Final publication is available at http://journals.lww.com/otology-neurotology/Pages/default.aspx / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19574号 / 医博第4081号 / 新制||医||1013(附属図書館) / 32610 / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邉 大, 教授 伊佐 正, 教授 一山 智 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Ménière’s disease (MD) is an idiopathic inner ear disorder, characterised by episodes of vertigo, tinnitus, sensorineural hearing loss, and aural fullness in the affected ear. The relatively high variability of symptomological changes renders it difficult to confirm the MD diagnosis. The purpose of this study is to compare the diagnostic power of an instrumental method, electrocochleography (ECochG), and two subjective methods, including the criteria based on the clinical guidelines provided by the American Academy of Otolaryngology-Head and Neck Surgery Committee on Hearing Equilibrium (AAO-HNS CHE) and Gibson’s Score. A quota sampling method was used to include subjects. A total of 250 potential MD patients who were referred to the Department of Otolaryngology at the Christchurch Hospital between year 1994 and 2009 have had their signs and symptoms documented and ECochG testing completed. A selection of details obtained from both AAO-HNS CHE and ECochG assessment results were examined as a chart review in regard to its function as a diagnostic tool for MD. The between-method reliability was found to be high, with a few disagreements on individual diagnosis. Based on a receiver operating characteristic (ROC) curve analysis, the ECochG measures were shown to be pertinent to the diagnosis of MD. It was also found that patients tested “positive”, as compared with those tested “negative”, tended to show higher correlations among the four key symptoms of MD and among the ECochG measures derived from the auditory evoked responses to tone bursts at frequencies in close proximity to each other.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 5 uppsatser.

Abstract The symptom complex originating from the inner ear, known as Meniere's disease, was studied especially from the epidemiologic point of view. A total of 442 patients' charts were retrospectively analysed in several hospital districts of Finland. The period of 1992-1996 was covered. The main focus was on the epidemiological assessment of the disease in Finland. To clarify the epidemiological figures, the validity of the diagnostic assessment was examined using the latest guidelines (1995) of the Committee on Hearing and Equilibrium of the American Academy of Otolaryngology - Head and Neck Surgery (AAO-HNS) as a gold standard. The diagnostic tools used in the different hospitals were documented and evaluated, and diagnostic accuracy at the different levels of the health care system was evaluated. The clinical picture of Meniere's disease was characterised, and the therapeutic modalities used were evaluated. The audiometric configurations were classified according to two principles. The prognosis of hearing impairment was specified by creating a multivariable model. Half of the patients (N = 221) fulfilled the AAO-HNS criteria for definite disease. The prevalence and incidence of definite cases of Meniere's disease appeared to be lower in Finland than could be expected based on previous international studies. A prevalence of at least 43 per 100,000 and an average annual incidence of 4.3 per 100,000 were obtained. The prevalence rates in the catchment areas of the university and central hospitals did not differ statistically, but a significant (p < 0.001) difference was found between the average prevalences in the northern and southern Finnish hospital districts. Fluctuation of hearing in repeated audiometric measurements appeared to be a highly sensitive (94%) diagnostic test to detect definite Meniere's disease. According to the multivariable model created in this study, the hearing impairment in Meniere's disease affects equally males and females, and the deterioration is about 1 dB per year due to the duration of the disease and 0.5 dB per year due to aging. The disease was controlled conservatively in 69% of the cases. A gently sloping high-frequency audiometric pattern was most prevalent according to the EU Work Group classification and a flat pattern according to the mid-frequency-based classification. The variability of diagnostic criteria, diagnostic tools and therapeutic modalities shows an evident need for up-to-date therapy recommendations for Meniere's disease in Finland.

Ménière’s disease is the third most common inner ear disorder. The individual course of Ménière’s disease in different patients makes it difficult to diagnose on the basis of symptomatology alone. The impact of Ménière’s disease on quality of life has highlighted the importance of an additional tool to support the diagnosis of Ménière’s disease. Apart from the patient’s history, audiological data provide the most relevant information for confirming the diagnosis. The aim of this study was to analyse and describe the clinical and audiological features of a cohort of subjects diagnosed with Ménière’s disease, in order to develop understanding of the pathophysiology of the disease and to facilitate the diagnostic process. The research is based on a retrospective study of the medical records of 135 subjects with Ménière’s disease which were selected according to a non-probability sample. Descriptive statistics were used to organize, analyse and interpret the data. Sixty one percent of subjects presented with definite Ménière’s disease, 14 % with probable Ménière’s disease and 25 % with possible Ménière’s disease. The results showed a higher incidence of Ménière’s disease in females especially in the vestibular type. Three percent of subjects indicated a family history of Ménière’s disease. Bilateral Ménière’s disease presented in 39 % of subjects. The results confirmed that vertigo was the most debilitating symptom in Ménière’s disease. Correlating the clinical features of subjects with audiometric and vestibular tests highlighted the clinical value of an audiological test battery including the following tests: Pure tone audiometry, Speech discrimination, Oto-acoustic emissions, Electronystagmography and Electrocochleography. This confirms the role of the audiologist in the diagnostic and rehabilitation process in patients with Ménière’s disease. / Dissertation (Communication Pathology)--University of Pretoria, 2007. / Speech-Language Pathology and Audiology / unrestricted

<p>Topical treatment of several inner ear diseases through the round window membrane (RWM) might be feasible in the near future. Bacteria toxins, ototoxic drugs and noise trauma seem to harm the inner ear by a common pathway which involves, excessive outflow of the afferent neurotransmitter glutamate and formation of nitric oxide (NO), which can severely damage cells/nerve endings and lead to cell death.</p><p>In this study we used 98 Sprague-Dawley rats and seven human temporal bones. Various substances were instilled into the middle ear of the rat, such as Pseudomonas Aeruginosa Exotoxin (PaExoA), gentamicin, NO-inhibitor N-Omega-Nitro-L-Arginine Methyl Ester (L-NAME), and glucocorticoids. The effects of the substances were studied by morphological analysis of RWM and the endolymphatic sac (ES) by light and electron microscopic. Hearing level was measured in the rats by ABR technique. The human temporal bones were studied immunomorphologically to search for glutamate.</p><p>In the human inner ear, glutamate receptors and glutamine synthetase, were identified. In the rat, we found, following PaExoA exposure, reversible and permanent hearing loss and morphological changes in the RWM. The ES showed increased numbers of macrophages and thickening of the epithelia. When L-NAME was used as an otoprotector from gentamicin ototoxicity a therapeutic effect in the high frequency area was found. Hydrocortisone (but not dexamethasone) exposure of the RWM resulted in membrane thickening, and adjacent to the membrane, inflammatory cells.</p><p>The importance of the RWM as a portal for toxic substances and topical treatment of inner ear diseases was highlighted in this study. The difficulties of applying drugs in the round window niche were exposed. The results of this study add important knowledge concerning certain mechanisms of inner ear injury and help us to understand possibilities and problems of local treatment of inner ear diseases in patients.</p>

Topical treatment of several inner ear diseases through the round window membrane (RWM) might be feasible in the near future. Bacteria toxins, ototoxic drugs and noise trauma seem to harm the inner ear by a common pathway which involves, excessive outflow of the afferent neurotransmitter glutamate and formation of nitric oxide (NO), which can severely damage cells/nerve endings and lead to cell death. In this study we used 98 Sprague-Dawley rats and seven human temporal bones. Various substances were instilled into the middle ear of the rat, such as Pseudomonas Aeruginosa Exotoxin (PaExoA), gentamicin, NO-inhibitor N-Omega-Nitro-L-Arginine Methyl Ester (L-NAME), and glucocorticoids. The effects of the substances were studied by morphological analysis of RWM and the endolymphatic sac (ES) by light and electron microscopic. Hearing level was measured in the rats by ABR technique. The human temporal bones were studied immunomorphologically to search for glutamate. In the human inner ear, glutamate receptors and glutamine synthetase, were identified. In the rat, we found, following PaExoA exposure, reversible and permanent hearing loss and morphological changes in the RWM. The ES showed increased numbers of macrophages and thickening of the epithelia. When L-NAME was used as an otoprotector from gentamicin ototoxicity a therapeutic effect in the high frequency area was found. Hydrocortisone (but not dexamethasone) exposure of the RWM resulted in membrane thickening, and adjacent to the membrane, inflammatory cells. The importance of the RWM as a portal for toxic substances and topical treatment of inner ear diseases was highlighted in this study. The difficulties of applying drugs in the round window niche were exposed. The results of this study add important knowledge concerning certain mechanisms of inner ear injury and help us to understand possibilities and problems of local treatment of inner ear diseases in patients.

Objectifs: La pathophysiologie de la maladie de Ménière (MM) demeure mal comprise. Nous avons identifié dans la littérature un groupe de protéines exprimées sur le sac endolymphatique (SEL) et impliquées dans la régulation du volume endolymphatique : l’Aquaporine-2 (AQP2), le récepteur V2R de vasopressine (AVP), le Co-transporteur de Sodium Potassium et Chlorure type 2 (NKCC2) et le canal TRP type V4 (TRPV4). Notre objectif est de déterminer si leur expression sur le SEL est altérée dans la MM, pour améliorer notre compréhension de la physiologie de l’hydrops endolymphatique. Méthodes: Recrutement des cas de MM et schwannomes vestibulaires (SV) comme contrôles, le jour de leurs chirurgies respectives. Prélèvement de biopsies de SEL et sang pour AVP. L’immunohistochimie pour AQP2, V2R, NKCC2 et TRPV4 fut effectuée, et les lames scannées pour analyse digitale de densité d’expression par un logiciel spécialisé (VIS par Visiopharm®). Résultats: Total de 27 cas MM et 23 contrôles. Les scores générés par le logiciel représentent la densité d’expression totale et relative des protéines, exclusivement sur l’épithélium du SEL. Les scores d’AQP2 sont élevés de façon significative dans la MM comparée aux contrôles (p = 0.018). Nous ne rapportons aucune variation significative pour AVP, V2R, NKCC2 et TRPV4. Conclusion: Cette étude originale évalue l’expression simultanée de AQP2, V2R, NKCC2 et TRPV4 sur le SEL dans la MM, avec un groupe contrôle (SV). Nos résultats démontrent une augmentation isolée de l’AQP2 dans la MM. Nous proposons une surexpression constitutive de cette dernière, indépendante de son axe de régulation (AVP-V2R). Une mutation somatique au niveau des séquences régulatrices pourrait justifier nos observations. / Objectives: Endolymphatic sac (ELS) pathophysiology in Ménière’s Disease (MD) remains poorly understood. We identified from the literature a group of proteins expressed on the ELS and involved in endolymph volume regulation: Aquaporin-2 (AQP2), vasopressin receptor V2R, Sodium Potassium Chloride Cotransporter type 2 (NKCC2) and TRP channel type V4 (TRPV4). Our objective was to determine whether their ELS expression was altered in MD, to better understand the pathophysiology of endolymphatic hydrops. Methods: Patients with definite MD undergoing endolymphatic duct blockage surgery were recruited, as well as controls undergoing surgery for vestibular schwannomas (VS). ELS biopsies and blood samples for plasma Arginine Vasopressin (AVP) were obtained. Immunohistochemistry for AQP2, V2R, NKCC2 and TRPV4 was performed. Slides were scanned digitally for highly sensitive pixel density analysis by specialized software (VIS by Visiopharm®). Results: 27 definite MD patients and 23 VS controls were included. Global scores generated by the software represent total and relative protein expression density of 3 staining intensity levels, exclusively on ELS epithelium. AQP2 expression density was significantly elevated in MD compared to VS (p = 0.018). There was no significant difference in plasma AVP, V2R, NKCC2 and TRPV4 expression. Conclusion: This original study evaluates simultaneous in-situ expression of AQP2, V2R, NKCC2 and TRPV4 on the human ELS in MD, with a VS control group. Our results show only AQP2 up regulation on the ELS of MD patients. We suggest a constitutively increased expression of AQP2 in MD, independent of its regulatory axis (AVP-V2R). Acquired regulator sequence mutations could support this model.

Ein tieffrequenter lauter Suppressorton verlagert das Corti-Organ periodisch in Richtung Scala vestibuli und Scala tympani. Simultan registrierte DPOAE (Distorsionsprodukte otoakustischer Emissionen) werden in beiden Richtungen unterschiedlich supprimiert. Bei Vorliegen eines endolymphatischen Hydrops (EH) ist die Beweglichkeit der Basilarmembran eingeschränkt, so daß keine oder eine nur geringe Modulation des DPOAE-Pegels entstehen kann. In dieser Arbeit wird die diagnostische Aussagekraft von Messungen tieftonmodulierter DPOAE bei zwei Patientenkollektiven mit Verdacht auf EH im Vergleich mit einem Normalkollektiv (n = 22) geprüft: bei Patienten mit M. Menière (n = 23) und Patienten mit Ohrdruckgefühl ohne Schwindelsymptomatik (n = 8). Bei den M. Menière-Patienten sind die ipsilateralen Modulationstiefen (MD) im Median hochsignifikant geringer als die des Normalkollektivs. Dies wird als Hinweis auf einen EH gewertet. Bei Primärtonpegeln mit L2 = 20 dB SL ergibt sich für den Grenzwert der MD mit 6 dB die Sensitivität von 64% und die Spezifität von 90%. Die kontralateralen MD der M. Menière-Patienten sind im Median signifikant geringer als die des Normalkollektivs. Für Primärtonpegel mit L2 = 20 dB SL liegen 33% der Werte unter dem Grenzwert, von diesen Ohren ist die Hälfte symptomfrei. Auch im kontralateralen Ohr kann ein – eventuell asymptomatischer – Hydrops vorliegen. Die Ergebnisse der Patienten mit Ohrdruckgefühl ohne Schwindel zeigen im Median hochsignifikant geringere MD als die der Normalhörenden und unterscheiden sich nicht signifikant von den Werten der ipsilateralen Ohren der M. Menière-Patienten. Das Ohrdruckgefühl kann auf einen cochleären Hydrops hinweisen und die weitere Entwicklung eines EH ankündigen. Bei den Verlaufsuntersuchungen zeigen die MD beider Patientenkollektive, deren Symptomatik sich während dieses Zeitraums änderte, Variabilitäten: mit Zunahme der Heftigkeit der spezifischen Symptome nimmt die MD ab und umgekehrt. Die Tieftonmodulation scheint den Zustand der Cochlea widerspiegeln zu können. Im Vergleich mit den in der Klinik gängigen Verfahren zur Hydropsdiagnostik wie der ECochG oder dem Glyceroltest erweist sich das in dieser Arbeit angewandte objektive Verfahren als vorteilhaft: es ist schnell durchführbar, nicht belastend und nicht invasiv. Es eignet sich als Screeningverfahren und kann zur Verlaufskontrolle eingesetzt werden. / The cochlear partition is moved periodically towards scala vestibuli and scala tympani by a low-frequency high-level suppressor tone. Simultaneously recorded DPOAEs (distortion product otoacoustic emissions) are suppressed differently in both directions. This modulation of the DPOAE level may be reduced or even missing if the displacement of the basilar membrane is inhibited by endolymphatic hydrops (EH). In this thesis the diagnostic significance of the low-frequency modulation of DPOAEs is tested in two patient groups with suspected EH: patients with Menière’s disease (n = 23) and patients with aural fullness without vertigo (n = 8), compared to a control group of normal hearing adults (n = 22). In the patients with Menière’s disease the ipsilateral modulation depths (median) are high significantly lower than in the control group. This can be interpreted as a sign of EH. At primary tone levels with L2 = 20 dB SL and a limiting value of 6 dB modulation depth (MD), a sensitivity of 64% and a specificity of 90% are found. The contralateral MDs of the patients with Menière’s disease (median) are significantly lower than in the control group. At primary tone levels with L2 = 20 dB SL, 33% of the MDs are below the limiting value, half of these ears are symptom-free. So in the contralateral ear a possibly asymptomatic hydrops may be present as well. The patients with aural fullness without vertigo show high significantly lower MDs (median) than the normal hearing adults and no significant difference to the ipsilateral MDs of the patients with Menière’s disease. Aural fullness can be a sign of cochlear hydrops and may indicate the further development of EH. During the course of disease the MDs of both patient groups vary when symptoms change: with increasing intensity of the specific symptoms the MD is reduced and vice versa. Low-frequency modulation seems to reflect the state of the cochlea. Compared to the generally used clinical tests for the assessment of EH like ECochG or the glycerol test, the objective method presented in this thesis is advantageous: it is fast, not straining and non-invasive. It is suitable for screening and can be used to monitor the course of disease.