Yasuhiro Inoue

Identification of CRYM as a Candidate Responsible for Nonsyndromic Deafness, through cDNA Microarray Analysis of Human Cochlear and Vestibular Tissues*

Through cDNA microarray analysis of gene expression in human cochlea and vestibule, we detected strong expression of mu-crystallin (CRYM; also known as NADP-regulated thyroid hormone-binding protein) only in these inner-ear tissues. In a subsequent search for mutations of CRYM, among 192 patients with nonsyndromic deafness, we identified two mutations at the C-terminus; one was a de novo change (X315Y) in a patient with unaffected parents, and the other was a missense mutation (K314T) that segregated dominantly in the probands family. When the mutated proteins were expressed in COS-7 cells, their subcellular localizations were different from that of the normal protein: the X315Y mutant showed vacuolated distribution in the cytoplasm, and the K314T mutant localized in perinuclear areas, whereas normal protein was distributed homogeneously in the cytoplasm. Aberrant intracellular localization of the mutated proteins might cause dysfunction of the CRYM product and result in hearing impairment. In situ hybridization analysis using mouse tissues indicated its expression in the lateral region of the spiral ligament and the fibrocytes of the spiral limbus, implying its possible involvement in the potassium-ion recycling system. Our results strongly implicate CRYM in normal auditory function and identify it as one of the genes that can be responsible for nonsyndromic deafness.

Effect of prostaglandin E1 on idiopathic sudden sensorineural hearing loss: a double-blinded clinical study.

Objective and Study Design The authors conducted a prospective, randomized, double-blinded clinical trial for the purpose of elucidating the effects of prostaglandin E1 (PGE1) on idiopathic sudden sensorineural hearing loss. Setting and Patients With the approval of the institute ethics committee, a total of 57 consecutive patients with diagnoses of idiopathic sudden sensorineural hearing loss were included in the study. The patients in the PGE1 group received continuous infusion containing 60 &mgr;g PGE1 and 100 mg hydrocortisone for 7 days, and the patients in the placebo group were treated with continuous infusion containing an inactive placebo and 100 mg hydrocortisone. Results No significant differences were observed in the improvements of pure-tone average and subjective symptoms between the PGE1 and the placebo groups. However, the hearing improvement at high frequencies (4 kHz and 8 kHz) was significantly higher in the PGE1 group than in the placebo group, especially in the patients with severe tinnitus. Conclusions These results failed to prove a beneficial effect of PGE1 in the treatment of idiopathic sudden sensorineural hearing loss. Further studies will be needed to clarify the pharmacologic actions of PGE1 in the cochlea.

Quality of life of vestibular schwannoma patients after surgery

The quality of life of vestibular schwannoma (VS) patients after surgery was investigated. The subjects consisted of 236 unilateral VS patients who underwent tumor removal between 1990 and 1997. A questionnaire was sent to all patients regarding their hearing, tinnitus, dizziness and the changes in their daily life after surgery; 176 out of 204 patients (86%) who received the questionnaire completed and returned it. The answers were compared with recent data reported in other clinical studies. Ninety percent of the patients with postoperative class A hearing were satisfied with their hearing. However, only 30% of patients with postoperative class B hearing were satisfied. Tinnitus worsened after surgery more often in patients who underwent a labyrinthectomy than in those who did not. Dizziness improved after surgery in the majority of VS patients. However, 30% of patients had difficulty driving a car and 50% of patients could not enjoy activities such as playing sport after surgery.The quality of life of vestibular schwannoma (VS) patients after surgery was investigated. The subjects consisted of 236 unilateral VS patients who underwent tumor removal between 1990 and 1997. A questionnaire was sent to all patients regarding their hearing, tinnitus, dizziness and the changes in their daily life after surgery; 176 out of 204 patients (86%) who received the questionnaire completed and returned it. The answers were compared with recent data reported in other clinical studies. Ninety percent of the patients with postoperative class A hearing were satisfied with their hearing. However, only 30% of patients with postoperative class B hearing were satisfied. Tinnitus worsened after surgery more often in patients who underwent a labyrinthectomy than in those who did not. Dizziness improved after surgery in the majority of VS patients. However, 30% of patients had difficulty driving a car and 50% of patients could not enjoy activities such as playing sport after surgery.

Effect of single-drug treatment on idiopathic sudden sensorineural hearing loss

OBJECTIVESnIn order to evaluate the effect of a medical administration for the sudden deafness patients, single-drug treatment for idiopathic sudden sensorineural hearing loss (ISSHL) was assessed at multi-centers participating in the Acute Severe Hearing Loss Study Group sponsored by the Ministry of Health, Labor and Welfare of Japan.nnnMETHODSnThe subjects consisted of ISSHL patients who were (1) 20 years of age or older, (2) diagnosed within 2 weeks after the onset of hearing loss, (3) showing a mean hearing level of 40-90 dB at five frequencies from 250 to 4000 Hz, (4) previously untreated, and (5) with normal for age in hearing of the opposite ear. The drugs used in this study were ATP, alprostadil, hydrocortisone and amidotrizoate, which were administered intravenously, and beraprost sodium and betamethasone, which were given orally. Two drugs were assigned to each center, one of which was selected according to the code hidden in envelopes and administered for 1 week. The treatment after the single-drug administration was conducted at the discretion of each center. The hearing gain and recovery rate at 1 week after the initiation of single-drug treatment and at 1 month or over when the hearing level was fixed, were evaluated based on the criteria for hearing recovery prepared by the Acute Severe Hearing Loss Study Group.nnnRESULTSnThere was no statistically significant difference in the recovery rate among drugs either at 1 week after the initiation of single-drug treatment or at the time of fixed hearing level. At the time when the hearing level was fixed, a statistically significant difference in the complete recovery rate was detected only between amidotrizoate and beraprost sodium.nnnCONCLUSIONnFrom these results, we could not find any specific drugs recommended for ISSNHL. In evaluating the effect of the drugs, however, several problems in the clinical trial for ISSHL should be considered.

Acoustic Neuromas Presenting as Sudden Hearing Loss

Progressive hearing loss is well known as a usually existing complaint in patients with acoustic neuromas. However, sudden hearing loss is also a relatively frequent condition in acoustic neuroma patients. In our review of 132 patients with surgically proven unilateral acoustic neuromas, 29 (22.0%) presented a history of sudden hearing loss. We investigated the clinical and audiological characteristics of these patients, and discuss the etiology of sudden hearing loss in patients with acoustic neuromas. The characteristics of patients with AN presenting sudden hearing loss were as follows: 1) a small tumor, 2) short duration after onset, 3) low incidences of vertigo, dizziness, facial and trigeminal nerve symptoms, 4) the trough type in the audiogram configuration, 5) normal caloric response. Based on the analysis of these results, we conclude that a conduction block of the cochlear nerve is likely to be the etiology of sudden hearing loss.

Calbindin-D28K localization in the primate inner ear

The distribution of one of the calcium-binding proteins, calbindin-D28K (CB-D28K), was studied in the adult human and squirrel monkey inner ear by means of immunocytochemical methods. Inner and outer hair cells in the organ of Corti and vestibular hair cells showed CB-D28K immunoreactivity, though some vestibular hair cells were devoid of immunoreactivity. In the spiral and vestibular ganglion, immunoreactive cells were found in both the squirrel monkey and human. The present results indicate that CB-D28K is localized within afferent neuronal components in these sensory organs and may regulate Ca++ levels for optimal neurotransmission in the primate auditory and vestibular systems. This study also provides evidence of two nonneuronal localizations of CB-D28K in the squirrel monkey. Subpopulations of fibrocytes in the spiral ligament and vestibular end organs were enriched with CB-D28K, suggesting that these cells are possibly equipped with the function to regulate Ca++ concentration in the perilymphatic fluid. In the maculae, many CB-D28K-immunoreactive particles were found in the otoconial membrane, indicating that CB-D28K may participate in the formation of otoconia.

Influence of depressive symptoms, state anxiety, and pure-tone thresholds on the tinnitus handicap inventory in Japan

Abstract Objective: To assess factors that contribute to Tinnitus Handicap Inventory (THI) scores in Japan. Design: Case series with chart review. Study sample: Two hundred and eighty-five tinnitus patients at tertiary referral center, who completed the Japanese version of the THI, the Self-rating Depression Scale (SDS), and the State Trait Anxiety Inventory (STAI). Results: In multiple regression analysis, the SDS score contributed the most to the THI score. The state section of the STAI score and pure tone average (PTA) at four high frequencies also contributed significantly, but to lesser degrees. The other following factors were not statistically significant: age, gender, time from the onset of tinnitus to the first clinical visit, PTA at three mid frequencies, and trait section of the STAI score. This model may account for approximately 45% of THI score variability. Conclusions: The THI scores may be influenced by depressive symptoms, state anxiety, and pure tone thresholds in Japan. Sumario Objetivo: Evaluar los factores que contribuyen a la puntuación del Inventario de Impedimento por el Acúfeno (THI) en Japón. Diseño: Serie de casos con revisión del expediente. Muestra: Doscientos ochenta y cinco pacientes en un tercer nivel de referencia que completaron la versión japonesa del THI, la escala de auto-evaluación de la depresión (SDS), y el Inventario de Rasgos del Estado de Ansiedad (STAI). Resultados: En un análisis de regresión múltiple, el puntaje de SDS tuvo la mayor contribución en el puntaje del THI. La sección de estado del STAI y el promedio de los tonos puros (PTA) en cuatro frecuencias altas también contribuyó significativamente, pero en un grado menor. Los factores siguientes no fueron significativos: edad, género, tiempo desde el inicio del acúfeno hasta la primera visita clínica, el PTA en tres frecuencias medias y la sección de rasgos en el STAI. Este modelo puede contribuir hasta aproximadamente 45% en la variabilidad del puntaje del THI. Conclusiones: el puntaje de THI en Japón, puede estar influido por síntomas depresivos, estado de ansiedad y los umbrales de los tonos puros.

Effects of Selective Serotonin Reuptake Inhibitor on Treating Tinnitus in Patients Stratified for Presence of Depression or Anxiety

We evaluated the effects of a selective serotonin reuptake inhibitor, paroxetine, on treating tinnitus.Tinnitus patients stratified for the presence of depression and anxiety were studied retrospectively. Fifty-six patients were observed for more than 6 months. They were initially treated with paroxetine only at a dose of 10 mg/day for 2–4 weeks; thereafter, the dose was increased to 20 mg/day. Tinnitus distress was evaluated with the Tinnitus Handicap Inventory (THI) and with visual analog scales (VASs) for tinnitus loudness and annoyance. Depression and anxiety were measured with the Self-Rating Depression Scale (SDS) and the trait section of the State-Trait Anxiety Inventory (STAI). The patients were grouped according to their SDS and STAI scores, and each variable was compared at baseline and the 6-month follow-up. Changes among these variables were also examined to determine whether reduced tinnitus distress was related to the improvement of depression or anxiety. Patients with both depression and anxiety showed better results (decrease in THI, VASs, SDS and STAI scores) than patients with anxiety alone, or patients without depression and anxiety. In patients with depression and anxiety, changes in tinnitus variables and changes in depression and anxiety scores were strongly correlated. In other patients, however, changes in tinnitus variables and changes in depression and anxiety scores were not correlated. These results suggest that paroxetine is effective in treating distressed tinnitus patients with depression and anxiety by reducing their tinnitus severity as well as their depression and anxiety.

Endoscopic diagnosis of idiopathic perilymphatic fistula

The usefulness of endoscopic examination for the diagnosis of idiopathic perilymphatic fistula (IPLF) was investigated. Eight patients presenting with unilateral sensorineural hearing loss and vertigo underwent endoscopic examination by the transtubal or transtympanic approach. In 5 out of the 8 patients, transtubal endoscopy was carried out using a superfine flexible endoscope. With this approach, no abnormal findings were visualized. A perilymphatic leak from the round window was observed in 2 patients by means of transtympanic examination using a needle scope. These findings were confirmed in both patients by microscopic observation during tympanotomy. In one patient who was finally diagnosed with IPLF, the transtympanic endoscopy failed to detect perilymphatic leakage. Although incision of the tympanic membrane is necessary for the examination, transtympanic endoscopy is useful for the diagnosis of IPLF. Further improvement of the superfine flexible fiberscope is necessary before transtubal observation of the tympanic cavity can be effectively conducted.

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

OBJECTIVEnThere 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.nnnMETHODSnSixteen 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.nnnRESULTSnA 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.nnnCONCLUSIONnThese 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.