Dominik Brors

Long-Term Study of Endonasal Duraplasty and Review of the Literature

Many different techniques have been proposed to repair frontobasal dura mater lesions. Because of its low mocthe anterior skull base. This article presents a retrospective evaluation of 136 endonasal duraplasties (126 patients) performed between July 1980 and May 1998 at a tertiary care facility. Follow-up consisted of clinical examinations including nasal endoscopy, objective measures, and telephone interviews. The following measures were used to evaluate the results of these duraplasties: postoperative nasal fluorescein endoscopy in 71 cases, computed tomographic cisternography in 2, nasal fluorescein endoscopy with computed tomographic cisternography in 19, magnetic resonance imaging in 6, and nasal fluorescein endoscopy with magnetic resonance imaging in 1. Tight closure was accomplished in 129 dural lesions (94.9%) on the first attempt. In 3 cases, recurrence of cerebrospinal fluid leakage was treated successfully by I endonasal revision, and in I case, a tight duraplasty was achieved after 2 endonasal revisions. Its high success rate, low rate of morbidity, and good long-term results recommend endonasal duraplasty as a primary treatment modality for frontobasal dural lesions. For extended frontobasal dural lesions, for which intracranial dural repair is the preferred approach, the endonasal approach should be used to close additional dural leaks of the sphenoid sinus.

EphA4 provides repulsive signals to developing cochlear ganglion neurites mediated through ephrin-B2 and -B3.

The ephrins and Eph receptors make up two large families of bi‐directional signaling molecules that are known to play a role in the development of the nervous system. Recently, expression of EphA4 in the developing cochlea was shown, with strong expression in cells lining the osseous spiral lamina (OSL) through which afferent dendrites must pass to reach the organ of Corti (OC). It was also demonstrated that ephrin‐B2 and ‐B3, both of which are known to interact with EphA4, are expressed by spiral ganglion (SG) neurons. To investigate the functional role of EphA4 in the development of inner ear neurons, neonatal rat SG explants were cultured for 72 hours on uniformly coated surfaces or near stripes of EphA4/IgG‐Fc‐chimera. Control explants were cultured on or near IgG‐Fc and EphA1/IgG‐Fc‐chimera. To assess the roles of ephrin‐B2 and ‐B3 in EphA4 signaling, SG explants were cultured with or without anti‐ephrin‐B2 and/or ‐B3 blocking antibodies. Growth patterns of SG neurites at the border of EphA4 receptor stripes showed repulsion, characterized by turning, stopping and/or reversal. In the case of IgG‐Fc and EphA1, the neurites grew straight onto the stripes. Treatment with either anti‐ephrin‐B2 or ‐B3 blocking antibodies significantly reduced the repulsive effect of an EphA4 stripe. Moreover, when both antibodies were used together, neurites crossed onto EphA4 stripes with no evidence of repulsion. The results suggest that EphA4 provides repulsive signals to SG neurites in the developing cochlea, and that ephrin‐B2 and ‐B3 together mediate this response. J. Comp. Neurol. 462:90–100, 2003.

Involvement of ras activation in toxic hair cell damage of the mammalian cochlea

To identify possible intracellular mediators of hair cell (HC) death due to ototoxins, we treated basal-turn, neonatal, rat HCs in vitro with several intracellular signaling inhibitors, prior to and during gentamicin exposure. The general guanine nucleotide-binding protein (G-protein) inhibitor, GDP-betaS (1 mM), provided potent HC protection, suggesting involvement of G-proteins in the intracellular pathway linking gentamicin exposure to HC death. ADP-betaS had minimal effect, indicating that the protection is specific to guanosine diphosphate (GDP)-binding, rather than a general reaction to nucleotides. Azido-GTP(32) photolabeling and gel electrophoresis indicated activation of an approximately 21 kDa G-protein in HCs after exposure to gentamicin. Spectroscopic analysis of peptide fragments from this band matched its sequence with H-Ras. The Ras inhibitors B581 (50 microM) and FTI-277 (10 microM) provided potent protection against damage and reduced c-Jun activation in HC nuclei, suggesting that activation of Ras is functionally involved in damage to these cells due to gentamicin.

Magnetic resonance imaging in patients with sudden hearing loss, tinnitus and vertigo.

Objective The etiopathogenesis in audiovestibular symptoms can be elusive, despite extensive differential diagnosis. This article addresses the value of magnetic resonance imaging (MRI) in analysis of the complete audiovestibular pathway. Study Design Retrospective evaluation. Setting Tertiary referral center. Patients Consecutive sample of 354 patients (mean age 49 years, range 8 to 86 years) with audiovestibular disorders. Intervention Contrast-enhanced MRI of the head with thin-slice investigation of the inner ear, internal auditory meatus, and cerebellopontine angle. Main Outcome Measure All MRIs were evaluated by experienced independent investigators. Statistical analysis was performed using the Statistical Package of Social Sciences data analysis 9.0. Results MRI abnormalities were seen in 122 of 354 patients (34.5%). The MRIs revealed the following: 4 pathologic conditions (1.1%) of the cochlea/labyrinth, 23 abnormalities (6.5%) at the internal auditory meatus/cerebellopontine angle, 12 pathologic lesions (3.4%) that involved the central audiovestibular tract at the brainstem, 78 microangiopathic changes of the brain (22%), 3 focal hyperintensities of the brain that turned out to be the first evidence of multiple sclerosis in 2 patients and sarcoidosis in 1 patient, and 1 temporal metastasis. Other pathologic conditions, such as parotid gland or petrous bone apex tumors, were unrelated to the audiovestibular symptoms. Conclusions This study indicates that contrast-enhanced MRI can be used to assess a significant number of different pathologic conditions in patients with audiovestibular disorders.

Interaction of spiral ganglion neuron processes with alloplastic materials in vitro

The cochlear implant (CI) involves the introduction of alloplastic materials into the cochlea. While current implants interact with cochlear neurons at a distance, direct interactions between spiral ganglion (SG) neurites and implants could be fostered by appropriate treatment with neurotrophic factors. The interactions of fibroblasts and osteoblasts with alloplastic materials have been well studied in vitro and in vivo. However, interactions of inner ear neurons with such alloplastic materials have yet to be described. To investigate survival and growth behavior of SG neurons on different materials, SG explants from post-natal day 5 rat SG were cultured for 72 h in the presence of neurotrophin-3 (10 ng/ml) on titanium, gold, stainless steel, platinum, silicone and plastic surfaces that had been coated with laminin and poly-L-lysine. Neurite outgrowth was investigated after immunohistological staining for neurofilament, by image analysis to determine neurite extension and directional changes. Neurite morphology and adhesion to the alloplastic material were also evaluated by scanning electron microscopy (SEM). On titanium, SG neurites reached the highest extent of outgrowth, with an average length of 662 microm and a mean of 31 neurites per explant, compared to 568 microm and 21 neurites on gold, 574 microm and 24 neurites on stainless steel, 509 microm and 16 neurites on platinum, 281 microm and 12 neurites on silicone and 483 microm and 31 neurites on plastic. SEM revealed details of adhesion of neurites and interaction with non-neuronal cells. The results of this study indicate that the growth of SG neurons in vitro is strongly influenced by alloplastic materials, with titanium exhibiting the highest degree of biocompatibility with respect to neurite extension. The knowledge of neurite interaction with different alloplastic materials is of clinical interest, as development in CI technology leads to closer contact of implanted electrodes with surviving inner ear neurons.

Rescue of auditory hair cells from aminoglycoside toxicity by Clostridium difficile toxin B, an inhibitor of the small GTPases Rho/Rac/Cdc42.

The hair cells (HCs) are the most vulnerable elements in the cochlea and damage to them is the most common cause of sensorineural hearing loss. Understanding the intracellular events that lead to the death of HCs is a key to developing protective strategies. Recently, it has been shown that the c-Jun-N-terminal kinase (JNK) pathway is activated in HCs in response to aminoglycosides (J. Neurosci. 20 (2000) 43). We have studied the upstream events leading to JNK activation in aminoglycoside toxicity in vitro. The small GTPases Rac and Cdc42 are well known upstream activators of JNK in other cell types. Clostridium difficile toxin B monoglucosylates all members of the Rho GTPase subfamily (Rho, Rac and Cdc42 isoforms) and inhibits GTP binding by steric interference (Nature 341 (1989) 209). Organ of Corti explants from p5 rat basal turns were maintained in tissue culture and treated with C. difficile toxin B for 12 h. They were then treated with toxin B plus gentamicin for 72 h. Significantly less HC death was observed compared to with gentamicin alone. Toxin B alone had no effect on HCs at the highest concentration used. Using antibodies against phospho-c-Jun, we observed background immunoreactivity in control explants, strong staining of outer hair cell nuclei in gentamicin treated explants, and weaker immunostaining in explants treated with gentamicin and C. difficile toxin B. We conclude that Rho family small GTPases play a role in aminoglycoside toxicity signaling as upstream activators of the JNK signaling pathway.

Postoperative magnetic resonance imaging findings after transtemporal and translabyrinthine vestibular schwannoma resection.

Objectives/Hypothesis Magnetic resonance imaging (MRI) has become the investigation of choice to follow up patients after vestibular schwannoma resection.

In vivo adenoviral transduction of the neonatal rat cochlea and middle ear

Virally mediated gene transfer to the adult mammalian ear appears to be a powerful strategy to investigate gene function in the auditory system and to develop new therapeutic treatment for hearing impaired patients. However, there has been little work done in the neonatal middle and inner ear. In this study, a recombinant adenoviral (AdV) vector was used for gene transfer of a beta-galactosidase (beta-gal) reporter gene to the neonatal middle ear and cochlea of 5 day old rats. For transduction of middle ear, AdV was injected through the tympanic membrane into the tympanic cavity. Three and 7 days later, strong expression of beta-gal was observed in epithelial cells of the mucosa, but not in the underlying stroma or mesenchyme. There was little or no infiltration of leukocytes. No expression of beta-gal was detected inside the cochlea or vestibular system. When AdV was injected into the basal turn of the cochlea, high levels of beta-gal expression were observed in cells lining the perilymphatic space and in parts of the spiral ligament 3, 7 and 21 days later. Spiral ganglion cells did not express beta-gal. However, virally mediated gene transfer was observed in some cells of the organ of Corti. A moderate infiltration of leukocytes into the labyrinth was observed, but no vestibular or auditory dysfunction. These results demonstrate that neonatal middle ear and cochlear cells can be successfully transduced with an AdV vector in vivo, without obvious morphological signs of inflammation or cellular damage. AdV vectors provide a tool for investigation of the role of genes in influencing the development of middle and inner ear structures. Virally mediated expression of protective genes could also be used to rescue hair cells or spiral ganglion cells from congenital degeneration or damage.

The Disintegrin Kistrin Inhibits Neurite Extension from Spiral Ganglion Explants Cultured on Laminin

The influence of laminin-1 (LN) and tenascin-C (TN), extracellular matrix molecules expressed spatially and temporally along the neural growth route from spiral ganglion (SG) neurons to the cochlear sensory cells, was evaluated in cultured SG explants from postnatal day 4 rats. Increasing concentrations of LN resulted in a strong, dose-dependent increase in the length of neurites and in a higher number of neural processes, while varying TN concentrations had relatively minor effects on both parameters. The results suggest differential receptor activation by LN and TN. When explants grown on LN were treated with Kistrin, an inhibitor of the αvβ3 integrin, the LN-induced increase in neurite length was reduced in a dose-dependent manner. However, the number of extending neurites was not affected, indicating that different receptors mediate this response, perhaps by increasing neuronal survival.

Inhibition of the c-Jun N-terminal kinase signaling pathway influences neurite outgrowth of spiral ganglion neurons in vitro.

Objectives Inhibitors of the c‐Jun N‐terminal kinase (JNK) signaling pathway have been demonstrated to protect hair cells of the auditory system and different types of neurons from various insults, and their use for future therapeutic applications has been proposed. In the study, we evaluated the effects of inhibition of the JNK pathway on process outgrowth from spiral ganglion neurons.