Efficacy and safety of N-acetylcysteine in prevention of noise induced hearing loss: a randomized clinical trial.

Despite a robust hearing conservation program, military personnel continue to be at high risk for noise induced hearing loss (NIHL). For more than a decade, a number of laboratories have investigated the use of antioxidants as a safe and effective adjunct to hearing conservation programs. Of the antioxidants that have been investigated, N-acetylcysteine (NAC) has consistently reduced permanent NIHL in the laboratory, but its clinical efficacy is still controversial. This study provides a prospective, randomized, double-blinded, placebo-controlled clinical trial investigating the safety profile and the efficacy of NAC to prevent hearing loss in a military population after weapons training. Of the 566 total study subjects, 277 received NAC while 289 were given placebo. The null hypothesis for the rate of STS was not rejected based on the measured results. While no significant differences were found for the primary outcome, rate of threshold shifts, the right ear threshold shift rate difference did approach significance (p = 0.0562). No significant difference was found in the second primary outcome, percentage of subjects experiencing an adverse event between placebo and NAC groups (26.7% and 27.4%, respectively, p = 0.4465). Results for the secondary outcome, STS rate in the trigger hand ear, did show a significant difference (34.98% for placebo-treated, 27.14% for NAC-treated, p-value = 0.0288). Additionally, post-hoc analysis showed significant differences in threshold shift rates when handedness was taken into account. While the secondary outcomes and post-hoc analysis suggest that NAC treatment is superior to the placebo, the present study design failed to confirm this. The lack of significant differences in overall hearing loss between the treatment and placebo groups may be due to a number of factors, including suboptimal dosing, premature post-exposure audiograms, or differences in risk between ears or subjects. Based on secondary outcomes and post hoc analyses however, further studies seem warranted and are needed to clarify dose response and the factors that may have played a role in the observed results.

Does interferon beta-1a impact pure-tone hearing sensitivity among individuals with multiple sclerosis?

BACKGROUND: Previous studies reported that particular types of interferon medications might contribute to hearing loss in some patients. The package insert included in the original Food and Drug Administration application for intramuscular interferon beta-1a (Avonex) stated that some patients in the treatment group reported decreased hearing sensitivity. OBJECTIVE: The purpose of the present investigation was to assess if individuals with multiple sclerosis (MS) taking intramuscular interferon beta-1a have significantly poorer hearing thresholds than those not currently using any disease-modifying therapies. METHODS: This was a secondary analysis of data collected as part of two larger studies evaluating auditory function in patients with MS. The goal of this analysis was to determine if users of interferon beta-1a do not have significantly worse hearing thresholds than nonusers of disease-modifying therapies, after adjusting for potential confounders. A linear mixed model was fit to the audiometric thresholds of our subjects. This model included interferon beta-1a use, MS disease subtype, gender, test frequency, age, disease duration (number of years), and the Expanded Disability Status Scale score. RESULTS AND CONCLUSIONS: With all subjects included, there is insufficient evidence to say that intramuscular interferon-beta 1a is not ototoxic (in relation to nonuse of a disease-modifying therapy) at all frequencies tested except 3000 and 6000 Hz. After removing two influential subjects, the results indicated that there is statistical support for no ototoxic effect of intramuscular interferon beta-1a at test frequencies from 250 to 6000 Hz. There is insufficient evidence, however, to rule out an ototoxic effect at 8000 Hz. Future studies should further evaluate the effect of interferon on auditory function in patients with MS. Neuroscience nurses should monitor their patients' hearing throughout the course of treatment.

Neurotrophins differentially stimulate the growth of cochlear neurites on collagen surfaces and in gels.

The electrodes of a cochlear implant are located far from the surviving neurons of the spiral ganglion, which results in decreased precision of neural activation compared to the normal ear. If the neurons could be induced to extend neurites toward the implant, it might be possible to stimulate more discrete subpopulations of neurons, and to increase the resolution of the device. However, a major barrier to neurite growth toward a cochlear implant is the fluid filling the scala tympani, which separates the neurons from the electrodes. The goal of this study was to evaluate the growth of cochlear neurites in three-dimensional extracellular matrix molecule gels, and to increase biocompatibility by using fibroblasts stably transfected to produce neurotrophin-3 and brain-derived neurotrophic factor. Spiral ganglion explants from neonatal rats were evaluated in cultures. They were exposed to soluble neurotrophins, cells transfected to secrete neurotrophins, and/or collagen gels. We found that cochlear neurites grew readily on collagen surfaces and in three-dimensional collagen gels. Co-culture with cells producing neurotrophin-3 resulted in increased numbers of neurites, and neurites that were longer than when explants were cultured with control fibroblasts stably transfected with green fluorescent protein. Brain-derived neurotrophic factor-producing cells resulted in a more dramatic increase in the number of neurites, but there was no significant effect on neurite length. It is suggested that extracellular matrix molecule gels and cells transfected to produce neurotrophins offer an opportunity to attract spiral ganglion neurites toward a cochlear implant.

Development and validation of a cisplatin dose-ototoxicity model.

BACKGROUND: Cisplatin is effective in the treatment of several cancers but is a known ototoxin resulting in shifts to hearing sensitivity in up to 50-60% of patients. Cisplatin-induced hearing shifts tend to occur first within an octave of a patient's high frequency hearing limit, termed the sensitive range for ototoxicity (SRO), and progress to lower frequencies. While it is currently not possible to know which patients will experience ototoxicity without testing their hearing directly, monitoring the SRO provides an early indication of damage. A tool to help forecast susceptibility to ototoxic-induced changes in the SRO in advance of each chemotherapy treatment visit may prove useful for ototoxicity monitoring efforts, patient counseling, and therapeutic planning. PURPOSE: This project was designed to (1) establish pretreatment risk curves that quantify the probability that a new patient will suffer hearing loss within the SRO during treatment with cisplatin and (2) evaluate the accuracy of these predictions in an independent sample of Veterans receiving cisplatin for the treatment of cancer. STUDY SAMPLE: Two study samples were used. The Developmental sample contained 23 subjects while the Validation sample consisted of 12 subjects. DATA COLLECTION AND ANALYSIS: Risk curve predictions for SRO threshold shifts following cisplatin exposure were developed using a Developmental sample comprised of data from a total of 155 treatment visits obtained in 45 ears of 23 Veterans. Pure-tone thresholds were obtained within each subject's SRO at each treatment visit and compared with baseline measures. The risk of incurring an SRO shift was statistically modeled as a function of factors related to chemotherapy treatment (cisplatin dose, radiation treatment, doublet medication) and patient status (age, pre-exposure hearing, cancer location and stage). The model was reduced so that only statistically significant variables were included. Receiver-operating characteristic (ROC) curve analyses were then used to determine the accuracy of the risk curve predictions in an independent Validation sample of observations from over 62 treatment visits obtained in 24 ears of 12 Veterans. RESULTS: Only cumulative cisplatin dose and pre-exposure hearing were found to be significantly related to the risk for hearing shift. The dose-ototoxicity risk curve predictions developed from the Developmental sample yielded area under the ROC curve accuracy estimates of 0.85 when applied to an independent Validation sample. CONCLUSIONS: Cumulative cisplatin dose in combination with pre-exposure hearing provides an indication of whether hearing will shift in the SRO in advance of cisplatin administration. The validated dose-ototoxicity risk curves described herein can be used before and during treatment to anticipate hearing loss. While having such a tool would not replace serial hearing testing, it would be of great benefit to an ototoxicity monitoring program. It would promote relevant pretreatment counseling. Furthermore, for those found to be at risk of SRO shifts within the speech frequencies, the oncology treatment plan could incorporate anticipated dosing adjustments that could stave off the impact that ototoxicity might bring.

Development and evaluation of a portable audiometer for high-frequency screening of hearing loss from ototoxicity in homes/clinics.

Cancer treatment often requires patients to be exposed to drugs that can damage hearing. Drugs such as cisplatin can cause permanent damage to hearing if not detected early. Damage typically occurs first in the more basal regions of the cochlea which are specific for high-frequency (HF) hearing and progresses to more apical regions that are relevant to speech understanding. Monitoring of HF hearing loss can be an effective means for early detection of ototoxicity caused by chemotherapy. Once ototoxicity is detected, the oncology medical team could adjust the drug dosage or switch to medications that are less ototoxic. Telehealth technology may improve access to ototoxicity monitoring. Patients could monitor their own hearing using a device that alerts healthcare professionals in the event of a change in hearing. A portable audiometer is currently not available that is 1) capable of automatic or manual (by an audiologist) operation; 2) designed with precision pure-tone functionality up to 20 kHz; and 3) able to remotely transfer health status information to a healthcare professional. This paper describes the design of a technology, the ototoxicity identification (OtoID), that includes a portable audiometer with HF test functionality that meets ANSI/ASA S3.6-2010 standards and is capable of reliably detecting a person's drug-related hearing changes relative to a baseline period (i.e., before ototoxic drugs) using an automated test. The system includes a wireless cellular modem capable of notifying a remote healthcare professional in the event that a significant change in hearing has occurred in the patient. The system was evaluated on test subjects within a sound-proof booth, a noisy hospital ward, and within their homes. Results indicate that the OtoID system can be used by patients to effectively monitor hearing changes remotely within their home or in a hospital ward, ultimately enabling early detection of ototoxicity and potentially avoiding hearing loss.

Influence of acute hyperglycemia on otoacoustic emissions and the medial olivocochlear reflex.

Stimulus-frequency (SF) otoacoustic emission (OAE) amplitude and the amplitude of medial olivocochlear (MOC) inhibition of SF OAEs for ipsilateral, contralateral and bilateral MOC reflex elicitors were recorded in six subjects with type 2 diabetes during a glucose tolerance test (GTT). Five of the six subjects were tested twice for a total of 11 trials and three subjects were tested in a control experiment. During the GTT experiment, the subjects' blood glucose was elevated from a euglycemic level below 150 mg/dL to a hyperglycemic level above 160 mg/dL following the consumption of a bolus of 80 g of sugar. A subset of three subjects were tested in a control experiment during which SF OAE and MOC reflex measurements were made while blood sugar levels remained constant within the euglycemic region. Mean SF OAE amplitudes were elevated following glucose consumption. A statistically significant increase in MOC inhibition amplitude was observed during elevated sugar levels for the 11 GTT trials. Maximum inhibition occurred about an hour after glucose consumption when blood glucose levels peaked. Results indicate that acute hyperglycemia influences efferent control of the cochlea in people with type 2 diabetes.

Age-related changes in the auditory brainstem response.

PURPOSE: This cross-sectional study had two goals: (1) Identify and quantify the effects of aging on the auditory brainstem response (ABR); (2) Describe how click rate and hearing impairment modify effects of aging. RESEARCH DESIGN AND ANALYSIS: ABR measures were obtained from 131 predominately male Veteran participants aged 26 to 71 yr. Metrics analyzed include amplitude and latency for waves I, III, and V, and the I-V interpeak latency interval (IPI) at three repetition rates (11, 51, and 71 clicks/sec) using both polarities. In order to avoid confounding from missing data due to hearing impairment, participants had hearing thresholds <40 dB HL at 2 kHz and 70 dB HL at 4 kHz in at least one ear. Additionally, the median 2, 3, and 4 kHz pure tone threshold average (PTA2,3,4) for the sample, ∼17 dB HL, was used to delineate subgroups of better and worse hearing ears, and only the better hearing sample was modeled statistically. We modeled ABR responses using age, repetition rate, and PTA2,3,4 as covariates. Random effects were used to model correlation between the two ears of a subject and across repetition rates. Inferences regarding effects of aging on ABR measures at each rate were derived from the fitted model. Results were compared to data from subjects with poorer hearing. RESULTS: Aging substantially diminished amplitudes of all of the principal ABR peaks, largely independent of any threshold differences within the group. For waves I and III, age-related amplitude decrements were greatest at a low (11/sec) click rate. At the 11/sec rate, the model-based mean wave III amplitude was significantly smaller in older compared with younger subjects even after adjusting for wave I amplitude. Aging also increased ABR peak latencies, with significant shifts limited to early waves. The I-V IPI did not change with age. For both younger and older subjects, increasing click presentation rate significantly decreased amplitudes of early peaks and prolonged latencies of later peaks, resulting in increased IPIs. Advanced age did not enhance effects of rate. Instead, the rate effect on wave I and III amplitudes was attenuated for the older subjects due to reduced peak amplitudes at lower click rates. Compared with model predictions from the sample of better hearing subjects, mean ABR amplitudes were diminished in the group with poorer hearing, and wave V latencies were prolonged. CONCLUSIONS: In a sample of veterans, aging substantially reduced amplitudes of all principal ABR peaks, with significant latency shifts limited to waves I and III. Aging did not influence the I-V IPI even at high click rates, suggesting that the observed absolute latency changes associated with aging can be attributed to changes in auditory nerve input. In contrast, ABR amplitude changes with age are not adequately explained by changes in wave I. Results suggest that aging reduces the numbers and/or synchrony of contributing auditory nerve units. Results also support the concept that aging reduces the numbers, though perhaps not the synchrony, of central ABR generators.

Performance on tests of central auditory processing by individuals exposed to high-intensity blasts.

Thirty-six blast-exposed patients and twenty-nine non-blast-exposed control subjects were tested on a battery of behavioral and electrophysiological tests that have been shown to be sensitive to central auditory processing deficits. Abnormal performance among the blast-exposed patients was assessed with reference to normative values established as the mean performance on each test by the control subjects plus or minus two standard deviations. Blast-exposed patients performed abnormally at rates significantly above that which would occur by chance on three of the behavioral tests of central auditory processing: the Gaps-In-Noise, Masking Level Difference, and Staggered Spondaic Words tests. The proportion of blast-exposed patients performing abnormally on a speech-in-noise test (Quick Speech-In-Noise) was also significantly above that expected by chance. These results suggest that, for some patients, blast exposure may lead to difficulties with hearing in complex auditory environments, even when peripheral hearing sensitivity is near normal limits.

Implications of blast exposure for central auditory function: a review.

Auditory system functions, from peripheral sensitivity to central processing capacities, are all at risk from a blast event. Accurate encoding of auditory patterns in time, frequency, and space are required for a clear understanding of speech and accurate localization of sound sources in environments with background noise, multiple sound sources, and/or reverberation. Further work is needed to refine the battery of clinical tests sensitive to the sorts of central auditory dysfunction observed in individuals with blast exposure. Treatment options include low-gain hearing aids, remote-microphone technology, and auditory-training regimens, but clinical evidence does not yet exist for recommending one or more of these options. As this population ages, the natural aging process and other potential brain injuries (such as stroke and blunt trauma) may combine with blast-related brain changes to produce a population for which the current clinical diagnostic and treatment tools may prove inadequate. It is important to maintain an updated understanding of the scope of the issues present in this population and to continue to identify those solutions that can provide measurable improvements in the lives of Veterans who have been exposed to high-intensity blasts during the course of their military service.

Distortion-product otoacoustic emission test performance for ototoxicity monitoring.

INTRODUCTION: A nonbehavioral method for monitoring ototoxicity in patients treated with cisplatin is needed because patients enduring chemotherapy may not be well or cooperative enough to undergo repeated hearing tests. Distortion-product otoacoustic emissions (DPOAEs) provide a nonbehavioral measure of auditory function that is sensitive to cisplatin exposure. However, interpreting DPOAE findings in the context of ototoxicity monitoring requires that their accuracy be determined in relation to a clinically accepted gold standard test. OBJECTIVES: Among patients receiving cisplatin for the treatment of cancer, we sought to (1) identify the combination of DPOAE metrics and ototoxicity risk factors that best classified ears with and without ototoxic-induced hearing changes; and (2) evaluate the test performance achieved by the composite measure as well as by DPOAEs alone. DESIGN: Odds of experiencing hearing changes at a given patient visit were determined using data collected prospectively from 24 Veterans receiving cisplatin. Pure-tone thresholds were examined within an octave of each subject's high-frequency hearing limit. DPOAE were collected as a set of four response growth (input/output) functions near the highest f2 frequency that yielded a robust response at L2 = L1 = 65 dB SPL. Logistic regression modeled the risk of hearing change using several DPOAE metrics, drug treatment factors, and other patient factors as independent variables. An optimal discriminant function was derived by reducing the model so that only statistically significant variables were included. Receiver operating characteristic curve analyses were used to evaluate test performance. RESULTS: At higher cisplatin doses, ears with better hearing at baseline were more likely to exhibit ototoxic hearing changes than those with poorer hearing. Measures of pre-exposure hearing, cumulative drug dose, and DPOAEs generated a highly accurate discriminant function with a cross-validated area under the receiver operating characteristic curve of 0.9. DPOAEs alone also provided an indication of ototoxic hearing change when measured at the highest DPOAE test frequency that yielded a robust response. CONCLUSIONS: DPOAEs alone and especially in combination with pre-exposure hearing and cisplatin dose provide an indication of whether or not hearing has changed as a result of cisplatin administration. These promising results need to be validated in a separate sample.

Audiometric hearing status of individuals with and without multiple sclerosis.

The purpose of the present investigation was to determine whether differences exist in audiometric hearing status between individuals with and without multiple sclerosis (MS) and between individuals with relapsing-remitting MS (RRMS) and individuals with secondary progressive MS (SPMS). Forty-seven subjects with MS (26 with RRMS and 21 with SPMS) and forty-nine control subjects without MS completed both a comprehensive case-history questionnaire and a conventional hearing evaluation. Statistical analyses, accounting for the potential confounding factors of age, sex, noise exposure, and use of ototoxic medications, revealed significant differences in hearing thresholds between subjects with and without MS at select audiometric test frequencies (p < 0.05). At these audiometric test frequencies, the subjects with MS had poorer hearing thresholds. Additional analyses revealed significant differences in hearing sensitivity at select audiometric frequencies between the subjects with RRMS and the subjects with SPMS, such that those with SPMS had poorer hearing thresholds. These findings have significant clinical implications for practitioners working with patients with MS.

Ototoxicity risk assessment combining distortion product otoacoustic emissions with a cisplatin dose model.

An objective method for identifying ototoxic hearing loss among patients receiving cisplatin is necessary since the ability of patients to take a behavioral test may change over the course of treatment. Data from 56 monitoring visits by 19 Veterans taking cisplatin were used to identify combinations of distortion-product otoacoustic emission (DPOAE) metrics and ototoxicity risk factors that best identified ototoxic hearing loss. Models were tested that incorporated DPOAE metrics generated statistically using partial least-squares analysis. Models were also tested that incorporated a priori DPOAE change criteria, such as a minimum DPOAE level shift of 6 dB. Receiver Operating Characteristic analysis was used to compare the accuracy of these models. The best performing model incorporated weighted combinations of pre-treatment hearing, cumulative cisplatin dose and DPOAE metrics that were determined using partial least-squares and evaluated over a quarter octave range near each subjects' high frequency DPOAE limit. Using this model and the DPOAE recording methods described herein, the chance of ototoxic hearing change can be determined at any given observed change in DPOAE level. This approach appears to provide an accurate and rapid ototoxicity risk assessment (ORA) that once validated can be used clinically.

Tinnitus onset rates from chemotherapeutic agents and ototoxic antibiotics: results of a large prospective study.

BACKGROUND AND PURPOSE: To report on the incidence and relative risk of tinnitus onset from a variety of drug therapies known to be ototoxic. Two main questions were asked: (1) What is the prevalence and incidence of tinnitus among patients treated with cisplatin, carboplatin, or ototoxic antibiotic therapies? (2) Do commonly reported treatment or subject factors confound or modify the incidence of tinnitus onset? DATA COLLECTION AND ANALYSIS: A prospective observational study design was used to evaluate occurrence of significant otologic changes in 488 veterans (962 ears) receiving chemotherapeutic agents (cisplatin, carboplatin), ototoxic antibiotics (primarily aminoglycoside), or nonototoxic drugs (control medications). A subset of 260 veterans lacking tinnitus prior to drug exposure was used to compare rates of tinnitus onset. Subjects were tested prior to, during, and following their treatment. Planned comparisons using logistic regression, analysis of variance (ANOVA), and chi(2) statistics were made among groups by the type of medication taken, age, presence of preexisting hearing loss, days on drug, and cumulative dose of drug. RESULTS: Baseline tinnitus rates were high (nearly 47%) relative to the general population of a similar age. Subjects with exposure to ototoxic medications had significantly increased risk for developing tinnitus. Those on chemotherapeutic agents were found to have the greatest risk. Cisplatin elevated the risk by 5.53 times while carboplatin increased the risk by 3.75 over nonototoxic control medications. Ototoxic antibiotics resulted in borderline risk (2.81) for new tinnitus. Contrary to other reports, we did not find that subject factors (increased age or pre-existing hearing loss) or treatment factors (days on drug or cumulative dose) contributed to rates of tinnitus onset during treatment. CONCLUSIONS: This large prospective study confirms that new tinnitus during treatment is associated with chemotherapy and with certain ototoxic antibiotic treatment. Cisplatin and carboplatin were found to be the most potent ototoxic agents causing tinnitus at much greater numbers than the other drugs studied. Implications for counseling and audiological resource allocation are discussed.

Evaluation of audiometric threshold shift criteria for ototoxicity monitoring.

BACKGROUND: There is disagreement about ototoxicity monitoring methods. Controversy exists about what audiometric threshold shift criteria should be used, which frequencies should be tested, and with what step size. An evaluation of the test performance achieved using various criteria and methods for ototoxicity monitoring may help resolve these issues. PURPOSE: (1) Evaluate test performance achieved using various significant threshold shift (STS) definitions for ototoxicity monitoring in a predominately veteran population; and (2) determine whether testing in (1/6)- or (1/3)-octave steps improves test performance compared to (1/2)-octave steps. RESEARCH DESIGN: A prospective, observational study design was used in which STSs were evaluated at frequencies within an octave of each subject's high-frequency hearing limit at two time points, an early monitoring test and the final monitoring test. STUDY SAMPLE: Data were analyzed from 78 ears of 41 patients receiving cisplatin and from 53 ears of 28 hospitalized patients receiving nonototoxic antibiotics. Cisplatin-treated subjects received a cumulative dosage > or =350 mg by the final monitoring test. Testing schedule, age, and pre-exposure hearing characteristics were similar between the subject groups. DATA COLLECTION AND ANALYSIS: Threshold shifts relative to baseline were examined to determine whether they met criteria based on magnitudes of positive STS (shifts of > or =5, 10, 15, or 20 dB) and numbers of frequencies affected (shifts at > or =1, 2, or 3 adjacent frequencies) for data collected using approximately (1/6)-, (1/3)-, or (1/2)-octave steps. Thresholds were confirmed during monitoring sessions in which shifts were identified. Test performance was evaluated with receiver operating characteristic (ROC) curves developed using a surrogate "gold standard"; true positive (TP) rates were derived from the cisplatin-exposed group and false positive (FP) rates from the nonexposed, control group. Best STS definitions were identified that achieved the greatest areas under ROC curves or resulted in the highest TP rates for a fixed FP rate near 5%, chosen to minimize the number of patients incorrectly diagnosed with ototoxic hearing loss. RESULTS: At the early monitoring test, average threshold shifts differed only slightly across groups. Test-frequency step size did not affect performance, and changes at one or more frequencies yielded the best test performance. At the final monitoring test, average threshold shifts were +10.5 dB for the cisplatin group, compared with -0.2 dB for the control group. Compared with the (1/2)-octave step size used clinically, use of smaller frequency steps improved test performance for threshold shifts at > or =2 or > or =3 adjacent frequencies. Best overall test performance was achieved using a criterion cutoff of > or =10 dB threshold shift at > or =2 adjacent frequencies tested in (1/6)-octave steps. Best test performance for the (1/2)-octave step size was achieved for shifts > or =15 dB at one or more frequencies. CONCLUSIONS: An ototoxicity monitoring protocol that uses an individualized, one-octave range of frequencies tested in (1/6)-octave steps is quick to administer and has an acceptable FP rate. Similar test performance can be achieved using (1/3)-octave test frequencies, which further reduces monitoring test time.

Diabetes-related changes in auditory brainstem responses.

OBJECTIVES/HYPOTHESIS: Determine effects on auditory brainstem response (ABR) of diabetes mellitus (DM) severity. STUDY DESIGN: A cross-sectional study investigating DM severity and ABR in military Veteran subjects with (166) and without (138) DM and with no more than moderate hearing loss. METHODS: Subjects were classified by three age tertiles (<50, 50-56, and 57+). DM severity was classified as insulin-dependent (IDDM), non-insulin-dependent (NIDDM), or no DM. Other DM measures included serum glucose, HbA1c, and several DM-related complications. ABR measures included wave I, III, and V latencies; I-III, III-V, and I-V latency intervals; and wave V amplitude; for each ear at three repetition rates (11, 51, and 71 clicks/second), and both polarities. Outcomes were stratified by age tertile and adjusted for pure tone threshold at 3 kHz. Repeated measures multivariate analysis of covariance modeled the ABR response at each repetition rate for DM severity (main effect) and hearing at 3 kHz (covariate). Modeled contrasts between ABR variables in subjects with and without DM were examined. RESULTS: Significant differences existed between no DM and IDDM groups in the younger tertile only. Adjusting for threshold at 3 kHz had minimal effect. Self-reported noise exposure was not related to ABR differences, but HbA1c and poor circulation were. CONCLUSIONS: IDDM is associated with an increased wave V latency, wave I-V interval, and reduced wave V amplitude among Veterans under 50 years. Results were related to several DM complications.

Diabetes-related changes in hearing.

OBJECTIVES/HYPOTHESIS: Determine the effects on hearing of diabetes mellitus (DM) severity. STUDY DESIGN: We conducted a cross-sectional study among Veterans to investigate the relationship of diabetes severity and hearing in randomly selected subjects with (165) and without (137) DM and who had no more than a moderate hearing loss. METHODS: Subjects were classified by three age tertiles (<50, 50-56, and 57+ years). Diabetes severity was classified as insulin-dependent (IDDM), noninsulin-dependent (NIDDM), or no DM. Other DM measures included concurrent serum glucose, serum HbA(1c), duration of disease, and several measures of DM-related complications. Pure-tone thresholds were measured in both ears of each subject at frequencies from 250 Hz through 14,000 Hz. Outcome measures were adjusted for age and frequency and analyzed for differences between subject groups using analysis of variance. Contrasts of the mean NIDDM and IDDM thresholds at each frequency to the DM group, and controlled for the effects of frequency, age, and interactions were modeled. RESULTS: There was greater hearing loss in younger tertile DM subjects compared to those without DM. Significant hearing differences were at all frequencies for NIDDM subjects, but for IDDM subjects, differences were at 1,000 Hz and below, and 10,000 Hz and above. Over age 50 years, there were significant associations between hearing at low frequencies and IDDM only. Self-report of prior noise exposure did not explain observed differences. CONCLUSIONS: Diabetes is associated with an increased risk of hearing loss, and this difference is manifest particularly in adults <50 years old.

Auditory and vestibular dysfunction associated with blast-related traumatic brain injury.

The dramatic escalation of blast exposure in military deployments has created an unprecedented amount of traumatic brain injury (TBI) and associated auditory impairment. Auditory dysfunction has become the most prevalent individual service-connected disability, with compensation totaling more than 1 billion dollars annually. Impairment due to blast can include peripheral hearing loss, central auditory processing deficits, vestibular impairment, and tinnitus. These deficits are particularly challenging in the TBI population, as symptoms can be mistaken for posttraumatic stress disorder, mental-health issues, and cognitive deficits. In addition, comorbid factors such as attention, cognition, neuronal loss, noise toxicity, etc., can confound assessment, causing misdiagnosis. Furthermore, some auditory impairments, such as sensorineural hearing loss, will continue to progress with age, unlike many other injuries. In the TBI population, significant clinical challenges are the accurate differentiation of auditory and vestibular impairments from multiple, many times overlapping, symptoms and the development of multidisciplinary rehabilitation strategies to improve treatment outcomes and quality of life for these patients.

Factors affecting sensitivity of distortion-product otoacoustic emissions to ototoxic hearing loss.

OBJECTIVES: (1) To determine the ototoxicity detection rate (sensitivity) for distortion-product otoacoustic emissions (DPOAEs) testing in adults who received ototoxic medications and experienced pure-tone threshold changes during the course of treatment; (2) to determine the extent to which DPOAE sensitivity to ototoxicity depends on the type of drug administered (platinum or antibiotic), magnitude of ototoxic threshold shifts, pre-exposure pure-tone threshold, and DPOAE data; and (3) to build a model to predict DPOAE sensitivity. DESIGN: DPOAE and audiometric data were obtained as part of a prospective Veterans Affairs study investigating methods of ototoxicity monitoring. Data were analyzed from 90 ears of 53 subjects receiving ototoxic medications and showing significant hearing changes in at least one ear. Pure-tone threshold data were obtained at frequencies from 0.5 to 20 kHz, using 1/6-octave precision near the upper frequency limit of hearing. DPOAE data are reported for f2's from 0.8 to 8.0 kHz in 1/6-octave increments using primary levels (L1/L2) of 65/59 dB SPL and a primary frequency ratio (f2/f1) of 1.2. Test results were evaluated at various times during drug treatment to determine whether DPOAE level changes were associated with behavioral hearing changes. Univariate and multivariate analysis techniques were used to determine factors that affected DPOAE sensitivity to ototoxic damage. RESULTS: Of the 90 ears examined, 82 (91%) had DPOAEs that could be monitored for changes. Sixty-four of these 82 ears (78%) had DPOAEs that were reduced or absent following drug treatment. DPOAE sensitivity to ototoxicity was unrelated to the type of ototoxic drug administered. Rather, DPOAE sensitivity depended on the magnitude of postexposure hearing changes and on variables related to pre-exposure audiogram and DPOAE measurements. Behavioral hearing changes not detected by DPOAEs were small on average (<7 dB). DPOAE sensitivity was reduced in ears with poorer pre-exposure hearing, and in ears with measurable DPOAE frequencies limited to f2's below 2.5 kHz or more than one octave from the frequency region where hearing change occurred. Results of logistic regression modeling showed that DPOAEs present at f2's greater than 2.5 kHz were associated with the eventual success of ototoxicity monitoring with DPOAEs. However, independent variables examined could not explain differences in the relative timing of behavioral and DPOAE changes. A roughly equivalent proportion of ears experienced DPOAE changes before, during, or after behavioral hearing changes. CONCLUSIONS: DPOAEs are a useful screening tool for ototoxicity in adults with pre-exposure hearing loss, but are less sensitive compared with a behavioral test method that targets thresholds near the upper limit of a subject's audible frequency range. Ears successfully monitored for ototoxicity with DPOAEs are those with better pre-exposure hearing, greater postexposure hearing changes, and baseline DPOAEs near the highest behavioral test frequencies and present at high f2's. Results suggest that successful monitoring of ototoxicity with DPOAEs may be predicted clinically by assessing the measurable DPOAE f2 frequency range and its relation to the highest behavioral test frequencies.

On the synthesis of multiple frequency tone burst stimuli for efficient high frequency auditory brainstem response.

The development and digital waveform synthesis of a multiple-frequency tone-burst (MFTB) stimulus is presented. The stimulus is designed to improve the efficiency of monitoring high-frequency auditory-brainstem-response (ABR) hearing thresholds. The pure-tone-based, fractional-octave-bandwidth MFTB supports frequency selective ABR audiometry with a bandwidth that falls between the conventional click and single-frequency tone-burst stimuli. The MFTB is being used to identify high frequency hearing threshold change due to ototoxic medication which most generally starts at the ultra-highest hearing frequencies and progresses downwards but could be useful in general limited-bandwidth testing applications. Included is a Mathcad implementation and analysis of our MFTB synthesis technique and sample performance measurements of the MFTB stimulus configuration used in a clinical research ABR system.