The glucocorticoid antagonist mifepristone attenuates sound-induced long-term deficits in auditory nerve response and central auditory processing in female rats.

Systemic corticosteroids have been the mainstay of treatment for various hearing disorders for more than 30 yr. Accordingly, numerous studies have described glucocorticoids (GCs) and stressors to be protective in the auditory organ against damage associated with a variety of health conditions, including noise exposure. Conversely, stressors are also predictive risk factors for hearing disorders. How both of these contrasting stress actions are linked has remained elusive. Here, we demonstrate that higher corticosterone levels during acoustic trauma in female rats is highly correlated with a decline of auditory fiber responses in high-frequency cochlear regions, and that hearing thresholds and the outer hair cell functions (distortion products of otoacoustic emissions) are left unaffected. Moreover, when GC receptor (GR) or mineralocorticoid receptor (MR) activation was antagonized by mifepristone or spironolactone, respectively, GR, but not MR, inhibition significantly and permanently attenuated trauma-induced effects on auditory fiber responses, including inner hair cell ribbon loss and related reductions of early and late auditory brainstem responses. These findings strongly imply that higher corticosterone stress levels profoundly impair auditory nerve processing, which may influence central auditory acuity. These changes are likely GR mediated as they are prevented by mifepristone.-Singer, W., Kasini, K., Manthey, M., Eckert, P., Armbruster, P., Vogt, M. A., Jaumann, M., Dotta, M., Yamahara, K., Harasztosi, C., Zimmermann, U., Knipper, M., Rüttiger, L. The glucocorticoid antagonist mifepristone attenuates sound-induced long-term deficits in auditory nerve response and central auditory processing in female rats.

Recruiting ENT and Audiology patients into pharmaceutical trials: evaluating the multi-centre experience in the UK and USA.

OBJECTIVE: Recruiting into clinical trials on time and on target is a major challenge and yet often goes unreported. This study evaluated the adjustment to procedures, recruitment and screening methods in two multi-centre pharmaceutical randomised controlled trials (RCTs) for hearing-related problems in adults. DESIGN: Recruitment monitoring and subsequent adjustment of various study procedures (e.g. eligibility criteria, increasing recruiting sites and recruitment methods) are reported. Participants were recruited through eight overarching methods: trial registration, posters/flyers, print publications, Internet, social media, radio, databases and referrals. The efficiency of the recruitment was measured by determining the number of people: (1) eligible for screening as a percentage of those who underwent telephone pre-screening and (2) randomised as a percentage of those screened. STUDY SAMPLE: A total of 584 participants completed the pre-screening steps, 491 screened and 169 participants were randomised. RESULTS: Both RCTs completed adjustments to the participant eligibility, added new study sites and additional recruitment methods. No single recruitment method was efficient enough to serve as the only route to enrolment. CONCLUSION: A diverse portfolio of methods, continuous monitoring, mitigation strategy and adequate resourcing were essential for achieving our recruitment goals.

The role of intracochlear drug delivery devices in the management of inner ear disease.

INTRODUCTION: Diseases of the inner ear include those of the auditory and vestibular systems, and frequently result in disabling hearing loss or vertigo. Despite a rapidly expanding pipeline of potential cochlear therapeutics, the inner ear remains a challenging organ for targeted drug delivery, and new technologies are required to deliver these therapies in a safe and efficacious manner. In addition to traditional approaches for direct inner ear drug delivery, novel microfluidics-based systems are under development, promising improved control over pharmacokinetics over longer periods of delivery, ultimately with application towards hair cell regeneration in humans. AREAS COVERED: Advances in the development of intracochlear drug delivery systems are reviewed, including passive systems, active microfluidic technologies and cochlear prosthesis-mediated delivery. This article provides a description of novel delivery systems and their potential future clinical applications in treating inner ear disease. EXPERT OPINION: Recent progresses in microfluidics and miniaturization technologies are enabling the development of wearable and ultimately implantable drug delivery microsystems. Progress in this field is being spurred by the convergence of advances in molecular biology, microfluidic flow control systems and models for drug transport in the inner ear. These advances will herald a new generation of devices, with near-term applications in preclinical models, and ultimately with human clinical use for a range of diseases of the inner ear.

Application of ozone therapy in the vestibulocochlear syndrome.

The aim of this study was to evaluate the efficacy of ozone therapy in the treatment of 50 patients with peripheral vestibulocochlear syndrome. Ozone was injected in the cervical region C2-C3, for 20 sessions. Evaluation criteria was based in the evolution of nystagmus, tinnitus, hearing loss and vertigo. Also, oxidative stress parameters were measured. Results demonstrated that patient improvements, according to vertigo, hearing loss, tinnitus and nystagmus, were of 90, 80, 65 and 100%, respectively. These patients were initially under condition of systemic oxidative stress, however, at the end of the study a redox balance was achieved. No side effects were observed.

The influence of botulinum toxin on auditory disturbances in hemifacial spasm.

BACKGROUND AND PURPOSE: Hemifacial spasm (HFS) is frequently accompanied by other symptoms, such as visual and auditory disturbances or pain. The aim of the study was to assess the occurrence of auditory symptoms accompanying HFS using subjective and objective methods, their relation with other HFS symptoms, and their resolution after botulinum toxin (BTX-A) treatment. MATERIAL AND METHODS: The occurrence of hypoacusis, ear clicks and tinnitus was assessed by questionnaire in 126 HFS patients from an electronic database which included medical data such as severity of HFS rated by clinical scale and magnetic resonance imaging focused on the presence of vascular nerve VII and VIII conflict. Forty consecutive patients treated with BTX-A and 24 controls matched by sex and age underwent laryngological examination including audiometry, tympanometry and acoustic middle ear reflex before injection and two weeks later. RESULTS: About 45.2% of patients complained of auditory disturbances (31.7% hypoacusis, 30.2% ear clicks and 7.1% tinnitus) on the side of HFS. Auditory disturbances correlated with severity of HFS symptoms but not with age, disease duration, or neurovascular conflict with nerves VII and VIII. We did not find abnormalities in audiometric and tympanometric assessment in patients in comparison with controls. No abnormalities were detected in brainstem evoked potentials comparing the sides with and without HFS symptoms. Tinnitus and absence of ipsilateral acoustic middle ear reflex occurred more often in patients with auditory symptoms than those without them. BTX-A treatment caused resolution of subjective acoustic symptoms without any improvement in audiometric assessment. CONCLUSIONS: Auditory disturbances accompanying HFS are probably caused by dysfunction of the Eustachian tube, which improves after BTX-A treatment.

Profile of minocycline neuroprotection in bilirubin-induced auditory system dysfunction.

Excessive hyperbilirubinemia in human neonates can cause permanent dysfunction of the auditory system, as assessed with brainstem auditory evoked potentials (BAEPs). Jaundiced Gunn rat pups (jjs) exhibit similar BAEP abnormalities as hyperbilirubinemic neonates. Sulfadimethoxine (sulfa) administration to jjs, which displaces bilirubin from serum albumin into tissues including brain, exacerbates acute toxicity. Minocycline administered prior to sulfa in jjs protects against BAEP abnormalities. This study evaluates the neuroprotective capabilities of minocycline HCl (50 mg/kg) administered 30 or 120 min after sulfa (200 mg/kg) in 16 days old jjs. BAEPs are recorded at 6 or 24 h post-sulfa. Abnormal BAEP waves exhibit increased latency and decreased amplitude. The sulfa/saline treated jjs exhibited a significantly increased interwave interval between waves I and II (I-II IWI) and significantly decreased amplitudes of waves II and III compared to the saline/saline jjs. The minocycline 30 min post-sulfa (sulfa/mino+30) group was not significantly different from the saline/saline control group, indicating neuroprotection. The minocycline 120 min post-sulfa (sulfa/mino+120) group had a significantly decreased amplitude of wave III at both 6 and 24h. These studies indicate that minocycline has a graded neuroprotective effect when administered after acute bilirubin neurotoxicity.

Antioxidant micronutrient impact on hearing disorders: concept, rationale, and evidence.

PURPOSE: Although auditory disorders are complex conditions, device-related modalities dominate current treatment. However, dysfunction from the central cortex to the inner ear apparatus is increasingly thought to be related to biochemical pathway abnormalities and to free radical-induced oxidative damage and chronic inflammation. Therefore, considering appropriate biologic therapy as an adjunct to standard care against these damaging factors may provide rational expansion of treatment options for otolaryngologists and audiologists. METHODS: This review outlines the biologic concepts related to some auditory and vestibular conditions and details the current rationale for utilizing antioxidants for a spectrum of hearing disorders. The strategy is based on the authors' collective experience in antioxidant science and supported with published research, pilot animal data and preliminary clinical observations. RESULTS: A comprehensive micronutrient approach was developed to exploit these pathways, and demonstrated safety and efficacy against oxidative damage and inflammation and clinically relevant neuroprotection. Cooperative research with Department of Defense institutions used prospective, randomized designs to show (1) reduction in oxidative damage measured in plasma and urine over six months, (2) protection against oxidative damage during 12 weeks of intense military training, (3) protection against inflammation after total body blast exposure (rodents), (4) strong neuroprotection against chemically-induced Parkinson's disease (rodents), (5) nerve VIII function improvement after concussive head injury in military personnel, and (6) tinnitus improvement in majority of patients after 90-day evaluation. CONCLUSION: This systematic review of biologic strategies against hearing disorders combined with new animal and human observations may provide a rational basis for expanding current practice paradigms.

Aescin and troxerutin as a successful combination for the treatment of inner ear perfusion disturbances.

A fixed combination of aescin and troxerutin has been developed for treating inner ear perfusion problems of different aetiology. The efficacy of this combination is tested versus pentoxyfyllin in a randomized clinical study as group comparison with 34 patients for each group. The improvement of hearing after 40-44 days of treatment is determined as end point of treatment. Hearing was measured by threshold, whereby a difference of more than 10dB is judged as a significant improvement. After the treatment with the combination of aescin and troxerutin hearing is significantly improved, in 23 of 34 patients the threshold is changed more than 10dB, which is checked by sign-test with p<0.05. With pentoxyfyllin hearing is also improved, although to a lesser degree. Both drugs are well tolerated, major adverse drug effects are not observed with either treatment.

Vestibular and auditory deficits in Fabry disease and their response to enzyme replacement therapy.

Progressive hearing (pHL) and vestibular (pVL) loss are frequent deficits in Fabry disease (FD). Recently, enzyme replacement therapy (ERT) with human alpha-galactosidase A has become available. Here, we investigate the association between pHL and pVL in FD and their ERT responses. Pure tone audiometry (PTA) and head impulse testing (HIT) were administered at baseline in 47 patients (25 male, 18-60 y; 22 female, 17-74 y), of whom 24 also received caloric irrigation (CI). Of the 47 patients, 38 (24 male) were tested both before and during ERT (follow- up < or = 60 months). ERT consisted of agalsidase alfa infusions. At baseline, pHL was present in 88% of males and 86% of females. Over all tested frequencies (range: 0.5-6 kHz), pHL was significantly (two-way ANOVA: p < 0.05) greater at higher age and in males,with largest deficits at high frequencies. When assessed with HIT, 80% of males and 77% of females had pVL. pVL was significantly greater at higher age and in males. Tested with CI, 21% of males and 0% of females had pVL. No associations among individual semicircular canal (SCC) deficits, as tested by HIT, and hearing was observed in individual ears. After > or = 18 months of ERT, pVL was significantly smaller than at baseline (ANOVA for HIT: p < 0.01). In contrast, pHL remained unchanged by ERT over 60 months (p > 0.05). We conclude that pHL and pVL prevalences are similar in FD. To detect pVL, HIT is more sensitive than CI. We speculate that pHL and pVL emerge from lesions within the vestibulocochlear labyrinth, because no specific patterns of vestibulo-cochlear deficits were observed, as expected if lesions were more proximal along the inferior or superior branch of the vestibulo-cochlear nerve or labyrinthine artery. Finally, ERT stabilizes auditory and even improves vestibular function.

Dietary thyroid hormone replacement ameliorates hearing deficits in hypothyroid mice.

Thyroid hormone (TH) insufficiency causes variable hearing impairment and mental deficiency in humans. Rodents lacking TH have congenital hearing deficiency that has been attributed to physiologic, morphologic, and developmental abnormalities of the auditory system. We examined four genetically defined strains of hypothyroid mice for development of hearing and response to TH replacement initiated during late gestation and continued through six weeks of age. Auditory brain stem response studies showed variable hearing impairment in homozygous mutants of each strain at three weeks of age relative to normal littermates. Mutants from three of the strains still had hearing deficiencies at six weeks of age. TH-enriched diet significantly improved hearing in three-week-old mutants of each strain relative to untreated mutants. Differences in the level of hearing impairment between the Prop1df and Pit1dw mutants, which have defects in the same developmental pathway, were determined to be due to genetic background modifier genes. Further physiologic and morphologic studies in the Cgatm1Sac strain indicated that poor hearing was due to cochlear defects. We conclude that TH supplement administered during the critical period of hearing development in mice can prevent deafness associated with congenital hypothyroidism of heterogeneous genetic etiology.

Endonasal approach of salpingopharyngeus muscle for the treatment of ear click related to palatal tremor.

Palatal tremor (PT) is a rare disease associated with rhythmic movements of the soft palate. It can be separated into two distinct clinical entities: symptomatic and essential. Most patients with essential PT complain of the rhythmic ear clicks and in some cases tinnitus, but usually have an uneventful medical history. Symptomatic PT patients are often unaware of the palatal movements and have symptoms and signs of brainstem or cerebellar dysfunction. We describe the case of a 25-year-old patient who developed severe essential PT, with very distressing bilateral objective tinnitus, constantly perceived as ear clicks. Several oral medications were prescribed with poor results. No significant improvement was obtained with repetitive injections of botulinum toxin type A (BTX A) distributed in soft palate muscles. Because of the continuous tinnitus and its impact on the patient's quality of life, chemical denervation of the salpingopharyngeus muscles, which is involved in the production of tinnitus, with BTX A was performed endonasally under endoscopic guidance. The result was very satisfactory. Tinnitus due to essential PT may be satisfactorily treated by endonasal injection of BTX into the salpingopharyngeus and palatopharyngeus muscles.

Treatment of Susac syndrome with gamma globulin and corticosteroids.

Susac syndrome is a rare vasculopathy characterized by visual, hearing, and cognitive dysfunction. Optimal treatment is unknown, but many patients require chemotherapy to control disease activity. We describe two patients with Susac syndrome and their response to intravenous immune globulin (IVIg) and corticosteroids. Both patients improved following acute treatment with IVIg and intravenous methylprednisolone (IVMP), and no further relapses were observed. One patient showed significant improvement in hearing and MRI lesions shortly following acute treatment. Treatment with IVIg and corticosteroids provides a therapeutic option that avoids the toxicities of chemotherapy and suggests the possible importance of pathologic antibodies in the pathogenesis of Susac syndrome.

Topical antibiotics without steroids for chronically discharging ears with underlying eardrum perforations.

BACKGROUND: Chronic suppurative otitis media (CSOM) causes ear discharge and impairs hearing. OBJECTIVES: Assess topical antibiotics (excluding steroids) for treating chronically discharging ears with underlying eardrum perforations (CSOM). SEARCH STRATEGY: The Cochrane Ear, Nose and Throat Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 1, 2005), MEDLINE (January 1951 to March 2005), EMBASE (January 1974 to March 2005), LILACS (January 1982 to March 2005), AMED (1985 to March 2005), CINAHL (January 1982 to March 2005), OLDMEDLINE (January 1958 to December 1965), PREMEDLINE, metaRegister of Controlled Trials (mRCT), and article references. SELECTION CRITERIA: Randomised controlled trials; any topical antibiotic without steroids, versus no drug treatment, aural toilet, topical antiseptics, or other topical antibiotics excluding steroids; participants with CSOM. DATA COLLECTION AND ANALYSIS: One author assessed eligibility and quality, extracted data, entered data onto RevMan; two authors inputted where there was ambiguity. We contacted investigators for clarifications. MAIN RESULTS: Fourteen trials (1,724 analysed participants or ears). CSOM definitions and severity varied; some included otitis externa, mastoid cavity infections and other diagnoses. Methodological quality varied; generally poorly reported, follow-up usually short, handling of bilateral disease inconsistent. Topical quinolone antibiotics were better than no drug treatment at clearing discharge at one week: relative risk (RR) was 0.45 (95% confidence interval (CI) 0.34 to 0.59) (two trials, N = 197). No statistically significant difference was found between quinolone and non-quinolone antibiotics (without steroids) at weeks one or three: pooled RR were 0.89 (95% CI 0.59 to 1.32) (three trials, N = 402), and 0.97 (0.54 to 1.72) (two trials, N = 77), respectively. A positive trend in favour of quinolones seen at two weeks was largely due to one trial and not significant after accounting for heterogeneity: pooled RR 0.65 (0.46 to 0.92) (four trials, N = 276) using the fixed-effect model, and 0.64 (95% CI 0.35 to 1.17) accounting for heterogeneity with the random-effects model. Topical quinolones were significantly better at curing CSOM than antiseptics: RR 0.52 (95% CI 0.41 to 0.67) at one week (three trials, N = 263), and 0.58 (0.47 to 0.72) at two to four weeks (four trials, N = 519). Meanwhile, non-quinolone antibiotics (without steroids) compared to antiseptics were more mixed, changing over time (four trials, N = 254). Evidence regarding safety was generally weak. AUTHORS' CONCLUSIONS: Topical quinolone antibiotics can clear aural discharge better than no drug treatment or topical antiseptics; non-quinolone antibiotic effects (without steroids) versus no drug or antiseptics are less clear. Studies were also inconclusive regarding any differences between quinolone and non-quinolone antibiotics, although indirect comparisons suggest a benefit of topical quinolones cannot be ruled out. Further trials should clarify non-quinolone antibiotic effects, assess longer-term outcomes (for resolution, healing, hearing, or complications) and include further safety assessments, particularly to clarify the risks of ototoxicity and whether quinolones may result in fewer adverse events than other topical treatments.

Use of topiramate (topamax) in a subgroup of migraine-vertigo patients with auditory symptoms.

Five-three percent of the patients who suffer from migraine present severe incapacity and need rest in bed. If we add to this the incapacity produced by vertigo, then the quality of life of these patients is seriously affected. Migraine/Vertigo (MV) should be another criterion in the selection of preventive treatment even when other criteria are not fulfilled. Auditory symptoms may accompany MV. We treated 10 patients with Topiramate in an open trial, twice a day, with an average dose of 100 mg/day. The treatment period for these patients ranges between 6 and 16 months, with a mean of 9. As of today, all patients present no crisis. Regarding auditory symptoms, all the patients referred that they were stabilized. The effect began quickly, from the first month in most patients as it has been reported in other studies.

Randomized double-blinded, placebo-controlled clinical trial of famciclovir for reduction of Ménière's disease symptoms.

OBJECTIVE: To conduct a clinical trial of famciclovir for symptom control in Meniere's disease. STUDY DESIGN AND SETTING: Randomized, double-blinded placebo-controlled clinical trial in a tertiary referral center, with 12 subjects in the active treatment arm and 11 subjects in the placebo arm. RESULTS: There were no serious adverse events. Twenty-five percent of the famciclovir group and 18% of the placebo group showed a reduction in number of vertigo spells, the primary efficacy endpoint. This difference was not statistically significant. All subjects improved in dizziness and health-related quality of life. There was a trend for the famciclovir arm to have less fluctuation in hearing relative to the placebo arm. CONCLUSION: No dramatic effects of famciclovir were found on vertigo or dizziness. Some promising effects on reduction of the fluctuation in hearing were observed. SIGNIFICANCE: Famciclovir may suppress the fluctuation of hearing in Meniere's disease, but had a minimal effect on vertigo or dizziness symptoms in this study. The probable multifactorial etiology in Meniere's disease requires that further studies be conducted to determine the effects of antiviral medications. EBM RATING: A.

Typical and atypical Cogan's syndrome: 32 cases and review of the literature.

OBJECTIVE: To report our experience on a multicentre series of 32 patients with either typical or atypical Cogan's syndrome, to combine our results with a detailed review of the literature, and to compare the clinical manifestations of typical and atypical Cogan's syndrome. METHODS: Patients were identified from a survey conducted with physicians affiliated to the French National Society for Internal Medicine, and were classified into typical or atypical Cogan's syndrome according to the Haynes criteria. Clinical data were collected in a standardized manner. A comprehensive literature review using the Medline database and the reference lists of identified articles was performed. RESULTS: Seventeen patients had typical Cogan's syndrome and 15 had atypical Cogan's syndrome. Apart from non-syphilitic interstitial keratitis, the ocular manifestations of patients with atypical Cogan's syndrome were mainly uveitis and episcleritis. All but one patient presented with Ménière-like syndrome, and at the end of follow-up 11 were deaf and 19 additional patients had developed a significant decrease in auditory acuity. Twenty-five patients (78%) developed systemic manifestations, including aortitis in four. Comparison of typical and atypical Cogan's syndrome showed that some systemic manifestations were more common in atypical Cogan's syndrome, but these differences may be explained by reporting bias in the literature. CONCLUSION: Differences regarding the associated systemic manifestations of typical and atypical Cogan's syndrome may reflect reporting bias in the literature. However, the diversity of the ocular and audiovestibular manifestations and the acceptable lengthy delay between the two types of involvement in atypical Cogan's syndrome should make one cautious before accepting this diagnosis as the diagnosis may mimic various other systemic diseases.