[On the interdisciplinary S3 guidelines for the treatment of chronic idiopathic tinnitus]. / Zur interdisziplinären S3-Leitlinie für die Therapie des chronisch-idiopathischen Tinnitus.

INTRODUCTION: Tinnitus is a frequent symptom, which, particularly in combination with comorbidities, can result in a severe disease-related burden. Chronic idiopathic tinnitus (CIT) is the most frequent type of tinnitus. A considerable number of treatment strategies are used to treat CIT-for many of which there is no evidence of efficacy. In order to enable scientific evidence-based treatment of CIT, German interdisciplinary S3 guidelines have recently been constructed for the first time. Here we present a short form of these S3 guidelines. MATERIALS AND METHODS: The guidelines were constructed based on a meta-analysis of the treatment of chronic tinnitus performed by the authors. Additionally, a systematic literature search was performed in the PubMed and Cochrane Library databases. Furthermore, a systematic search for international guidelines was performed in Google, as well as in the Guidelines International Network and National Guideline Clearinghouse (USA) database. Evidence was classified according to the Oxford Centre for Evidence-Based Medicine system. RESULTS: According to the guidelines, alongside counselling, manualized structured tinnitus-specific cognitive behavioral therapy (tCBT) with a validated treatment manual is available as evidence-based therapy. In addition, the guidelines recommend concurrent treatment of comorbidities, including drug-based treatment, where appropriate. Particularly important is treatment of anxiety and depression. Where a psychic or psychiatric comorbidity is suspected, further diagnosis and treatment should be performed by an appropriately qualified specialist (psychiatrist, neurologist, psychosomatic medicine consultant) or psychological psychotherapist. In cases accompanied by deafness or hearing loss bordering on deafness, cochlear implants may be indicated. CONCLUSION: No recommendations can be made for drug-based treatment of CIT, audiotherapy, transcranial magnetic or electrical stimulation, specific forms of acoustic stimulation or music therapy; or such recommendations must remain open due to the lack of available evidence. Polypragmatic tinnitus treatment with therapeutic strategies for which there is no evidence of efficacy from controlled studies is to be refused.

[Differential indication of active middle ear implants]. / Differenzialindikation aktiver Mittelohrimplantate.

INTRODUCTION: Hearing aids (HA) provide adequate support for many patients with hearing loss, but not all. Around one third of 10.000 patients provided with hearing aids in the Abbreviated Profile of Hearing Aid Benefit felt no actual benefit when using the hearing aid, although they demonstrated the necessary hearing improvement on speech audiometry. Epidemiological data show bad compliance, especially in older people. Only one in three hearing aid owners wears their device regularly. For this subpopulation of patients active middle ear implants (AMEIs) have been used since 1998. In the present review, the current indications for AMEIs are presented. MATERIAL AND METHODS: A selective literature search in PubMed, as well as a guideline search at the Arbeitsgemeinschaft der Wissenschaftlichen Fachgesellschaften e. V. (German Association of Scientific Societies), was carried out. RESULTS: The present review shows that when there is an adequate indication the hearing capacity of patients can be thoroughly rehabilitated and thus their quality of life improved with the help of AMEIs. Although most commercially available systems have a satisfactory risk profile, increased extrusion rates, malfunctioning and facial paresis have been reported in older implant series. The advantages of AMEIs include increased hearing gain, reduced feedback, increased hearing quality, increased speech discrimination in the presence of background noise, and an absence of occlusion. CONCLUSIONS: The audiological indication for AMEIs in primary care is usually controversial, since the functional hearing gain and increase in speech discrimination may be small compared with modern conventional hearing aids. AMEIs thus play a main role in the secondary care of patients who do not have sufficient benefit or who have side effects after having a conventional hearing aid fitted.

[Tracheotomy or planned prolonged intubation after surgery for patients with OSAS]. / Tracheotomie oder geplante Nachbeatmung nach Operationen bei Patienten mit OSAS.

BACKGROUND: Patients suffering from obstructive sleep apnea syndrome (OSAS) and obesity have an elevated risk of postoperative complications independent of each other. Within the framework of expert opinions for courts the question arose whether postoperative prolonged intubation or tracheotomy are standard routine approaches which are to be carried out in the normal course of operations on patients with OSAS. MATERIAL AND METHODS: A search of the literature was performed using PubMed, Web of Science, Scopus, EMBASE, the Cochrane database of systematic reviews and the Cochrane central register of controlled trials. Furthermore, 78 German otorhinolaryngology (ENT) departments participated in a nationwide survey. RESULTS: The results of the survey showed that after normal complication-free surgery planned postoperative prolonged intubation is not performed in the majority of ENT departments and no department performs a tracheotomy. In contrast, the standard approach for patients with OSAS and obesity who undergo two-level surgery is intubation and subsequent monitoring without ventilation for the first postoperative day. In the literature no evidence of a scientific basis for carrying out prolonged intubation or a tracheotomy could be found. CONCLUSION: Neither tracheotomy nor prolonged intubation are standard procedures for OSAS patients with obesity after complication-free surgery.

Design study of a miniaturized displacement transducer (MDT) for an active middle ear implant system.

People suffering from moderate to severe hearing loss can be treated with active middle ear implants. A new approach in this field is to implant an electromechanical transducer onto the round window membrane in order to improve coupling and be able to treat patients with middle-ear problems. In this paper the design study for a miniaturized displacement transducer (MDT) for the round window is presented. Based on a requirement analysis, the basic principle and analytical modeling of the actuator is shown. A parameter variation study results in an optimized actuator configuration that is able to generate an amplification of 110 dB SPL theoretically. As a next step this actuator has to be manufactured and tested.

[Personalized molecular medicine: new paradigms in the treatment of cochlear implant and cancer patients]. / Molekulare personalisierte Medizin: Paradigmenwechsel in der Krankenversorgung von Cochlear-Implant- und Tumorpatienten.

OBJECTIVES: To evaluate present options for the indication of cochlear implants (CI) and new forms of treatment for head and neck cancer, melanomas and basal cell carcinomas, with emphasis on future perspectives. METHODS: A literature search was performed in the PubMed database. Search parameters were "personalized medicine", "individualized medicine" and "molecular medicine". RESULTS: Personalized medicine based on molecular-genetic evaluation of functional proteins such as otoferlin, connexin 26 and KCNQ4 or the Usher gene is becoming increasingly important for the indication of CI in the context of infant deafness. Determination of HER2/EGFR mutations in the epithelial growth factor receptor (EGFR) gene may be an important prognostic parameter for therapeutic decisions in head and neck cancer patients. In basal cell carcinoma therapy, mutations in the Hedgehog (PCTH1) and Smoothened (SMO) pathways strongly influence the indication of therapeutic Hedgehog inhibition, e.g. using small molecules. Analyses of c-Kit receptor, BRAF-600E and NRAS mutations are required for specific molecular therapy of metastasizing melanomas. The significant advances in the field of specific molecular therapy are best illustrated by the availability of the first gene therapeutic procedures for treatment of RPE65-induced infantile retinal degradation. CONCLUSION: The aim of personalized molecular medicine is to identify patients who will respond particularly positively or negatively (e.g. in terms of adverse side effects) to a therapy using the methods of molecular medicine. This should allow a specific therapy to be successfully applied or preclude its indication in order to avoid serious adverse side effects. This approach serves to stratify patients for adequate treatment.

[Palliative medicine]. / Palliativmedizin.

INTRODUCTION: This paper investigates the qualitative and quantitative situation of palliative care medicine in Germany. The challenge of palliative care is the improvement of the quality of life of patients who are expected to die within months. In head and neck surgery most of these patients are suffering from cancer. Palliative care may incorporate symptom control and may support self-determination, including psychological, social and spiritual aspects. Treatment is not intended to cure the patients. Palliative care focuses on care of the patient and family rather than on the underlying disease. MATERIALS AND METHODS: A databank search was performed using key words such as palliative medicine, palliative care, hospice, AAPV, SAPV and PCT. RESULTS: The search demonstrates the restoration of quality of life as a guiding principle of palliative care in Germany. This may be achieved by symptom control and support of self-determination as well as psychosocial or spiritual support. Furthermore, relatives including children receive emotional support. A further principle is the proactive coordination of palliative procedures. CONCLUSION: Improved legal conditions for realistic specialized ambulatory palliative care (spezialisierte ambulante Palliativversorgung, SAPV) as well as strengthening of general palliative care (allgemeine ambulante Palliativversorgung, AAPV) should be encouraged so that a sustainable palliative care net with cooperation of SAPV and AASP can be developed throughout Germany.

Totally implantable active middle ear implants: ten years' experience at the University of Tübingen.

Active middle ear implants do not produce acoustic sounds but, rather, micromechanical vibrations. The stimulating signal does not leave the transducer as sound, but as a mechanical vibration, directly coupled to the auditory system and bypassing the normal route via air. In this paper, we review our experience with the TICA and the Carina middle ear implants. Both are totally implantable and are coupled to the ossicular chain or to perilymph. The design requirements for electronic hearing implants for patients with conductive hearing loss differ from those for sensorineural hearing loss. Conductive hearing loss requires an implant that replaces impedance transformation and acts as an impedance transforming implant (ITI). In many respects, there are fewer demands on an ITI than on an electronic hearing aid for patients with sensorineural hearing loss.

[Laser Doppler vibrometric measurements of DPOAE in humans. Eardrum vibrations reflect middle- and inner-ear characteristics]. / Laser-Doppler-vibrometrische Messungen von DPOAE an Menschen. Trommelfellschwingungen spiegeln Mittel- und Innenohrcharakteristika wider.

BACKGROUND: Up to now, laser interferometric vibration measurements of the human eardrum have not provided any information about cochlear function, because the measurement devices have not been sufficiently sensitive. METHODS: After designing a new type of laser Doppler vibrometer (LDV) that allows detection of displacement amplitudes down to about 1 pm, we used this device in 20 subjects to measure growth functions of the distortion products of otoacoustic emissions (DPOAE) as vibrations of the umbo. For comparison, DPOAE growth functions were also measured conventionally with an acoustic probe in the closed external auditory meatus. Hearing thresholds were estimated from both sets of measurements and compared with Békésy thresholds. RESULTS: The standard deviation of the threshold estimate obtained from the vibration DPOAEs was 8.6 dB, which is significantly smaller than that of the threshold estimate (16.7 dB) obtained from the acoustic DPOAEs. We attribute the smaller standard deviation for the LDV data to the fact that these measurements are made in an open sound field and are therefore less susceptible to pressure calibration errors. CONCLUSIONS: Being relatively free of sound-field measurement artefacts, the LDV method allows precise estimation of the hearing threshold. Vibration measurements of the umbo have, therefore, considerable potential for the differential diagnosis of mechanical dysfunction of the middle and inner ear.

Distortion product otoacoustic emissions measured as vibration on the eardrum of human subjects.

It has previously not been possible to measure eardrum vibration of human subjects in the region of auditory threshold. It is proposed that such measurements should provide information about the status of the mechanical amplifier in the cochlea. It is this amplifier that is responsible for our extraordinary hearing sensitivity. Here, we present results from a laser Doppler vibrometer that we designed to noninvasively probe cochlear mechanics near auditory threshold. This device enables picometer-sized vibration measurements of the human eardrum in vivo. With this sensitivity, we found the eardrum frequency response to be linear down to at least a 20-dB sound pressure level (SPL). Nonlinear cochlear amplification was evaluated with the cubic distortion product of the otoacoustic emissions (DPOAEs) in response to sound stimulation with two tones. DPOAEs originate from mechanical nonlinearity in the cochlea. For stimulus frequencies, f1 and f2, with f2/f1 = 1.2 and f2 = 4-9.5 kHz, and intensities L1 and L2, with L1 = 0.4L(2) + 39 dB and L2 = 20-65 dB SPL, the DPOAE displacement amplitudes were no more than 8 pm across subjects (n = 20), with hearing loss up to 16 dB. DPOAE vibration was nonlinearly dependent on vibration at f2. The dependence allowed the hearing threshold to be estimated objectively with high accuracy; the standard deviation of the threshold estimate was only 8.6 dB SPL. This device promises to be a powerful tool for differentially characterizing the mechanical condition of the cochlea and middle ear with high accuracy.

Olivocochlear reflex effect on human distortion product otoacoustic emissions is largest at frequencies with distinct fine structure dips.

Activity of the medial olivocochlear efferents can be inferred by measuring the change of the level of distortion product otoacoustic emissions (DPOAE) during ipsilateral or contralateral acoustic stimulation, the so-called medial olivocochlear reflex (MOCR). A limitation of this measurement strategy, however, is the distinct variability of MOCR values depending on DPOAE primary tone levels and frequency, which makes selection of the stimulus parameters difficult. The objective of this study was to evaluate the dependence of MOCR values on DPOAE fine structure in humans. MOCR during contralateral acoustic stimulation was measured at frequencies with distinct non-monotonicity ("dip") in the DPOAE fine structure, and in frequencies with flat fine structure. One hundred and twenty one different primary tone level combinations were used (L(1)=50-60dB SPL, L(2)=35-45dB SPL, 1dB steps). The measurement was repeated on another day. The major findings were: (1) Largest MOCR effects can be found in frequencies which exhibit a distinct dip in DPOAE fine structure. (2) Primary tone levels have a critical influence on the magnitude of the MOCR effect. MOCR changes of up to 23dB following a L(1) change of only 1dB were observed. Averages of the maximum MOCR change per 1dB step were in the 3-5dB-range. Both findings can be interpreted in the light of the DPOAE two-generator model [Heitmann, J., Waldmann, B., Schnitzler, H.U., Plinkert, P.K., Zenner, H.P. 1998. Suppression of distortion product otoacoustic emissions (DPOAE) near 2f1-f2 removes DP-gram fine structure - evidence for a secondary generator. Journal of the Acoustical Society of America 103, 1527-1531]. According to the present results we propose, that assessing MOCR specifically at frequencies with a distinct dip in the DPOAE fine structure, in combination with fine variation of the stimulus tone levels, allows for a more targeted search for maximum MOCR effects. Future studies must show if this approach can contribute to the further clarification of the physiological roles of the olivocochlear efferents.

Deficient membrane integration of the novel p.N14D-GJB2 mutant associated with non-syndromic hearing impairment.

Mutations in GJB2, the gene encoding for the Gap Junction protein Connexin 26 (Cx26), have been established as the major cause of hereditary, non-syndromic hearing impairment (HI). We report here the identification of a novel point mutation in GJB2, c.40A>G [p.N14D], detected in compound heterozygosity with the c.35delG mutation in two brothers with moderate non-syndromic sensorineural HI. The mother who carried one wildtype and a p.N14D allele displayed normal hearing. The mutation leads to substitution of the neutral amino acid asparagine (N) by the negatively charged aspartic acid (D) at amino acid number 14, a position that is conserved among Cx26 of different organisms and among many other connexin isoforms. To investigate the impact of this mutation on protein function, Cx26 activity was measured by depolarization activated hemichannel conductance in non-coupled Xenopus laevis oocytes. Oocytes injected with the p.N14D mutant cRNA showed strongly reduced currents compared to wildtype. Coinjection of wildtype and mutant cRNA at equimolar levels restored the conductive properties supporting the recessive character of this mutation. Total Cx26 protein expression and cell surface abundance examined by western blotting and by quantitative immunoassays revealed that the hemichannel was properly synthesized but not integrated into the plasma membrane. In this study we have shown that the GJB2 mutation p.N14D is associated with recessively inherited HI and exhibits a defective phenotype due to diminished expression at the cell surface.

[Variable length titanium prostheses for type III tympanoplasty. Intraoperative length adjustment and fixation of the cartilage overlay]. / Längenvariable Titanprothesen bei Typ-III-Tympanoplastik. Intraoperative Längeneinstellung und Fixation der Knorpelauflage.

INTRODUCTION: For type III tympanoplasty by partial ossicular replacement prosthesis (PORP) or total ossicular replacement prosthesis (TORP), the length of the prosthesis must match the individual intraoperative anatomical and physiological characteristics. MATERIALS AND METHODS: Databanks were used to determine the necessary sizer length of the sizer disc. The measurement template for the size of the cartilage to overlay the prosthesis headplate was derived from the headplates of the Tübinger titanium prostheses (TTP) and the Dresdener titanium prostheses. Finally all functions were integrated into a synthetic plate. RESULTS: The result was a simple and reasonably priced disposable multifunctional instrument (Tübinger sizer disc TSD) which allowed an exact measurement for every prosthesis in TORP and PORP. For the TTP-Variac, the TSD enabled the simple intraoperative production of prostheses with the length desired by the surgeon. For PORP the TSD enabled an adaptation of the diameter of the prosthesis foot for TTP, TTP-Vario and TTP-Variac and provided a template for the size determination of the cartilage overlay of the titanium prosthesis head. The sizers and the resulting prostheses were used for initial tympanoplastic operations. Audiometric investigations carried out 6 weeks postoperatively gave results corresponding to those previously obtained in a study with TTP and TTP-Vario using the old instrumentation. CONCLUSIONS: The new instrumentation leads to an improvement of the intraoperative practicability and a simplification. The audiological results remain the same.

[Laser-based quality assurance for robot-assisted milling at the base of the skull]. / Laserbasierte Qualitätssicherung für die robotergestützte Fräsabtragung an der Schädelbasis.

BACKGROUND: Implanting active hearing devices in the lateral base of the skull requires high-precision, secure fixation of the electromagnetic transducer and long-life anchorage using osteosynthetic fixation plates referred to as mountain brackets. Nonlinear distortion in the acoustic signal path and consecutive implant loosening can only be avoided by exact osseous milling to create the necessary cavity bed while avoiding excessive milling. Robot technology is ideal for high-precision milling. However, safety measures are necessary in order to prevent errors from occurring during the reduction process. Ideally, a robot should be guided by a navigation system. However, robotic systems so far available do not yet have an integrated global navigation system. MATERIALS AND METHODS: We used an animal model under laboratory conditions to examine the extent to which the semiautomatic ROBIN assistant system developed could be expected to increase osseous milling accuracy before implanting active electronic hearing devices into the recipient tissue in the cranium. An existing prototype system for robot-assisted skull base surgery was equipped with laser sensors for geometric measurement of the operation site. The three-dimensional measurement data was compared with CT simulation data before, during, and after the robot-assisted operation. The experiments were conducted on test objects as well as on animal models. RESULTS: Under ideal conditions, the operation site could be measured at a spatial resolution of better than 0.02 mm in each dimension. However, reflections and impurities in the operation site from bleeding and rinsing fluids did have a considerable effect on data collection, necessitating specialised registering procedures. Using an error-tolerant procedure specifically developed, the effective registering error could be kept under 0.3 mm. After milling, the resulting shape matched the intended form at an accuracy level of 0.8 mm. CONCLUSION: The results show that robot systems can reach the accuracy required for reliable microsurgery on the cranial base. High-resolution laser-based geometric measurement of the operation site enables head registration without additional artificial landmarks. During the navigated operation, the procedure can be used to ensure that the resulting cavity matches the intended shape as determined in the preoperative planning phase. This will enable quantitative analysis of, and improvement in the quality of robot-assisted surgery in the future.

Olivocochlear activity and temporary threshold shift-susceptibility in humans.

STUDY OBJECTIVES: Animal studies (guinea pig, cat, chinchilla) have shown that activity of the medial olivocochlear efferents can exert noise-protective effects on the cochlea. It is not yet known whether such effects are also existent in humans. Olivocochlear activity can be estimated indirectly by contralateral suppression (CS) of otoacoustic emissions (OAE). MATERIAL AND METHODS: We measured Input/Output functions of distortion products of OAE (DPOAE), with and without contralateral acoustic stimulation by white noise, in 94 normal hearing young male subjects. Seven stimuli with L2 between 20 and 60 dB SPL and L1 = 39 dB + 0.4 L2 ("scissor paradigm") were used at f2 = 2, 3, 4, 5, and 6 kHz. The measurement was repeated 2 weeks later. In 83 subjects of the same group, pure tone audiometry was registered before and 6 minutes after shooting exercises to evaluate individual susceptibility to develop a temporary threshold shift (TTS). RESULTS: Test-retest repeatability of CS was generally good. CS averaged 0.98 dB SPL (SD 1.19 dB, median 0.56 dB). As expected, CS was greatest at low stimulus levels (median 1.06 dB at L2 = 20 dB, as compared with 0.33 dB at L2 = 60 dB). The smallest average CS was found at 4 kHz, and the greatest CS appeared at 2 kHz. A TTS occurred in 7 of 83 (8.5%) subjects. Statistical analysis did not reveal any correlation between the amount of CS and individual TTS susceptibility. CONCLUSIONS AND OUTLOOK: 1) Measurement of CS of DPOAE using an extensive measurement paradigm revealed good test-retest repeatability, confirming the reliability of this audiologic tool. 2) CS of DPOAE does not predict individual susceptibility to mild TTS induced by impulse noise in humans. Possible explanations for the missing association are discussed. Future perspectives include longitudinal studies to further elucidate the association between medial olivocochlear bundle-activity and permanent threshold shift in humans. The goal is to develop a diagnostic tool for the prediction of individual noise vulnerability in humans, thereby preventing noise-induced hearing loss.

[Mitochondrial A1555G mutation. Molecular genetic diagnosis in sporadic cases of non-syndromic hearing impairment]. / Mitochondriale A1555G-Mutation. Molekulargenetische Diagnostik bei sporadischen Fällen nichtsyndromaler Schwerhörigkeit.

BACKGROUND: The A1555G mutation in mitochondrial DNA is the cause of hearing impairment in about 50% of all carriers. The severity and onset of this impairment is predominantly affected by the use of aminoglycosides. PATIENTS AND METHODS: A total of 391 patients displaying sporadic, non-syndromic, mild to severe hearing impairment were analyzed for the A1555G mutation using molecular genetic methods. RESULTS: We analysed additional family members of the two patients (0.5% of the total) who had the mutation. All maternal relatives carried the mutation, but only three individuals from the two families displayed a variable sensorineural hearing loss. CONCLUSION: The A1555G mutation is infrequently involved as a genetic cause of sporadic, non-syndromic hearing impairment. Nevertheless, based on the variable clinical outcome of hearing impairment and the possibility of preventive steps, a genetic test in this patient subgroup is indicated.