Marlan R. Hansen

Hybrid 10 clinical trial: preliminary results.

Acoustic plus electric (electric-acoustic) speech processing has been successful in highlighting the important role of articulation information in consonant recognition in those adults that have profound high-frequency hearing loss at frequencies greater than 1500 Hz and less than 60% discrimination scores. Eighty-seven subjects were enrolled in an adult Hybrid multicenter Food and Drug Administration clinical trial. Immediate hearing preservation was accomplished in 85/87 subjects. Over time (3 months to 5 years), some hearing preservation was maintained in 91% of the group. Combined electric-acoustic processing enabled most of this group of volunteers to gain improved speech understanding, compared to their preoperative hearing, with bilateral hearing aids. Most have preservation of low-frequency acoustic hearing within 15 dB of their preoperative pure tone levels. Those with greater losses (>30 dB) also benefited from the combination of electric-acoustic speech processing. Postoperatively, in the electric-acoustic processing condition, loss of low-frequency hearing did not correlate with improvements in speech perception scores in quiet. Sixteen subjects were identified as poor performers in that they did not achieve a significant improvement through electric-acoustic processing. A multiple regression analysis determined that 91% of the variance in the poorly performing group can be explained by the preoperative speech recognition score and duration of deafness. Signal-to-noise ratios for speech understanding in noise improved more than 9 dB in some individuals in the electric-acoustic processing condition. The relation between speech understanding in noise thresholds and residual low-frequency acoustic hearing is significant (r = 0.62; p < 0.05). The data suggest that, in general, the advantages gained for speech recognition in noise by preserving residual hearing exist, unless the hearing loss approaches profound levels. Preservation of residual low-frequency hearing should be considered when expanding candidate selection criteria for standard cochlear implants. Duration of profound high-frequency hearing loss appears to be an important variable when determining selection criteria for the Hybrid implant.

Small acoustic neuromas: surgical outcomes versus observation or radiation.

Objective: Evaluate factors affecting outcomes of small acoustic neuroma (AN) removal via a middle cranial fossa (MCF) approach, and compare results to published data on observation and radiation therapy. Study Design: Retrospective chart review. Setting: Academic tertiary referral center. Methods: 162 consecutive patients (ages 19-70) with unilateral AN (0.2-2.5 cm in largest dimension) removed through a MCF approach were reviewed focusing on preservation of hearing, facial nerve function and complications. One hundred thirteen patients had pre-operative word recognition scores (WRS) >70%. Results: Both tumor size and pre-operative WRS were related to post-operative WRS (p < 0.01). Overall, at least some hearing was preserved in 94 (60%) of the 156 patients who had hearing before surgery. If the WRS was also >70% (N = 113), 56 (50%) maintained WRS >70%. Importantly, WRS for 12 others improved to >70% after surgery. When the patients were stratified by tumor size, the patients with small tumors (2-10 mm) faired better than the overall group. At least some hearing was preserved in 65 (72%) of the 90 patients. If the WRS was also >70% (N = 66), 39 (59%) maintained WRS >70%. WRS for eight others improved to >70% after surgery. When the tumor was 1.1-1.4 cm (N = 34), the chance of preserving some hearing decreased to 42% (14/33). If the WRS was also >70% (N = 23), 9 (39%) maintained WRS >70%. WRS for three others improved to >70% after surgery. When the tumor reached 1.5-2.5 cm (N = 35), the hearing preservation rate was 43%. If the WRS was also >70% (N = 24), only eight (33%) maintained WRS of 70%, and one other improved to >70%. The addition of intra-operative whole eighth nerve near field monitoring improved results during small tumor (≤ 1.0 cm) removal preserving some hearing in 80% (32/40) and preserving >70% WRS in 76% (22/29) of those with >70% pre-operative WRS. Good facial nerve function (HB I-II) was achieved in 97% (86% HB I). When tumor size was ≤ 1.0 cm (N = 93), however, good facial nerve function was obtained in 100% (94% HB I). Complications included CSF leak: 9 (5.5%); seizure: 2 (1.2%); and recurrence: 1 (0.6%). Conclusion: Our results suggest that removal of unilateral AN through an MCF approach when the tumor is small and hearing is good provides the best opportunity for hearing preservation and normal facial nerve function. Observation historically results in tumor growth in young and middle-age patients with subsequent hearing loss. Radiation may prevent most tumors from growing, and more data are needed to determine long-term tumor control and hearing preservation rates.

Stapedectomy Versus Stapedotomy: Comparison of Results With Long-Term Follow-up

Objective/Hypothesis To compare the effectiveness and long‐term stability of hearing results between stapedectomy and small fenestra stapedotomy in patients with conductive hearing loss due to otosclerosis.

Strategies to preserve or regenerate spiral ganglion neurons.

Degeneration of spiral ganglion neurons following hair cell loss carries critical implications for efforts to rehabilitate severe cases of hearing loss with cochlear implants or hair cell regeneration. This review considers recently identified neurotrophic factors and therapeutic strategies which promote spiral ganglion neuron survival and neurite growth. Replacement of these factors may help preserve or regenerate the auditory nerve in patients with extensive hair cell loss. Recent findingsSpiral ganglion neurons depend on neurotrophic factors supplied by hair cells and other targets for their development and continued survival. Loss of this trophic support leads to spiral ganglion neuron death via apoptosis. Hair cells support spiral ganglion neuron survival by producing several peptide neurotrophic factors such as neurotrophin-3 and glial derived neurotrophic factor. In addition, neurotransmitter release from the hair cells drives membrane electrical activity in spiral ganglion neurons which also supports their survival. In animal models, replacement of peptide neurotrophic factors or electrical stimulation with an implanted electrode attenuates spiral ganglion neuron degeneration following deafferentation. Cell death inhibitors can also preserve spiral ganglion neuron populations. Preliminary studies show that transfer of stem cells or neurons from other ganglia are two potential strategies to replace lost spiral ganglion neurons. Inducing the regrowth of spiral ganglion neuron peripheral processes to approximate or contact cochlear implant electrodes may help optimize signaling from a diminished population of neurons. SummaryRecent studies of spiral ganglion neuron development and survival have identified several trophic and neuritogenic factors which protect these specialized cells from degeneration following hair cell loss. While still preliminary, such strategies show promise for future clinical applications.

Outcomes after cochlear implantation for patients with single-sided deafness, including those with recalcitrant Ménière's disease.

Objective Compare preoperative and postoperative performance in patients undergoing cochlear implantation (CI) for unilateral severe-to-profound sensorineural hearing loss (single-sided deafness, SSD). Study Design IRB-approved, prospective Setting Tertiary center Patients Twenty-nine patients have undergone CI for SSD. SSD was due to Ménière’s disease (MD) in 10 subjects; these also suffered from recalcitrant vertigo spells and in these 10 patients along with 2 others the CI was placed simultaneous with a labyrinthectomy. Intervention(s) CI with or without labyrinthectomy. Main Outcome Measure(s) CNC word and AzBio sentences in quiet were administered to the implanted ear. A multiple-loudspeaker sound localization test was administered in the bilateral listening condition. All data were collected preoperatively and 3, 6, and 12 months postoperatively with postoperative data available for 19 subjects. Additionally, a tinnitus handicap questionnaire is administered pre- and 12-months post-operatively. Results CNC word and AzBio sentence scores showed improvement in the implanted ear. Sound localization appeared to improve in an experience-dependent fashion in some patients. Most patients reported diminished tinnitus after cochlear implantation. All patients undergoing labyrinthectomy experienced resolution of vertigo attacks. Conclusion CI restores auditory function to the deafened ear. Additionally, the binaural input appears to improve sound localization for most patients. In patients with severe hearing loss and recalcitrant vertigo attacks because of MD, simultaneous labyrinthectomy and CI effectively relieves vertigo attacks and improves auditory function.

Ca2+/calmodulin-dependent protein kinases II and IV both promote survival but differ in their effects on axon growth in spiral ganglion neurons

Spiral ganglion neuron (SGN) survival in vitro can be maintained by neurotrophins, permeant cAMP analogs, and depolarization in an additive manner, with depolarization being the most efficacious. Therefore, we used cultured SGNs to determine the mechanism by which depolarization promotes neuronal survival. Our data implicate Ca2+/calmodulin‐dependent protein kinase (CaMK) activity by showing that it is induced by depolarization, that CaMK activity is necessary for at least part of the survival‐promoting effect of depolarization, and that CaMKII or CamKIV activity suffices to support neuronal survival in the absence of other trophic stimuli. First, that depolarization of SGNs activates CaMKs is evidenced by observation of increased CaMKII phosphorylation and of CaMK‐dependent CREB phosphorylation. Second, the requirement for CaMKs is shown by a reduction of SGN survival under depolarizing conditions in the presence of CaMK inhibitors. Third, transfection of COOH‐terminal‐truncated (lacking regulatory domain), constitutively active CaMKII or CaMKIV, but not of normal, full‐length CAMKs, promotes SGN survival in the absence of other trophic stimuli, indicating that CaMK activity is sufficient to promote survival. The survival‐promoting effect of truncated CaMKs is additive with that of depolarization, neurotrophins, or cyclic AMP. Although both CaMKII and CaMKIV activities converge in promoting survival, their actions on axon growth are markedly different: Transfection of truncated CaMKII, but not of truncated CaMKIV, into SGNs prevents axon outgrowth.

BDNF synthesis in spiral ganglion neurons is constitutive and CREB-dependent

Brain-derived neurotrophic factor (BDNF), which supports spiral ganglion neuron (SGN) survival in vivo and in vitro, is synthesized by SGNs. The BDNF gene generates multiple different transcripts, each from its own promoter region. Using reverse transcriptase-polymerase chain reaction (RT-PCR), we find that SGNs express only the downstream transcripts III and IV in vivo and in vitro. Using RT-PCR assays of BDNF transcripts and transfection of BDNF promoter-reporter constructs, we tested the hypothesis, originally derived from studies of cortical neurons, that depolarization induces BDNF expression via a signaling pathway that includes Ca2+/calmodulin-dependent kinases (CaMKs) and the transcription factor, Ca2+/cyclic AMP response element binding protein (CREB). In contrast, we found that in SGNs in vivo BDNF expression is constitutive and is not increased by electrical activation. Similarly, BDNF expression in vitro is not increased by stimuli that activate CREB, including depolarization, cAMP, or transfection of activated CaMK mutants. However, transfection of dominant-negative CREB mutants did abrogate gene expression driven by BDNF promoters III and IV, indicating that CREB is necessary for constitutive BDNF expression. Thus, BDNF synthesis within SGNs makes possible an autocrine or paracrine mechanism that can contribute to support SGN survival but SGNs are distinctive in that this mechanism is constitutive and not activity-regulated.

Constitutive neuregulin-1/ErbB signaling contributes to human vestibular schwannoma proliferation

Vestibular schwannomas (VSs) are benign tumors that arise from the Schwann cells (SCs) lining the vestibular nerve. VS cells survive and proliferate far from neurons and axonally derived growth factors. We have previously shown that VSs produce the glial growth factor, neuregulin‐1 (NRG1), and its receptors, ErbB2 and ErbB3. In the present work, we explore the contribution of constitutive NRG1:ErbB signaling to human VS cell proliferation. We confirm that human VSs, which express markers of immature and denervated SCs, also express endogenous NRG1 and activated ErbB2. We find that a blocking anti‐NRG1 antibody and trastuzumab (Herceptin®, HCN), a humanized anti‐ErbB2 inhibitory monoclonal antibody, effectively inhibit NRG1 induced SC proliferation. Treatment of primary VS cultures with anti‐NRG1 or HCN reduces cell proliferation in the absence of exogenous NRG1. Furthermore, conditioned medium from VS cell cultures contains NRG1 and stimulates SC proliferation in SC cultures, an effect that is inhibited by anti‐NRG1 and HCN. These data suggest an autocrine pathway of VS growth stimulation involving NRG and ErbB receptors. Inhibition of constitutive NRG:ErbB signaling reduces VS cell proliferation in vitro and may have therapeutic potential for patients with VSs.

Membrane depolarization inhibits spiral ganglion neurite growth via activation of multiple types of voltage sensitive calcium channels and calpain

The effect of membrane electrical activity on spiral ganglion neuron (SGN) neurite growth remains unknown despite its relevance to cochlear implant technology. We demonstrate that membrane depolarization delays the initial formation and inhibits the subsequent extension of cultured SGN neurites. This inhibition depends directly on the level of depolarization with higher levels of depolarization causing retraction of existing neurites. Cultured SGNs express subunits for L-type, N-type, and P/Q type voltage-gated calcium channels (VGCCs) and removal of extracellular Ca(2+) or treatment with a combination of L-type, N-type, and P/Q-type VGCC antagonists rescues SGN neurite growth under depolarizing conditions. By measuring the fluorescence intensity of SGNs loaded with the fluorogenic calpain substrate t-butoxy carbonyl-Leu-Met-chloromethylaminocoumarin (20 microM), we demonstrate that depolarization activates calpains. Calpeptin (15 microM), a calpain inhibitor, prevents calpain activation by depolarization and rescues neurite growth in depolarized SGNs suggesting that calpain activation contributes to the inhibition of neurite growth by depolarization.

Long-Term Hearing Preservation After Microsurgical Excision of Vestibular Schwannoma

Objective: To examine long-term hearing outcomes after microsurgical excision of vestibular schwannoma (VS). Study Design: Retrospective case review. Setting: Tertiary referral center. Patients: Forty-nine subjects at a single institution who had undergone microsurgical excision of a VS via middle cranial fossa (MCF) approach between 1994 and 2007 with immediate postoperative (PO) hearing preservation and for whom long-term audiograms were available. Intervention: Diagnostic. Main Outcome Measures: Word Recognition Score (WRS) is defined by speech discrimination scores (SDS) greater than 70% (grade I), 50% to 70% (grade II), less than 50% (grade III), and 0% (grade IV). Results: For subjects with more than 2 years of follow-up, WRS I hearing was present PO in 42 of 49 patients and was preserved at the latest follow-up in 38 (90%) of 42 patients. No subjects fell beyond WRS II. WRS I hearing was maintained in 23 (88%) of 26 patients with more than 5 years of follow-up. Postoperative WRS I to II hearing was maintained in 28 (96%) of 29 patients with more than 5 years of follow-up. The patient who lost significant hearing in the ear operated on had sensorineural hearing loss that paralleled deterioration in her ear that was not operated on. Conclusion: Most subjects maintain their initial PO SDS after microsurgical VS removal, and therefore, the initial PO WRS is predictive of long-term hearing. Postsurgical changes do not alter the natural rate or pattern of progressive bilateral sensorineural hearing loss in individual subjects.