Cochlear Implantation in Cases of Inner Ear Malformation: A Novel and Simple Grading, Intracochlear EABR, and Outcomes of Hearing.

OBJECTIVE: To propose a simple grading of inner ear malformation (IEM) and investigate intracochlear electrical auditory brainstem response (EABR) and outcomes for hearing in terms of the novel grading system. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Sixty patients with IEMs who received cochlear implants. INTERVENTION: Grading according to observation of modiolus deficiency and/or internal auditory canal (IAC) cochlear nerve deficiency (CND). MAIN OUTCOME MEASURE: Intracochlear EABR and categories of auditory performance (CAP) scores were assessed; children in school were categorized according to the type of school attended. RESULTS: Among 60 patients, 38% were classified as Grade I (modiolus present + normal cochlear nerve), 22% as grade II (modiolus deficiency + normal cochlear nerve), 33% as grade III (modiolus present + IAC CND), and 7% as grade IV (modiolus deficiency + IAC CND). During the operation, 93% of Grade I, 36% of Grade II, 23% of Grade III, and 50% of Grade IV patients showed typical EABR waves. CAP scores of 4 or more were obtained from 91% of Grade I, 62% of Grade II, 35% of Grade III, and 25% of Grade IV. Whereas none of children in Grades III and IV entered main stream school, 55% of Grade I and 25% of Grade II entered mainstream schools. CONCLUSIONS: Outcomes of hearing with cochlear implantations in IEM children depend on the severity of IEM and IAC CND. Our novel grading of IEM is simple and can be useful for understanding the severity of IEM.

Age-related change of auditory functional connectivity in Human Connectome Project data and tinnitus patients.

BACKGROUND: We reported that tinnitus patients showed reduced levels of auditory functional connectivity (FC) in comparison with normal hearing control subjects, and that we succeeded in objective diagnosis of tinnitus with 86% sensitivity and 74% specificity by focusing only on auditory-related FC. However, the age-related change of auditory FC is not clarified. In this study, we examine age-related change of the auditory FC using the database of Human Connectome Project (HCP) and compared with our database of tinnitus patients. METHOD: From the HCP database HCP Lifespan Pilot project, we studied five age groups, 8 to 9 years old, 14 to 15, 25 to 35, 45 to 55, and 65 to 75. We also applied our tinnitus patients' resting-state functional magnetic resonance imaging (fMRI) database, which is divided into three generations; 20 to 40 years old, 40 to 60, and 60 to 80 to compare with the HCP database. The resting state fMRI analyses were performed using the CONN toolbox version 18. As auditory-related regions, Heschl's gyrus, planum temporale, planum polare, operculum, insular cortex, and superior temporal gyrus were set as the regions of interest from our previous reports. RESULT: Auditory FC is strongest among adolescents and reduces with age. But the auditory FC of tinnitus patients were significantly less than those of HCP data in each generation. CONCLUSION: Although auditory FC decreases with age, tinnitus patients have less auditory FC compared with age-matched controls. The age-matched cutoff values are necessary for an objective diagnosis of tinnitus with resting state fMRI.

A clinical and genetic study of 16 Japanese families with Waardenburg syndrome.

The purpose of this study is to profile the clinical and genetic features of Japanese Waardenburg syndrome (WS) patients and validate the W index. Sixteen Japanese WS families with congenital sensorineural hearing loss were included in the study. The inner canthal, interpupillary, and outer canthal distances (ICD, IPD, and OCD) were measured for all patients, and patients were screened for presence of PAX3, MITF, SOX10, and EDNRB mutations. The WS patients were clinically classified under the current W index as follows: 13 families with WS1, 2 families with WS2, and 1 family with WS4. In the 13 WS1 families, genetic tests found PAX3 mutations in 5 families, MITF mutations in 4 families, SOX10 mutations in 3 families, and EDNRB mutations in 1 family. 61% of clinically classified WS1 patients under the current W index conflicted with the genetic classification, which implies W index is not appropriate for Japanese population. Resetting the threshold of W index or novel index formulated with ethnicity matched samples is necessary for clinical classification which is consistent with genetic classification for WS patients with distinct ethnicity.

Elongated EABR wave latencies observed in patients with auditory neuropathy caused by OTOF mutation.

OBJECTIVES: We sought to determine how the pathology altered electrically evoked auditory brainstem responses (EABRs) in patients with hearing loss by evaluating EABRs in auditory neuropathy patients with OTOF mutations comparing with various types of congenital deafness. METHODS: We included 15 patients with congenital hearing loss, grouped according to pathology: OTOF mutations (n = 4), GJB2 mutations (n = 4), SLC26A4 mutations (n = 4), or cytomegalovirus infections (n = 3). EABRs were recorded when patients underwent cochlear implantation surgery. We evaluated the latencies and amplitudes of the recorded EABRs and compared them statistically between four groups. RESULTS: The EABR latencies of Wave III and Wave V, and of the interval between them, were significantly longer in the OTOF mutation group than in the GJB2 and SLC26A4 mutation groups (Wave III) and in all three other groups (Wave V and Wave III-V latency); amplitudes were not significantly different between groups. CONCLUSIONS: Our results suggest OTOF mutations cause delayed (or slowed) postsynaptic neurotransmission, although the presumed mechanism involved reduced presynaptic transmission between hair cells and spiral ganglion neurons. LEVEL OF EVIDENCE: Mainly a case report.

Auditory Related Resting State fMRI Functional Connectivity in Tinnitus Patients: Tinnitus Diagnosis Performance.

OBJECTIVE: The purpose of the present study was to investigate functional connectivity in tinnitus patients with and without hearing loss, and design the tinnitus diagnosis performance by resting state functional magnetic resonance imaging (rs-fMRI). SUBJECTS AND METHODS: Nineteen volunteers with normal hearing without tinnitus, 18 tinnitus patients with hearing loss, and 11 tinnitus patients without hearing loss were enrolled in this study. The subjects were evaluated with rs-fMRI, and region of interests (ROIs) based correlation analyses were performed using the CONN toolbox version 16 and SPM version 8. The correlation coefficients from individual level results were converted into beta values. RESULTS: With a beta threshold of more than 0.2, 91% of all possible connections between auditory-related ROIs (Heschl's gyrus, planum temporale, planum polare, operculum, insular cortex, superior temporal gyrus) in the control group remained intact, whereas 83 and 66% of such connections were present in the hearing loss and the normal-hearing tinnitus group. However, between non-auditory-related ROIs, the rates of intact connections at a beta threshold of more than 0.2 were 17% in the control group, and 16 and 15% in the tinnitus groups. When resting state fMRI positive is defined as less than 9% of all possible connections between auditory-related ROIs with a beta threshold of more than 0.7, the sensitivity and specificity of tinnitus diagnosis is 86 and 74%, respectively. CONCLUSIONS: The associations between auditory-related networks are weakened in tinnitus patients, even if they have normal hearing. It is possible that rs-fMRI can be a tool for objective examination of tinnitus, by focusing the auditory-related areas.

A rare case of bilateral vagus nerve schwanomatosis.

Schwanomatosis is the third most common form of neurofibromatosis. Schwanomatosis affecting the vagus nerve is particularly rare. In this report, we describe an extremely rare case bilateral vagus nerve schwanomatosis in a 45-year-old male patient. The patient initially presented with bilateral neck tumors and hoarseness arising after thoracic surgery. We performed left neck surgery in order to diagnose and resect the remaining tumors followed by laryngeal framework surgery to improve vocal cord closure and symptoms of hoarseness. Voice recovery was successfully achieved after surgery. An appropriate diagnosis and surgical tumor resection followed by phonosurgery improved patient quality of life in this rare case.

Microbiomes of the normal middle ear and ears with chronic otitis media.

OBJECTIVE: The aim of this study was to profile and compare the middle ear microbiomes of human subjects with and without chronic otitis media. STUDY DESIGN: Prospective multicenter cohort study. METHODS: All consecutive patients undergoing tympanoplasty surgery for chronic otitis media or ear surgery for conditions other than otitis media were recruited. Sterile swab samples were collected from the middle ear mucosa during surgery. The variable region 4 of the 16S rRNA gene in each sample were amplified using region-specific primers adapted for the Illumina MiSeq sequencer (Illumina, CA, USA)). The sequences were subjected to local blast and classified using Metagenome@KIN (World Fusion, Tokyo, Japan). RESULTS: In total, 155 participants were recruited from seven medical centers. Of these, 88 and 67 had chronic otitis media and normal middle ears, respectively. The most abundant bacterial phyla on the mucosal surfaces of the normal middle ears were Proteobacteria, followed by Actinobacteria, Firmicutes, and Bacteroidetes. The children and adults with normal middle ears differed significantly in terms of middle ear microbiomes. Subjects with chronic otitis media without active inflammation (dry ear) had similar middle ear microbiomes as the normal middle ears group. Subjects with chronic otitis media with active inflammation (wet ear) had a lower prevalence of Proteobacteria and a higher prevalence of Firmicutes than the normal middle ears. CONCLUSION: The human middle ear is inhabited by more diverse microbial communities than was previously thought. Alteration of the middle ear microbiome may contribute to the pathogenesis of chronic otitis media with active inflammation. LEVEL OF EVIDENCE: 2b. Laryngoscope, 127:E371-E377, 2017.

[Brodmann Areas 20, 21, and 22 in the Cerebral Cortex].

The 20, 21, and 22 areas in the temporal lobe as classified by Brodmann are almost identical with Economo and Koskinas's TA, TE1, and TE2, and, generally, with the gyrus, middle temporal gyrus, and inferior temporal gyrus according to brain anatomy. Before Brodmann's classification, Flechsig published his book "Soul and Brain" in 1897, in which primary, secondary, and association areas in the brain were classified. More recently, results from research using magnetic resonance imaging (MRI) and fMRI support the parcellation of the cerebral cortex proposed by Flechsig, Brodmann, and Economo more than one century ago.

Clinical characteristics of a Japanese family with hearing loss accompanied by compound heterozygous mutations in LOXHD1.

OBJECTIVE: To report two novel LOXHD1 mutations, including missense mutations and the clinical features of the patients. METHODS: We studied a three-generation Japanese family with hearing loss. Targeted next-generation sequencing was used for genetic analysis. Conditional orientation response audiometry and pure tone audiometry were used to assess hearing. SWISS-MODEL was used for molecular modeling of the PLAT domain in LOXHD1 protein. RESULTS: The two sisters, who had either mild or severe high-frequency hearing loss, were compound heterozygous for two novel mutations (c.5674G>T [p.V1892F] and c.4212+1G>A) in LOXHD1, which is responsible for autosomal-recessive nonsyndromic hearing loss DFNB77. These cases showed less severe hearing impairment than the previously reported cases carrying LOXHD1 mutations, but their hearing loss appeared to be progressive. Molecular modeling predicted that distorted structure of the PLAT domain in the p.V1892F mutant could lead to decreased affinity of the protein to lipid membrane resulting in hair cell dysfunction. CONCLUSION: We report a Japanese family carrying compound heterozygotes of truncating and nontruncating mutations in LOXHD1 identified by targeted NGS analysis. The fact of lower degree of hearing impairment in our cases than previously reported and the molecular modeling of the missense mutant provide insight to the genotype-phenotype correlation of DFNB77.

Auditory resting-state functional connectivity in tinnitus and modulation with transcranial direct current stimulation.

CONCLUSIONS: The functional connectivity (FC) between the right and left auditory cortex is weak in tinnitus patients. Transcranial direct current stimulation (tDCS) over the auditory cortex has potential as a tool to modulate auditory-based FC. OBJECTIVE: This study investigated the effects of applying tDCS in tinnitus patients, and searched for modulation of brain networks in resting-state functional magnetic resonance imaging (rs-fMRI) through an analysis of FC with the stimulated brain region. SUBJECTS AND METHODS: Nine male patients with chronic tinnitus and 10 male volunteers with normal hearing were enrolled. The subjects were evaluated with rs-fMRI immediately before and after tDCS. The tinnitus patients filled out the self-evaluation questionnaires designed to measure tinnitus conditions before tDCS treatment and 1 week afterwards. RESULTS: The FC between the right and left auditory cortex was significantly weaker in tinnitus patients than in controls. After tDCS treatment, in the tinnitus group, the primary auditory cortex showed a reduction in the amount of statistically significant connectivity with the somatosensory area and motor area, but maintained strong significant connectivity (p < 0.005) with the auditory area and insular cortex. In contrast, in the control group, there remained strong significant connectivity between the primary auditory cortex and the somatosensory area, motor area, insular cortex, and auditory area.

Usefulness of measuring electrically evoked auditory brainstem responses in children with inner ear malformations during cochlear implantation.

CONCLUSIONS: EABR is a reliable and effective way of objectively confirming device function and implant-responsiveness of the peripheral auditory neurons up to the level of the brainstem in cases of inner ear malformation. OBJECTIVE: To investigate the usefulness of measuring the intra-operative electrically evoked compound action potential (ECAP) and electrically evoked auditory brainstem response (EABR) in patients with and without congenital inner ear anomalies during cochlear implantation. METHOD: Thirty-eight consecutive children (40 ears) aged 5 or younger with congenital profound hearing loss. Twenty-four (25 ears) lacked congenital inner ear anomalies. The 14 patients (15 ears) with a malformation had common cavities (four ears), incomplete partition type I (three ears), cochlea hypoplasia type III (three ears), enlarged vestibular aqueduct (four ears), and cochlear nerve canal stenosis (one ear). Main outcome measures are ECAP and EABR responses. RESULTS: Of the 25 ears lacking any malformation, 21, three, and one showed 'Good', 'Variable', and 'No' ECAP responses, respectively, and 24 and one showed 'Good' and 'Variable' intra-cochlear responses, respectively. Of the 15 ears with a malformation, two showed 'Good' ECAP responses, nine had 'Variable' ECAP responses, and four showed 'No' ECAP responses. Moreover, five showed 'Good' EABR responses and 10 showed 'Variable' EABR responses.

GJB2-associated hearing loss undetected by hearing screening of newborns.

The hearing loss caused by GJB2 mutations is usually congenital in onset, moderate to profound in degree, and non-progressive. The objective of this study was to study genotype/phenotype correlations and to document 14 children with biallelic GJB2 mutations who passed newborn hearing screening (NHS). Genetic testing for GJB2 mutations by direct sequencing was performed on 924 individuals (810 families) with hearing loss, and 204 patients (175 families) were found to carry biallelic GJB2 mutations. NHS results were obtained through medical records. A total of 18 pathological mutations were identified, which were subclassified as eight inactivating and 10 non-inactivating mutations. p.I128M and p.H73Y were identified as novel missense GJB2 mutations. Of the 14 children with biallelic GJB2 mutations who passed NHS, eight were compound heterozygotes and 3 were homozygous for the c.235delC mutation in GJB2, and the other three combinations of non-c.235delC mutations identified were p.Y136X-p.G45E/p.V37I heterozygous, c.512ins4/p.R143W heterozygous, and p.V37I/p.R143W heterozygous. These 14 cases demonstrate that the current NHS does not identify all infants with biallelic GJB2 mutations. They suggest that the frequency of non-penetrance at birth is approximately 6.9% or higher in DFNB1 patients and provide further evidence that GJB2 hearing loss may not always be congenital in onset.

Comorbidity of GJB2 and WFS1 mutations in one family.

It is rarely reported that two distinct genetic mutations affecting hearing have been found in one family. We report on a family exhibiting comorbid mutation of GJB2 and WFS1. A four-generation Japanese family with autosomal dominant sensorineural hearing loss was studied. In 7 of the 24 family members, audiometric evaluations and genetic analysis were performed. We detected A-to-C nucleotide transversion (c.2576G>C) in exon 8 of WFS1 that was predicted to result in an arginine-to-proline substitution at codon 859 (R859P), G-to-A transition (c.109G>A) in exon 2 of GJB2 that was predicted to result in a valine-to-isoleucine substitution at codon 37 (V37I), and C-to-T transition (c.427C>T) in exon 2 of GJB2 that was predicted to result in an arginine-to-tryptophan substitution at codon 143 (R143W). Two individuals who had heterozygosity of GJB2 mutations and heterozygosity of WFS1 mutations showed low-frequency hearing loss. One individual who had homozygosity of GJB2 mutation without WFS1 mutation had moderate, gradual high tone hearing loss. On the other hand, a moderate flat loss configuration was seen in one individual who had compound heterozygosity of GJB2 and heterozygosity of WFS1 mutations. Our results indicate that the individual who has both GJB2 and WFS1 mutations can show GJB2 phenotype.

Repetitive transcranial magnetic stimulation (rTMS) for treatment of chronic tinnitus.

OBJECTIVE: There is compelling evidence that tinnitus is associated with functional alterations in the central nervous system. Repetitive transcranial magnetic stimulation (rTMS) is a potent tool for modifying neural activity at the stimulated area and at a distance along the functional anatomical connections. Depending on the stimulation parameters, cortical networks can be functionally disturbed or modulated in their activities. Low-frequency rTMS has been shown to result in a decrease in cortical excitability. The technique can alleviate tinnitus by modulating the excitability of neurons in the auditory cortex. We aimed to investigate the effects of low-frequency rTMS in patients and determine the factors that predict a beneficial outcome with rTMS treatment. METHODS: Sixteen patients (male 10, female 6) with chronic tinnitus underwent low-frequency (1Hz) rTMS (intensity: 110% motor threshold; number of stimuli: 1200) to the left auditory cortex. The treatment outcome was assessed with a visual analog scale (VAS) of loudness, annoyance and duration, loudness balance test, and tinnitus handicap inventory (THI). Therapeutic success was studied according to the patients' clinical characteristics. RESULTS: A significant reduction in the VAS (loudness and annoyance) occurred immediately after rTMS, with a gradual return to pretreatment levels after 7 days. The tinnitus patients with sudden deafness were significant resistant to rTMS treatment compared with those diagnosed with age-related hearing loss. CONCLUSION: These results support the potential of rTMS as a new therapeutic tool for the treatment of chronic tinnitus. Because this study was performed with a small sample size and showed high interindividual variability in treatment effects, further development of the technique is needed before it can be recommended for clinical applications.

Spindle cell carcinoma of the palatine tonsil: report of a diagnostic pitfall and literature review.

Spindle cell carcinomas of the tonsil are very rare tumors. We present an additional case that occurred in a 58-year-old woman. She presented with a tumor of the right tonsil. Histologic sections of tonsillar biopsies suggested that this tumor was a squamous cell carcinoma. She underwent a transoral resection of the right oropharynx. The final diagnosis was spindle cell carcinoma. We emphasize the difficulties in diagnosing this type of tumor and discuss therapeutic approaches to this rare tumor, which shows little response to radiotherapy; the literature is reviewed. We offer this case study in an effort to increase awareness of this rare malignancy.

Bcl-2 genes regulate noise-induced hearing loss.

Proteins of the Bcl-2 family have been implicated in control of apoptotic pathways modulating neuronal cell death, including noise-induced hearing loss. In this study, we assessed the expressions of anti- and proapoptotic Bcl-2 genes, represented by Bcl-xL and Bak following noise exposures, which yielded temporary threshold shift (TTS) or permanent threshold shift (PTS). Auditory brainstem responses (ABRs) were assessed at 4, 8, and 16 kHz before exposure and on days 1, 3, 7, and 10 following exposure to 100 dB SPL, 4 kHz OBN, 1 hr (TTS) or 120 dB SPL, 4 kHz OBN, 5 hr (PTS). On day 10, subjects were euthanized. ABR thresholds increased following both exposures, fully recovered following the TTS exposure, and showed a 22.6 dB (4 kHz), 42.5 dB (8 kHz), and 44.9 dB (16 kHz) mean shift on day 10 following the PTS exposure. PTS was accompanied by outer hair cell loss progressing epically and basally from the 4-kHz region. Additional animals were euthanized for immunohistochemical assessment. BcL-xL was robustly expressed in outer hair cells following TTS exposure, whereas Bak was expressed following PTS exposure. These results indicate an important role of the Bcl-2 family proteins in regulating sensory cell survival or death following intense noise. Bcl-xL plays an essential role in prevention of sensory cell death following TTS levels of noise, and PTS exposure provokes the expression of Bak and, with that, cell death.

Creatine and tempol attenuate noise-induced hearing loss.

To define the role of free radical formation and potential energy depletion in noise induced hearing loss (NIHL), we measured the effectiveness of tempol (free radical scavenger) and creatine (enhances cellular energy storage) alone and in combination to attenuate NIHL. Guinea pigs were divided into four treatment groups: controls, 3% creatine diet (2 weeks prior to noise exposure), tempol (3 mM in drinking water 2 weeks prior to exposure), and creatine plus tempol and exposed to 120 dB SPL one-octave band noise centered at 4 kHz for 5 h. The noise-only control group showed frequency-dependent auditory threshold shifts (measured by auditory brainstem response, ABR) of up to 73 dB (16 kHz) on day 1, and up to 50 dB (8 kHz) on day 10. Creatine-treated subjects had significantly smaller ABR threshold shifts on day 1 and on day 10. Tempol alone significantly reduced ABR threshold shifts on day 10 but not on day 1. ABR shifts after combination treatment were similar to those in the creatine group. Hair cell loss on day 10 was equally attenuated by creatine and tempol alone or in combination. Our results indicate that the maintenance of ATP levels is important in attenuating both temporary and permanent NIHL, while the scavenging of free radicals provides protection from permanent NIHL.

Mechanisms of noise-induced hearing loss indicate multiple methods of prevention.

Recent research has shown the essential role of reduced blood flow and free radical formation in the cochlea in noise-induced hearing loss (NIHL). The amount, distribution, and time course of free radical formation have been defined, including a clinically significant late formation 7-10 days following noise exposure, and one mechanism underlying noise-induced reduction in cochlear blood flow has finally been identified. These new insights have led to the formulation of new hypotheses regarding the molecular mechanisms of NIHL; and, from these, we have identified interventions that prevent NIHL, even with treatment onset delayed up to 3 days post-noise. It is essential to now assess the additive effects of agents intervening at different points in the cell death pathway to optimize treatment efficacy. Finding safe and effective interventions that attenuate NIHL will provide a compelling scientific rationale to justify human trials to eliminate this single major cause of acquired hearing loss.

AIF and EndoG in noise-induced hearing loss.

Apoptosis plays a critical role in neuronal cell death, including sensory cell death in noise-induced hearing loss. The purpose of this study is to investigate the role of a caspase-independent apoptotic pathway, involving apoptosis-inducing factor (AIF) and endonuclease G (EndoG) in cell death in the inner ear after intense noise exposure (120 dB SPL, 4 kHz OBN, 5 h). EndoG was translocated to the nucleus after noise trauma, whereas immunostaining for AIF was expressed only in the cytosol. These findings indicate that EndoG is a factor in noise-induced caspase-independent apoptosis. In contrast, AIF may not be involved in cell death, but act as a redox factor in response to noise-induced oxidant stress.

Antioxidant protection in a new animal model of cisplatin-induced ototoxicity.

Mortality is a major complication in animal models of cisplatin-induced hearing loss due to the systemic toxicity of the drug. Here we report on a novel two-cycle treatment in rats, each cycle consisting of four days of cisplatin injections (1 mg/kg, i.p., twice daily) separated by 10 days of rest. This regimen, similar to clinical courses of cancer chemotherapy, produced significant hearing loss without mortality. Auditory brain stem evoked responses were unchanged after the first cycle but were elevated by 40-50 dB at 16 and 20 kHz after the second. Loss of outer hair cells occurred after the second cycle, predominantly in the base of the cochlea. Total cochlear antioxidants declined progressively during drug treatment and were reduced to 60% of control values after the second cisplatin cycle. Co-administration of salicylate (100 mg/kg, s.c., twice daily) during both cycles or during the second cycle restored antioxidant levels and reduced cisplatin-induced threshold shifts. This model of cisplatin ototoxicity without mortality eliminates potentially confounding factors that may determine the survival of a special cohort of animals. The results also support the notion that reactive oxygen species are involved in cisplatin ototoxicity and show the potential usefulness of antioxidant treatment.