Hiromitsu Miyazaki

Role of Gbx2 and Otx2 in the formation of cochlear ganglion and endolymphatic duct

The boundary of gene expression of transcription factors often plays a role in making a signaling center in development. In the otic vesicle, Gbx2 is expressed in the dorso‐medial region including the endolymphatic duct, and Otx2 in the ventral region. Fgf10 is expressed between their expression boundaries, and the cochleovestibular ganglion develops close to the medial side of the Fgf10 expressing domain. Similar expression patterns are observed in the central nervous system, where Otx2 and Gbx2 expression abut at the mid–hindbrain boundary, and the repressive interaction between Otx2 and Gbx2 defines the mid–hindbrain boundary. These analogous expression patterns raise a question about the role of the interaction between Gbx2 and Otx2 in the otic vesicle. To address this, we misexpressed Gbx2 and Otx2 to the otic epithelium. Ectopic Gbx2 expression could repress Otx2 expression and vice versa. In addition, Fgf10 expression was repressed and cochlear ganglion formation was interfered with. Moreover, endolymphatic duct was severely hypomorphic in the Otx2 misexpressing embryos. These results suggest that the interaction between Gbx2 and Otx2 in developing inner ear defines Fgf10 expression domain to induce the cochlear ganglion. It is also suggested that Gbx2 expression is important for the formation of the endolymphatic duct.

Relationship Between Clinical Test Results and Morphologic Severity Demonstrated by Sitting 3-D CT in Patients With Patulous Eustachian Tube.

Objective: To investigate the correlation of sitting 3-D computed tomography (CT) scans of the Eustachian tube (ET) with subjective and objective findings in patients with patulous Eustachian tube (PET). Study Design: Retrospective. Setting: Tertiary referral center. Subjects: A retrospective survey of medical records in Sen-En Hospital identified 40 patients and 62 ears with PET between September 2014 and June 2015. Method: Diagnosis of PET was based on the presence of three characteristic aural symptoms (autophony of voice or breathing sounds, and aural fullness), as well as verification of synchronous movement of the tympanic membrane in response to forced breathing under an endoscope. Any pressure changes in the external auditory canal (EAC) elicited by deep breathing and sniffing were detected by tubotympanoaerodynamography (TTAG). In addition, sonotubometry was performed where two parameters were used determined to evaluate ET function. Patients were examined by 3-D CT (Accuitomo; Morita, Kyoto, Japan) in the sitting position. The length of the closed ET lumen section was measured. Ears were divided into three groups as follows: completely open, closed-short (3 mm or less), and closed-long (longer than 3 mm). Results: The median length of the closed section of the ET lumen was 1.85 ± 2.69 mm in positive findings of PET. The three groups were significantly different in both aural fullness (p = 0.023) and, similarly, the difference in tympanic membrane movement (p = 0.032) among these three groups was also significantly different (p = 0.032). However, for autophony of breathing sounds, there was no significant difference with regard to autophony of breathing sounds among these three groups (p = 0.324). Although TTAG findings were did not reveal any significantly difference among these three groups (p = 0.589), the difference was significant (p = 0.001) in degree of EAC pressure change in TTAG. The difference among the three groups was significant (p = 0.001) based on sonotubometry findings. Conclusion: Under resting conditions, the lengths of the closed area of the ETs in PET groups are clearly shorter than in groups without PET based on sitting position CT scans in resting condition. Among the symptoms and clinical test findings including the ET function test results, the presence of tympanic membrane movement induced by respiration, the high degree of EAC pressure change in TTAG, as well as the positive results of sonotubometry are significantly correlated with the positive findings of sitting CT revealing the open ET.

Effects of Contralateral Noise on the 20-Hz Auditory Steady State Response - Magnetoencephalography Study

The auditory steady state response (ASSR) is an oscillatory brain response, which is phase locked to the rhythm of an auditory stimulus. ASSRs have been recorded in response to a wide frequency range of modulation and/or repetition, but the physiological features of the ASSRs are somewhat different depending on the modulation frequency. Recently, the 20-Hz ASSR has been emphasized in clinical examinations, especially in the area of psychiatry. However, little is known about the physiological properties of the 20-Hz ASSR, compared to those of the 40-Hz and 80-Hz ASSRs. The effects of contralateral noise on the ASSR are known to depend on the modulation frequency to evoke ASSR. However, the effects of contralateral noise on the 20-Hz ASSR are not known. Here we assessed the effects of contralateral white noise at a level of 70 dB SPL on the 20-Hz and 40-Hz ASSRs using a helmet-shaped magnetoencephalography system in 9 healthy volunteers (8 males and 1 female, mean age 31.2 years). The ASSRs were elicited by monaural 1000-Hz 5-s tone bursts amplitude-modulated at 20 and 39 Hz and presented at 80 dB SPL. Contralateral noise caused significant suppression of both the 20-Hz and 40-Hz ASSRs, although suppression was significantly smaller for the 20-Hz ASSRs than the 40-Hz ASSRs. Moreover, the greatest suppression of both 20-Hz and 40-Hz ASSRs occurred in the right hemisphere when stimuli were presented to the right ear with contralateral noise. The present study newly showed that 20-Hz ASSRs are suppressed by contralateral noise, which may be important both for characterization of the 20-Hz ASSR and for interpretation in clinical situations. Physicians must be aware that the 20-Hz ASSR is significantly suppressed by sound (e.g. masking noise or binaural stimulation) applied to the contralateral ear.

Congenital cholesteatoma is predominantly found in the posterior-superior quadrant in the Asian population: systematic review and meta-analysis, including our clinical experience.

Objective The study compares the clinical features of patients with congenital cholesteatoma seen in our institution over the most recent 10 years versus those seen in the previous decade. Furthermore, this study includes a systematic review and meta-analysis investigating whether differences in site predilection of congenital cholesteatoma exist between patients from Asian and Western countries. Data Sources The retrospective review consisted of 31 cases encountered from 2001 to 2011 as compared with 40 cases previously described. For systematic review, data were retrieved from PubMed, EmBase, and the Japan Medical Abstracts Society Database (January 1995 through May 2012). Study Selections Articles addressing site predilection of congenital cholesteatoma were selected with no language preference. Data Extraction The database was searched using the keywords “congenital cholesteatoma.” After critical review of 408 studies, 27 studies were eligible for quantitative synthesis. Data Synthesis A retrospective analysis of our departmental cases showed that more than 70% (8/11) of the Potsic’s stage I or II cases had a predilection for the anterior-superior quadrant (ASQ). None of the Stage III (17) or IV (3) cases had a similar site predilection. Consistent with our previous chart review, Stage III was the most common, comprising more than 60% of cases. Meta-analysis of the 27 eligible studies provided sufficient information regarding locations of congenital cholesteatoma, and Asian studies showed less frequent ASQ involvement (overall estimate, 0.54; 95% confident interval [CI], 0.49–0.59) when compared with Western studies (overall estimate, 0.76; 95% CI, 0.73–0.80). Moreover, the involvement of posterior-superior quadrant (PSQ) in Asian studies was estimated as 0.69 (95% CI, 0.64–0.73), which was higher than that associated with involvement of ASQ. Conclusion In contrast to Western studies, PSQ was more frequently involved than ASQ in Asian studies of congenital cholesteatoma. The posteriorly located lesions might have a completely distinct pathophysiologic origin when compared with lesions originating from the ASQ.

Identification of Actinomyces meyeri actinomycosis in middle ear and mastoid by 16S rRNA analysis

Actinomycosis of the middle ear and mastoid is extremely rare. Here, we report a unique case of actinomycosis of the middle ear and mastoid caused by Actinomyces meyeri diagnosed by 16S rRNA gene sequence analysis.

New Scoring System for Evaluating Patulous Eustachian Tube Patients.

OBJECTIVE To assess the efficacy of patulous Eustachian tube handicap inventory (PHI) for patulous Eustachian tube (PET) patients. STUDY DESIGN Prospective. SETTING Tertiary referral center. SUBJECTS A prospective survey of medical records in Sen-En Hospital identified 31 ears of 31 patients with definite PET who received insertion of the silicone plug as surgical treatment group, 29 ears of 29 patients treated with self-instillation of physiological saline solution as conservative treatment group, and 29 ears of 29 patients of sensorineural hearing loss without findings of PET treated between June 2015 and December 2015. METHOD Diagnosis of definite PET was based on the proposal on PET diagnosis criteria announced by the Otological Society of Japan. The evaluation scale of PHI was modified from the Japanese version of the tinnitus handicap inventory-12 (THI-12). The classification for grading of severity is defined as follows: 1) no handicap (0-8), 2) mild handicap (10-16), 3) moderate handicap (18-24), and 4) severe handicap (26-40), matching the severity grades of tinnitus handicap inventory-25 (THI-25). The outcome measurement was modified from the previous scoring system and is defined as 1) complete relief, 2) significant improvement, 3) slight improvement, 4) unchanged, and 5) worse, and is applied according to the classification for grading of severity. The PHI was conducted at the first visit to our center for all patients in the three groups. For cases requiring surgery for plug insertion, patulous Eustachian tube handicap inventory 10 (PHI 10) was also conducted postsurgery after the treatment (postsurgery). RESULTS The findings from questions 1 to 7 and 9 to 11 were significantly different between the surgical (presurgery) and conservative treatment groups (p < 0.05). Taking these results, we analyzed 10 questions excluding questions 8 and 12 (PHI 10). The total score of PHI 10 averaged 19.5 ± 9.3 (n = 31) and 30.6 ± 8.6 (n = 29) in the surgical treatment (presurgery) and conservative treatment groups, respectively, with a significant difference (p < 0.05). Internal consistency reliability testing of the PHI 10 yielded a Cronbach α of 0.887 for all questions. In the surgical treatment (presurgery) and conservative treatment groups, there were 0 (0%) and 3 cases (12%) of no handicap, 3 (10%) and 13 cases (50%) of mild handicap, 6 (19%) and 4 cases (15%) of moderate handicap, and 22 (71%) and 6 cases (23%) of severe handicap, respectively. There was a significant correlation between the PHI 10 and Likert scale (r = 0.796, p < 0.01). In the surgical group, the presurgery and postsurgery PHI 10 scores (n = 25) were 29.6 ± 8.5 and 7.8 ± 11.3, respectively. CONCLUSION The PHI 10 is suitable for evaluating severity of PET if the patients have been diagnosed as definite PET. Furthermore, this scoring system could be suitable for surgical treatment assessment.

POU4F3 mutation screening in Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis identified novel variants associated with autosomal dominant hearing loss

A variant in a transcription factor gene, POU4F3, is responsible for autosomal dominant nonsyndromic hereditary hearing loss, DFNA15. To date, 14 variants, including a whole deletion of POU4F3, have been reported to cause HL in various ethnic groups. In the present study, genetic screening for POU4F3 variants was carried out for a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA15 in the Japanese population. Massively parallel DNA sequencing of 68 target candidate genes was utilized in 2,549 unrelated Japanese HL patients (probands) to identify genomic variations responsible for HL. The detailed clinical features in patients with POU4F3 variants were collected from medical charts and analyzed. Novel 12 POU4F3 likely pathogenic variants (six missense variants, three frameshift variants, and three nonsense variants) were successfully identified in 15 probands (2.5%) among 602 families exhibiting autosomal dominant HL, whereas no variants were detected in the other 1,947 probands with autosomal recessive or inheritance pattern unknown HL. To obtain the audiovestibular configuration of the patients harboring POU4F3 variants, we collected audiograms and vestibular symptoms of the probands and their affected family members. Audiovestibular phenotypes in a total of 24 individuals from the 15 families possessing variants were characterized by progressive HL, with a large variation in the onset age and severity with or without vestibular symptoms observed. Pure-tone audiograms indicated the most prevalent configuration as mid-frequency HL type followed by high-frequency HL type, with asymmetry observed in approximately 20% of affected individuals. Analysis of the relationship between age and pure-tone average suggested that individuals with truncating variants showed earlier onset and slower progression of HL than did those with non-truncating variants. The present study showed that variants in POU4F3 were a common cause of autosomal dominant HL.

Audiological evidence of therapeutic effect of steroid treatment in neuromyelitis optica with hearing loss.

Neuromyelitis optica (NMO) is an autoimmune astrocytopathy caused by anti-aquaporin 4 antibody. Only two patients with NMO have been reported presenting with hearing disorders to our knowledge. We recently treated a 40-year-old woman with NMO complaining of right hearing loss. Audiometry showed minimal asymmetry, but the auditory brainstem responses (ABR) were severely attenuated on the right. The attenuated ABR and her aural symptoms (hearing loss and fullness) improved after steroid treatment. The present case shows that the retrocochlear-type hearing loss may be associated with NMO.

The efficacy of the Eustachian Tube Dysfunction Questionnaire (ETDQ-7) for patulous Eustachian tube patient

Abstract Objective: To assess the efficacy of the Eustachian Tube Dysfunction Questionnaire (ETDQ-7) for patulous Eustachian tube (PET) patients. Methods: A prospective survey of medical records identified 36 patients and 47 ears with PET, and 15 patients and 15 ears as control. The ETDQ-7, patulous Eustachian tube handicap inventory-10 (PHI-10) and Likert scale were evaluated. PET patients were divided into two groups based on severity of symptoms using the PHI score. Results: The Cronbach α value of the PET group was 0.765. The average total score of the ETDQ-7 in the control group was 7.6 ± 1.1 and 22.5 ± 10.0 in the PET group (p < .01). No correlation was found between ETDQ-7 and Likert scale (r = 0.248, p = .09). The average total score of the ETDQ-7 in the mild or moderate PET group was 19.9 ± 9.0 and 25.3 ± 11.1 in the severe PET group and this was not statistically different (p = .08). Conclusion: The highest ETDQ-7 score was also observed in PET patients and in ET dysfunction patients. These findings necessitate careful discrimination between ET dysfunction and PET in balloon dilation Eustachian tuboplasty (BET) based on ETDQ-7.

Tubal function tests with optional myringotomy detect Eustachian tube closing failure in acquired pars flaccida retraction cholesteatoma

OBJECTIVE To re-evaluate the incidence of Eustachian tube closing failure in acquired middle ear cholesteatoma. METHOD Thirty-one cases with acquired middle ear cholesteatoma who received surgery were enrolled. Presence of Eustachian tube closing failure was determined through two Eustachian tube function tests. First Step Tests: Test 1: Positive sniff test identified by retraction of the tympanic membrane upon sniffing was observed. Test 2: The pressure in the external auditory meatus was found to change synchronously with that of the nasopharynx during respiration or upon sniffing. Second step test: For cases with negative First Step Tests, myringotomy was performed and Test 2 was repeated. RESULTS Test 1 was positive in six (19.4%) and Test 2 was initially positive in nine (29.0%) out of 31 cases. Twelve out of 31 cases (38.7%) were positive for either one of the tests. The remaining 19 cases with initial negative test results subsequently received myringotomy and were subjected to Test 2 again. Positive results were obtained in five (13.9%) additional cases, and a final total of 17 (54.8%) out of 31 cases were positive for Eustachian tube closing failure. CONCLUSION Sniff test with optional myringotomy may be useful for preoperative diagnosis of Eustachian tube closing failure.