serious complications, such as irreversible sensorineural hearing loss, of current interventions. Therefore, preventing hearing loss due to the natural course of the disease and complications of surgery is a challenging issue for an otologist. Improvements have been reported recently in the treatment of vestibular schwannomas. These include advances in intraoperative monitoring systems for vestibular schwannoma surgery where the risk of hearing loss as a complication is decreased. Precise genomic analysis of the tumor would be helpful in determining the characteristics of the tumor for each patient, leading to a better hearing prognosis. These procedures are expected to help improve the treatment of vestibular schwannomas. This review summarizes recent advances in vestibular schwannoma management and treatment, especially in hearing preservation. In addition, recent advances in the understanding of the molecular mechanisms underlying vestibular schwannomas and how these advances can be applied in clinical practice are outlined and discussed, respectively. Moreover, the future directions from the bedside to the bench side are presented from the perspective of otologists.

Relationship between social anxiety and coping profile in adults who stutter.

INTRODUCTION: Stuttering is a condition that can be severely disabling in the workplace and socially. Although many stuttering cases resolve, some adults who stutter (AWS) continue to be affected not only by dysfluent speech, but also by other social and psychological conditions that may develop as a result of stuttering. The aim of the present study was to determine the relationship between severity of stuttering, severity of social anxiety, and coping profile. METHODS: We objectively assessed adults who stutter (n = 44; mean age = 27.5 years) and age-matched non-stuttering control subjects on four variables: stuttering frequency, communication attitude, social anxiety, and coping profile. Stuttering frequency was calculated as the percentage stuttered morae in the Kitsuon-kensa-ho test. All subjects were assessed on the Japanese versions of the Modified Erickson's Communication Attitude Scale (S-24-J), Liebowitz Social Anxiety Scale (LSAS-J), and the Brief Scale for Coping Profile (BSCP). RESULTS: Compared to the non-stuttering group, the stuttering group had a higher average score on the S-24-J and LSAS-J, and tended to "avoid and suppress" instead of "seek help for resolution" on the BSCP. Comparison of individual stutterers' S-24-J scores whose LSAS-J scores were above or below the LSAS-J cutoff score revealed that their the S-24-J scores tended to be higher. Also, BSCP participants tended to engage in "proactive resolution" and "emotional venting involving others," not "seeking help for resolution." The stuttering group (vs. the non-stuttering group) and the high social-anxiety group (vs. the low social-anxiety group) adopted non-adaptive coping strategies. CONCLUSIONS: This suggests that the coping profile of AWS may contribute to the cycle of social anxiety and stuttering to a greater or lesser extent. Thus, therapy that reduces anxiety and helps AWS to adopt more adaptive coping strategies may improve stuttering.

Cell death-inducing cytotoxicity in truncated KCNQ4 variants associated with DFNA2 hearing loss.

KCNQ4 encodes the homotetrameric voltage-dependent potassium ion channel Kv7.4, and is the causative gene for autosomal dominant nonsyndromic sensorineural hearing loss, DFNA2. Dominant-negative inhibition accounts for the observed dominant inheritance of many DFNA2-associated KCNQ4 variants. In addition, haploinsufficiency has been presumed as the pathological mechanism for truncated Kv7.4 variants lacking the C-terminal tetramerization region, as they are unlikely to exert a dominant-negative inhibitory effect. Such truncated Kv7.4 variants should result in relatively mild hearing loss when heterozygous; however, this is not always the case. In this study, we characterized Kv7.4Q71fs (c.211delC), Kv7.4W242X (c.725G>A) and Kv7.4A349fs (c.1044_1051del8) in heterologous expression systems and found that expression of these truncated Kv7.4 variants induced cell death. We also found similar cell death-inducing cytotoxic effects in truncated Kv7.1 (KCNQ1) variants, suggesting that the generality of our findings could account for the dominant inheritance of many, if not most, truncated Kv7 variants. Moreover, we found that the application of autophagy inducers can ameliorate the cytotoxicity, providing a novel insight for the development of alternative therapeutic strategies for Kv7.4 variants.

Severe sudden sensorineural hearing loss related to risk of stroke and atherosclerosis.

The cause of idiopathic sudden sensorineural hearing loss (idiopathic SSNHL)-diagnosed after excluding other causes of hearing loss, such as SSNHL associated with vestibular schwannoma (VS)-is unknown. The presumed pathogenesis of idiopathic SSNHL includes circulatory disorders (e.g., cochlear infarction). We tested the hypothesis that patients with SSNHL who are at high stroke risk will have a lower rate of VS compared to those with low stroke risk. The rationale is that the primary cause of SSNHL in patients with high stroke risk might be a circulatory disturbance. We conducted a retrospective study in six hospitals. Our sampling of SSNHL patients included those diagnosed with idiopathic SSNHL and VS-associated SSNHL. SSNHL patients who had a head MRI were stratified by severity of hearing loss and evaluated for differences in the detection rate of VS between the high-scoring CHADS2 (CHADS2-H-), an index of stroke risk, and low-scoring CHADS2 (CHADS2-L-) groups. We identified 916 patients who met the inclusion criteria. For severe hearing loss, the CHADS2-H group had a significantly lower rate of VS than the CHADS2-L group (OR 0 [95% CI 0.00-0.612]; P = 0.007). These results indirectly support the hypothesis that a primary cause of severe idiopathic SSNHL in those at high risk of stroke might be a circulatory disorder.

The impact of second-hand smoke on ear, nose, and throat diseases and head and neck cancers in Japan: a cross-sectional study using a questionnaire and secondary data from the national health and nutrition survey.

BACKGROUND: The risk of head and neck cancers (HNCs) and ear, nose, and throat (ENT) diseases due to second-hand smoke (SHS) have not been fully assessed. OBJECTIVE: To determine which ENT diseases or HNCs are associated with SHS. MATERIAL AND METHODS: Data from a survey of a cross-sectional sample of ENT patients (n = 1228) on SHS exposure were compared to control-subject data (n = 6598) from a Japan National Health Survey. Multivariate logistic regression and estimated odds ratios (ORs) determined whether SHS-disease associations were related to exposure location and disease occurrence. RESULTS: SHS was significantly associated with acute tonsillitis (OR in workplaces, 2.24 [95% CI, 1.34-3.75]; OR in restaurants, 4.24 [95% CI, 2.50-7.19]; OR in leisure places, 4.72 [95% CI, 2.93-7.62]); recurrent tonsillitis (OR in restaurants, 4.24 [95% CI, 2.52-7.13]; OR in leisure places, 5.29 [95% CI, 3.31-8.46]); facial palsy (OR in home, 2.18 [95% CI, 1.25-3.81]; OR in leisure places, 3.41 [95% CI, 1.97-5.89]); hypopharyngeal cancer (OR in home, 2.51 [95% CI, 1.18-5.36]; OR in workplaces, 2.53 [95% CI, 1.24-5.15]); and laryngeal cancer (OR in home, 2.44 [95% CI, 1.04-5.68]; OR in leisure places, 2.25 [95% CI, 1.00-5.07]). CONCLUSIONS AND SIGNIFICANCE: SHS may contribute to HNCs and ENT diseases, suggesting that merely being in the presence of smokers could increase the risk of head and neck morbidities.

Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma.

The high incidence of germline variants in pheochromocytoma and paraganglioma (PPGL) has been reported mainly in Europe, but not among Japanese populations in Asia. We aimed to study the prevalence of germline variants in Japanese PPGL patients and the genotype-phenotype correlation. We examined 370 PPGL probands, including 43 patients with family history and/or syndromic presentation and 327 patients with apparently sporadic (AS) presentation. Clinical data and blood samples were collected, and the seven major susceptibility genes (MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET) were tested using Sanger sequencing. Overall, 120/370 (32.4%) patients had pathogenic or likely pathogenic variants, with 81/327 (24.8%) in AS presentation. SDHB was the most frequently mutated gene (57, 15.4%), followed by SDHD (27, 7.3%), and VHL (18, 4.9%). The incidence of metastatic PPGL was high in SDHB carriers (21/57, 36.8%). A few unique recurrent variants (SDHB c.137G>A and SDHB c.470delT) were detected in this Japanese cohort, highlighting ethnic differences. In summary, almost a quarter of patients with apparently sporadic PPGL in Japan harboured germline variants of the targeted genes. This study reinforces the recommendation in Western guidelines to perform genetic testing for PPGL and genotype-based clinical decision-making in the Japanese population.

Patterns of hearing changes in women and men from denarians to nonagenarians.

BACKGROUND: Hearing loss needs to be diagnosed and treated early, especially in older individuals, since presbycusis potentially increases the risk of depression and dementia. However, standard data on hearing thresholds across the life-span in Japanese individuals are lacking. METHODS: In a retrospective consecutive sample of 10681 native-Japanese speakers (37.3% men; 10-99 years; left-right hearing threshold difference of <15 dB for all tested pure tones; free of external, middle, or inner ear disease), we determined standard age-decade and sex-specific pure-tone air-conduction (125, 250, 500, 1000, 2000, 4000, and 8000 Hz) hearing threshold norms. The main outcome measures were pure-tone averages for both ears by age-decade and sex. FINDINGS: For participants in their 20s, hearing thresholds at higher frequencies (>1000 Hz) were significantly worse in men than in women. For participants ≥70 years, hearing thresholds at low frequencies were higher in women. Hearing thresholds at 1000, 2000, and 4000 Hz tended to deteriorate, starting in the teenage years through the 50s, with some decades showing significantly worse decline. Sex differences were absent in the youngest and oldest groups. INTERPRETATION: Standard age- and sex-specific audiometric data reported here for Japanese individuals over nine age-decades are based on the largest dataset analyzed to date. While hearing thresholds of men and women in the very young and the very old age groups were indistinguishable in their cohorts, patterns of hearing changes for other age cohorts differed by direction and sex. FUNDING: The authors had no outside funding for this study.