RORγt⁺ innate lymphoid cells acquire a proinflammatory program upon engagement of the activating receptor NKp44.

RORγt⁺ innate lymphoid cells (ILCs) are crucial players of innate immune responses and represent a major source of interleukin-22 (IL-22), which has an important role in mucosal homeostasis. The signals required by RORγt⁺ ILCs to express IL-22 and other cytokines have been elucidated only partially. Here we showed that RORγt⁺ ILCs can directly sense the environment by the engagement of the activating receptor NKp44. NKp44 triggering in RORγt⁺ ILCs selectively activated a coordinated proinflammatory program, including tumor necrosis factor (TNF), whereas cytokine stimulation preferentially induced IL-22 expression. However, combined engagement of NKp44 and cytokine receptors resulted in a strong synergistic effect. These data support the concept that NKp44⁺ RORγt⁺ ILCs can be activated without cytokines and are able to switch between IL-22 or TNF production, depending on the triggering stimulus.

Gender-specific risk factors in post-tonsillectomy hemorrhage.

There are gender-specific differences in the frequency and course of different diseases. Specifically, some studies have shown an increased risk of post-tonsillectomy hemorrhage (PTH). The aim of the study was to investigate gender-specific risk factors for hemorrhage after tonsillectomy (TE)/abscess-TE. We anonymously reviewed and recorded the relevant data of all patients (≥14 years) who underwent a TE/abscess-TE between 2011 and 2013 in the ENT Clinic of the Charité Universitätsmedizin Berlin, Campus Benjamin Franklin. A patient survey was used to complete missing data. We analyzed gender-specific risk factors for PTH. During the study period, 460 operations were performed and the data of 250 patients were analyzed (213 TE and 37 abscess-TE). The median patient age was 27 years (ranging from 14 to 83 years). The rate of primary PTH (<24 h after TE/abscess-TE) was 3 %, and the rate of secondary PTH (>24 h) was 23 %. A significantly higher PTH rate was associated with males (p = 0.037), which was still apparent in ages 21-30 after sub-classification. Multivariate analysis calculated diagnosis, regular alcohol consumption and administration of glucocorticoids to be independent risk factors associated with gender. In conclusion, the PTH rate is gender-specific, and male patients are at higher risk, especially in young adulthood. Therefore, doctors should advise male patients of the increased risk of bleeding and stress the importance of compliance. Also, close postoperative follow-up is desirable.

Meta-analysis of survival in patients with HNSCC discriminates risk depending on combined HPV and p16 status.

Data indicate a better prognosis for human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). HPV and p16 detection are established markers for HPV-related HNSCC. Both are accepted as survival-independent predictors. Previous studies investigating the survival in HNSCC patients depending on HPV(+/-) and p16(+/-) status consistently found discordant results with p16(-)/HPV(+) and p16(+)/HPV(-). However, no meta-analysis regarding the survival according to combined HPV/p16 status has been performed yet. The objective of this study was to discriminate the impact of combined HPV(+/-) and p16(+/-) status on survival. Data sources were identification and review of publications assessing survival of the distinct subgroups with both p16 and HPV investigated in HNSCC until February, 2015. A meta-analysis was performed to classify survival and clinical outcomes. 18 out of 397 articles (4424 patients) were eligible for the meta-analysis. The percent proportion of the subgroups was 25 % for HPV(+)/p16(+), 61.2 % for HPV(-)/p16(-), 7.1 % for HPV(-)/p16(+) and 6.8 % for HPV(+)/P16(-). The meta-analysis showed a significantly improved 5-year overall survival (OS), 5-year disease-free survival and their corresponding hazard ratio for HPV(+)/p16(+) HNSCC in comparison to HPV(-)/p16(-), HPV(+)/p16(-) and HPV(-)/p16(+). The 5-year OS of the HPV(-)/p16(+) subgroup was intermediate while HPV(+)/p16(-) and HPV(-)/p16(-) HNSCC had the shortest survival. With current therapeutic strategies, survival of patients with HNSCC is better if associated with HPV(+)/p16(+) or HPV(-)/p16(+). Clinical trials are needed to confirm the distinct survival pattern and to investigate possible differences in survival for HPV(+)/p16(-) and HPV(-)/p16(+) HNSCC. To further differentiate p16(+) HNSCC, HPV testing may be advisable.

Alterations in early auditory evoked potentials and brainstem transmission time associated with tinnitus residual inhibition induced by auditory electrical stimulation.

INTRODUCTION: Residual inhibition (RI) is the temporary inhibition of tinnitus by use of masking stimuli when the device is turned off. OBJECTIVE: The main aim of this study was to evaluate the effects of RI induced by auditory electrical stimulation (AES) in the primary auditory pathways using early auditory-evoked potentials (AEPs) in subjective idiopathic tinnitus (SIT) subjects. MATERIALS AND METHODS: A randomized placebo-controlled study was conducted on forty-four tinnitus subjects. All enrolled subjects based on the responses to AES, were divided into two groups of RI and Non-RI (NRI). The results of the electrocochleography (ECochG), auditory brain stem response (ABR) and brain stem transmission time (BTT) were determined and compared pre- and post-AES in the studied groups. RESULTS: The mean differences in the compound action potential (CAP) amplitudes and III/V and I/V amplitude ratios were significantly different between the RI, NRI and PES controls. BTT was significantly decreased associated with RI. CONCLUSION: The observed changes in AEP associated with RI suggested some peripheral and central auditory alterations. Synchronized discharges of the auditory nerve fibers and inhibition of the abnormal activity of the cochlear nerve by AES may play important roles associated with RI. Further comprehensive studies are required to determine the mechanisms of RI more precisely.

Coactivation of different neurons within an isofrequency lamina of the inferior colliculus elicits enhanced auditory cortical activation.

The phenomenal success of the cochlear implant (CI) is attributed to its ability to provide sufficient temporal and spectral cues for speech understanding. Unfortunately, the CI is ineffective for those without a functional auditory nerve or an implantable cochlea required for CI implementation. As an alternative, our group developed and implanted in deaf patients a new auditory midbrain implant (AMI) to stimulate the central nucleus of the inferior colliculus (ICC). Although the AMI can provide frequency cues, it appears to insufficiently transmit temporal cues for speech understanding. The three-dimensional ICC consists of two-dimensional isofrequency laminae. The single-shank AMI only stimulates one site in any given ICC lamina and does not exhibit enhanced activity (i.e., louder percepts or lower thresholds) for repeated pulses on the same site with intervals <2-5 ms, as occurs for CI pulse or acoustic click stimulation. This enhanced activation, related to short-term temporal integration, is important for tracking the rapid temporal fluctuations of a speech signal. Therefore, we investigated the effects of coactivation of different regions within an ICC lamina on primary auditory cortex activity in ketamine-anesthetized guinea pigs. Interestingly, our findings reveal an enhancement mechanism for integrating converging inputs from an ICC lamina on a fast scale (<6-ms window) that is compromised when stimulating just a single ICC location. Coactivation of two ICC regions also reduces the strong and long-term (>100 ms) suppressive effects induced by repeated stimulation of just a single location. Improving AMI performance may require at least two shanks implanted along the tonotopic gradient of the ICC that enables coactivation of multiple regions along an ICC lamina with the appropriate interstimulus delays.

Auditory midbrain implant: a review.

The auditory midbrain implant (AMI) is a new hearing prosthesis designed for stimulation of the inferior colliculus in deaf patients who cannot sufficiently benefit from cochlear implants. The authors have begun clinical trials in which five patients have been implanted with a single shank AMI array (20 electrodes). The goal of this review is to summarize the development and research that has led to the translation of the AMI from a concept into the first patients. This study presents the rationale and design concept for the AMI as well a summary of the animal safety and feasibility studies that were required for clinical approval. The authors also present the initial surgical, psychophysical, and speech results from the first three implanted patients. Overall, the results have been encouraging in terms of the safety and functionality of the implant. All patients obtain improvements in hearing capabilities on a daily basis. However, performance varies dramatically across patients depending on the implant location within the midbrain with the best performer still not able to achieve open set speech perception without lip-reading cues. Stimulation of the auditory midbrain provides a wide range of level, spectral, and temporal cues, all of which are important for speech understanding, but they do not appear to sufficiently fuse together to enable open set speech perception with the currently used stimulation strategies. Finally, several issues and hypotheses for why current patients obtain limited speech perception along with several feasible solutions for improving AMI implementation are presented.

Artifacts caused by cochlear implants with non-removable magnets in 3T MRI: phantom and cadaveric studies.

The aim of this study was to evaluate artifacts produced by cochlear implants (CI) during 3.0 Tesla (T) magnetic resonance imaging of the brain using different sequences on phantom and cadaveric specimens. A phantom and three cadaveric specimens with CIs were imaged using a 3.0 T clinical scanner. Artifacts were analyzed quantitatively and according to the sequence used. Different brain regions were evaluated for image distortion and limitation of diagnostic significance. In cadaver studies, all sequences generated signal-void areas around the implant. In T2-weighted sequences, additional periodic shadowing was discovered. Anatomical structures of the brain on the contralateral side of the CI were for the most part undistorted. At 3T, artifacts around CIs with non-removable magnets compromise image quality of the nearby brain regions and diagnosis of brain lesions is limited. In the contralateral hemisphere, diagnostic accuracy is only marginally limited.

Electrical stimulation of the midbrain for hearing restoration: insight into the functional organization of the human central auditory system.

The cochlear implant can restore speech perception in patients with sensorineural hearing loss. However, it is ineffective for those without an implantable cochlea or a functional auditory nerve. These patients can be implanted with the auditory brainstem implant (ABI), which stimulates the surface of the cochlear nucleus. Unfortunately, the ABI has achieved limited success in its main patient group [i.e., those with neurofibromatosis type 2 (NF2)] and requires a difficult surgical procedure. These limitations have motivated us to develop a new hearing prosthesis that stimulates the midbrain with a penetrating electrode array. We recently implanted three patients with the auditory midbrain implant (AMI), and it has proven to be safe with minimal movement over time. The AMI provides loudness, pitch, temporal, and directional cues, features that have shown to be important for speech perception and more complex sound processing. Thus far, all three patients obtain enhancements in lip reading capabilities and environmental awareness and some improvements in speech perception comparable with that of NF2 ABI patients. Considering that our midbrain target is more surgically exposable than the cochlear nucleus, this argues for the use of the AMI as an alternative to the ABI. Fortunately, we were able to stimulate different midbrain regions in our patients and investigate the functional organization of the human central auditory system. These findings provide some insight into how we may need to stimulate the midbrain to improve hearing performance with the AMI.

The auditory midbrain implant: effects of electrode location.

The auditory midbrain implant (AMI) is a new hearing prosthesis designed for stimulation of the inferior colliculus in patients who do not receive sufficient benefit from cochlear or brainstem prostheses. We have begun clinical trials in which three patients have been implanted with the AMI. Although the intended target was the central nucleus of the inferior colliculus (ICC), the electrode array was implanted into different locations across patients (i.e., ICC, dorsal cortex of inferior colliculus, lateral lemniscus). In this paper, we will summarize the effects of electrical stimulation of these different midbrain regions on various psychophysical properties and speech perception performance. The patient implanted within the intended target, the ICC, exhibited the greatest improvements in hearing performance. However, this patient has not yet achieved open-set speech perception to the performance level typically observed for cochlear implant patients, which we believe is partially due to the location of the array within the ICC. We will present findings from previous AMI studies in guinea pigs demonstrating the existence of spatially distinct functional output regions within the ICC and suggesting that further improvements in performance may be achieved by stimulating within a rostral-ventral region. Remaining questions include if a similar organization exists in the human ICC and if stimulation of its rostral-ventral region with currently available strategies (i.e., those designed for cochlear implants) can restore sufficient speech perception.

Demagnetization of cochlear implants and temperature changes in 3.0T MRI environment.

OBJECTIVE: To investigate the level of demagnetization of the magnets and temperature changes in cochlear implants (Cis) in a 3.0 tesla (3.0T) MRI. STUDY DESIGN: Experimental. SUBJECTS AND METHODS: Demagnetization and remagnetization measurements were done on magnets for different types of CIs. Temperature of different body and electrode sides was measured in the MRI environment. RESULTS: Demagnetization of the magnets of the CI is dependent on the angle between the magnetic field of the CI magnet and the MRI. When this angle was greater than 80 degrees, relevant demagnetization occurred and sufficient remagnetization was not possible with the 3.0T MRI magnet. Maximum temperature rise was 0.5 degrees C. CONCLUSIONS: Patients carrying CIs with non-removable magnets should not enter a 3.0T MRI device in a routine clinical setup. Under special conditions (angle between the two magnets less than 80 degrees) imaging in a 3.0T MRI may be possible without harming the patient or the implant.

A true minimally invasive approach for cochlear implantation: high accuracy in cranial base navigation through flat-panel-based volume computed tomography.

OBJECTIVE: High-precision intraoperative navigation using high-resolution flat-panel volume computed tomography makes feasible the possibility of minimally invasive cochlear implant surgery, including cochleostomy. Conventional cochlear implant surgery is typically performed via mastoidectomy with facial recess to identify and avoid damage to vital anatomic landmarks. To accomplish this procedure via a minimally invasive approach--without performing mastoidectomy--in a precise fashion, image-guided technology is necessary. With such an approach, surgical time and expertise may be reduced, and hearing preservation may be improved. INTERVENTIONS: Flat-panel volume computed tomography was used to scan 4 human temporal bones. A drilling channel was planned preoperatively from the mastoid surface to the round window niche, providing a margin of safety to all functional important structures (e.g., facial nerve, chorda tympani, incus). MAIN OUTCOME MEASURES: Postoperatively, computed tomographic imaging and conventional surgical exploration of the drilled route to the cochlea were performed. RESULTS: All 4 specimens showed a cochleostomy located at the scala tympani anterior inferior to the round window. The chorda tympani was damaged in 1 specimen--this was preoperatively planned as a narrow facial recess was encountered. CONCLUSION: Using flat-panel volume computed tomography for image-guided surgical navigation, we were able to perform minimally invasive cochlear implant surgery defined as a narrow, single-channel mastoidotomy with cochleostomy. Although this finding is preliminary, it is technologically achievable.

Auditory midbrain implant: a combined approach for vestibular schwannoma surgery and device implantation.

HYPOTHESIS: The lateral suboccipital approach is a well-established route for safe removal of vestibular schwannomas in neurofibromatosis Type 2 (NF2) patients. The goal of this study was to assess if this approach can be extended to a lateral supracerebellar infratentorial approach to enable insertion of an auditory midbrain implant (AMI) penetrating array along the tonotopic gradient of the inferior colliculus central nucleus (ICC). BACKGROUND: The AMI is a new auditory prosthesis designed for penetrating stimulation of the ICC in patients with neural deafness. The initial candidates are NF2 patients who, because of the growth and/or surgical removal of bilateral acoustic neuromas, develop neural deafness and are unable to benefit from cochlear implants. The ideal surgical approach in NF2 patients must first enable safe removal of vestibular schwannomas and then provide sufficient exposure of the midbrain for AMI implantation. METHODS: This study was performed on formalin-fixed and fresh cadaver specimens. Computed tomography scan and magnetic resonance imaging were used to study the heads of the specimens and for surgical navigation. RESULTS: The lateral suboccipital craniotomy enabled sufficient exposure of the cerebellopontine angle and internal auditory canal for tumor removal. It could then be extended to a lateral supracerebellar infratentorial approach that provided good exposure of the dorsolateral aspect of the tentorial hiatus and mesencephalon for implantation of the AMI along the tonotopic gradient of the ICC. This approach did not endanger the trochlear nerve or any major midline venous structures in the quadrigeminal cistern. CONCLUSION: This modified lateral suboccipital approach ensures safe removal of large vestibular schwannomas and provides sufficient exposure of the inferior colliculus for ideal AMI implantation.

Auditory midbrain implant: histomorphologic effects of long-term implantation and electric stimulation of a new deep brain stimulation array.

HYPOTHESIS: Chronic implantation and electric stimulation with a human prototype auditory midbrain implant (AMI) array within the inferior colliculus achieves minimal neuronal damage and does not cause any severe complications. BACKGROUND: An AMI array has been developed for patients with neural deafness and, based on animal studies, has shown to possess potential as an auditory prosthesis in humans. To investigate the safety of the AMI for clinical use, we characterized the histomorphologic effects of chronic implantation and stimulation within its target structure, the inferior colliculus. METHODS: Eight cats were chronically implanted for 3 months, and histologic sections were analyzed to assess long-term tissue effects. Four of the 8 cats were additionally stimulated for 60 days (4 h/d) starting 4 weeks after implantation to assess if clinically relevant stimuli further affected the tissue response. RESULTS: In general, both neurons and neuropil surrounding the implant track were apparently unaffected, whereas a fibrillary sheath (approximately 50 microm thick) developed around the array. There was a significant decrease in neuron density 50 to 100 microm away from the track with a significantly elevated number of glial cells out to approximately 250 to 350 microm. Chronic stimulation seemed to improve the tissue response and neuronal survival around the implant, although further studies are needed to confirm this finding. CONCLUSION: The histomorphologic effects and extent of neuronal damage observed for our AMI array are similar to those of other neural implants currently and safely used in humans. The minimal tissue damage surrounding the implanted array is encouraging with regard to the safety of the array for human use.

Primary central nervous system lymphoma presenting as bilateral tumors of the internal auditory canal.

The increasing incidence of central nervous system (CNS) lymphoma in the general population, especially in young adults with AIDS, should alert the otolaryngologist that in future there will be an even greater incidence of this rare disease. It may be responsible for hearing loss accompanied by other neurological deficits. CNS lymphoma often has a rapidly progressive course. Early diagnosis and rapid therapy are crucial for a better prognosis. We report a case of primary CNS lymphoma involving both internal auditory canals that presented with sudden deafness and disequilibrium accompanied by facial and abducens nerve palsy.

A case of multiple primary tumors of the anterior skull base.

We report a case of synchronous olfactory bulb meningioma and undifferentiated carcinoma of the nose and paranasal sinuses that involved and destroyed the anterior skull base and mimicked intracranial invasion by a carcinoma. The heterogeneity of tissue types in the skull base gives rise to a diverse variety of benign and malignant neoplasms which have totally different prognoses. Synchronous development of benign and malignant primary tumors both originating from and involving the skull base at the same location is very rare and may cause confusion for both the skull base surgeon and neuroradiologist.

Active middle ear implant coupled bilaterally to the round window despite bilateral implanted stapes prostheses.

After stapes surgery, patients with mixed or moderate hearing loss have limited possibilities for hearing improvement. We are reporting on a patient who underwent stapedotomy bilaterally 20 years ago and had sensorineural and mixed hearing loss. Recurrent otitis externa prevented the use of hearing aids. This patient was treated bilaterally with the Vibrant Soundbridge (Med-El, Innsbruck, Austria) successively. The Schuknecht piston stapes prostheses remained in situ. The Floating Mass Transducer (FMT; Med-El) was coupled to the round window (RW) and provided good acoustic reinforcement bilaterally. In conclusion, for patients with otosclerosis and stapes surgery, the FMT-RW coupling (Bess AG, Berlin, DE) is a safe procedure with good acoustic amplification. Laryngoscope, 2016 127:500-503, 2017.

Medial and mediolateral orbital decompression in intractable Graves' Orbitopathy.

OBJECTIVE: Graves' Orbitopathy (GO) has well established treatment guidelines; however, its management is still controversial. The aim was to evaluate the results of medial and mediolateral orbital decompression (OD) in intractable GO. METHODS: Retrospective chart review of all patients with advanced stages of GO, who underwent medial (1-wall) or mediolateral (2-wall) OD between May 2012 and November 2014 in our institution. Ophthalmologic examinations included visual acuity, Hertel exophthalmometry (proptosis), intraocular pressure (IOP), visual field (30:2) and diplopia. Follow-up was performed 1 week, 3 months and 1 year postoperatively. Additionally, a questionnaire was used to investigate subjective benefits. RESULTS: The study included 34 eyes of 20 patients. In our study, GO patients who underwent mediolateral OD had significantly higher IOP preoperatively (p<0.05) and lower visual acuity, proptosis and visual field compared with patients who underwent medial OD. After 1- and 2-wall OD, visual acuity, proptosis, visual field and IOP in upgaze improved significantly. Using a questionnaire, the patients reported significant improvements in impaired vision, eye pain and pressure, vitality and social life. 94% of all patients reported they would repeat the operation. After 2-wall OD, the surgical scar had little effect. CONCLUSION: With GO patients in advanced stages, both medial (1-wall) and mediolateral (2-wall) OD procedures are convincing therapeutic options. In more advanced GO stages with high IOP, 2-wall OD should be prioritized, as mediolateral OD had superior long-term functional outcomes.

Electrophysiological validation of a human prototype auditory midbrain implant in a guinea pig model.

The auditory midbrain implant (AMI) is a new treatment for hearing restoration in patients with neural deafness or surgically inaccessible cochleae who cannot benefit from cochlear implants (CI). This includes neurofibromatosis type II (NF2) patients who, due to development and/or removal of vestibular schwannomas, usually experience complete damage of their auditory nerves. Although the auditory brainstem implant (ABI) provides sound awareness and aids lip-reading capabilities for these NF2 patients, it generally only achieves hearing performance levels comparable with a single-channel CI. In collaboration with Cochlear Ltd. (Lane Cove, Australia), we developed a human prototype AMI, which is designed for electrical stimulation along the well-defined tonotopic gradient of the inferior colliculus central nucleus (ICC). Considering that better speech perception and hearing performance has been correlated with a greater number of discriminable frequency channels of information available, the ability of the AMI to effectively activate discrete frequency regions within the ICC may enable better hearing performance than achieved by the ABI. Therefore, the goal of this study was to investigate if our AMI array could achieve low-threshold, frequency-specific activation within the ICC, and whether the levels for ICC activation via AMI stimulation were within safe limits for human application. We electrically stimulated different frequency regions within the ICC via the AMI array and recorded the corresponding neural activity in the primary auditory cortex (A1) using a multisite silicon probe in ketamine-anesthetized guinea pigs. Based on our results, AMI stimulation achieves lower thresholds and more localized, frequency-specific activation than CI stimulation. Furthermore, AMI stimulation achieves cortical activation with current levels that are within safe limits for central nervous system stimulation. This study confirms that our AMI design is sufficient for ensuring safe and effective activation of the ICC, and warrants further studies to translate the AMI into clinical application.

The auditory midbrain implant: a new auditory prosthesis for neural deafness-concept and device description.

The auditory midbrain implant (AMI) is a new central auditory prosthesis designed for penetrating stimulation of the human inferior colliculus. The major group of candidates for the AMI consists of neurofibromatosis type 2 (NF2) patients who develop neural deafness because of growth and/or surgical removal of bilateral acoustic neuromas. Because of the absence of a viable auditory nerve, these patients cannot benefit from cochlear implants. An alternative solution has been the auditory brainstem implant (ABI), which stimulates the cochlear nucleus. However, speech perception performance in NF2 ABI patients has been limited. The fact that the ABI is able to produce high levels of speech perception in nontumor patients (with inaccessible cochleae or posttraumatic damage to the cochlear nerve) suggests that limitations in ABI performance in NF2 patients may be associated with cochlear nucleus damage caused by the tumors or the tumor removal process. Thus, stimulation of the auditory midbrain proximal to the damaged cochlear nucleus may be a better alternative for hearing restoration in NF2 patients. We propose the central nucleus of the inferior colliculus (ICC) as the potential site. A penetrating electrode array aligned along the well-defined tonotopic gradient of the ICC should selectively activate different frequency regions, which is an important elementfor supporting good speech understanding. The goal of this article is to present the ICC as an alternative site for an auditory implant for NF2 patients and to describe the design of the first human prototype AMI. Practical considerations for implementation of the AMI will also be discussed.