Hubert Löwenheim

Randomized, double blind, placebo controlled trial on the safety and efficacy of continuous intratympanic dexamethasone delivered via a round window catheter for severe to profound sudden idiopathic sensorineural hearing loss after failure of systemic therapy.

To study the safety and efficacy of continuous intratympanic dexamethasone‐phosphate (Dex‐P) for severe to profound sudden idiopathic sensorineural hearing (ISSHL) or sudden idiopathic anacusis after failure of systemic therapy.

Outcomes research analysis of continuous intratympanic glucocorticoid delivery in patients with acute severe to profound hearing loss: Basis for planning randomized controlled trials

Conclusions. The data presented herein form the basis for conducting randomized placebo-controlled clinical trials evaluating the safety and efficacy of salvage treatment in patients with idiopathic sudden severe sensorineural hearing loss (but not anacusis) refractory to initial systemic therapy. Comparison of different application protocols and drug delivery systems will allow assessment of the value of continuous versus intermittent intratympanic glucocorticoid drug delivery. Objectives. To describe and critically evaluate the results of continuous intratympanic glucocorticoid delivery in patients with acute unilateral severe and profound sensorineural hearing loss refractory to initial systemic therapy and to compare the outcome with a historical control group. Material and methods. In a retrospective chart review, treatment results were analyzed in 23 patients with acute severe and profound hearing loss and failure of systemic standard therapy who received a continuous intratympanic delivery of glucocorticoids as a salvage treatment. Audiological results were compared within the local therapy group and with the results of an historical control group who did not receive salvage treatment. The study and control groups were matched with respect to hearing loss after initial systemic treatment failure. Results. The average pure-tone threshold after intratympanic salvage treatment showed a statistically significant improvement of 15 dB (95% CI 7–24 dB; p<0.001). After exclusion of patients with complete anacusis, i.e. a non-measurable hearing threshold, the local therapy group showed a significantly better improvement (mean 19 dB; 95% CI 6–32 dB) than the historical control group (mean 5 dB; 95% CI  − 2–11 dB; p<0.05).

PARP1 Gene Knock-Out Increases Resistance to Retinal Degeneration without Affecting Retinal Function

Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases affecting photoreceptors and causing blindness in humans. Previously, excessive activation of enzymes belonging to the poly-ADP-ribose polymerase (PARP) group was shown to be involved in photoreceptor degeneration in the human homologous rd1 mouse model for RP. Since there are at least 16 different PARP isoforms, we investigated the exact relevance of the predominant isoform - PARP1 - for photoreceptor cell death using PARP1 knock-out (KO) mice. In vivo and ex vivo morphological analysis using optic coherence tomography (OCT) and conventional histology revealed no major alterations of retinal phenotype when compared to wild-type (wt). Likewise, retinal function as assessed by electroretinography (ERG) was normal in PARP1 KO animals. We then used retinal explant cultures derived from wt, rd1, and PARP1 KO animals to test their susceptibility to chemically induced photoreceptor degeneration. Since photoreceptor degeneration in the rd1 retina is triggered by a loss-of-function in phosphodiesterase-6 (PDE6), we used selective PDE6 inhibition to emulate the rd1 situation on non-rd1 genotypes. While wt retina subjected to PDE6 inhibition showed massive photoreceptor degeneration comparable to rd1 retina, in the PARP1 KO situation, cell death was robustly reduced. Together, these findings demonstrate that PARP1 activity is in principle dispensable for normal retinal function, but is of major importance for photoreceptor degeneration under pathological conditions. Moreover, our results suggest that PARP dependent cell death or PARthanatos may play a major role in retinal degeneration and highlight the possibility to use specific PARP inhibitors for the treatment of RP.

Technical note on microcatheter implantation for local inner ear drug delivery: surgical technique and safety aspects.

Hypothesis: Despite its invasiveness, the temporary implantation of a microcatheter into the middle ear cavity is an appropriately safe method for providing continuous drug delivery to the inner ear. Background: For the application of drugs to the inner ear, different delivery strategies are available ranging from intratympanic injections to temporarily implanted microcatheters. It has recently been demonstrated that the choice of the drug delivery system influences the pharmacokinetics in the inner ear. If a continuous drug application over several weeks is required, a secure placement of the delivery device (i.e., the microcatheter) is necessary to guarantee efficient drug delivery and to avoid unwanted side effects. Study Design: Retrospective chart review. Materials and Methods: During 2000 to 2005, 25 patients with acute unilateral severe-to-profound hearing loss or anacusis and failure of systemic high-dose glucocorticoid and rheological therapy were offered an intratympanic delivery of glucocorticoids via a temporarily implanted catheter and an external pump for up to 4 weeks as a salvage treatment option. The standardized surgical implantation and fixation technique developed for the microcatheter were characterized by six elements: 1) a medial and a lateral tunnel connected by a groove in the posterior wall of the bony ear canal, 2) stabilization of the catheter with bone wax and soft tissue plugs in the tunnels, 3) an ear canal packing, 4) a series of fixating sutures along the catheter, 5) an adhesive dressing, and 6) additional tapes at the connecting line between pump and catheter. At the end of the implantation period, the catheter was removed by a second surgical procedure allowing for evaluation of the catheter position and the condition of the middle ear space. Results: Adverse events included catheter dislocation, catheter obstruction, formation of mild granulation tissue in the middle ear cavity, tympanic membrane defects, and ear canal skin defects. With introduction of an improved implantation and fixation technique, the number of catheter dislocations could be significantly reduced. No complications were observed on long-term follow-up. Conclusion: If the pharmacokinetics or pharmacodynamics of a specific local inner ear therapy approach requires a continuous intratympanic drug application (e.g., to restore hearing in patients with severe or profound hearing loss), the temporary implantation of a microcatheter by a standardized surgical technique is a feasible and appropriately safe method for providing continuous drug delivery to the inner ear.

Differentiating imaging findings in primary and secondary tumors of the jugular foramen

The preoperative diagnosis of a jugular foramen tumor may be challenging, since a large variety of unusual lesions may be located in this region. These tumors may be classified as primary lesions (which are located in the jugular foramen or extend from the jugular foramen into the surrounding structures) and as secondary lesions (that extend from the surrounding structures into the jugular foramen). Primary tumors include glomus jugulare tumors, schwannomas, meningiomas and peripheral primitive neuroectodermal tumors, while secondary tumors comprise chordomas, chondrosarcomas, chondroblastomas, giant-cell tumors, cholesterol granulomas, giant cholesterol cyst, endolymphatic sac tumors, reactive myofibroblastic tumors, temporal bone carcinomas and metastases. Accurate preoperative radiological suspicion is of great value for preoperative patient counseling and has a direct impact on the surgical planning in these cases. The present study describes and discusses the main differentiating imaging features of lesions involving the jugular foramen, whose accurate preoperative radiological evaluation is essential for proper surgical planning.

Transtympanic Endoscopy for Drug Delivery to the Inner Ear Using a New Microendoscope

Anatomic variations of the round window (RW) niche found in approximately 33% of human temporal bones may account for some ofthe problems associated with local drug delivery to the inner car. A microendoscope with a total outer diameter of 1.2 mm was developed in particular for easy visualization and of drug delivery to the RW niche. It incorporated a thin fiber optic, a working/laser channel (0.3 mm) and an irrigation/suction channel (0.27 mm). When compared to a common 30 degree lens optic, with the microendoscope a greater area of the round window niche could be overseen. In addition, the endoscope could be advanced directly upon the surface of the RW membrane (RWM). The microendoscope may be used for evaluation of the anatomy of the RW niche prior to the placement of local drug delivery systems, for application of drugs directly onto the surface of the RWM or to verify the correct placement of inner ear drug delivery systems.

Water channel proteins in the inner ear and their link to hearing impairment and deafness.

The inner ear is a fluid-filled sensory organ that transforms mechanical stimuli into the senses of hearing and balance. These neurosensory functions depend on the strict regulation of the volume of the two major extracellular fluid domains of the inner ear, the perilymph and the endolymph. Water channel proteins, or aquaporins (AQPs), are molecular candidates for the precise regulation of perilymph and endolymph volume. Eight AQP subtypes have been identified in the membranous labyrinth of the inner ear. Similar AQP subtypes are also expressed in the kidney, where they function in whole-body water regulation. In the inner ear, AQP subtypes are ubiquitously expressed in distinct cell types, suggesting that AQPs have an important physiological role in the volume regulation of perilymph and endolymph. Furthermore, disturbed AQP function may have pathophysiological relevance and may turn AQPs into therapeutic targets for the treatment of inner ear diseases. In this review, we present the currently available knowledge regarding the expression and function of AQPs in the inner ear. We give special consideration to AQP subtypes AQP2, AQP4 and AQP5, which have been studied most extensively. The potential functions of AQP2 and AQP5 in the resorption and secretion of endolymph and of AQP4 in the equilibration of cell volume are described. The pathophysiological implications of these AQP subtypes for inner ear diseases, that appear to involve impaired fluid regulation, such as Menières disease and Sjögrens syndrome, are discussed.

Determination of hair cell degeneration and hair cell death in neomycin treated cultures of the neonatal rat cochlea.

The spatial-temporal course of hair cell degeneration and hair cell death was examined in the mammalian cochlea following aminoglycoside treatment. Organotypic cultures were established from postnatal rats (P3) and treated with 1 mM neomycin sulfate for 12-48 h and analyzed using a live/dead assay under epifluorescence microscopy. Live hair cells were labeled with calcein, a probe whose fluorescence and cellular retention depends upon intracellular esterase activity and cell-membrane integrity, respectively. Hair cell death was determined by ethidium homodimer-1, a probe that can enter cells with compromised cell membranes only. Inside the cell it binds to DNA. Hair cell morphology was also examined using phalloidin labeling, scanning electron microscopy and semi-thin section analysis. Results showed that hair cell degeneration and hair cell death occurred in a time dependent gradient from base to apex. After 48 h of neomycin treatment, most apical hair cells survived while most basal hair cells died. Calcein labeling provides a sensitive functional assay for measuring hair cell survival.

The subcellular distribution of aquaporin 5 in the cochlea reveals a water shunt at the perilymph-endolymph barrier.

Aquaporins are membrane water channel proteins that have also been identified in the cochlea. Auditory function critically depends on the homeostasis of the cochlear fluids perilymph and endolymph. In particular, the ion and water regulation of the endolymph is essential for sensory transduction. Within the cochlear duct the lateral wall epithelium has been proposed to secrete endolymph by an aquaporin-mediated flow of water across its epithelial tight junction barrier. This study identifies interspecies differences in the cellular distribution of aquaporin 5 (AQP5) in the cochlear lateral wall of mice, rats, gerbils and guinea pigs. In addition the cellular expression pattern of AQP5 is described in the human cochlea. Developmental changes in rats demonstrate longitudinal and radial gradients along the cochlear duct. During early postnatal development a pancochlear expression is detected. However a regression to the apical quadrant and limitation to outer sulcus cells (OSCs) is observed in the adult. This developmental loss of AQP5 expression in the basal cochlear segments coincides with a morphological loss of contact between OSCs and the endolymph. At the subcellular level, AQP5 exhibits polarized expression in the apical plasma membrane of the OSCs. Complementary, the basolateral membrane in the root processes of the OSCs exhibits AQP4 expression. This differential localization of AQP5 and AQP4 in the apical and basolateral membranes of the same epithelial cell type suggests a direct aquaporin-mediated transcellular water shunt between the perilymph and endolymph in the OSCs of the cochlear lateral wall. In the human cochlea these findings may have pathophysiological implications attributed to a dysfunctional water regulation by AQP5 such as endolymphatic hydrops (i.e. in Menieres disease) or sensorineural hearing loss (i.e. in Sjögrens syndrome).

Management and outcome after internal carotid artery laceration during surgery of the paranasal sinuses.

Abstract Conclusions. The injury to the cavernous portion of the internal carotid artery (ICA) during endonasal sinus surgery is a potentially fatal complication, which can be prevented by systematic analysis of preoperative CT imaging in order to exclude vascular malformations. Immediate management is critical and requires interdisciplinary cooperation between the otolaryngologist and interventional neuroradiologist. Objective. The purpose of this article is to present two cases of injury to the cavernous portion of the ICA during routine endonasal sinus surgery for chronic sinusitis and to review the management and outcome of this vascular emergency. Patients and methods. A database of all patients surgically treated for chronic sinusitis between 1994 and 2004 was reviewed retrospectively. Additionally a review of the literature for all published case reports of ICA injury was performed. Results. We report two cases of ICA lacerations that occurred during routine endoscopic sinus surgery. Both patients were successfully treated by employing neuroradiological procedures including balloon and/or coil occlusion of various portions of the cavernous ICA. According to the literature the outcome depends on the presence or absence of vascular anomalies or aneurysm of the ICA with a very poor prognosis in cases of laceration of a pre-existing and unrecognized aneurysm.