<p>Fibroblasts continuously strive to organize and compact the surrounding extracellular matrix (ECM). Recent data suggest that this cellular contractility controls interstitial fluid homeostasis in loose connective tissues (CT). The aim of this thesis was to study the effects of prostaglandins on fibroblast contractility and to investigate whether fibroblasts in the interstitial CT surrounding the human endolymphatic duct (ED) can modulate inner ear fluid pressure and endolymph resorption. </p><p>Paper I shows that prostaglandin E1 (PGE₁) and prostacyclin inhibit fibroblast-mediated collagen matrix compaction <i>in vitro</i> and lower the interstitial fluid pressure <i>in vivo</i> in rat dermis. Paper II demonstrates that the inhibition of collagen matrix compaction by PGE₁ is protein kinase A-dependent. Furthermore, PGE₁ induces a complete but reversible actin depolymerization in human dermal fibroblasts by affecting the phosphorylation state of regulatory actin-binding proteins. Paper III describes that the cells of the interstitial CT encompassing the human ED are organized in a network based on intercellular- and cell-ECM contacts. Paper IV shows that two distinct cell phenotypes populate this interstitial CT: one expressing the lymph endothelial marker podoplanin and the other a fibroblast marker. Furthermore, CT cells isolated from human ED tissues exhibited the same tissue compacting properties <i>in vitro</i> as dermal fibroblasts. </p><p>In conclusion, PGE₁ inhibits fibroblast contractility by interfering with the stability and dynamics of the actin cytoskeleton, which leads to a loss of integrin-mediated adhesion to the ECM. These mechanisms are supposedly involved in edema formation in skin during inflammation and might be involved in the formation of endolymphatic hydrops in the inner ear of patients with Ménière’s disease.</p>

Fibroblasts continuously strive to organize and compact the surrounding extracellular matrix (ECM). Recent data suggest that this cellular contractility controls interstitial fluid homeostasis in loose connective tissues (CT). The aim of this thesis was to study the effects of prostaglandins on fibroblast contractility and to investigate whether fibroblasts in the interstitial CT surrounding the human endolymphatic duct (ED) can modulate inner ear fluid pressure and endolymph resorption. Paper I shows that prostaglandin E1 (PGE1) and prostacyclin inhibit fibroblast-mediated collagen matrix compaction in vitro and lower the interstitial fluid pressure in vivo in rat dermis. Paper II demonstrates that the inhibition of collagen matrix compaction by PGE1 is protein kinase A-dependent. Furthermore, PGE1 induces a complete but reversible actin depolymerization in human dermal fibroblasts by affecting the phosphorylation state of regulatory actin-binding proteins. Paper III describes that the cells of the interstitial CT encompassing the human ED are organized in a network based on intercellular- and cell-ECM contacts. Paper IV shows that two distinct cell phenotypes populate this interstitial CT: one expressing the lymph endothelial marker podoplanin and the other a fibroblast marker. Furthermore, CT cells isolated from human ED tissues exhibited the same tissue compacting properties in vitro as dermal fibroblasts. In conclusion, PGE1 inhibits fibroblast contractility by interfering with the stability and dynamics of the actin cytoskeleton, which leads to a loss of integrin-mediated adhesion to the ECM. These mechanisms are supposedly involved in edema formation in skin during inflammation and might be involved in the formation of endolymphatic hydrops in the inner ear of patients with Ménière’s disease.

Cervical vestibular evoked myogenic potential (cVEMP) testing is widely used in the assessment of vestibular disorders in clinical practice (Welgampola & Colebatch, 2003). Ocular vestibular evoked myogenic potentials (oVEMPs) are similar to the cervical VEMPs in that the vestibular system is also stimulated by a loud sound. The difference is that the response is measured on the inferior oblique muscle of the eye as opposed to the sternocleidomastoid muscle (SCM) of the neck (Chihara, Iwasaki, Ushio, & Murofushi, 2007). The current study compares the standard cervical VEMP to the ocular VEMP in both control subjects and participants with “clinically certain” Ménière’s disease. By investigating cervical VEMPs in comparison to ocular VEMPs we aimed to improve the ability to stage and diagnose Ménière’s disease using the ocular VEMP. 22 control participants and 19 participants with confirmed unilateral Ménière’s disease took part in the study. The peak latency and amplitudes of the ocular and cervical VEMP tests were recorded and analysed. In addition, the background electromyographic (EMG) activity of both the inferior oblique and sternocleidomastoid muscles was recorded throughout testing. A questionnaire was also distributed to all participants to compare the relative difficulty of the VEMP tests. Statistical analysis using the paired t-test, standard t-test and the one-way ANOVA on ranks test was applied to determine a difference between the control and patient groups for both the ocular and cervical VEMP tests. Overall, the threshold and IAD ratio measures did not produce any significant results when sound was presented to the affected ear for the cervical and ocular VEMP tests. A significant reduction in amplitude of the VEMPs from the Ménière’s groups was found compared to the control groups for the ocular the cervical VEMPs. Overall, an increase in P2 and N3 latency of the ocular VEMP response in Ménière’s patients was determined. Results from the questionnaire suggest that the ocular VEMP test was more tolerable to the cervical VEMP test in this current study. Furthermore, statistical analyses revealed no significant differences in EMG level between the control and Ménière’s group for both the ocular and cervical VEMP data. Overall, results suggest that both the cervical and ocular VEMP tests provide information regarding the integrity of the saccule, owing to the abnormal VEMP findings in the participants with Ménière’s disease. In addition, this study provides evidence that the ocular VEMP is as useful a tool in diagnosing Ménière’s disease as the cervical VEMP.

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.

Cervical vestibular evoked myogenic potential (cVEMP) testing is widely used in the assessment of vestibular disorders in clinical practice (Welgampola & Colebatch, 2003). Ocular vestibular evoked myogenic potentials (oVEMPs) are similar to the cervical VEMPs in that the vestibular system is also stimulated by a loud sound. The difference is that the response is measured on the inferior oblique muscle of the eye as opposed to the sternocleidomastoid muscle (SCM) of the neck (Chihara, Iwasaki, Ushio, & Murofushi, 2007). The current study compares the standard cervical VEMP to the ocular VEMP in both control subjects and participants with “clinically certain” Ménière’s disease. By investigating cervical VEMPs in comparison to ocular VEMPs we aimed to improve the ability to stage and diagnose Ménière’s disease using the ocular VEMP. 22 control participants and 19 participants with confirmed unilateral Ménière’s disease took part in the study. The peak latency and amplitudes of the ocular and cervical VEMP tests were recorded and analysed. In addition, the background electromyographic (EMG) activity of both the inferior oblique and sternocleidomastoid muscles was recorded throughout testing. A questionnaire was also distributed to all participants to compare the relative difficulty of the VEMP tests. Statistical analysis using the paired t-test, standard t-test and the one-way ANOVA on ranks test was applied to determine a difference between the control and patient groups for both the ocular and cervical VEMP tests. Overall, the threshold and IAD ratio measures did not produce any significant results when sound was presented to the affected ear for the cervical and ocular VEMP tests. A significant reduction in amplitude of the VEMPs from the Ménière’s groups was found compared to the control groups for the ocular the cervical VEMPs. Overall, an increase in P2 and N3 latency of the ocular VEMP response in Ménière’s patients was determined. Results from the questionnaire suggest that the ocular VEMP test was more tolerable to the cervical VEMP test in this current study. Furthermore, statistical analyses revealed no significant differences in EMG level between the control and Ménière’s group for both the ocular and cervical VEMP data. Overall, results suggest that both the cervical and ocular VEMP tests provide information regarding the integrity of the saccule, owing to the abnormal VEMP findings in the participants with Ménière’s disease. In addition, this study provides evidence that the ocular VEMP is as useful a tool in diagnosing Ménière’s disease as the cervical VEMP.

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

Fragestellung: Mögliche Interaktionen zwischen Mittelohrdruck und Gleichgewichtsstörungen werden seit vielen Jahren diskutiert. Der Rolle der druckausgelösten Trommelfellbewegungen, die bei degenerativ fixierten Ossikelgelenken aufgrund des Hydraulikfaktors eine viel grössere Kraft ausüben als der direkte Druck an den Innenohrfenstern, wurde dabei nur geringe Aufmerksamkeit gewidmet. Patienten und Methodik: Wir untersuchten bei 19 Patienten mit einseitigem Morbus Ménière die durch wechselnde Drucke im äusseren Gehörgang (analog zur Tympanometrie) ausgelösten Interaktionen zwischen Trommelfellauslenkungen und vestibulären Reaktionen in der Elektronystagmographie und in der Posturographie. Ergebnisse und Schlussfolgerungen: Bei schnellen und langsamen Druckwechseln konnten zwischen –600 und +400 daPa weder auf dem gesunden noch auf dem erkrankten Ohr im Elektronystagmogramm Nystagmen nachgewiesen werden. Die posturographische Aufzeichnung der vestibulospinalen Reaktionen auf einer Luzerner Messplatte erwies sich dagegen als sensibler. Die Längenzunahme der Schwankungslinie zeigte bei beiden durchgeführten Druckwechseln auf dem kranken Ohr signifikante Unterschiede gegenüber der Messung bei Reizung des gesunden Ohres. Diese Methode ist somit der klassischen Prüfung des Hennebertschen Fistelsymptoms überlegen. Das vestibulospinale System reagiert möglicherweise empfindlicher als das vestibulookuläre auf Druckschwankungen der Perilymphe. Darüber hinaus könnte der nachgewiesene Zusammenhang der druckausgelösten Trommelfellbewegungen mit cochleovestibulären Symptomen bei einigen Patienten mit M. Ménière den Erfolg einer Paukenröhrcheneinlage erklären, da hiermit aussendruckinduzierte Trommelfellbewegungen und damit verbundene Perilymphschwankungen von vornherein unterbunden werden. / Objectives: Interactions between middle ear pressure and vestibular disturbances have been discussed for many years. Less attention has been paid to the influence of ear drum movements caused by pressure changes in the external auditory meatus. Because of the hydraulic amplification in case of fixed ossicular joints the impact of these movements is bigger than the direct pressure on the internal ear windows. Material and Patients: We examined the interaction between ear drum movements and vestibular reactions caused in the external auditory meatus of 19 patients suffering from unilateral Ménière’s disease. Results and Conclusions: Both fast as well as slow pressure changes between –600 and +400 daPa were not able to induce nystagmus in the electronystagmogram of either the healthy or the damaged ear. Posturographic recordings of the vestibulospinal responses on the ‘Luzerner measuring platform’ were significantly more sensitive. The increase in length of the postural staggering line showed significant differences between the healthy and the damaged ear for fast and for slow pressure changes compared to calibration. In conclusion, the sensitivity of this examination is superior to the classical examination of Hennebert’s fistula symptom. The vestibulospinal system is more sensitive towards pressure changes of the perilymph than the vestibuloocular system. The proven correlation between ear drum movements and internal ear symptomatology could explain the success of the treatment of patients suffering from Ménière’s disease with tympanic grommets. Thus grommets prevent the pressure-induced ear drum movements and avoid perilymph movements induced by pressure changes. / Chez les patients souffrant de la maladie de Ménière, les variations de pression entraıˆnent des mouvements du tympan, influant ainsi sur les réactions vestibulaires. Objectifs: Si l’on s’est longtemps intéressé aux possibles interactions entre la pression de l’oreille moyenne et les troubles de l’équilibre, on a en revanche prêté moins d’attention à l’influence que peuvent exercer les mouvements du tympan dus aux variations de pression dans le conduit auditif externe. Or, lorsque les articulations ossiculaires sont bloquées, l’amplification hydraulique fait que ces mouvements ont un impact plus important que la pression directe exercée aux fenêtres de l’oreille interne. Méthodes et patients: Chez 19 malades souffrant d’un syndrome de Ménière unilatéral, nous avons étudié par ENG et posturographie la relation entre les réactions vestibulaires et les mouvements du tympan que déclenchent les variations de pression dans le conduit auditif externe. Résultats et conclusions: Qu’il s’agisse de variations de pression lentes ou rapides (entre –600 et +400 daPa), de l’oreille saine ou déficiente, l’ENG n’a révélé aucun nystagmus. En revanche, les enregistrements posturographiques des réactions vestibulo-spinales sur la plate-forme de mesure de Lucerne ont été plus sensibles. L’allongement de la courbe de variation a montré des différences significatives entre l’oreille saine et déficiente, que ce soit lors de variations de pression rapides ou lentes. En conclusion, la précision de ce type d’examen se révèle nettement supérieure à celle de l’examen classique du signe de la fistule d’Hennebert (signe d’Hennebert). Le système vestibulo-spinal réagit apparemment de manière plus sensible que le système vestibulo-oculaire aux variations de pression du périlymphe. De plus, la relation que l’on a établie entre les mouvements du tympan dus aux variations de pression et les symptômes vestibulo-cochléaires pourrait expliquer les succès de la pose de diabolos chez certains patients souffrant de la maladie de Ménière. Ces diabolos empêchent les mouvements du tympan liés au changement de pression, évitant ainsi les mouvements du périlymphe. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Fragestellung: Mögliche Interaktionen zwischen Mittelohrdruck und Gleichgewichtsstörungen werden seit vielen Jahren diskutiert. Der Rolle der druckausgelösten Trommelfellbewegungen, die bei degenerativ fixierten Ossikelgelenken aufgrund des Hydraulikfaktors eine viel grössere Kraft ausüben als der direkte Druck an den Innenohrfenstern, wurde dabei nur geringe Aufmerksamkeit gewidmet. Patienten und Methodik: Wir untersuchten bei 19 Patienten mit einseitigem Morbus Ménière die durch wechselnde Drucke im äusseren Gehörgang (analog zur Tympanometrie) ausgelösten Interaktionen zwischen Trommelfellauslenkungen und vestibulären Reaktionen in der Elektronystagmographie und in der Posturographie. Ergebnisse und Schlussfolgerungen: Bei schnellen und langsamen Druckwechseln konnten zwischen –600 und +400 daPa weder auf dem gesunden noch auf dem erkrankten Ohr im Elektronystagmogramm Nystagmen nachgewiesen werden. Die posturographische Aufzeichnung der vestibulospinalen Reaktionen auf einer Luzerner Messplatte erwies sich dagegen als sensibler. Die Längenzunahme der Schwankungslinie zeigte bei beiden durchgeführten Druckwechseln auf dem kranken Ohr signifikante Unterschiede gegenüber der Messung bei Reizung des gesunden Ohres. Diese Methode ist somit der klassischen Prüfung des Hennebertschen Fistelsymptoms überlegen. Das vestibulospinale System reagiert möglicherweise empfindlicher als das vestibulookuläre auf Druckschwankungen der Perilymphe. Darüber hinaus könnte der nachgewiesene Zusammenhang der druckausgelösten Trommelfellbewegungen mit cochleovestibulären Symptomen bei einigen Patienten mit M. Ménière den Erfolg einer Paukenröhrcheneinlage erklären, da hiermit aussendruckinduzierte Trommelfellbewegungen und damit verbundene Perilymphschwankungen von vornherein unterbunden werden. / Objectives: Interactions between middle ear pressure and vestibular disturbances have been discussed for many years. Less attention has been paid to the influence of ear drum movements caused by pressure changes in the external auditory meatus. Because of the hydraulic amplification in case of fixed ossicular joints the impact of these movements is bigger than the direct pressure on the internal ear windows. Material and Patients: We examined the interaction between ear drum movements and vestibular reactions caused in the external auditory meatus of 19 patients suffering from unilateral Ménière’s disease. Results and Conclusions: Both fast as well as slow pressure changes between –600 and +400 daPa were not able to induce nystagmus in the electronystagmogram of either the healthy or the damaged ear. Posturographic recordings of the vestibulospinal responses on the ‘Luzerner measuring platform’ were significantly more sensitive. The increase in length of the postural staggering line showed significant differences between the healthy and the damaged ear for fast and for slow pressure changes compared to calibration. In conclusion, the sensitivity of this examination is superior to the classical examination of Hennebert’s fistula symptom. The vestibulospinal system is more sensitive towards pressure changes of the perilymph than the vestibuloocular system. The proven correlation between ear drum movements and internal ear symptomatology could explain the success of the treatment of patients suffering from Ménière’s disease with tympanic grommets. Thus grommets prevent the pressure-induced ear drum movements and avoid perilymph movements induced by pressure changes. / Chez les patients souffrant de la maladie de Ménière, les variations de pression entraıˆnent des mouvements du tympan, influant ainsi sur les réactions vestibulaires. Objectifs: Si l’on s’est longtemps intéressé aux possibles interactions entre la pression de l’oreille moyenne et les troubles de l’équilibre, on a en revanche prêté moins d’attention à l’influence que peuvent exercer les mouvements du tympan dus aux variations de pression dans le conduit auditif externe. Or, lorsque les articulations ossiculaires sont bloquées, l’amplification hydraulique fait que ces mouvements ont un impact plus important que la pression directe exercée aux fenêtres de l’oreille interne. Méthodes et patients: Chez 19 malades souffrant d’un syndrome de Ménière unilatéral, nous avons étudié par ENG et posturographie la relation entre les réactions vestibulaires et les mouvements du tympan que déclenchent les variations de pression dans le conduit auditif externe. Résultats et conclusions: Qu’il s’agisse de variations de pression lentes ou rapides (entre –600 et +400 daPa), de l’oreille saine ou déficiente, l’ENG n’a révélé aucun nystagmus. En revanche, les enregistrements posturographiques des réactions vestibulo-spinales sur la plate-forme de mesure de Lucerne ont été plus sensibles. L’allongement de la courbe de variation a montré des différences significatives entre l’oreille saine et déficiente, que ce soit lors de variations de pression rapides ou lentes. En conclusion, la précision de ce type d’examen se révèle nettement supérieure à celle de l’examen classique du signe de la fistule d’Hennebert (signe d’Hennebert). Le système vestibulo-spinal réagit apparemment de manière plus sensible que le système vestibulo-oculaire aux variations de pression du périlymphe. De plus, la relation que l’on a établie entre les mouvements du tympan dus aux variations de pression et les symptômes vestibulo-cochléaires pourrait expliquer les succès de la pose de diabolos chez certains patients souffrant de la maladie de Ménière. Ces diabolos empêchent les mouvements du tympan liés au changement de pression, évitant ainsi les mouvements du périlymphe. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.