Marilyn F. Dille

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.

Meta-Analysis of Distortion Product Otoacoustic Emission Retest Variability for Serial Monitoring of Cochlear Function in Adults.

Objective: Distortion product otoacoustic emissions (DPOAEs) have long been heralded as a means to objectively monitor cochlear function and increasingly are becoming a key component in hearing surveillance programs for individuals at risk for ototoxic- and occupational noise-related hearing loss. Yet clinicians are unsure how to define clinically meaningful shifts in DPOAE level. In this study, a meta-analysis approach is used to synthesize the DPOAE level test–retest literature to construct a set of DPOAE level shift reference limits that can be used clinically to define a statistically significant emission change. Design: The authors reviewed all published articles identified through a Medline search using the terms “Otoacoustic Emission Variability,” “Otoacoustic Emission Reliability,” “Otoacoustic Emission Repeatability,” and “Otoacoustic Emission Test Retest” restricted to DPOAEs, adults, and English language. Articles with DPOAE level data elicited by moderate stimulus levels for f2 frequencies of 1000, 2000, 4000, or 6000 Hz were selected because these stimulus parameters were relatively well represented in the literature. The authors only included articles that reported the standard error of the measurement (SEM) or from which the SEM could be calculated. Meta-analysis was used to estimate the population mean SEM over the included studies. Models were fit separately for each f2 primary and included days since baseline and study-specific random effects. Results: Ten DPOAE test–retest studies met inclusion criteria for this meta-analysis. The SEM values varied widely across published studies (0.57 to 3.9 dB) and were provided for relatively short time intervals (less than 15 days on average). Time, or days since baseline, was statistically significant at higher f2 frequencies (4000 and 6000 Hz). From the model results, 90% reference limits specific to the f2 and elapsed time between baseline and follow-up measurements were established. Reference limits provided correspond to negative (emission decrement) and positive (emission enhancement) shifts indicative of the amount of measurement variability that, using this approach, must be tolerated as “normal” fluctuations over time. Changes larger than the reference limits are considered significant and warrant follow-up testing. Conclusions: The meta-analysis presented provides reference limits that are appropriate for a set of specific f2 frequencies and time intervals. The meta-analysis concerns the SEM statistic directly, so that any preferred reference limit can be computed from the results and should be predicated upon the screening application. The presumed advantage of this meta-analytic approach is increased precision relative to limits suggested by any of the individual studies included in the analysis.

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 persons 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.

Proposed comprehensive ototoxicity monitoring program for VA healthcare (COMP-VA).

Prevention and rehabilitation of hearing loss and tinnitus, the two most commonly awarded service-connected disabilities, are high priority initiatives in the Department of Veterans Affairs (VA). At least 4,000 Veterans, most with significant hearing loss, will receive cisplatin this year, with more than half sustaining permanent hearing shift and nearly 40% developing new tinnitus. With improved survivability following cancer treatment, Veterans treated with cisplatin are approached with the dual goals of effective treatment and preserved quality of life. This article describes COMP-VA, a comprehensive ototoxicity monitoring program developed for VA patients receiving cisplatin. The program includes an individualized pretreatment prediction model that identifies the likelihood of hearing shift given cisplatin dose and patient factors. It supports both manual and automated hearing testing with a newly developed portable audiometer capable of performing the recommended procedures on the chemotherapy unit during treatment. It also includes objective methods for identifying outer hair cell changes and predicting audiogram changes using distortion-product otoacoustic emissions. We describe this program of evidence-based ototoxicity monitoring protocols using a case example to give the reader an understanding of how this program would be applied, along with a plan for future work to accomplish the final stages of program development.

The Statistical Basis for Serial Monitoring in Audiology

Objectives: Audiologists regularly use serial monitoring to evaluate changes in a patient’s auditory function over time. Observed changes are compared with reference standards to determine whether further clinical action is necessary. Reference standards are established in a control sample of otherwise healthy subjects to identify the range of auditory shifts that one might reasonably expect to occur in the absence of any pathological insult. Statistical approaches to this seemingly mundane problem typically invoke 1 of 3 approaches: percentiles of the cumulative distribution, the variance of observed shifts, and the “standard error of measurement.” In this article, the authors describe the statistical foundation for these approaches, along with a mixed model–based alternative, and identify several necessary, although typically unacknowledged assumptions. Regression to the mean, the phenomenon of an unusual measurement typically followed by a more common one, can seriously bias observed changes in auditory function and clinical expectations. An approach that adjusts for this important effect is also described. Design: Distortion product otoacoustic emissions (DPOAEs) elicited at a single primary frequency, f2 of 3175 Hz, were collected from 32 healthy subjects at baseline and 19 to 29 days later. Ninety percent test–retest reference limits were computed from these data using each statistical approach. DPOAE shifts were also collected from a sample of 18 cisplatin patients tested after 120 to 200 mg of cisplatin. Reference limits established according to each of the statistical approaches in the healthy sample were used to identify clinically alarming DPOAE shifts in the cisplatin patient sample. Results: Reference limits established with any of the parametric methods were similar. The percentile-based approach gave the widest and least precisely estimated intervals. The highest sensitivity for detecting clinically alarming DPOAE shifts was based on a mixed model approach that adjusts for regression to the mean. Conclusions: Parametric methods give similar serial monitoring criteria as long as certain critical assumptions are met by the data. The most flexible method for estimating test–retest limits is based on the linear mixed model. Clinical sensitivity may be further enhanced by adjusting for regression to the mean.

Diabetes-Associated Changes in Cortical Auditory-Evoked Potentials in Relation to Normal Aging.

Objectives: (1) To characterize the influence of type 2 diabetes mellitus (DM) on cortical auditory-evoked potentials (CAEPs) separate from the effects of normal aging, and (2) to determine whether the disease-related effects are modified by insulin dependence. Design: A cross-sectional study was conducted in a large cohort of Veterans to investigate the relationships among type 2 DM, age, and CAEPs in randomly selected participants with (N = 108) and without (N = 114) the disease and who had no more than a moderate hearing loss. Participants with DM were classified as insulin-dependent (IDDM, N = 47) or noninsulin-dependent (NIDDM, N = 61). Other DM measures included concurrent serum glucose, HbA1c, and duration of disease. CAEPs were evoked using a passive homogeneous paradigm (single repeating stimulus) by suprathreshold tones presented to the right ear, left ear, or both ears. Outcome measures were adjusted for the pure-tone threshold average for frequencies of 0.5, 1, and 2 kHz and analyzed for differences in age effects between participant groups using multiple regression. Results: There is little variation across test ear conditions (left, right, binaural) on any CAEP peak in any of the groups. Among no-DM controls, P2 latency increases about 9 msec per decade of life. DM is associated with an additional delay in the P2 latency of 7 and 9 msec for the IDDM and NIDDM groups, respectively. Moreover, the slope of the function relating P2 latency with age is similar across participant groups and thus the DM effect appears constant across age. Effects on N1 latency are considerably weaker, with age effects of less than 4 msec per decade across all groups, and DM effects of only 2 (IDDM) or 3 msec (NIDDM). In the NIDDM group, the slope relating N1 latency to age is steeper relative to that observed for the no-DM group, providing some evidence of accelerated “aging” for this CAEP peak. DM does not substantially reduce N1–P2 amplitude and age relationships with N1–P2 amplitude are effectively absent. There is no association between pure-tone average at 0.5, 1, and 2 kHz and any aspect of CAEPs in this cohort. Conclusions: In a large cohort of Veterans, we found that type 2 DM is associated with prolonged N1 and P2 latencies regardless of whether insulin is required to manage the disease and independent of peripheral hearing thresholds. The DM-related effects on CAEP latencies are threefold greater for P2 compared with N1, and there is little support that at the cortical level, IDDM participants had poorer responses compared with NIDDM participants, although their responses were more variable. Overall, these results indicate that DM is associated with slowed preattentive neural conduction. Moreover, the observed 7 to 9 msec P2 latency delay due to DM is substantial compared with normal age changes in P2, which are 9 msec per decade of life in this cohort. Results also suggest that whereas N1 latency changes with age are more pronounced among individuals with DM versus without DM, there was no evidence for more rapid aging of P2 among patients with DM. Thus, the damage responsible for the major DM-related differences may occur early in the DM disease process. These cross-sectional results should be verified using a longitudinal study design.

ABR obtained from time-efficient train stimuli for cisplatin ototoxicity monitoring.

BACKGROUND Nonbehavioral methods for identifying cisplatin ototoxicity are important for testing patients with cancer who become too tired or sick to provide a reliable response. The auditory brainstem response (ABR) is a nonbehavioral test that is sensitive to ototoxicity but can be time consuming to implement over a range of frequencies and/or levels. To address this issue, trains of stimuli were developed that offer reliable ABR testing over a range of tone-burst frequencies and levels at a time savings of 77% relative to tone-burst stimuli presented individually. The clinical accuracy of this new method has yet to be determined on a clinical population. PURPOSE This project was designed to determine the test performance of a time-effective ABR methodology aimed at identifying hearing shifts from cisplatin among veterans. A secondary goal was to determine whether improved test performance could be achieved by including our previously developed ototoxicity risk assessment model in the ABR prediction algorithm. RESEARCH DESIGN A set of discriminant functions were derived using logistic regression to model the risk for cisplatin-induced hearing change. Independent variables were one of several ABR metrics alone and combined with an ototoxicity risk assessment model that includes pre-exposure hearing and cisplatin dose. Receiver operating characteristic curve analysis was used to evaluate the test performance of these discriminant functions. STUDY SAMPLE Twenty-two male veterans treated with cisplatin for various cancers provided data from a total of 71 monitoring appointments. DATA COLLECTION AND ANALYSIS Data were collected prospectively from one ear of each participant as designated below. Hearing shift was determined for frequencies within an octave of each patients high-frequency hearing limit, tested in 1/6th-octave steps. ABRs were monitored using a set of two intensity trains from the highest two multiple frequency tone-burst center frequencies (up to 11.3 kHz) that yielded a robust response at baseline. Each intensity train was presented at 65-105 dB peSPL in 10 dB steps. Scorable ABRs were generally limited to the highest two intensities; therefore, analyses concern those levels. RESULTS The ABR measurement failure was high, up to 52% for some frequencies and levels. Furthermore, the ABR was not frequently obtained at levels below 85 dB peSPL, consistent with previous studies that suggest a stimulus level of greater than 80 dB peSPL is required to obtain a reliable response to trained stimuli. Using multivariate metrics that included the dose-ototoxicity model, the most accurate scoring function was change in amplitude at lowest half-octave frequency obtained at 105 dB (change in wave V amplitude at frequency 2/105). However, absence of wave V at a monitor patient visit of the ABR response at levels 105 or 95 dB peSPL was deemed the preferred scoring function, because it had lower measurement failure and was within one standard error of the most accurate function. CONCLUSIONS Because of the large number of responses that could not be measured at baseline, this technique as implemented holds limited value as an ototoxicity-monitoring method.