|Year : 2018 | Volume
| Issue : 1 | Page : 13-17
Role of otoacoustic emissions in the early detection and prevention of ototoxicity
Anil Kaul1, Tarun Malhotra2, Shazia Khan3
1 Department of ENT, INHS Asvini, Mumbai, Maharashtra, India
2 Department of ENT, INHS Kalyani, Visakhapatnam, Andhra Pradesh, India
3 Chief Audiologist, Department of ENT, INHS Asvini, Mumbai, Maharashtra, India
|Date of Web Publication||9-Jul-2018|
Surg Capt Tarun Malhotra
Department of ENT, INHS Kalyani, Visakhapatnam - 530 005
Source of Support: None, Conflict of Interest: None
Introduction: Evaluating Otoacoustic Emissions (OAEs) is one of the audiological methods for ototoxicity monitoring. The absence of OAEs indicates cochlear damage. The aim of this study was to study the usefulness of OAEs in early detection and prevention of ototoxicity. Materials and Methods: A prospective, comparative study was conducted to evaluate Transient-Evoked OAEs (TEOAEs) and Distortion-Product OAEs (DPOAEs) as they relate to Pure Tone Audiometry (PTA) in cases of ototoxicity. Hearing assessments of study group of 55 individuals exposed to ototoxic drugs were evaluated and compared at regular intervals, within the group and with control group of 25 individuals using PTA, TEOAEs, and DPOAEs. The abnormal OAE responses were calculated as predictive of significant changes in PTA thresholds. Student's t-test (independent samples, two-tailed) and ANOVA used for analysis. Results: PTA thresholds in the study group remained unaffected in the first three follow-ups whereas TPOAEs and DPOAEs were both found affected at the third follow-up, in significant number of ears in the study group. Significantly lower PTA thresholds were found in study group only at the fourth follow-up. Conclusions: Changes in TEOAEs and DPOAEs precede changes in PTA thresholds in ototoxicity and have high sensitivity and specificity in predicting hearing loss in such cases.
Keywords: Otoacoustic emissions, ototoxicity, sensorineural hearing loss
|How to cite this article:|
Kaul A, Malhotra T, Khan S. Role of otoacoustic emissions in the early detection and prevention of ototoxicity. J Mar Med Soc 2018;20:13-7
| Introduction|| |
Various therapeutic medications including certain drugs used to fight cancer and life-threatening infectious diseases damage the inner ear. Ototoxicity results in auditory and/or vestibular dysfunction that is often permanent. Histopathological studies and electron microscopy have shown that ototoxic drugs such as aminoglycosides lead to outer hair cell degeneration, initially in the basal region of cochlear with subsequent progression through the basal, medial, and finally apical regions. Unfortunately, hearing loss due to ototoxicity may go unnoticed by patients until difficulty in understanding speech is apparent. Similarly, by the time, a patient complains of dizziness, permanent vestibular system damage probably has already occurred. Since symptoms of ototoxicity are poorly correlated with drug dosage, peak serum levels, and other toxicities, the only way to detect ototoxicity is by assessing auditory and vestibular function directly.
The early detection of hearing impairment caused by ototoxic drugs has been the aim of research worldwide. The standard method for ototoxicity monitoring is comparison of baseline data, ideally obtained before ototoxic drug administration, to the results of subsequent monitoring on Pure Tone Audiometry (PTA).
We know that OAEs reflect the functional status of the outer hair cells and constitute the only noninvasive means of objective cochlear investigation. Thus, they are definitely more sensitive for monitoring the effects of ototoxicity on cochlear function., The primary objective of ototoxicity monitoring is to document the early evidence of cochlear dysfunction, preferably before the appearance of hearing loss on PTA.
The purpose of this study was to evaluate longitudinal changes in OAEs for early detection and prevention of ototoxicity by comparing OAE measurements and PTA. Furthermore, the study evaluated changes in OAEs as predictors of subsequent development of ototoxicity.
| Materials and Methods|| |
This prospective comparative study was conducted at ENT Department of a tertiary care hospital. The study consisted of the study group, i.e. Group I with 55 subjects and control group, i.e. Group II with 25 subjects. Group I consisted of adults and children in age range of 3–55 years who were exposed to potential ototoxic drugs as a part of their treatment for various diseases during this study. Group II consisted of subjects with normal hearing in the age range of 3–55 years.
The inclusion criteria for both the groups included subjects within the age range of 3–55 years and normal hearing sensitivity in both ears on initial assessment by PTA. Further, inclusion criteria for Group I included subjects' history of exposure to ototoxic drugs. The exclusion criteria for both groups included history of exposure to loud noise, hearing loss in one or both ears on initial assessment (by PTA), history of head injury and history of middle ear disorder. Further, exclusion criteria for Group II included the history of exposure to ototoxic drugs and history of any serious medical illness.
A detailed case history, complete otorhinolaryngological examination and 226 Hz probe tone tympanometry was used to screen subjects before hearing evaluation. Baseline evaluation was conducted before the treatment plan. These evaluations were normal and were used as baseline for comparison with subsequent evaluation. Audiological evaluation consisted of PTA, transient-evoked OAEs (TEOAEs), and distortion-product OAEs (DPOAEs).
Pure tone threshold testing was done using Grason-Stadler Inc., GSI 68 audiometer in a standard sound-treated audiometric room. Air conduction hearing thresholds were measured at 0.5, 1, 2, 3, 4, 6, and 8 KHz. Findings were considered as normal when threshold at each frequency was <25 dB.
TEOAEs and DPOAEs were measured using Madsen Capella instrument in a relatively quiet room. TEOAEs were recorded and analyzed using 2000 sweeps of 40 μs click stimulus of 80 dB sound pressure level (SPL), presented at the rate of 50/s in fast screen mode. The responses were recorded and analyzed at 1, 2, 3, and 4 KHz. TEOAE inclusion criteria in the baseline evaluation included signal to noise ratio (SNR) of 3 dB or greater SPL for frequency bands and correlation of at least 60%.
DPOAEs corresponding to the frequency 2 f1–f2 (DP1) were recorded as DP-grams; f1 = 70 dBSPL, f2 = 60 dBSPL, f2/f1 ratio = 1.22 while f1 and f2 varied from 1818 to 5480 Hz and 2225–6701 Hz, respectively. Subjects were included in the study only if the baseline SNR values were 6 dB SPL or greater for all f2 frequencies tested.
After the baseline assessment, Group I and II subjects were subjected to the follow-up tests. Subjects of Group I who were exposed to aminoglycosides and/or loop diuretics were subjected to PTA, TEOAE, and DPOAE on weekly basis for 3 weeks. Subjects of Group I who were exposed to Cisplatin were subjected to test just before the beginning of each cycle, i.e., thrice. The final follow-up of Group I occurred after 6 weeks of conclusion of therapy. Thus, all the subjects of Group I underwent a baseline assessment before the onset of treatment and four follow-ups. These subjects were accordingly compared with control Group II.
Ototoxicity first affects high frequencies, the criteria used to define significant PTA threshold change on follow-up testing were 20 dBHL or greater change at any of the frequencies 2, 3, 4, 6, and 8 KHz and 10 dBHL change at any two consecutive test frequencies between 2 and 8 KHz.
TEOAE was considered as abnormal when SNR was <3 dBSPL or emission strength (amplitude) <3 dBSPL between 2 and 4 KHz. DPOAE measures with SNR <6 dBSPL between 2 and 6 KHz were considered as abnormal. PTA, TEOAEs, and DPOAEs results were compared between Group I and Group II for the baseline and follow-up assessment by Student's t-test (independent samples, two-tailed). Longitudinal changes in TEOAEs and DPOAEs and PTA thresholds were analyzed using multiple analyses of variance for repeated measures. Tukey post hoc test was used to identify the source of significance variances. The sensitivity, specificity, positive, and negative predictive values of abnormal OAE response were calculated for TEOAEs and DPOAEs on third follow-up examination as predictive of significant changes in PTA thresholds at fourth follow-up examinations.
| Results|| |
Of the 55 (110 ears) subjects, only 32 (64 ears) could complete four follow-ups. The drop in number of follow-ups were due to relocation to other stations. From control Group II, 18 (36 ears) completed the specific testing. Data of only those subjects were analyzed who were present for baseline evaluation and follow-up tests. The details of group distribution are presented below [Table 1].
In Group I, the mean age of subjects who completed follow-up testing was 32.93 years, with a standard deviation (SD) of 7.94. In Group II, the mean age of subjects who completed the follow-up testing was 35.26 years with an SD of 7.89.
The distribution of subjects in Group I who completed four follow-ups is represented in the following pie diagram [Figure 1].
|Figure 1: Distribution of subjects (after four follow-ups) exposed to ototoxic drugs|
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Comparison of Group I and II for baseline and follow-up evaluation
PTA thresholds did not differ in Group I and II in the baseline assessment. Similarly, no significant changes were observed on first, second, and third follow-ups in Group I and Group II. On fourth follow-up, significantly lower thresholds were found in Group I when compared to Group II for 2, 3, 4, 6, and 8 KHz in both ears (P < 0.001, P < 0.04, P < 0.003, P < 0.005, and P < 0.001, respectively).
The TEOAE amplitude did not show any change in baseline assessment between Group I and Group II. Similarly, on the first- and second follow-up, testing no significant changes were seen in Group I when compared to Group II. On third and fourth follow-up testing, significant number of subjects in Group I showed abnormal TEOAE when compared to Group II at 1, 2, 3, and 4 KHz.
The DPOAE did not differ in baseline assessment between Group I and Group II. On the first and second follow-up testing, no significant changes were found in Group I and Group II. On third follow-up testing, a significant number of subjects in Group I showed abnormal DPOAEs at 4 and 6 KHz when compared to Group II (P < 0.002 and P < 0.003, respectively). On fourth follow-up testing, significant changes were observed in Group I when compared to Group II at 1, 2, 3, 4, and 6 KHz (P < 0.004, P < 0.006, P < 0.001, P < 0.002, and P < 0.001, respectively).
Longitudinal changes in test values of Group I and II
Significant elevation of threshold was found in Group I only at 3, 4, 6, and 8 KHz in both ears. Tukey post hoc test revealed the source for the change was the difference between the result of third follow-up testing and fourth follow-up finding.
Significant longitudinal decrements in TEOAE amplitudes were observed in Group I only on the third and fourth follow-up testing for 3 and 4 KHz in both ears. These significant changes originated from the difference between the second and third follow-up findings.
Longitudinal intrasubject analysis of Group I showed significant reductions of DPOAE amplitudes at 3, 4, and 6 KHz. The significant changes were due to the differences between second, third, and fourth follow-up findings. No significant longitudinal changes were found in Group II.
Predictive value of otoacoustic emissions
On the fourth follow-up evaluation, nine right ears (28%) and nine left ears (28%) met our criteria for thresholds change. Since abnormal TEOAEs and DPOAEs were found on third follow-up, the predictive value of abnormal OAE results toward the prediction of elevated thresholds on fourth follow-up was examined. This is represented in [Table 2] which shows OAE's responses (TEOAE and DPOAE for each ear individually), along with the hearing assessment results by PTA for the respective subjects on evaluation at the third follow-up. From the statistical analysis of [Table 2] data, the specificity, sensitivity, and predictive values of both TEOAE and DPOAE were calculated for the prediction of elevated PTA thresholds on fourth follow-up:
|Table 2: Profile of otoacoustic emissions responses in relation to the pure tone audiometry assessment on third follow-up of Group I subjects (n=32)|
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- Sensitivity of TEOAEs and DPOAEs for the right ear was 88.89% and for the left ear was 88.9% and 77.78%, respectively
- Specificity of TEOAEs and DPOAEs for the right ear was 86.96% and 73.91% and for left ear, 78.26% and 69.57%, respectively
- Positive predictive values for the right ear were 72.73% and 57.14% and for the left ear, 61.53% and 50%, respectively
- Negative predictive values for the right ear were 95.24% and 94.44% and for the left ear 94.74% and 88.89%, respectively
- False negative of the right ear was 13.04% and 26.09% and for the left ear 21.74% and 33.33%, respectively.
| Discussion|| |
Group of subjects exposed to potential ototoxic drugs were compared with a control group using PTA, TEOAEs, and DPOAEs measures. At the end of second follow-up testing, no significant changes were found in control group and study group. Significant changes in TEOAEs and DPOAEs were found on third follow-up testing in Group I, but no such changes were found in PTA thresholds. However, on fourth follow-up testing, significant number of ears of subjects of Group I showed elevated thresholds on PTA. The trend shows that OAEs are first to indicate ototoxic changes, followed by PTA. This finding has been reported by some other researchers.
Knight et al found that DPOAEs have the potential to reveal early changes in hearing sensitivity due to ototoxicity due to cisplatin much before the conventional audiometry does. They even suggested that DPOAEs are valuable in monitoring early ototoxicity in young children who do not give reliable responses on audiometry. Plinkert and Krober  compared PTA with TEOAE in 29 patients receiving Cisplatin chemotherapy. They found that TEOAEs were better at detecting early cochlear dysfunction when compared to PTA. Mulheran and Degg  found that 14 out of 15 of the cystic fibrosis patients who had normal hearing, required significant elevation of the stimulus levels to generate a 2f1-f2 DPOAE ≤10 dBSPL at 4 KHz suggesting that OAEs can serve as early indicator or marker of functional deficit in the cochlea.
On fourth follow-up, significant elevation of threshold was found at 2, 3, 4, 6, and 8 KHz in both ears. Similarly, lower TEOAE levels were noticed at 1, 2, 3, and 4 KHz and DPOAEs at 4 and 6 KHz on third follow-up. The trend shows that the high frequencies are first to get affected due to ototoxicity as indicated by both OAE and PTA. This suggests that high frequencies are more vulnerable to ototoxicity. Stavroulaki et al. have reported similar findings. They found that both TEOAEs and DPOAEs were significantly affected at the higher frequencies following recent gentamicin exposure in children with cystic fibrosis in the presence of normal hearing thresholds. They suggested that decreased emissions in the presence of normal behavioral hearing may indicate an underlying pathologic condition, which, if allowed to continue, might result in a clinically significant hearing loss. Similar to our study, Mulheran and Degg  observed that significant decrease in DPOAE amplitude occurred for f2 frequencies >3000 Hz posttreatment.
We have evaluated the capacity of early changes in OAEs in the prediction of later ototoxicity reflected as elevated thresholds on PTA. The sensitivity of TEOAEs and DPOAEs was found to be 88.89% for the right ears and 88.89 and 77.88% for the left ears, respectively. The best sensitivity was found for TEOAEs reaching 89% with negative predictive values of 95% and low false-negative rates of 12% and 13% for the left and right ears. This suggests that OAEs are sensitive in predicting hearing loss due to ototoxicity.
At present, no clinical tests can identify patients who are more susceptible to ototoxicity. Thus, physiological test such as OAE can be used to predict susceptibility to hearing loss even in absence of elevated thresholds on PTA in ototoxicity.
| Conclusions|| |
Audiological monitoring provides information about the onset and progression of hearing loss. In ototoxicity, changes in TEOAE and DPOAE precede audiometric threshold change. TEOAE and DPOAE have high sensitivity and specificity in predicting hearing loss in individual exposed to ototoxic drugs. They must be used in ototoxicity monitoring to identify the cases at risk of developing hearing loss. In our study, we found that TEOAE is more sensitive than DPOAE in predicting cochlear damage in ototoxicity. TEOAE and DPOAE as physiological tests are useful in predicting susceptibility to hearing loss.
When treatment cannot be altered, early detection of hearing loss will help in planning for early rehabilitative services. Individuals who show abnormal OAEs in the presence of normal hearing can be counseled and be better prepared for the psychological trauma of later manifestation of hearing loss.
Department of Medicine, INHS Asvini, Mumbai, Maharashtra.
Financial support and sponsorship
This study was financially supported by AFMRC.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]