Does N-acetylcysteine Improve Established Hearing Loss in Guinea Pigs?

Objective: To assess whether multiple injections of a powerful antioxidant can improve established sensorineural hearing loss in guinea pigs. Study Design: Animal study. Setting: Animal science laboratory, University of Manitoba. Methods: A total of 16 guinea pigs were used in our study: 8 underwent unilateral intracochlear neomycin injection, and 8 underwent unilateral saline to serve as controls. After a period of 3 weeks for hearing loss to stabilize, 4 guinea pigs from each group received weekly intraperitoneal injections of N-acetylcysteine (NAC) for 4 weeks. Click auditory brainstem response (ABR) testing was conducted at baseline, weekly after the start of NAC injections, and after the last injection. Pure tone ABR tests were conducted prior to intracochlear injections and at completion of the study. Results: Click ABR thresholds were significantly worse in ears treated with neomycin (P < .001), as expected, but not significantly different when treated with NAC (P = .664). Thresholds for pure tone ABR were also not statistically different in neomycin-treated ears with or without NAC (P > .99). Conclusions: The aggressive antioxidant therapy performed in this study was not successful in improving established hearing loss via an antioxidant regimen that is known to change the oxidation-reduction potential in the cochlea.

Reliability of caloric testing.

OBJECTIVE: To assess the long-term stability of caloric testing in patients. METHODS: In this retrospective study, Cronbach's alpha was used to determine whether caloric testing results are stable over time (up to 7 years) in patients who have not undergone interventions. After excluding invalid records, two hundred patients who underwent repeated caloric testing in the same lab over varying periods of time were included. RESULTS: Cronbach's alpha scores were 0.512 for unilateral weakness and 0.051 for the sum of caloric tests indicating that the stability of caloric tests is poor over long terms. CONCLUSION: The stability of caloric testing with repeated testing over long terms is not reliable.

Brain-derived nerve growth factor in the cochlea - a reproducibility study.

OBJECTIVE: Brain-derived nerve growth factor (BDNF) plays an important role in cochlear development so it is plausible that it could restore hearing loss if delivered directly into the cochlea. We wished to confirm our previous report that a single intracochlear injection of brain-derived nerve growth factor (BDNF) was beneficial for hearing in guinea pigs. We wished to assess the reproducibility of our results and assess possible improved methods with a view to developing a clinical treatment for sensorineural hearing loss. METHODS: CDDP was used to create partial hearing loss in 25 guinea pigs. After 30 days the animals underwent ABR testing and unilateral BDNF injection through the round window in one ear and saline injection into the other ear. After allowing possible effects to stabilize, thirty days later, ABR threshold testing was repeated to assess change in threshold. RESULTS: Final ABR thresholds were 60-70 dB and were about 11 dB better in the ears treated with BDNF. CONCLUSION: Our original finding that Intracochlear BDNF can improve hearing in guinea pigs was confirmed, but the improvement demonstrated by the methods in this paper is too small for clinical application.

Mannitol and the blood-labyrinth barrier.

BACKGROUND: Characterization of the blood labyrinth barrier (BLB) is extremely important to determine whether the BLB can be manipulated pharmacologically. However, experiments to investigate the BLB are technically difficult to perform. In this report, we demonstrated a unique method of controlling the BLB, and established the pharmacokinetics of gentamicin in perilymph, cerebrospinal fluid (CSF) and blood with and without mannitol. STUDY DESIGN: Controlled animal research project. METHODS: Permeability of the BLB and the blood brain barrier (BBB) to gentamicin with and without mannitol was studied by collecting 175 samples from 44 guinea pigs using concentrations relevant to human clinical situations. Samples were taken from two groups of 22 animals, with each animal undergoing sampling at a different time after administration of either 10 mg/ml gentamicin (4 mg/kg) (Gardena, CA) alone or gentamicin with 20% mannitol (250 mg/kg) (Mallinckrodt Inc., KY). The sample times varied from 0.5 to 17.5 h post-infusion. Samples were also taken from 4 animals as negative controls after administration of normal saline. Our goal was to simultaneously assess the pharmacokinetics of gentamicin in each of three different fluid samples in the same animal. Thus at the pre-determined post-infusion sampling time, each animal was sampled once for perilymph, CSF, and blood before being euthanized. Each animal contributed to a single time point on the subsequent pharmacokinetic curves with more than one animal per time point. RESULTS: Mannitol increased the rate of entry and egress of gentamicin through BLB significantly (p = 0.0044) but the effects on the BBB did not reach statistical significance (p = 0.581). Mannitol did not alter renal clearance of gentamicin from the blood (p = 0.433). The concentration of gentamicin in perilymph and CSF was always significantly lower than in blood. CONCLUSIONS: Mannitol administration transiently increases the permeability of the BLB. Potential clinical benefits may accrue from selected timing of administration of osmotic agents such as mannitol augmenting the rate of entry and egress of compounds such as gentamicin into and out of perilymph.

Statistical Considerations in Otolaryngology Journals.

Statistics can be intimidating for clinicians and reviewers. Statistics are often important and useful but can mislead. Elaborate statistics can support conclusions that contradict clinical experience. This article explores some statistically related insights. Statistical reasons for rejecting papers were collated, and the frequency and complexity of statistical tests in accepted, published papers in otolaryngology journals were then studied. Most statistical errors in papers are logical misinterpretations of information rather than lack of understanding of statistics. Otolaryngology papers tend to employ relatively straightforward statistics that should be useful for clinicians. Although evidence-based medicine has changed medical publishing, clinical knowledge is more important that statistical knowledge for clinical applications of statistics.

Tinnitus Treatment Trends.

OBJECTIVE: The American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) recently published guidelines on the treatment of tinnitus. This paper examines the possible impact of those guidelines on otologic practice. DESIGN: A survey was sent to the members of the American Neurotology Society before and after the publication of Clinical practice guideline: tinnitus. The goals of this study were to see if the guidelines changed attitudes of otologists, confirm what treatments and explanations are being used in the field before and after the guidelines were published. MAIN OUTCOMES: Five hundred fifty-eight surveys were sent out and there were 216 responses. Otologists generally seemed to practice in accordance with the recommendations of the guidelines even before these were published. Drugs and sound therapies were not commonly used for primary tinnitus either before or after publication of the guidelines. One treatment that otologists seemed to have confidence in that was omitted from the guidelines was surgical treatment of hearing loss. CONCLUSION: Opinions regarding the treatment of tinnitus vary considerably. The AAO-HNS clinical practice guideline: tinnitus has not significantly altered the practices of otologists, but the guidelines provide meaningful, important information for other clinicians who deal infrequently with tinnitus.

Methods considerations for nystagmography.

OBJECTIVES: 1. To assess the reproducibility of eye movement velocity measurement using two methods: traditional electro-oculography (EOG) and infrared video-oculography (VOG) and, 2. Determine whether the normal values for unilateral weakness and bilateral reduction of caloric responses vary according to method employed. BACKGROUND: Vestibular testing frequently involves measurement of eye movements. EOG has been the standard method for decades, but VOG and other methods have recently become popular. The assumption has been that all methods measure eye movements equally and accurately but this assumption has not been validated. In this paper we examine this assumption. METHODS: Eye movements were recorded simultaneously with commercially available EOG and VOG methods to evaluate differences in results for nineteen normal subjects undergoing caloric tests with warm and cold water. Examination of the records permitted identification and simultaneous measurement of 840 nystagmus beats. RESULTS: EOG and VOG measurements were correlated but the correlation was not strong (Spearman rho = 0.529, p < 0.01). Eye velocities recorded by the VOG system were greater than that for the EOG system. The mean VOG/EOG ratio was 1.71. Normal values used at our centre were adjusted to accommodate the use of video technology to account for the differences in sensitivity between EOG and VOG methods. CONCLUSION: The traditional EOG-based normal value for bilateral reduction of caloric response, 30 degree per second (d/s) based on traditional EOG measurements should be revised to 50 d/s for modern VOG testing in our lab. Normal values for vestibular testing may need to be re-evaluated when new technology is introduced. Each lab should verify normal values for their own methods and equipment.

Elevated auditory brainstem response thresholds in mice with Connexin36 gene ablation.

CONCLUSION: Expression of connexin36 (Cx36) and electrical synapses formed by Cx36-containing gap junctions contribute to normal auditory brainstem response thresholds in mice. OBJECTIVES: Electrical synaptic transmission mediated by gap junctions has not been intensively studied in the auditory system. This study used transgenic mice with knockout of the gene coding for the major protein that forms neuronal gap junctions in mammalian brain (Cx36) to evaluate the role of Cx36 in murine hearing. METHODS: Auditory brainstem response (ABR) thresholds and distortion product otoacoustic emissions (DPOAEs) were measured in 26 wild-type and 26 Cx36 knockout mice. ABR thresholds were used to assess auditory brainstem function at four frequencies. DPOAEs were delivered for seven frequency pairs to assess cochlear function. RESULTS: The magnitudes of the 2f1-f2 distortion products were not different between Cx36 knockout and wild-type mice, suggesting similar cochlear function in the two groups. ABR thresholds were significantly elevated in the Cx36 knockout compared with the wild-type groups, suggesting impaired function in the auditory brainstem. The results suggest that electrical synapses formed by Cx36-containing gap junctions contribute to auditory sound processing and function at the level of the brainstem, not the cochlea. These findings may be important for understanding human auditory pathology.

Normal Values for Cervical Vestibular-Evoked Myogenic Potentials.

OBJECTIVES: To assess the variability of normal values for cervical vestibular-evoked myogenic potentials (cVEMP) testing and to provide guidance regarding which parameters should be reported for clinical practice. STUDY DESIGN: Forty-eight normal subjects with no history of hearing loss or vestibular symptoms underwent cVEMP testing. Measurement parameters were tabulated and compared to other sets of cVEMP normal values in the literature. The literature was reviewed to assess the clinical significance of abnormal cVEMP results. The distributions of threshold and symmetry ratios for normal subjects were compared to the distributions of 90 patients who underwent cVEMP testing. SETTING: Tertiary academic center. RESULTS: Upper limits of 42% symmetry ratio and the range of 65 to 95 dB HL for threshold were established for our center.The quartile coefficients of dispersion were much less than 1.0 for all cVEMP parameters in the literature, suggesting that the variability in normal ranges across the literature is small. The distributions for threshold and symmetry ratio were similar between normal and patient groups. There is a lack of information in the literature regarding the impairment of function resulting from various degrees of abnormality of VEMP results. CONCLUSIONS: Normal values for cVEMP parameters are statistically consistent in the literature. The clinical significance of abnormal values has not been validated. For clinical purposes, cVEMP "thresholds" should be reported. Reporting of other parameters is optional.

Clinical practice guideline: tinnitus.

OBJECTIVE: Tinnitus is the perception of sound without an external source. More than 50 million people in the United States have reported experiencing tinnitus, resulting in an estimated prevalence of 10% to 15% in adults. Despite the high prevalence of tinnitus and its potential significant effect on quality of life, there are no evidence-based, multidisciplinary clinical practice guidelines to assist clinicians with management. The focus of this guideline is on tinnitus that is both bothersome and persistent (lasting 6 months or longer), which often negatively affects the patient's quality of life. The target audience for the guideline is any clinician, including nonphysicians, involved in managing patients with tinnitus. The target patient population is limited to adults (18 years and older) with primary tinnitus that is persistent and bothersome. PURPOSE: The purpose of this guideline is to provide evidence-based recommendations for clinicians managing patients with tinnitus. This guideline provides clinicians with a logical framework to improve patient care and mitigate the personal and social effects of persistent, bothersome tinnitus. It will discuss the evaluation of patients with tinnitus, including selection and timing of diagnostic testing and specialty referral to identify potential underlying treatable pathology. It will then focus on the evaluation and treatment of patients with persistent primary tinnitus, with recommendations to guide the evaluation and measurement of the effect of tinnitus and to determine the most appropriate interventions to improve symptoms and quality of life for tinnitus sufferers. ACTION STATEMENTS: The development group made a strong recommendation that clinicians distinguish patients with bothersome tinnitus from patients with nonbothersome tinnitus. The development group made a strong recommendation against obtaining imaging studies of the head and neck in patients with tinnitus, specifically to evaluate tinnitus that does not localize to 1 ear, is nonpulsatile, and is not associated with focal neurologic abnormalities or an asymmetric hearing loss. The panel made the following recommendations: Clinicians should (a) perform a targeted history and physical examination at the initial evaluation of a patient with presumed primary tinnitus to identify conditions that if promptly identified and managed may relieve tinnitus; (b) obtain a prompt, comprehensive audiologic examination in patients with tinnitus that is unilateral, persistent (≥ 6 months), or associated with hearing difficulties; (c) distinguish patients with bothersome tinnitus of recent onset from those with persistent symptoms (≥ 6 months) to prioritize intervention and facilitate discussions about natural history and follow-up care; (d) educate patients with persistent, bothersome tinnitus about management strategies; (e) recommend a hearing aid evaluation for patients who have persistent, bothersome tinnitus associated with documented hearing loss; and (f) recommend cognitive behavioral therapy to patients with persistent, bothersome tinnitus. The panel recommended against (a) antidepressants, anticonvulsants, anxiolytics, or intratympanic medications for the routine treatment of patients with persistent, bothersome tinnitus; (b) Ginkgo biloba, melatonin, zinc, or other dietary supplements for treating patients with persistent, bothersome tinnitus; and (c) transcranial magnetic stimulation for the routine treatment of patients with persistent, bothersome tinnitus. The development group provided the following options: Clinicians may (a) obtain an initial comprehensive audiologic examination in patients who present with tinnitus (regardless of laterality, duration, or perceived hearing status); and (b) recommend sound therapy to patients with persistent, bothersome tinnitus. The development group provided no recommendation regarding the effect of acupuncture in patients with persistent, bothersome tinnitus.

Clinical practice guideline: tinnitus executive summary.

The American Academy of Otolaryngology--Head and Neck Surgery Foundation (AAO-HNSF) has published a supplement to this issue featuring the new Clinical Practice Guideline: Tinnitus. To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 13 recommendations developed address the evaluation of patients with tinnitus, including selection and timing of diagnostic testing and specialty referral to identify potential underlying treatable pathology. It will then focus on the evaluation and treatment of patients with persistent primary tinnitus, with recommendations to guide the evaluation and measurement of the impact of tinnitus and to determine the most appropriate interventions to improve symptoms and quality of life for tinnitus sufferers.

Steroids in aminoglycoside-containing ear drops: do they reduce cochlear toxicity?

OBJECTIVES/HYPOTHESIS: To determine whether betamethasone (BM) reduces the cochlear toxicity of otic gentamicin (GM) if given together. STUDY DESIGN: Controlled animal study. METHODS: Thirty-four mice were assigned at random to receive intratympanic injections of either 0.1 % BM (11 mice), 0.3% GM (13 mice), or a combination of both (GM/BM) with benzalkonium chloride (10 mice) in the left ear (treated) and saline on the right (untreated). Six injections were given on alternate days. Auditory brainstem response thresholds were assessed at 1 month, 2 months, and >2 months. RESULTS: There was a significantly greater degree of hearing loss in the BM-treated ears compared to the untreated ears (6.48 dB hearing loss, P = .007) and in the GM-treated ears compared to untreated ears (6.59 dB hearing loss, P = .010,). However, otic GM/BM and benzalkonium chloride did not cause significant additional hearing loss compared with the untreated ears (3.56 dB hearing loss, P = .242). CONCLUSIONS: Our data suggest that hearing loss caused by GM otic drops may be reduced by the inclusion of BM and benzalkonium chloride. Our finding that BM alone was associated with hearing loss suggests that the benzalkonium chloride may be the protective agent in combination otic drops.

Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale.

PURPOSE: The platinum chemotherapy agents cisplatin and carboplatin are widely used in the treatment of adult and pediatric cancers. Cisplatin causes hearing loss in at least 60% of pediatric patients. Reducing cisplatin and high-dose carboplatin ototoxicity without reducing efficacy is important. PATIENTS AND METHODS: This review summarizes recommendations made at the 42nd Congress of the International Society of Pediatric Oncology (SIOP) in Boston, October 21-24, 2010, reflecting input from international basic scientists, pediatric oncologists, otolaryngologists, oncology nurses, audiologists, and neurosurgeons to develop and advance research and clinical trials for otoprotection. RESULTS: Platinum initially impairs hearing in the high frequencies and progresses to lower frequencies with increasing cumulative dose. Genes involved in drug transport, metabolism, and DNA repair regulate platinum toxicities. Otoprotection can be achieved by acting on several these pathways and generally involves antioxidant thiol agents. Otoprotection is a strategy being explored to decrease hearing loss while maintaining dose intensity or allowing dose escalation, but it has the potential to interfere with tumoricidal effects. Route of administration and optimal timing relative to platinum therapy are critical issues. In addition, international standards for grading and comparing ototoxicity are essential to the success of prospective pediatric trials aimed at reducing platinum-induced hearing loss. CONCLUSION: Collaborative prospective basic and clinical trial research is needed to reduce the incidence of irreversible platinum-induced hearing loss, and optimize cancer control. Wide use of the new internationally agreed-on SIOP Boston ototoxicity scale in current and future otoprotection trials should help facilitate this goal.

Patients with cochlear implants in the OR--issues and concerns.

Safety standards for patients with cochlear implants are difficult to find. Safety standards are, in fact, constantly evolving as more information becomes available. This article provides an overview of current philosophies and guidelines for most medical/surgical interventions, with emphasis on the operating room environment, as indicated by the three manufacturers authorized to market cochlear implants in Canada.

Addressing animal model issues in auditory research.

OBJECTIVE: To better understand the differences in auditory systems across species. METHODS: Auditory brainstem response (ABR) click thresholds were obtained from normal 3- to 6-week-old animals including 15 guinea pigs, 62 mice, and 6 rats. Pure-tone ABR thresholds were obtained in 7 guinea pigs, 6 mice, and 13 rats. Threshold variability was then considered a function of basilar membrane length, mean body weight, basal metabolic rate, and longevity as identified in the literature. RESULTS: Interspecies variability of auditory thresholds for normal-hearing animals is not explained by differences in mean body weight, metabolic rate, or longevity. Simple linear models appear to adequately describe threshold variability across the parameters studied. Click thresholds, with significant low-frequency content, suggest that mice have better hearing than rats or guinea pigs. CONCLUSION: In spite of wide variations in cochlear anatomy and metabolic factors, different species have evolved similar auditory thresholds across species in normal, young animals.

Does sodium thiosulphate delay presbyacusis?

INTRODUCTION: This study compares the effects of sodium thiosulphate (STS) and normal saline on the prevention of hearing loss. SETTING: Animal research laboratory. METHODS: Sixteen mice were randomized to receive intraperitoneal injections of either normal saline or STS. Auditory brainstem response testing was used to determine baseline and posttreatment hearing thresholds over the course of 1 year. RESULTS: Compared with saline, treatment with STS resulted in a statistically significant improvement in click and pure-tone thresholds until the end of the year. CONCLUSION: STS can significantly delay hearing loss associated with age in this murine model.

Comparison of three methods of testing hearing in mice.

INTRODUCTION: This study compares the reliability and validity of three methods of testing hearing in mice. SETTING: Animal research laboratory. METHODS: Three methods of testing hearing were used in 18 mice: (1) auditory brainstem response (ABR), (2) electrocochleography with a needle electrode, and (3) electrocochleography with a soft, cotton-wick electrode. RESULTS: Reliability was good for all three tests, but ABR testing was the easiest and provided the lowest thresholds and least variability. The results for these tests under other conditions may vary. CONCLUSION: ABR testing can be considered an optimal test method under the circumstances in this study.

Post-tonsillectomy bleeding: how much is too much?

Complication rates become important in discussions for informed surgical consent and for quality assurance purposes. In an attempt to quantify literature-based rates for post-tonsillectomy bleeding, a MEDLINE search was carried out. Of 4,610 papers 63 reported post-tonsillectomy bleeding rates. The weighted mean, standard deviation and 95% confidence intervals were calculated for those papers. The mean (4.5%) plus 2 standard deviations (9.4%) suggests a maximum "expected" sustained bleeding rate of 13.9%. In the literature, which should reflect optimum results, there were 3 reports of bleed rates in the 18-20% range. These data may be useful for quality assurance committees and individual clinicians.