Klaus Ehrenberger

Evaluation of Performance with the COMBI 40 Cochlear Implant in Adults: A Multicentric Clinical Study

The present multicentric clinical study involves 19 centres, 16 of them in German-speaking countries, 1 British, 1 Polish and 1 Hungarian. 60 postlingually deafened adults with a mean age of 47.5 years (20-70) and mean duration of deafness of 5.3 years (0.5-20) have been evaluated with the MED-EL COMBI 40 cochlear implant which implements a high-rate continuous-interleaved-sampling strategy with 8 channels. Safety and effectiveness data have been collected. Speech perception tests include a 16-consonant, an 8-vowel, a sentence and a monosyllabic-word test in all languages and a 2-digit figure test in all languages but English. Test intervals are 1, 3, 6 months and 1 year after first fitting. 41 of the 60 postlingually deafened adult study patients have completed their 6-month evaluation. While their pre-operative monosyllabic-word score was 0%, their mean monosyllabic-word score 6 months after first fitting was 48% (8-90) with a median of 50%. The mean sentence understanding was 84% (24-100) with a median of 90%. The respective values for the 1-year evaluations with 25 patients are a mean of 50% (5-85), with a median of 60% for the monosyllables and a mean of 89% (30-100), with a median of 97%, for the sentences.

Calcium-dependent immunoglobulin E recognition of the apo- and calcium-bound form of a cross-reactive two EF-hand timothy grass pollen allergen, Phl p 7

Type I allergy, an immunodisorder that affects almost 20% of the population worldwide, is based on the immunoglobulin E (IgE) recognition of per se innocuous antigens (allergens). Pollen from wind‐pollinated plants belong to the most potent allergen sources. We report the isolation of a cDNA coding for a 8.6 kDa two EF‐hand calcium binding allergen, Phl p 7, from a timothy grass (Phleum pratense) pollen expression cDNA library, using serum IgE from a grass pollen allergic patient. Sequence analysis identified Phl p 7 as a member of a recently discovered subfamily of pollen‐specific calcium binding proteins. Recombinant Phl p 7 was expressed in Escherichia coli and purified to homogeneity as determined by mass spectroscopy. Approximately 10% of pollen allergic patients displayed IgE reactivity to rPhl p 7 and Phl p 7‐homologous allergens present in pollens of monocotyledonic and dicotyledonic plants. Circular dichroism analysis of the calcium‐bound and apo‐rPhl p 7 indicated that differences in IgE recognition may be due to calcium‐induced changes in the protein conformation. The fact that patients mount IgE antibodies against different protein conformations is interpreted as a footprint of a preferential sensitization against either form. The biological activity of rPhl p 7 was demonstrated by its ability to induce basophil histamine release and immediate type skin reactions in sensitized individuals. In conclusion, IgE binding to Phl p 7 represents an example for the conformation‐dependent IgE recognition of an allergen. Recombinant Phl p 7 may be used for diagnosis and perhaps treatment of a group of patients who suffer from allergy to pollens of many unrelated plant species.—Niederberger, V., Hayek, B., Vrtala, S., Laffer, S., Twardosz, A., Vangelista, L., Sperr, W. R., Valent, P., Rumpold, H., Kraft, D., Ehrenberger, K., Valenta, R., Spitzauer, S. Calcium‐dependent immunoglobulin E recognition of the apo‐ and calcium‐bound form of a cross‐reactive two EF‐hand timothy grass pollen allergen, Phl p 7. FASEB J. 13, 843–856 (1999)

Cochlear Implant Deep Electrode Insertion: Extent of Insertional Trauma

We have recently undertaken deep insertions of the Combi-40 cochlear implant electrode (Med-E1 Corp., Innsbruck, Austria) into apical regions of the scala tympani using a cochleostomy approach. In order to examine the extent of the insertional trauma, 12 fresh human temporal bones were implanted with original Combi-40 electrodes. The specimens were histologically processed with the implants in place by employing a sawing and grinding technique. In most cases, only very discrete distortions of the epithelium of the spiral ligament occurred within the middle cochlear turns. Furthermore, a slight displacement of the basilar membrane caused by the electrode was occasionally seen. However, in 2 cases more severe damage such as basilar membrane rupture and electrode displacement was found. Attempts to insert the electrode beyond the point of first resistance resulted in electrode kinking within the basal cochlear turn with subsequent fracture of the osseous spiral lamina. According to our results, deep electrode insertions do not aggravate the insertional trauma provided no force is applied when resistance is felt.

Glutamate receptors in afferent cochlear neurotransmission in guinea pigs.

With the aid of microinotophoretic techniques we tested the action of the transmitter candidate glutamate (Glu) at the afferent synapses of inner hair cells (IHC) in guinea pigs. In order to determine the various types of glutamate receptors, further agonistic excitatory amino acids (EAA) as well as competitive EAA-antagonists were used. Applied perisynaptically, Glu, aspartate, N-methyl-D-aspartate (NMDA), quisqualate (Q) and kainate (K) activate the subsynaptic, phasic firing activity of the afferent dendrites. The NMDA-induced activation is augmented by simultaneous application of glycine. The firing rate induced by Glu and NMDA is blocked by the specific NMDA-antagonist D-2-amino-7-phosphonoheptanoate (AP-7). Furthermore, activity induced by Glu and Q decreases under the influence of the selective Q-antagonist glutamic acid diethylester (GDEE). These results are consistent with the hypothesis that Glu acts as a possible afferent neurotransmitter of the IHC. This neurotransmission is mediated by postsynaptic EAA-receptor subpopulations which are sensitive to NMDA, Q and K. The activity of the NMDA-receptors depends, however, on the amount of glycine available. Our data suggest that the afferent synapses of the IHC possess functional properties which are equivalent to the properties of glutamatergic NMDA-sensitive and NMDA-non-sensitive synapses in the central nervous system.

The efferent modulation of mammalian inner hair cell afferents.

The results of immunocytochemical, enzymatic and electrophysiological studies have indicated that acetylcholine and GABA may act as neurotransmitters in lateral olivocochlear efferent endings on inner hair cell afferent dendrites. Since spike activity can be recorded in the dendritic region of inner hair cells, microiontophoretic techniques were used testing the possible neurotransmitter candidates, acetylcholine and GABA, on spontaneous and induced firing of the afferent dendrites. The experiments were carried out in anaesthetised guinea-pigs, the third and fourth turns of the cochlea being exposed for electrode penetration. Ejection of acetylcholine resulted in a pronounced dose-dependent increase in subsynaptic spiking activity. Furthermore, acetylcholine enhanced glutamate-induced activity. In contrast, even at high doses, GABA had very little effect on the spontaneous cochlear firing rate. When the firing rate had first been enhanced by glutamate or N-methyl-D-aspartate, however, this activation could be reduced by the ejection of GABA. A similar reduction was observed when the firing rate had been enhanced with acetylcholine. The results of our studies support the hypothesis that these substances are involved in efferent neurotransmission on inner hair cell afferent fibres. It should be pointed out, however, that besides acetylcholine and GABA, several opioids such as enkephalins and dynorphins seem to be involved in efferent cochlear innervation.

Caroverine in Tinnitus Treatment: A Placebo-Controlled Blind Study

This study was performed to examine whether a single infusion of caroverine, a quinoxaline-derivative, can be used successfully in the treatment of inner ear tinnitus. Microiontophoretical experiments in guinea-pigs have shown that caroverine acted as a potent competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazone-proprionic acid (AMPA) receptor antagonist and, in higher dosages, a non-competitive N-methyl-d-aspartate (NMDA) antagonist. According to our working hypothesis of the pathophysiology of inner ear tinnitus (cochlear-synaptic tinnitus), these forms of tinnitus occur when the physiological activity of the NMDA and AMPA receptors at the subsynaptic membranes of inner hair cell afferents is disturbed. In total, 60 patients with inner ear tinnitus of assumed cochlear-synaptic pathophysiology were included in the study: after computerized randomization, 30 were treated with caroverine and 30 with placebo. For a response to have occurred, tinnitus had to show a reduction in both subjective rating and psychoacoustic measurement (tinnitus matching). In the caroverine group, 63.3% responded to therapy immediately after the infusion. In the placebo group, none of the patients treated showed a significant response according to the defined success criteria. The results confirm our working hypothesis on the genesis of cochlear-synaptic tinnitus.

Receptor Pharmacological Models for Inner Ear Therapies with Emphasis on Glutamate Receptors: A Survey

With the aid of microiontophoretic techniques we evaluated the action of different postsynaptic glutamate receptor subtypes that mediate neurotransmission between the inner hair cell and the afferent neuron. The sensory input is modulated by axodendritic efferents. In the central nervous system, excessive activation of glutamate receptors is thought to be responsible for a wide variety of neurotoxic actions, and calcium is involved in the etiology of glutamate-induced cell damage. Glutamatergic neurotoxicity may form an appropriate pathophysiological model to explain a variety of inner ear diseases characterized by acute or progressive hearing loss and tinnitus. In clinical trials, three sites of action are thought to attenuate glutamatergic otoneurotoxicity: presynaptically, via the reduction of excessive transmitter release; postsynaptically, via competitive or noncompetitive receptor antagonism; and intracellularly, via blockage of glutamate receptor-dependent calcium stores. The drugs discussed in this paper are currently available clinically and have only recently been found to attenuate glutamate toxicity. Magnesium and the quinoxaline derivative Caroverine, which have already been tested in humans, exhibit a statistically significant otoneuroprotective action in noise-induced hearing loss and tinnitus. The intensive search for further drugs that enhance the survival of cochlear afferents without disrupting acoustic signal processing is one of the main goals of research in clinical otoneuropharmacology in the near future.

The Action of Putative Neurotransmitter Substances in the Cat Labyrinth

Possible neurotransmitter candidates were tested in the labyrinth of the cat with the aid of microiontophoretic techniques. Depending on the recording site, spontaneous regular or irregular fibre activity was obtained in the subsynaptic region of the macula sacculi. Ejection of GABA enhances the firing rate, whereas acetylcholine reduces the spontaneous activity. A similar application of glycine and proline produced no effect. The action of GABA was specifically blocked by the GABA antagonists bicuculline and picrotoxin. The alkaloids further induced a decrease in the spontaneous activity which lasted for several minutes.

Dopamine regulates the glutamatergic inner hair cell activity in guinea pigs.

Recent immunocytochemical and biochemical studies support a possible neurotransmitter function of dopamine (DA) in the efferent olivocochlear innervation of the guinea pig cochlea. However, the physiological role of DA in cochlear neurotransmission remains unknown. In the present study microiontophoretic techniques were used for testing the action of DA as well as D1- and D2-agonists and -antagonists on spontaneous and N-methyl-D-aspartic acid (NMDA)-, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-, kainic acid- or glutamate-induced firing of afferent fibres in the dendritic region of inner hair cells. Subsynaptic spike activities of anaesthetised guinea pigs were recorded after exposing the third or fourth turn of the cochlea for electrode penetration. Application of DA alone had very little effect on the spontaneous afferent firing rate. In contrast, firing induced by NMDA or AMPA could be depressed by additional administration of DA in a dose-dependent manner. A similar reduction of the induced spike activity was seen after co-administration of D1- or D2-agonists. The action of DA on glutamate agonist-induced firing could be blocked by D1- as well as D2-antagonists. These results show that DA can depress the activated firing rate of the afferent fibres and that this action is mediated by both D1- and D2-receptor subtypes.

Speech understanding in quiet and in noise with the CIS speech coding strategy (MED-EL combi-40) compared to the multipeak and spectral peak strategies (nucleus)

This study compares sentence understanding in quiet and in noise with 3 different speech coding strategies for cochlear implants. The results show that the spectral-peak (SPEAK) and continuous-interleaved-sampling (CIS) coding strategies, based on spectral signal analysis, allow for better speech understanding in quiet as well as in noise, than the multipeak (MPEAK) coding strategy, which relys on speech feature extraction. In the intrasubject comparison of the MPEAK and SPEAK strategies, the SPEAK coding strategy provided a considerable improvement in quiet and in noise for the majority of patients using the Nucleus 22 Mini-implant. In the intersubject comparisons, the mean results in noise with the CIS strategy were superior to both the MPEAK and the SPEAK strategies. The difference was greatest for the most difficult tests in noise. Understanding in noise was least reduced for the CIS strategy. Understanding in quiet was not significantly different between the CIS and the SPEAK strategies; both strategies were significantly better than the MPEAK strategy in quiet. These results are still preliminary, due to the relatively small number of patients and the great inherent intersubject variability of results.