[Enhanced quality of documentation for biologic therapy of chronic rhinosinusitis through structured digital reporting and indication?] / Qualitätssteigerung der Dokumentation zur Biologikatherapie der chronischen Rhinosinusitis durch digitale, strukturierte Befunderhebung und Indikationsstellung?

BACKGROUND: With targeted inhibition of type 2 inflammation, biologics represent the standard add-on therapy for inadequately controlled severe forms of chronic rhinosinusitis with nasal polyps (CRSwNP). Despite standardization with paper-based checklists, the documentation of medical history and current findings pertinent to indication criteria are a significant challenge for physicians. Through development of an application based on structured reporting, the current study aimed to improve documentation quality and simplify the decision-making process. Previously available paper checklists served as a comparison. METHODS: For this study, a digital incremental tool was programmed to record current findings and check for fulfilment of indication criteria. The tool was compared with other checklists in terms of completeness, time required, and readability. RESULTS: A total of 20 findings were collected for each of the three documentation options and included in the analysis. Documentation with the two paper-based checklists had comparable information content: 17.5 ± 5.1/21.7 ± 7.6 points out of a maximum of 43 points; p > 0.05. Documentation using the digital application led to a significant increase in information content compared to all paper-based documentation. The average score was 38.25 ± 3.7 (88.9% of maximum; p < 0.001). On average, user satisfaction was high (9.6/10). Use of the digital application was initially more time consuming, but as more cases were documented, the time taken improved significantly. CONCLUSION: In the future, structured reporting using apps could replace paper-based reporting for the indication of biologic therapy in CRSwNP patients and offer additional benefits in terms of data quality and traceability of results. The increasing volume of documentation in the future, the progress of digitalization, and the possibility of networking between individual centers make introduction of the app in the near future both likely and economical.

Symmetrically dotted tympanic membranes.

Key Clinical Message: Color changes of the tympanic membranes without an inflammatory component or perforation are rarely described. They may result from hemorrhage after barotrauma or spontaneously. Other explanatory models include discoloration due to otomycosis. Abstract: This is a case of a 61-year-old patient with an unexplained incidental of black dots located almost symmetrically on the antero-inferior quadrant of both tympanic membranes. This harmless anatomical rarity has not been published before. Underlying pathologies should be excluded in the case of discoloration of the tympanic membranes.

Dexamethasone prevents hearing loss by restoring glucocorticoid receptor expression in the guinea pig cochlea.

OBJECTIVES/HYPOTHESIS: Dexamethasone is widely used in the treatment of various inner ear diseases. However, knowledge about its direct impact on glucocorticoid receptor (GR) expression is still limited. STUDY DESIGN: Prospective animal study in male guinea pigs. METHODS: A therapeutic concentration of dexamethasone (8 mg/mL) or a physiological concentration of NaCl (0.9% solution) were intratympanically injected into the ears of guinea pigs (n = 10 in each case) 14 hours prior to 90 dB noise exposure (1 hour). Eighteen ears were exposed to noise only. Seven untreated ears were used as controls. Auditory brainstem responses were recorded prior to noise exposure or treatment and 2 hours thereafter. The cochleae were removed from the bullae, transferred to fixative, and embedded in paraffin. GR expression was identified immunohistochemically in the cochlea. Local staining intensities were quantified for seven regions by a computer. RESULTS: Dexamethasone application significantly lowered noise-induced hearing loss. Statistically significant alterations in the average GR expression levels were identified exclusively in the spiral ligament. Comparing GR expression at the level of individual ear, numerous highly significant local associations were identified in the other six cochlear regions. CONCLUSIONS: The intratympanic application of dexamethasone is suitable for supporting cochlear homeostasis under stress conditions. The lateral wall, mainly responsible for potassium recycling, seems to be the main target in glucocorticoid therapy.

Cell-specific accumulation patterns of gentamicin in the guinea pig cochlea.

Intratympanic gentamicin therapy has become a popular treatment modality for Ménière's disease (MD) through controlled elimination of vertigo spells caused by the balance organ. However, the known ototoxic properties of aminoglycosides lead to cochlear damage. In order to gain more information about cellular preferences for aminoglycoside accumulation within the cochlea, gentamicin was immuno histochemically localized by light microscopy in male guinea pigs 1 and 7 days after intratympanic application (n = 8 ears/incubation time). Differences in the gentamicin-specific cellular storage capacities were quantified by determination of the local immuno staining intensities. Gentamicin was detected in every cochlear cell type, but with spatiotemporal variability. One day after application, an intense staining reaction was found in all cell types except the spiral ganglion cells and the stria vascularis. Six days later, gentamicin staining intensities were additionally reduced in the nerve fibers and the spiral ligament. Statistic analysis revealed strong cellular associations in respect to aminoglycoside accumulation. Furthermore, associations with recorded hearing losses were identified comparing the cellular gentamicin content in the organ of Corti, in the stria vascularis, in the spiral ganglion cells and in fibrocytes of the Limbus. In the lateral wall, clear differences in cellular gentamicin accumulation were found between type I fibrocytes of the spiral ligament compared with basal and intermediate cells of the stria vascularis. This finding was unexpected as these three cell types belong to a well-developed gap-junction system which normally enables unhampered cell communication. Cellular differences in local gentamicin storage capacities, transport processes and inherent diffusion barriers are discussed.

Nitric oxide--a versatile key player in cochlear function and hearing disorders.

Nitric oxide (NO) is a signaling molecule which can generally be formed by three nitric oxide synthases (NOS). Two of them, the endothelial nitric oxide synthase (eNOS) and the neural nitric oxide synthase (nNOS), are calcium/calmodulin-dependent and constitutively expressed in many cell types. Both isoforms are found in the vertebrate cochlea. The inducible nitric oxide synthase (iNOS) is independent of calcium and normally not detectable in the un-stimulated cochlea. In the inner ear, as in other tissues, NO was identified as a multitask molecule involved in various processes such as neurotransmission and neuromodulation. In addition, increasing evidence demonstrates that the NO-dependent processes of cell protection or, alternatively, cell destruction seem to depend, among other things, on changes in the local cochlear NO-concentration. These alterations can occur at the cellular level or within a distinct cell population both leading to an NO-imbalance within the hearing organ. This dysfunction can result in hearing loss or even in deafness. In cases of cochlear malfunction, regulatory systems such as the gap junction system, the blood vessels or the synaptic region might be affected temporarily or permanently by an altered NO-level. This review discusses potential cellular mechanisms how NO might contribute to different forms of hearing disorders. Approaches of NO-reduction are evaluated and the transfer of results obtained from experimental animal models to human medication is discussed.

Doxycycline reduces nitric oxide production in guinea pig inner ears.

OBJECTIVE: Gentamicin application is an important therapeutic option to control vertigo spells in Ménière's disease. However, even in the case of low-dose intratympanic application, gentamicin might contribute to a pathological NO-increase leading to cochlear damage and hearing impairment. The study was performed to evaluate the nitric oxide (NO) reducing capacity of doxycycline in the inner ear after NO-induction by gentamicin. METHODS: In a prospective animal study, a single dose of gentamicin (10mg/kg body weight) was injected intratympanically into male guinea pigs (n=48). The auditory brainstem responses (ABRs) were recorded prior to application and 3, 5 and 7 days afterwards. The organ of Corti and the lateral wall of 42 animals were isolated after 7 days and incubated separately for 6h in cell culture medium. Doxycycline was adjusted to organ cultures of 5 animals. Two NOS inhibitors, N(G)-Nitro-l-arginine methyl ester (l-NAME) and NG-monomethyl-l-arginine monoacetate (l-NMMA), were applied in three different concentrations to the organ cultures of 30 animals in total (5 animals per concentration). As controls, seven animals received no further substance except gentamicin. The NO-production was quantified by chemiluminescence. Additional six gentamicin-treated animals were used for immunohistochemical studies. RESULTS: The ABRs declined continuously from the first to the seventh day after gentamicin application. Doxycycline reduced NO-production in the lateral wall by 54% (p=.029) comparable to the effect of the applied nitric oxide inhibitors. In the organ of Corti, NO-production was reduced by about 41% showing no statistical significance in respect to great inter-animal variations. CONCLUSION: The application of doxycycline might offer a new therapeutic approach to prevent NO-induced cochlea damage through ototoxic substances.

Gentamicin alters nitric oxide production in semicircular canals and otolith organs.

OBJECTIVES/HYPOTHESIS: Intratympanic application of gentamicin is an important therapeutic option to control vertigo spells in Ménière's disease. Low doses eliminate the function of semicircular canal ampullae (SCCA) and saccule in most patients, although utricular function is maintained in many cases. Local alteration in free radical production might be responsible for these differences. Therefore, the gentamicin-induced nitric oxide (NO) production was determined in an animal model using separate organ cultures of SCCA, saccule, and utricle. STUDY DESIGN: Prospective pilot study in male guinea pigs. METHODS: SCCA, saccule, and utricle of 28 guinea pigs were isolated and incubated separately for 6 hours in cell culture medium. Gentamicin was administered in two different concentrations (0.4 mg/mL and 0.8 mg/mL) to organ cultures of 16 animals. Tissues from 12 animals were used as controls. Nitric oxide was quantified by chemiluminescence. RESULTS: Gentamicin led to an NO increase of about 70% in the saccule, an NO reduction of more than 70% in SCCA, and an NO reduction of 36% in the utricle. CONCLUSIONS: The selective effects of gentamicin on the NO production in the different sensory areas of the vestibular organ have to be taken into account in the therapy of Ménière's disease.

Expression analysis suggests a potential cytoprotective role of Birc5 in the inner ear.

Hearing impairment is a worldwide health problem. Employing semi-quantitative immunological detection methods, we found that the apoptosis inhibitor protein Birc5 is expressed in cell types critical for hearing perception. In the guinea pig model, moderate noise exposure causing only a temporary mean hearing impairment of 33dB significantly enhanced Birc5 expression in the spiral ligament, nerve fibers and the organ of Corti. In contrast, intratympanic gentamicin injection inducing permanent cell damage and mean hearing loss of 24dB correlated with a significant Birc5 downregulation in the ligament, nerve fibers and the organ of Corti. The cytoprotective activity of the guinea pig and human Birc5 protein was confirmed by cloning of the gene and by subsequent ectopic expression and challenging studies against the ototoxin gentamicin in epithelial and auditory cell models. As the mammalian cochlea is unable to regenerate upon damage, these data suggest that modulation of Birc5 expression may represent a novel physiological mechanism to protect the inner ear against stress-induced cell damage. Hence, the targeted modulation of Birc5 levels may lead to novel otoprotective therapeutic strategies.

Low-frequency therapeutic ultrasound with varied duty cycle: effects on the ischemic brain and the inner ear.

Sonothrombolysis is a promising modality for acute stroke treatment. In vitro data suggest a duty cycle dependence of sonothrombolytic efficacy of low-frequency applications. The aim of our study was to examine its impact on safety issues in a rat model of middle cerebral artery occlusion. Rats were exposed to transcranial 60-kHz ultrasound with varied duty cycles. To determine effects on the inner ear, the acoustic threshold was determined in additional healthy animals (acoustic evoked potentials). A short duty cycle (20%) resulted in significant adverse effects (ischemic volume, hemorrhage, functional outcome), which was not observed in longer duty cycle (80%). Continuous-wave insonation produced high rates of mortality and subarachnoid hemorrhage. Hearing was impaired independent of duty cycle. In conclusion, cerebral side effects may be efficiently reduced by modulation of pulsed parameters, which is in line with data on an improved efficacy with longer duty cycle. However, side effects on the auditory system were found to be independent of parameter settings.

Evidence of unilateral isolated utricular hypofunction.

CONCLUSIONS: The findings demonstrate that an enduring unilateral utricular dysfunction, possibly together with canal hypofunction, can occur after labyrinthine disease or injury. They also suggest that unilateral, isolated utricular dysfunction - or utricle paresis - can occur, representing a novel entity in the differential diagnosis of peripheral vestibular function. The occurrence of subjective visual vertical (SVV) asymmetry in the presence of symmetric vestibular evoked myogenic potentials (VEMPs) also confirms that the information from the utricles, rather than the saccules, dominates SVV estimation. OBJECTIVES: To determine the incidence of unilateral utricular hypofunction. METHODS: The retrospective clinical study deals with a selection of those vestibular patients who showed pathological responses to utricle testing. Peripheral vestibular function was examined in a group of 110 patients. Utricular function was evaluated by estimation of SVV during unilateral centrifugation. Bithermal caloric testing was performed to assess unilateral semicircular canal function. Saccular function was tested by measurement of VEMPs. RESULTS: A total of 46 patients were found with asymmetric SVV findings (p < 0.001 for healthy versus lesioned ear), but symmetric caloric responses and VEMPs. Statistical testing also verified that their SVV asymmetry factors were significantly higher than those calculated for caloric responses and VEMPs (p < 0.001).

Gentamicin increases nitric oxide production and induces hearing loss in guinea pigs.

OBJECTIVES/HYPOTHESIS: Gentamicin application is an important therapeutic option for Ménière's disease. However, even if given at intervals, a destruction of the cochlea was often observed in various animal models together with an increased content of nitric oxide (NO) and reactive oxygen species. The present study was undertaken to identify the correlation between hearing threshold alteration and the NO production in the lateral wall and organ of Corti of the guinea pig in response to gentamicin application. STUDY DESIGN: Prospective animal study in guinea pigs. METHODS: A single dose of gentamicin (10 mg/kg body weight) was injected intratympanally into male guinea pigs and the auditory brainstem responses were recorded before treatment and 1, 2, and 7 days after application. The organ of Corti and the lateral wall were removed from the bulla, incubated separately for 6 hours in cell culture medium and the amount of NO production was determined by chemiluminescence. RESULTS: Gentamicin application resulted in a hearing threshold shift beginning on the second day after gentamicin application. This hearing impairment correlates simultaneously with an increased NO2(-) content--the stable oxidation product of NO--in the lateral wall. In the organ of Corti, a slight increase in NO2(-) production was seen as early as on day 1 after gentamicin injection. CONCLUSIONS: The correlation between hearing threshold shift and NO production in the cochlea leads to the assumption that increased NO contributes to gentamicin-induced hearing impairment.

Malignant paraganglioma caused by a novel germline mutation of the succinate dehydrogenase D-gene--a case report.

BACKGROUND: Paragangliomas of the head and neck are rare, mostly benign tumors. Approximately 10% to 15% of paragangliomas are caused by mutations in the succinate dehydrogenase (SDH) genes B, C, or D. These are often multifocal as part of paraganglioma syndromes and hormone secreting, and malignant particularly associated with mutations in SDHB. METHODS AND RESULTS: A 29-year-old man was seen with recurrent paraganglioma. The patient's father reportedly suffered from bilateral carotid body tumors. Imaging studies showed metastases in both lungs and the liver. There was no increased hormone production by the tumor. Sequence analysis of the SDH genes revealed a novel C to T nonsense mutation in the first exon of the SDHD gene (R17X). CONCLUSIONS: A novel mutation in the SDHD gene associated with malignant paraganglioma is reported. This case underscores the relevance of family history and genetic analysis, thus permitting early detection of unaffected carriers. These have to be monitored clinically, biochemically and by imaging techniques.

Ascorbic acid reduces noise-induced nitric oxide production in the guinea pig ear.

OBJECTIVES: Noise-induced hearing loss can be caused, among other causes, by increased nitric oxide (NO) production in the inner ear leading to nitroactive stress and cell destruction. Some studies in the literature suggest that the degree of hearing loss (HL) could be reduced in an animal model through ascorbic acid supplementation. To identify the effect of ascorbic acid on tissue-dependent NO content in the inner ear of the guinea pig, we determined the local NO production in the organ of Corti and the lateral wall separately 6 hours after noise exposure. STUDY DESIGN: Prospective animal study in guinea pigs. METHODS: Over a period of 7 days, male guinea pigs were supplied with minimum (25 mg/kg body weight/day) and maximum (525 mg/kg body weight/day) ascorbic acid doses, and afterwards exposed to noise (90 dB sound pressure level for 1 hour). The acoustic-evoked potentials were recorded before and after noise exposure. The organ of Corti and the lateral wall were incubated differently for 6 hours in culture medium, and the degree of NO production was determined by chemiluminescence. RESULTS: Ascorbic acid treatment reduced the hearing threshold shift after noise exposure depending on concentration. When the maximum ascorbic acid dose was substituted, NO production was significantly reduced in the lateral wall after noise exposure and slightly reduced in the organ of Corti. CONCLUSIONS: Oral supplementation of the natural radical scavenger ascorbic acid reduces the NO-production rate in the inner ear in noisy conditions. This finding supports the concept of inner ear protection by ascorbic acid supplementation.

Localization of congenital tegmen tympani defects.

OBJECTIVE: This study sets out to demonstrate the normal developmental steps of the tegmen tympani and thus explains the typical localization of congenital tegmental defects. SPECIMENS: For this study, 79 macerated and formalin-fixed human temporal bones from 14th fetal week to adults were observed and prepared. INTERVENTION: Macroscopic and microscopic examination of the prenatal and postnatal changes of the tegmen tympani during its development. MAIN OUTCOME MEASURE: Temporal bones from 14th fetal week to adults underwent descriptive anatomic studies to understand the normal development of the tegmen tympani and to find a possible cause of its congenital defects. RESULTS: The medial part of the tegmen tympani develops from the otic capsule during chondral ossification, thus forming the tegmental process of the petrous part. The lateral part shows membranous ossification. The tegmental process cases a temporary bony dehiscence lateral to the geniculate ganglion between the 23rd and 25th fetal week. CONCLUSION: Congenital defects develop near the geniculate ganglion and seem to be due to an incomplete development of tegmental process of otic capsule. Because of that, congenital lesion of the tegmen tympani can be defined as an inner ear defect.

Treatment of Ménière's disease by low-dosage intratympanic gentamicin application: effect on otolith function.

OBJECTIVES: The intratympanic application of a low dosage of gentamicin is increasingly favored as treatment for Ménière's disease. While posttreatment observations have confirmed a long-term success of the therapy of vertigo attacks, clear differences in the posttreatment recovery interval can be observed. In addition to differences in central-vestibular compensation, the degree of peripheral vestibular damage, i.e., to the saccule, utricle, and semicircular canal ampullae, varies among patients. This study provides comprehensive pre- and posttreatment results from unilateral functional tests of the individual vestibular receptors and of the cochlea in patients with Ménière's disease. STUDY DESIGN: Prospective clinical study. METHODS: Nineteen patients with unilateral Ménière's disease were treated by intratympanic application of gentamicin by injection of 0.3 mL (12 mg) through the tympanic membrane under local anesthesia. Tests were performed immediately previous to treatment and subsequently in the periods 4 to 8 weeks and 12 to 16 weeks after treatment. Unilateral saccular function was tested by means of acoustic-click, vestibular-evoked myogenic potentials (VEMP), and unilateral utricular function by subjective visual vertical (SVV) during unilateral centrifugation. Bithermal caloric testing was performed to assess unilateral semicircular canal function. RESULTS: Prior to gentamicin treatment, the caloric response from the diseased ear was normal in 3 patients, below normal in 14 patients, and in 2 cases almost completely absent. VEMP responses could be recorded bilaterally in 13 patients; while in 6, no VEMPs could be measured from the diseased ear. Utricular function measured by SVV estimation was found to be normal in 11 patients and marginally abnormal in 2 patients. In six cases, the SVV was clearly underestimated during centrifugation of the diseased side. The posttreatment findings demonstrate that VEMPs were absent in all treated patients, and the caloric response was abnormally low in all but one case. In contrast, only 12 of 19 patients produced abnormal SVV responses. CONCLUSION: The results demonstrate that incremental, intratympanic application of gentamicin effectively eliminates semicircular canal and saccular function. In contrast, utricular function appears to be maintained in 30 to 40% of cases.

Comparison of electronystagmography results with dynamic posturography findings in patients with vestibular schwannoma.

CONCLUSION: Condition-5-score (C5S) and condition-6-score (C6S) of computerized dynamic platform posturography (CDPP) can detect the presence of a functional deficit of the lateral semicircular canal (and the superior vestibular nerve), irrespective of the central vestibular compensatory status, in vestibular schwannoma (VS) patients. OBJECTIVES: To test whether CDPP findings differ between VS patients with and without asymmetry on caloric and/or rotational ENG studies. PATIENTS AND METHODS: This was a retrospective review of 216 consecutive patients with VS. C5S and C6S of CDPP (Equitest) were compared among patients with normal caloric and rotational studies, patients with asymmetry on caloric studies and normal rotational studies, and patients with asymmetric caloric and rotational studies using the Wilcoxon-Mann-Whitney test. RESULTS: C5S and C6S of VS patients with normal caloric and rotational studies were significantly higher than in VS patients with either asymmetry on both rotational and caloric test results (p<0.001 for both C5S and C6S) or normal rotational studies and asymmetry on caloric testing (p<0.001 for both C5S and C6S). Neither C5S nor C6S were significantly different between patients with asymmetry on caloric testing and normal rotational studies and patients with asymmetry on both rotational and caloric testing.

Otolith mass asymmetries in the utricle and saccule of flatfish.

The otolith mass of the saccules and utricles of plaice, Pleuronectes platessa (n = 39) and turbot, Psetta maxima (n = 21) was measured using an electronic microbalance. In the right-eyed plaice, the left utricular otoliths were found to be significantly heavier than the right (p < 0.0001), whereas no significant difference was found between left and right saccular otoliths (p < 0.751). In the left-eyed turbot, both the right utricular and saccular otoliths were found to be significantly heavier (in both cases, p < 0.0001). While the gene and regulative protein responsible for the peripheral biomineralisation process have been identified, it remains unclear how the symmetry between the right and left otoliths in fish species is regulated. Here it is likely that an additional central mechanism is involved. It must be assumed that similar processes govern the systematic asymmetry observed in flatfish such as the plaice and turbot. Taken together these findings are strongly suggestive of concomitant CNS modification and metamorphic plasticity, presumably represented in genetic code.