Krzysztof Morawski

Efficacy and safety of AM-111 in the treatment of acute sensorineural hearing loss: a double-blind, randomized, placebo-controlled phase II study.

Objective To evaluate the efficacy and safety of AM-111, a c-Jun N-terminal Kinase (JNK) ligand, in patients with acute sensorineural hearing loss (ASNHL). Study Design Prospective, double-blind, randomized, placebo-controlled study with follow-up visits on Days 3, 7, 30, and 90. Setting Twenty-five European sites (academic tertiary referral centers, private ENT practices). Patients Approximately 210 patients aged 18 to 61 years presenting within 48 hours after acute acoustic trauma or idiopathic sudden sensorineural hearing loss with mean hearing loss of 30 dB or greater at the 3 most affected contiguous test frequencies. Interventions Single-dose intratympanic injection of AM-111 (0.4 or 2.0 mg/ml) or placebo; optionally, oral prednisolone if hearing improvement was less than 10 dB at Day 7. Main Outcome Measures Efficacy was assessed by absolute hearing improvement (primary end point, Day 7), percentage hearing improvement, complete hearing recovery, speech discrimination improvement, and complete tinnitus remission. Safety was evaluated by the frequency of clinically relevant hearing deterioration and adverse events. Results The study failed to demonstrate a treatment benefit for the entire study population because mild-to-moderate ASNHL cases showed unexpectedly strong spontaneous recovery. In severe-to-profound ASNHL patients (threshold ≥60 dB), AM-111 0.4 mg/ml showed statistically significant, clinically relevant, and persistent improvements in hearing and speech discrimination and higher tinnitus remission compared with placebo. The study drug and the intratympanic injections were well tolerated. Conclusion The study established proof of concept for AM-111 in the treatment of severe-to-profound ASNHL. Control for spontaneous hearing recovery is essential for ASNHL studies.

Neuromonitoring of cochlea and auditory nerve with multiple extracted parameters during induced hypoxia and nerve manipulation

A system capable of comprehensive and detailed monitoring of the cochlea and the auditory nerve during intraoperative surgery was developed. The cochlear blood flow (CBF) and the electrocochleogram (ECochGm) were recorded at the round window (RW) niche using a specially designed otic probe. The ECochGm was further processed to obtain cochlear microphonics (CM) and compound action potentials (CAP). The amplitude and phase of the CM were used to quantify the activity of outer hair cells (OHC); CAP amplitude and latency were used to describe the auditory nerve and the synaptic activity of the inner hair cells (IHC). In addition, concurrent monitoring with a second electrophysiological channel was achieved by recording compound nerve action potential (CNAP) obtained directly from the auditory nerve. Stimulation paradigms, instrumentation and signal processing methods were developed to extract and differentiate the activity of the OHC and the IHC in response to three different frequencies. Narrow band acoustical stimuli elicited CM signals indicating mainly nonlinear operation of the mechano-electrical transduction of the OHCs. Special envelope detectors were developed and applied to the ECochGm to extract the CM fundamental component and its harmonics in real time. The system was extensively validated in experimental animal surgeries by performing nerve compressions and manipulations.

Role of mannitol in reducing postischemic changes in distortion-product otoacoustic emissions (DPOAEs): a rabbit model.

Objectives The aim of this study was to observe the effects of mannitol, administered topically at the round window (RW), on cochlear blood flow (CBF) and distortion‐product otoacoustic emission (DPOAE) after repeated episodes of cochlear ischemia.

Preventing hearing damage using topical dexamethasone during reversible cochlear ischemia: an animal model.

Hypothesis: Local application of dexamethasone to the round window (RW) niche prevents cochlear damage caused by local reversible ischemia. Background: Cochlear ischemia induced by internal auditory artery (IAA) compression/stretching is thought to cause postoperative sensory hearing loss after attempted hearing preservation removal of acoustic neuroma tumors. Dexamethasone administered to the RW niche traveling through the membrane to the cochlear fluids may prevent ischemic damage. Materials and Methods: Ten young albino rabbits were used for this study. Ischemic episodes were induced by compressing the IAA. Laser Doppler cochlear blood flow was measured using a probe positioned at the RW niche. Transtympanic electrocochleography was measured at 4, 8, and 12 kHz. In 5 test ears, dexamethasone was administered topically at the RW for approximately 50 minutes before the IAA compressions, whereas in 5 control ears, saline was applied in the same way. Each ear underwent one 10-minute IAA compression with a 60-minute postischemic period of transtympanic electrocochleography monitoring. Results: In both control- and dexamethasone-treated ears, ischemic episodes measured by Laser Doppler cochlear blood flow were comparable. Fifty minutes after IAA decompression, in dexamethasone-pretreated ears, cochlear microphonic and compound action potential amplitudes at all test frequencies were 10 to 15% less reduced than those in control ears. Compound action potential latencies in dexamethasone-pretreated ears resulted in shorter latency delay than in control ears. Conclusion: The RW seems to be an efficacious route for the administration of dexamethasone into the inner ear. Dexamethasone showed a protective effect on cochlear function after local ischemia. Transtympanic electrocochleography was found to be a sufficient and effective tool in monitoring hearing.

Simultaneous measurement of electrocochleography and cochlear blood flow during cochlear hypoxia in rabbits.

In this study, a new monitoring system is developed to measure cochlear blood flow (CBF) and electrocochleography (ECochG) during transient ischemic episodes of the cochlea. A newly designed otic probe was used for the simultaneous recordings of laser-Doppler CBF and ECochG directly from the round window (RW). The probe enabled the recording of high amplitude compound action potentials (CAP) and cochlear microphonics (CM) with few averages. Experiments were conducted on rabbits to generate episodes of cochlear ischemia by using timed compressions of the internal auditory artery (IAA). The computer monitoring system extracted and measured CAP and CM components from ECochG in real-time. Results indicate that CM and CAP generally followed CBF during compressions and releases of IAA. Both CBF values and CAP amplitudes showed an overshoot following the reperfusion. CAP amplitude measures were found to be very sensitive to ischemia showing very rapid amplitude, latency and morphological changes. CM amplitude decreased more slowly than the CAP and CBF. Simultaneous recordings of CBF and ECochG using the otic probe provide a valuable neuromonitoring tool to investigate the dynamic behavior of the cochlea during ischemia.

A model of real time monitoring of the cochlear function during an induced local ischemia.

The aim of this study was to investigate the utility of distortion product otoacoustic emissions (DPOAEs) in intraoperative monitoring (IM) of cochlear ischemic episodes in animals during internal auditory artery (IAA) compression. The IAA was exposed using the posterior fossa approach and then compressed for 3 and 5 min intervals to effect ischemia. DPOAE amplitudes and phases were measured at 4, 8, and 12 kHz geometric mean frequency (GMF). In each monitored ear, laser-Doppler cochlear blood flow (CBF) was measured. All IAA compressions resulted in rapid decrease of DPOAE amplitude and CBF, with simultaneous DPOAE phase increase. DPOAE phase changes were found to increase consistently within several seconds of IAA compression, while corresponding DPOAE amplitudes changed more slowly, with up to 30-40 s delays. Following IAA release, DPOAEs at 12 kHz GMF were characterized by longer delays in returning to baseline than those measured at lower frequencies. In some cases, CBF did not return to baseline. In this animal model, DPOAEs were found to be sensitive measures of cochlear function during transient cochlear ischemic episodes, suggesting the utility of DPOAE monitoring of auditory function during surgery of cerebello-pontine angle tumors.

Zastosowanie petrosektomii bocznej w patologii ucha i kości skroniowej

Summary Introduction Certain problems in ear surgery are caused by temporal bone cholestetoma and chronic otitis media complicated by deafness, facial nerve dysfunction, vertigo or meningcephalocele. Lateral petrosectomy offers possibility of radical treatment and prevention of temporal bone destruction and following complications. Aim of study It is an analysis of indications for lateral petrosectomy and its results as a treatment of otitis media and temporal bone cholesteatoma. The possibility of synchronous cochlear implantation is noted. Material Retrospective analysis of 62 patients after lateral petrosectomy, operated in the Department of Otolaryngology at the Medical University of Warsaw in 2001–2009. The group consisted of thirty one men and thirty one women. Results Thirty two patients suffered from chronic granuloma or chronic choleateatoma otitis media or temporal bone cholesteatoma. Seventeen patients suffered from deafness prior surgery. Cochlear implantation was possible in five patients: two of them after cranium fracture, two with deafness caused by chronic otitis media and one with deafness caused by osteoradionecrosis. Intraoperative CSF leak was observed of eight patients. In one case lateral perosectomy was used as a treatment of CSF leak after removal of cerebellopontine tumor. There was no evidence of CSF leak after surgery. Facial nerve dysfunction was observed in fifteen cases. Conclusions Lateral petrosectomy offers possibility of radical treatment in same patients with chronic otorrhea. The total removal of cholesteatoma prevents intracranial and intratemporal complications in case of chronic otitis media. Patients after lateral petrosectomy require systematic ENT and radiological (CT, NMR) examination.INTRODUCTION Certain problems in ear surgery are caused by temporal bone cholestetoma and chronic otitis media complicated by deafness, facial nerve dysfunction, vertigo or meningcephalocele. Lateral petrosectomy offers possibility of radical treatment and prevention of temporal bone destruction and following complications. AIM OF STUDY It is an analysis of indications for lateral petrosectomy and its results as a treatment of otitis media and temporal bone cholesteatoma. The possibility of synchronous cochlear implantation is noted. MATERIAL Retrospective analysis of 62 patients after lateral petrosectomy, operated in the Department of Otolaryngology at the Medical University of Warsaw in 2001-2009. The group consisted of thirty one men and thirty one women. RESULTS Thirty two patients suffered from chronic granuloma or chronic choleateatoma otitis media or temporal bone cholesteatoma. Seventeen patients suffered from deafness prior surgery. Cochlear implantation was possible in five patients: two of them after cranium fracture, two with deafness caused by chronic otitis media and one with deafness caused by osteoradionecrosis. Intraoperative CSF leak was observed of eight patients. In one case lateral perosectomy was used as a treatment of CSF leak after removal of cerebellopontine tumor. There was no evidence of CSF leak after surgery. Facial nerve dysfunction was observed in fifteen cases. CONCLUSIONS Lateral petrosectomy offers possibility of radical treatment in same patients with chronic otorrhea. The total removal of cholesteatoma prevents intracranial and intratemporal complications in case of chronic otitis media. Patients after lateral petrosectomy require systematic ENT and radiological (CT, NMR) examination.

Selecting Appropriate Dose Regimens for AM-101 in the Intratympanic Treatment of Acute Inner Ear Tinnitus

Inhibition of cochlear N-methyl-D-aspartate (NMDA) receptors with AM-101, a small molecule antagonist delivered by intratympanic injection, represents a novel approach to treat acute tinnitus triggered by glutamate excitotoxicity. An earlier double-blind, randomized, placebo-controlled phase II clinical trial (TACTT0) had demonstrated a significant and dose-dependent improvement in tinnitus triggered by acute acoustic trauma or otitis media from baseline to day 90. A second phase II trial (TACTT1) now sought to evaluate the most appropriate dose regimen for this treatment. Outcomes from the TACTT1 trial showed no significant difference in tinnitus improvement between a single-dose treatment and a dose regimen comprising three doses over 2 weeks. Taken together, three injections over 3 consecutive days showed the best results in the two phase II trials, suggesting that repeated and concentrated inhibition of cochlear NMDA receptors provides best treatment effects, while keeping the procedural impact on patients short.

Second stage of Universal Neonatal Hearing Screening – A way for diagnosis and beginning of proper treatment for infants with hearing loss

PURPOSE To analyze retrospectively the results of hearing testing in infants at the second stage of the Polish Universal Neonatal Hearing Screening Program carried out in the Department of Otolaryngology at the Medical University of Warsaw. MATERIAL/METHODS A total of 351 infants referred to our Department for the second stage of UNHS were included in the study. There were 39.60% infants referred due to positive result of hearing screening at the first stage of the Program performed in neonatal units, 55.27% with negative screening but risk factors present, and 5.13% without any tests due to equipment failure in the maternity unit. RESULTS Risk factors were identified in 86.61% of the infants. The most frequent ones were hyperbilirubinemia (71.51%), premature birth (63.25%), and ototoxic medication (62.11%). Otoacoustic emission test showed fail results in 17.66% of the infants, and auditory brainstem responses confirmed hearing loss in 16.81%. Correlation between risk factors and confirmed hearing loss was found for hyperbilirubinemia, low birth weight, intensive therapy for at least 7 days, low Apgar scores, and craniofacial abnormalities. CONCLUSIONS The early identification of infants with hearing loss is essential for early intervention. Not only infants who fail the initial screening but also the ones with risk factors of hearing impairment should be referred to the centers that are capable of providing the necessary diagnostic services required for the second stage of the UNHSP. Those two steps are needed to both minimize the risk of overlooking a child with hearing loss and properly diagnose hearing impairment.

Does effect of rehabilitation based on sensory conflicts in patients with vestibular deficits exceed learning effect

OBJECTIVE The purpose was to assess learning and rehabilitation effect and their influence on Sensory Organization Test results in young and elderly patients with peripheral, central and mixed vestibular pathology. MATERIAL AND METHODS 26 patients with different vestibular system deficits participated in this study. Rehabilitation was held five days a week, for two weeks. To assess learning effect, SOT was administered to each patient twice and compared: 1) on the day preceding the beginning of rehabilitation (SOT1), and 2) on the first day of rehabilitation (SOT2). To evaluate rehabilitation effect, results of SOT2 were compared to SOT3 (administered on the last day of rehabilitation). RESULTS Learning effect showed similar improvement in CS in all groups but young. Rehabilitation caused further improvement in CS in all groups but central pathology. This improvement was similar between those groups. There was no significant difference found between learning and rehabilitation effect in CS. CONCLUSIONS The results of our study indicate that none of the groups achieved significant benefit from rehabilitation based on sensory conflicts that would overcome the learning effect. However, the lack of significant advantage of rehabilitation over learning does not mean that it does not exist.