Doxycycline reduces mortality and injury to the brain and cochlea in experimental pneumococcal meningitis

Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 microM in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats.

Frameless linac-based (Novalis TX) stereotactic treatment for vestibular schwannoma that extend distally into the iac (Internal Acoustic Canal): an analysis of the dose to the cochlea

Objectives: We compare the dose parameters between 3 different radiosurgery delivery techniques which may have an impact on cochlea function. Methods: Five patients with unilateral vestibular schwannoma (VS) were selected for this study. Planning procedure was carried out using the BrainLAB® iPlan planning system v. 4.5. For each patient three different planning techniques were used: dynamic arc (DA) with 5 arcs per plan, hybrid arc (HA) with 5 arcs per plan and IMRT with 8 fields per plan. For each technique, two plans were generated with different methods: with the first method (PTV coverage) it was the goal to fully cover the PTV with at least 12 Gy (normalization: 12 Gy covered 99% of the PTV) and with the second method (cochlea sparing) it was the goal to spare the cochlea (normalization: 12 Gy covers 50% of the PTV/V4Gy of cochlea lower than 1%). Plan evaluation was done considering target volume and coverage (conformity and homogeneity) and OAR constraints (mean (Dmean) and maximum dose (Dmax) to cochlea, Dmax to brainstem and cochlea). The total number of monitor units (MU) was analyzed. Results: The median tumor volume was 0.95 cm³ (range, 0.86-3 cm³). The median PTV was 1.44 cm³ (range, 1-3.5 cm³). The median distance between the tumor and the cochlea's modiulus was 2.7 mm (range, 1.8-6.3 mm). For the PTV coverage method, when we compared the cochlear dose in VS patients planned with DA, HA and IMRT, there were no significant differences in Dmax (p = 0.872) and in Dmean (p= 0.860). We found a significant correlation (p< 0.05) between the target volume and the cochlear Dmean for all plans with Pearson's coefficient correlation of 0.90, 0.92 and 0.94 for the DA, HA and IMRT techniques, respectively. For the cochlea sparing method, when we compared the cochlear dose in VS patients planned with DA, HA and IMRT, there were no significant differences in Dmax (p = 0.310) and in Dmean (p= 0.275). However, in this group the V4Gy of the ipsilateral cochlea represents less than 1%. When using the HA or IMRT technique, the homogeneity and conformity in the PTV, but also the number of MUs were increased in comparison to the DA technique. Conclusion: VS tumors that extend distally into the IAC had an equivalent sparing of cochlea with DA approach compared with the HA and IMRT techniques. Disclosure: No significant relationships.

Steady streaming in a two-dimensional box model of a passive cochlea

Acoustic stimulation of the cochlea leads to a travelling wave in the cochlear fluids and on the basilar membrane (BM). It has long been suspected that this travelling wave leads to a steady streaming flow in the cochlea. Theoretical investigations suggested that the steady streaming might be of physiological relevance. Here, we present a quantitative study of the steady streaming in a computational model of a passive cochlea. The structure of the streaming flow is illustrated and the sources of streaming are closely investigated. We describe a source of streaming which has not been considered in the cochlea by previous authors. This source is also related to a steady axial displacement of the BM which leads to a local stretching of this compliant structure. We present theoretical predictions for the streaming intensity which account for these new phenomena. It is shown that these predictions compare well with our numerical results and that there may be steady streaming velocities of the order of millimetres per second. Our results indicate that steady streaming should be more relevant to low-frequency hearing because the strength of the streaming flow rapidly decreases for higher frequencies.

The floating mass transducer at the round window: direct transmission or bone conduction?

The round window placement of a floating mass transducer (FMT) is a new approach for coupling an implantable hearing system to the cochlea. We evaluated the vibration transfer to the cochlear fluids of an FMT placed at the round window (rwFMT) with special attention to the role of bone conduction. A posterior tympanotomy was performed on eleven ears of seven human whole head specimens. Several rwFMT setups were examined using laser Doppler vibrometry measurements at the stapes and the promontory. In three ears, the vibrations of a bone anchored hearing aid (BAHA) and an FMT fixed to the promontory (pFMT) were compared to explore the role of bone conduction. Vibration transmission to the measuring point at the stapes was best when the rwFMT was perpendicularly placed in the round window and underlayed with connective tissue. Fixation of the rwFMT to the round window exhibited significantly lower vibration transmission. Although measurable, bone conduction from the pFMT was much lower than that of the BAHA. Our results suggest that the rwFMT does not act as a small bone anchored hearing aid, but instead, acts as a direct vibratory stimulator of the round window membrane.

Factors improving the vibration transfer of the floating mass transducer at the round window

With the placement of a floating mass transducer (FMT) at the round window, a new approach of coupling an implantable hearing system to the cochlea has been introduced. The aim of the present experimental study is to examine the influence of different ways of FMT placement at the round window on the vibration energy transfer to the cochlea.

Integrating optical fiber force sensors into microforceps for ORL microsurgery

The delicate anatomy of the ear require surgeons to use great care when operating on its internal structures. One example for such an intervention is the stapedectomy, where a small crook shaped piston is placed in the oval window of the cochlea and connected to the incus through crimping thus bypassing the diseased stapes. Performing the crimp process with the correct force is necessary since loose crimps poorly transmit sound whereas tight crimps will eventually result in necrosis of the incus. Clinically, demand is high to reproducibly conduct the crimp process through a precise force measurement. For this reason, we have developed a fiber Bragg grating (FBG) integrated microforceps for use in such interventions. This device was calibrated, and tested in cadaver preparations. With this instrument we were able to measure for the first time forces involved in crimping a stapes prosthesis to the incus. We also discuss a method of attaching and actuating such forceps in conjunction with a robot currently under development in our group. Each component of this system can be used separately or combined to improve surgical accuracy, confidence and outcome.

Surgical planning tool for robotically assisted hearing aid implantation

PURPOSE : For the facilitation of minimally invasive robotically performed direct cochlea access (DCA) procedure, a surgical planning tool which enables the surgeon to define landmarks for patient-to-image registration, identify the necessary anatomical structures and define a safe DCA trajectory using patient image data (typically computed tomography (CT) or cone beam CT) is required. To this end, a dedicated end-to-end software planning system for the planning of DCA procedures that addresses current deficiencies has been developed. METHODS :    Efficient and robust anatomical segmentation is achieved through the implementation of semiautomatic algorithms; high-accuracy patient-to-image registration is achieved via an automated model-based fiducial detection algorithm and functionality for the interactive definition of a safe drilling trajectory based on case-specific drill positioning uncertainty calculations was developed. RESULTS :    The accuracy and safety of the presented software tool were validated during the conduction of eight DCA procedures performed on cadaver heads. The plan for each ear was completed in less than 20 min, and no damage to vital structures occurred during the procedures. The integrated fiducial detection functionality enabled final positioning accuracies of [Formula: see text] mm. CONCLUSIONS :    Results of this study demonstrated that the proposed software system could aid in the safe planning of a DCA tunnel within an acceptable time.

Differential distribution of stem cells in the auditory and vestibular organs of the inner ear

The adult mammalian cochlea lacks regenerative capacity, which is the main reason for the permanence of hearing loss. Vestibular organs, in contrast, replace a small number of lost hair cells. The reason for this difference is unknown. In this work we show isolation of sphere-forming stem cells from the early postnatal organ of Corti, vestibular sensory epithelia, the spiral ganglion, and the stria vascularis. Organ of Corti and vestibular sensory epithelial stem cells give rise to cells that express multiple hair cell markers and express functional ion channels reminiscent of nascent hair cells. Spiral ganglion stem cells display features of neural stem cells and can give rise to neurons and glial cell types. We found that the ability for sphere formation in the mouse cochlea decreases about 100-fold during the second and third postnatal weeks; this decrease is substantially faster than the reduction of stem cells in vestibular organs, which maintain their stem cell population also at older ages. Coincidentally, the relative expression of developmental and progenitor cell markers in the cochlea decreases during the first 3 postnatal weeks, which is in sharp contrast to the vestibular system, where expression of progenitor cell markers remains constant or even increases during this period. Our findings indicate that the lack of regenerative capacity in the adult mammalian cochlea is either a result of an early postnatal loss of stem cells or diminishment of stem cell features of maturing cochlear cells.

A two-microphone noise reduction system for cochlear implant users with nearby microphones. Part I: Signal processing algorithm design and development

Users of cochlear implant systems, that is, of auditory aids which stimulate the auditory nerve at the cochlea electrically, often complain about poor speech understanding in noisy environments. Despite the proven advantages of multimicrophone directional noise reduction systems for conventional hearing aids, only one major manufacturer has so far implemented such a system in a product, presumably because of the added power consumption and size. We present a physically small (intermicrophone distance 7 mm) and computationally inexpensive adaptive noise reduction system suitable for behind-the-ear cochlear implant speech processors. Supporting algorithms, which allow the adjustment of the opening angle and the maximum noise suppression, are proposed and evaluated. A portable real-time device for test in real acoustic environments is presented.

Isolation of sphere-forming stem cells from the mouse inner ear

The mammalian inner ear has very limited ability to regenerate lost sensory hair cells. This deficiency becomes apparent when hair cell loss leads to hearing loss as a result of either ototoxic insult or the aging process. Coincidently, with this inability to regenerate lost hair cells, the adult cochlea does not appear to harbor cells with a proliferative capacity that could serve as progenitor cells for lost cells. In contrast, adult mammalian vestibular sensory epithelia display a limited ability for hair cell regeneration, and sphere-forming cells with stem cell features can be isolated from the adult murine vestibular system. The neonatal inner ear, however, does harbor sphere-forming stem cells residing in cochlear and vestibular tissues. Here, we provide protocols to isolate sphere-forming stem cells from neonatal vestibular and cochlear sensory epithelia as well as from the spiral ganglion. We further describe procedures for sphere propagation, cell differentiation, and characterization of inner ear cell types derived from spheres. Sphere-forming stem cells from the mouse inner ear are an important tool for the development of cellular replacement strategies of damaged inner ears and are a bona fide progenitor cell source for transplantation studies.

Cochlear implantation in children and adults in Switzerland

The cochlear implant (CI) is one of the most successful neural prostheses developed to date. It offers artificial hearing to individuals with profound sensorineural hearing loss and with insufficient benefit from conventional hearing aids. The first implants available some 30 years ago provided a limited sensation of sound. The benefit for users of these early systems was mostly a facilitation of lip-reading based communication rather than an understanding of speech. Considerable progress has been made since then. Modern, multichannel implant systems feature complex speech processing strategies, high stimulation rates and multiple sites of stimulation in the cochlea. Equipped with such a state-of-the-art system, the majority of recipients today can communicate orally without visual cues and can even use the telephone. The impact of CIs on deaf individuals and on the deaf community has thus been exceptional. To date, more than 300,000 patients worldwide have received CIs. In Switzerland, the first implantation was performed in 1977 and, as of 2012, over 2,000 systems have been implanted with a current rate of around 150 CIs per year. The primary purpose of this article is to provide a contemporary overview of cochlear implantation, emphasising the situation in Switzerland.

Audiologie

Dieses Lehrbuch erklärt eingehend und leicht fassbar alle gängigen Methoden der Gehörsabklärung bei Erwachsenen und Kindern. Reintonaudiometrie, Vertäubung, Sprachaudiometrie in Ruhe und im Störschall, Tympanometrie, die Messung otoakustischer Emissionen und die Ableitung und Auswertung auditorisch evozierter Potenziale werden anhand von zahlreichen Schemazeichnungen und typischen Befunden anschaulich dargestellt. Informative Kapitel über Hörgeräte, Cochlea-Implantate und Tinnitus geben eine Übersicht über Möglichkeiten und Grenzen moderner therapeutischer Ansätze.

In vitro accuracy evaluation of image-guided robot system for direct cochlear access

HYPOTHESIS A previously developed image-guided robot system can safely drill a tunnel from the lateral mastoid surface, through the facial recess, to the middle ear, as a viable alternative to conventional mastoidectomy for cochlear electrode insertion. BACKGROUND Direct cochlear access (DCA) provides a minimally invasive tunnel from the lateral surface of the mastoid through the facial recess to the middle ear for cochlear electrode insertion. A safe and effective tunnel drilled through the narrow facial recess requires a highly accurate image-guided surgical system. Previous attempts have relied on patient-specific templates and robotic systems to guide drilling tools. In this study, we report on improvements made to an image-guided surgical robot system developed specifically for this purpose and the resulting accuracy achieved in vitro. MATERIALS AND METHODS The proposed image-guided robotic DCA procedure was carried out bilaterally on 4 whole head cadaver specimens. Specimens were implanted with titanium fiducial markers and imaged with cone-beam CT. A preoperative plan was created using a custom software package wherein relevant anatomical structures of the facial recess were segmented, and a drill trajectory targeting the round window was defined. Patient-to-image registration was performed with the custom robot system to reference the preoperative plan, and the DCA tunnel was drilled in 3 stages with progressively longer drill bits. The position of the drilled tunnel was defined as a line fitted to a point cloud of the segmented tunnel using principle component analysis (PCA function in MatLab). The accuracy of the DCA was then assessed by coregistering preoperative and postoperative image data and measuring the deviation of the drilled tunnel from the plan. The final step of electrode insertion was also performed through the DCA tunnel after manual removal of the promontory through the external auditory canal. RESULTS Drilling error was defined as the lateral deviation of the tool in the plane perpendicular to the drill axis (excluding depth error). Errors of 0.08 ± 0.05 mm and 0.15 ± 0.08 mm were measured on the lateral mastoid surface and at the target on the round window, respectively (n =8). Full electrode insertion was possible for 7 cases. In 1 case, the electrode was partially inserted with 1 contact pair external to the cochlea. CONCLUSION The purpose-built robot system was able to perform a safe and reliable DCA for cochlear implantation. The workflow implemented in this study mimics the envisioned clinical procedure showing the feasibility of future clinical implementation.

Estimation of tool pose based on force-density correlation during robotic drilling

The application of image-guided systems with or without support by surgical robots relies on the accuracy of the navigation process, including patient-to-image registration. The surgeon must carry out the procedure based on the information provided by the navigation system, usually without being able to verify its correctness beyond visual inspection. Misleading surrogate parameters such as the fiducial registration error are often used to describe the success of the registration process, while a lack of methods describing the effects of navigation errors, such as those caused by tracking or calibration, may prevent the application of image guidance in certain accuracy-critical interventions. During minimally invasive mastoidectomy for cochlear implantation, a direct tunnel is drilled from the outside of the mastoid to a target on the cochlea based on registration using landmarks solely on the surface of the skull. Using this methodology, it is impossible to detect if the drill is advancing in the correct direction and that injury of the facial nerve will be avoided. To overcome this problem, a tool localization method based on drilling process information is proposed. The algorithm estimates the pose of a robot-guided surgical tool during a drilling task based on the correlation of the observed axial drilling force and the heterogeneous bone density in the mastoid extracted from 3-D image data. We present here one possible implementation of this method tested on ten tunnels drilled into three human cadaver specimens where an average tool localization accuracy of 0.29 mm was observed.

Feasibility of Using EMG for Early Detection of the Facial Nerve During Robotic Direct Cochlear Access

HYPOTHESIS Facial nerve monitoring can be used synchronous with a high-precision robotic tool as a functional warning to prevent of a collision of the drill bit with the facial nerve during direct cochlear access (DCA). BACKGROUND Minimally invasive direct cochlear access (DCA) aims to eliminate the need for a mastoidectomy by drilling a small tunnel through the facial recess to the cochlea with the aid of stereotactic tool guidance. Because the procedure is performed in a blind manner, structures such as the facial nerve are at risk. Neuromonitoring is a commonly used tool to help surgeons identify the facial nerve (FN) during routine surgical procedures in the mastoid. Recently, neuromonitoring technology was integrated into a commercially available drill system enabling real-time monitoring of the FN. The objective of this study was to determine if this drilling system could be used to warn of an impending collision with the FN during robot-assisted DCA. MATERIALS AND METHODS The sheep was chosen as a suitable model for this study because of its similarity to the human ear anatomy. The same surgical workflow applicable to human patients was performed in the animal model. Bone screws, serving as reference fiducials, were placed in the skull near the ear canal. The sheep head was imaged using a computed tomographic scanner and segmentation of FN, mastoid, and other relevant structures as well as planning of drilling trajectories was carried out using a dedicated software tool. During the actual procedure, a surgical drill system was connected to a nerve monitor and guided by a custom built robot system. As the planned trajectories were drilled, stimulation and EMG response signals were recorded. A postoperative analysis was achieved after each surgery to determine the actual drilled positions. RESULTS Using the calibrated pose synchronized with the EMG signals, the precise relationship between distance to FN and EMG with 3 different stimulation intensities could be determined for 11 different tunnels drilled in 3 different subjects. CONCLUSION From the results, it was determined that the current implementation of the neuromonitoring system lacks sensitivity and repeatability necessary to be used as a warning device in robotic DCA. We hypothesize that this is primarily because of the stimulation pattern achieved using a noninsulated drill as a stimulating probe. Further work is necessary to determine whether specific changes to the design can improve the sensitivity and specificity.