Kai Helling

Treatment of Ménière's Disease by Low-Dosage Intratympanic Gentamicin Application : Effect on Otolith Function

Objectives: The intratympanic application of a low dosage of gentamicin is increasingly favored as treatment for Ménières disease. While posttreatment observations have confirmed a long‐term success of the therapy of vertigo attacks, clear differences in the posttreatment recovery interval can be observed. In addition to differences in central‐vestibular compensation, the degree of peripheral vestibular damage, i.e., to the saccule, utricle, and semicircular canal ampullae, varies among patients. This study provides comprehensive pre‐ and posttreatment results from unilateral functional tests of the individual vestibular receptors and of the cochlea in patients with Ménières disease.

Ascorbic Acid Reduces Noise‐Induced Nitric Oxide Production in the Guinea Pig Ear

Objectives: Noise‐induced hearing loss can be caused, among other causes, by increased nitric oxide (NO) production in the inner ear leading to nitroactive stress and cell destruction. Some studies in the literature suggest that the degree of hearing loss (HL) could be reduced in an animal model through ascorbic acid supplementation. To identify the effect of ascorbic acid on tissue‐dependent NO content in the inner ear of the guinea pig, we determined the local NO production in the organ of Corti and the lateral wall separately 6 hours after noise exposure.

Evidence of unilateral isolated utricular hypofunction

Abstract Conclusions: The findings demonstrate that an enduring unilateral utricular dysfunction, possibly together with canal hypofunction, can occur after labyrinthine disease or injury. They also suggest that unilateral, isolated utricular dysfunction – or utricle paresis – can occur, representing a novel entity in the differential diagnosis of peripheral vestibular function. The occurrence of subjective visual vertical (SVV) asymmetry in the presence of symmetric vestibular evoked myogenic potentials (VEMPs) also confirms that the information from the utricles, rather than the saccules, dominates SVV estimation. Objectives: To determine the incidence of unilateral utricular hypofunction. Methods: The retrospective clinical study deals with a selection of those vestibular patients who showed pathological responses to utricle testing. Peripheral vestibular function was examined in a group of 110 patients. Utricular function was evaluated by estimation of SVV during unilateral centrifugation. Bithermal caloric testing was performed to assess unilateral semicircular canal function. Saccular function was tested by measurement of VEMPs. Results: A total of 46 patients were found with asymmetric SVV findings (p < 0.001 for healthy versus lesioned ear), but symmetric caloric responses and VEMPs. Statistical testing also verified that their SVV asymmetry factors were significantly higher than those calculated for caloric responses and VEMPs (p < 0.001).

An otoprotective role for the apoptosis inhibitor protein survivin.

Hearing impairment caused by ototoxic insults, such as noise or gentamicin is a worldwide health problem. As the molecular circuitries involved are not yet resolved, current otoprotective therapies are rather empirical than rational. Here, immunohistochemistry and western blotting showed that the cytoprotective protein survivin is expressed in the human and guinea pig cochlea. In the guinea pig model, moderate noise exposure causing only a temporary hearing impairment transiently evoked survivin expression in the spiral ligament, nerve fibers and the organ of Corti. Mechanistically, survivin upregulation may involve nitric oxide (NO)-induced Akt signaling, as enhanced expression of the endothelial NO synthase and phosphorylated Akt were detectable in some surviving-positive cell types. In contrast, intratympanic gentamicin injection inducing cell damage and permanent hearing loss correlated with attenuated survivin levels in the cochlea. Subsequently, the protective activity of the human and the guinea pig survivin orthologs against the ototoxin gentamicin was demonstrated by ectopic overexpression and RNAi-mediated depletion studies in auditory cells in vitro. These data suggest that survivin represents an innate cytoprotective resistor against stress conditions in the auditory system. The pharmacogenetic modulation of survivin may thus provide the conceptual basis for the rational design of novel therapeutic otoprotective strategies.

Testing utricular function by means of on-axis rotation

Conclusions. Subjective visual vertical (SVV) estimation during on-axis rotation provides an efficient screening test of utricle function. The survey demonstrates that isolated disorders of peripheral utricular function can occur while SCC function appears normal. Objective. The present study aimed to investigate estimation of SVV during constant velocity yaw rotation (with the head held on-axis – to enhance any asymmetry between right and left utricular responses), as a useful screening test. Materials and methods. In all, 230 patients were recruited from the dizziness clinic. For each patient, the SVV was estimated (a) while held stationary, and (b) during constant angular velocity (240°/s), with the head centred on-axis. Bithermal caloric testing was also performed in 201 of the patients. Results. Of those patients with normal SVV results during stationary testing, 18.3% were pathological during rotation testing. In those cases with pathological SVV during stationary testing, a significantly greater deviation from the norm was observed during rotation (p<0.001). Of those patients with normal caloric responses, 44.4% showed pathological SVV estimates; this increased to 54.3% for cases with unilateral weakness, and 56.5% for unilateral loss. No clear correlation was found between reports of tilt illusion and pathological SVV, respectively, between rotatory vertigo and pathological caloric responses.

Gentamicin Increases Nitric Oxide Production and Induces Hearing Loss in Guinea Pigs

Objectives/Hypothesis: Gentamicin application is an important therapeutic option for Ménières disease. However, even if given at intervals, a destruction of the cochlea was often observed in various animal models together with an increased content of nitric oxide (NO) and reactive oxygen species. The present study was undertaken to identify the correlation between hearing threshold alteration and the NO production in the lateral wall and organ of Corti of the guinea pig in response to gentamicin application.

Nitric oxide--a versatile key player in cochlear function and hearing disorders.

Nitric oxide (NO) is a signaling molecule which can generally be formed by three nitric oxide synthases (NOS). Two of them, the endothelial nitric oxide synthase (eNOS) and the neural nitric oxide synthase (nNOS), are calcium/calmodulin-dependent and constitutively expressed in many cell types. Both isoforms are found in the vertebrate cochlea. The inducible nitric oxide synthase (iNOS) is independent of calcium and normally not detectable in the un-stimulated cochlea. In the inner ear, as in other tissues, NO was identified as a multitask molecule involved in various processes such as neurotransmission and neuromodulation. In addition, increasing evidence demonstrates that the NO-dependent processes of cell protection or, alternatively, cell destruction seem to depend, among other things, on changes in the local cochlear NO-concentration. These alterations can occur at the cellular level or within a distinct cell population both leading to an NO-imbalance within the hearing organ. This dysfunction can result in hearing loss or even in deafness. In cases of cochlear malfunction, regulatory systems such as the gap junction system, the blood vessels or the synaptic region might be affected temporarily or permanently by an altered NO-level. This review discusses potential cellular mechanisms how NO might contribute to different forms of hearing disorders. Approaches of NO-reduction are evaluated and the transfer of results obtained from experimental animal models to human medication is discussed.

Malignant paraganglioma caused by a novel germline mutation of the succinate dehydrogenase D-gene--a case report.

Paragangliomas of the head and neck are rare, mostly benign tumors. Approximately 10% to 15% of paragangliomas are caused by mutations in the succinate dehydrogenase (SDH) genes B, C, or D. These are often multifocal as part of paraganglioma syndromes and hormone secreting, and malignant particularly associated with mutations in SDHB.

Expression analysis suggests a potential cytoprotective role of Birc5 in the inner ear.

Hearing impairment is a worldwide health problem. Employing semi-quantitative immunological detection methods, we found that the apoptosis inhibitor protein Birc5 is expressed in cell types critical for hearing perception. In the guinea pig model, moderate noise exposure causing only a temporary mean hearing impairment of 33dB significantly enhanced Birc5 expression in the spiral ligament, nerve fibers and the organ of Corti. In contrast, intratympanic gentamicin injection inducing permanent cell damage and mean hearing loss of 24dB correlated with a significant Birc5 downregulation in the ligament, nerve fibers and the organ of Corti. The cytoprotective activity of the guinea pig and human Birc5 protein was confirmed by cloning of the gene and by subsequent ectopic expression and challenging studies against the ototoxin gentamicin in epithelial and auditory cell models. As the mammalian cochlea is unable to regenerate upon damage, these data suggest that modulation of Birc5 expression may represent a novel physiological mechanism to protect the inner ear against stress-induced cell damage. Hence, the targeted modulation of Birc5 levels may lead to novel otoprotective therapeutic strategies.

Localization of Congenital Tegmen Tympani Defects

Objective: This study sets out to demonstrate the normal developmental steps of the tegmen tympani and thus explains the typical localization of congenital tegmental defects. Specimens: For this study, 79 macerated and formalin-fixed human temporal bones from 14th fetal week to adults were observed and prepared. Intervention: Macroscopic and microscopic examination of the prenatal and postnatal changes of the tegmen tympani during its development. Main Outcome Measure: Temporal bones from 14th fetal week to adults underwent descriptive anatomic studies to understand the normal development of the tegmen tympani and to find a possible cause of its congenital defects. Results: The medial part of the tegmen tympani develops from the otic capsule during chondral ossification, thus forming the tegmental process of the petrous part. The lateral part shows membranous ossification. The tegmental process cases a temporary bony dehiscence lateral to the geniculate ganglion between the 23rd and 25th fetal week. Conclusion: Congenital defects develop near the geniculate ganglion and seem to be due to an incomplete development of tegmental process of otic capsule. Because of that, congenital lesion of the tegmen tympani can be defined as an inner ear defect.