DPOAE Changes in Young Children With Confirmed Hearing Loss Due to Ototoxicity NUALA BEAHAN,1,2 EMMA REICHMAN,1 JOSEPH KEI,1 CARLIE DRISCOLL,1 JUNE YOUNG,2 RAM SUPPIAH,3 MARY-LOU GROHN,2 RAVI SOCKALINGAM4 AND BRUCE CHARLES1 1The
University of Queensland, Australia 2Mater Health Services, Australia 3Mater Children’s Hospital, Australia 4Dalhousie University, Canada
The aim of this study was to examine the pattern of changes in distortion product otoacoustic emissions (DPOAEs) in children with ototoxic hearing loss during chemotherapy. The participants included a control group of 15 normal hearing children (3–12 years) and an experimental group of 7 paediatric oncology patients (1–13 years). Participants were tested using pure tone audiometry (PTA), tympanometry, and DPOAEs (primaries 65/55 dB SPL). The results revealed no perfect match between PTA and DPOAE results with respect to frequency and pattern of decrease/increase of DPOAE amplitudes. Further analysis of DPOAEs in the experimental group revealed three main patterns of change: (1) Concurrent decreases in DPOAEs that matched pure tone threshold (PTT) changes at approximately the same frequencies; (2) DPOAE changes prior to PTT change, suggesting possible predictive power in DPOAE testing and (3) DPOAE and PTT changes not related in terms of test frequency and direction of change, noted in a patient with a high cumulative carboplatin dose.
Chemotherapeutic drugs are known ototoxins that can cause hearing loss, tinnitus and balance problems. Ototoxic cochlear damage from platinum-based chemotherapeutics and aminoglycosides is typically bilateral and permanent, and may begin or progress following the cessation of drug administration (ASHA, 1994;
Huizing & DeGroot, 1987; Kakigi, Hirakawa, Harel, Mount, & Harrison, 1998). Histological findings reveal that ototoxicity from these drugs initially occurs due to a degeneration of the outer hair cells (OHCs) of the cochlea, with damage progressing from the basal to apical end of the cochlea. Within the three rows of outer hair cells in humans, degeneration begins in the first row and proceeds to the second and then to the third row (Leake, Kuntz, Moore, & Chambers, 1997; Marco-Algarra, Basterra, & Marco, 1985; Nakai et al., 1982; Peters, Preisler-Adams, Lavers-Kaminsky, Jurgens, & Lamprecht-Dinnesen, 2003). Should the ototoxicity progress further, inner hair cell (IHC) degeneration follows. Changes can also occur in the stria vascularis, but are usually moderate compared to damage in the organ of Corti (Nakai et al., 1982). This pattern of auditory damage is typical of that caused by ototoxic drugs such as cisplatin and aminoglycosides. Cisplatin is the most ototoxic chemotherapeutic drug in common clinical use (ASHA, 1994). As immunosuppression is a side effect of chemotherapy that makes the cancer patient susceptible to infection, the use of potentially ototoxic aminoglycoside antibiotics is often warranted (Bernig, Weigel, Mukodzi, & Reddemann, 2000; Seligmann, Podoshin,
Correspondence and reprint requests: Nuala Beahan, Department of Audiology, Mater Health Services, South Brisbane QLD 4101. E-mail:
[email protected]
90
THE AUSTRALIAN AND NEW ZEALAND JOURNAL OF AUDIOLOGY VOLUME 28 NUMBER 2 NOVEMBER 2006 pp. 90–105
DPOAE CHANGES IN YOUNG CHILDREN
Ben-David, Fradis, & Goldsher, 1996). Carboplatin is also increasingly being used in chemotherapy protocols, often as a cisplatin substitute. While the exact ototoxic impact of carboplatin is unknown, it is generally understood to be less ototoxic in humans than cisplatin (Schweitzer, 1993; Stern & Bunin, 2002). Kennedy, Fitzharris, Colls, and Atkinson (1990) report a 19% ototoxicity rate in adults being treated with carboplatin, but conclude that clinically significant deafness does not occur with conventional dosing. A recent study by Bergeron et al. (2005) documents an absence of significant ototoxicity in 30 paediatric neuroblastoma patients treated with carboplatin who had been disease-free for 6 years. Significant ototoxic hearing losses were noted above 8 kHz however. Animal ototoxicity studies exclusively using carboplatin are prolific and report varied patterns of cochlear damage depending on the species studied. Interestingly, the chinchilla cochlear response to carboplatin consists of destruction of the IHCs first, leaving the OHCs almost completely intact until carboplatin doses are high enough to completely ablate the IHCs. OHC damage then proceeds from the basal to the apical end of the cochlea (Takeno, Harrison, Ibrahim, Wake, & Mount, 1994; Wake, Takeno, Ibrahim, & Harrison, 1994; Wang et al., 1997). This pattern of IHC damage appears to be unique to the chinchilla and does not necessarily extend to other species (Watanabe et al., 2002; Taudy, Syka, Popelar, & Ulehlova, 1992). Irrespective of the anticancer drugs used, the sequelae of impairment, disability and handicap that result from ototoxicity should not be overlooked. As variability in an individual’s susceptibility to ototoxicity is high, assessment of hearing function remains the only reliable method for early detection of ototoxicity prior to symptomatic hearing loss (ASHA, 1994; Campbell & Durrant, 1993; Waters, Ahmad, Katsarkas, Stanmir, & McKay, 1991). Traditionally, conventional pure tone audiometry from 250 Hz through to 8 kHz has been used to monitor for ototoxic hearing loss, but it has several limitations as a monitoring tool for ototoxicity. First, it is a behavioural assessment of hearing
that requires the patient’s participation and concentration, which is a distinct disadvantage when testing very ill patients. Second, obtaining reliable audiological data can be challenging, even in healthy children under 5 years of age (Littman, Magruder & Strother, 1998). Third, variations in test–retest reliability due to ill patient responses or headphone placement can be mistaken for ototoxic changes. For instance, Brummet and Morrison (1990) tested 20 normal-hearing volunteers who were not taking any known ototoxic drugs. With the criterion of ≥ 15 dB change in pure tone thresholds (PTT) at two or more frequencies, or ≥ 20 dB at one or more frequencies, ‘ototoxicity’ rates of 20% and 33% respectively were observed. Furthermore, due to acoustical and physiological considerations such as standing waves in the ear canal and imprecise headphone placement, audiometry showed higher test–retest variability above 6 kHz than in lower frequencies (Seligmann, Podoshin, Ben-David, Fradis, & Goldsher, 1996; Dreschler, van der Hulst, Tange, & Urbanua, 1985). Therefore, the power of routine audiometry as a tool to monitor for ototoxicity is diminished to some extent. Otoacoustic emissions (OAEs) have been investigated extensively as a clinical tool to monitor ototoxicity, in both animal (Brown, McDowell, & Forge, 1989; Shi & Martin, 1997; Kakigi et al., 1998; Mills, Loos, & Henley, 1999) and human studies (Beahan et al., 2001; Hotz, Harris, & Probst, 1994; Katbamna, Homnick, & Marks, 1999; Littman, Magruder, & Strother,1998; Lonsbury-Martin, Martin, McCoy, & Whitehead., 1995; Mulheran & Degg, 1997; Ress et al., 1999). Both transient evoked otoacoustic emissions (TEOAEs) and distortion product otoacoustic emissions (DPOAEs) have been studied. However, the higher frequencies available make DPOAEs preferable for ototoxic monitoring (Beahan et al., 2001; Littman et al., 1998). OAE testing to monitor for ototoxicity has many advantages. Firstly, it is a sensitive, objective test that is quick and easy to administer (Arslan, Orzan, & Santarelli, 1999; Kemp, 1997). Secondly, OAEs are generated by the 91
NUALA BEAHAN ET AL.
OHCs within the cochlea, the initial and primary site of most human ototoxic damage (Astbury & Read, 1982; Brown, McDowell, & Forge, 1989; Hunter-Duvar & Mount, 1978; Lonsbury-Martin, Martin, Probst, & Coats, 1987). Hence, OAEs are logically the test of choice for monitoring the function of the OHCs, which impacts on hearing sensitivity. Thirdly, some studies have shown that changes in OAE measurements occur earlier than changes in corresponding pure tone thresholds (e.g., Beahan et al., 2001; Brown et al., 1989; Kakigi et al., 1998; Zorowka, Schmitt, & Gutjahr, 1993). Numerous studies have documented the strong relationship between cochlear hearing loss and reduction or absence of otoacoustic emissions (e.g., Gorga et al., 1997; Wagner & Plinkert, 1999). While absence of TEOAEs is indicative of hearing loss in excess of 30 dB HL (Kemp, 1997), the absence of DPOAEs suggests a hearing loss exceeding 50–60 (Harris & Probst, 1997). There is a general trend that the DPOAE amplitude decreases as the hearing loss increases. However, the correlation between DPOAE amplitude and degree of hearing loss is weak (Hall, 2000; Kemp, 1997; Lonsbury-Martin, Martin, & Whitehead, 1997). Multivariate analysis of DPOAEs has shown improved success in separating normal from impaired ears DPOAE responses (Dorn, Piskorski, Gora, Neely, & Keefe, 1999). Historically, studies on humans investigating drug-induced hearing loss have focused on decreases in OAE amplitudes to indicate that ototoxicity had occurred. In contrast, more easily controlled animal studies have revealed OAE increases as another likely ototoxicity indicator. For example, Brown et al. (1989) in their animal study of DPOAEs following gentamicin treatment, noted low frequency (< 3 kHz) increases in DPOAEs when the response to higher frequencies was depressed in ears with basal turn lesions. They hypothesised, as did Neely and Kim (1986), that the loss of the basal OHCs and the stiffness they contributed to the cochlear partition through their stereocilia might have allowed greater freedom for low frequency cochlear motion and 92
consequent increase in DPOAEs. Kakigi et al. (1998) also found that when the basal region of the cochlea was damaged, an increase in OAE amplitudes in the low frequency region often was noted. As the cochlear lesion progressed apically, there was a transient increase prior to a decrease in OAEs. Animal studies have clearly shown that there are patterns of DPOAE change associated with ototoxicity other than the commonly reported emission amplitude decreases. While detailed animal studies on ototoxicity abound, human studies are scarce and more commonly focus on adults rather than children. It is advantageous to conduct investigations of ototoxicity in young children using OAEs as they have more robust OAEs than adults. Hence, a change in OAE amplitude due to ototoxicity can be detected easily. Furthermore, young children are less likely than adults to have excessive noise exposure, which may be a confounding variable in OAE measures. A study by Beahan et al. (2001) conducted on 4 young children investigated the feasibility of using DPOAEs to monitor ototoxicity. They reported two patterns of DPOAE changes due to ototoxicity: an increase in low-to-mid frequency emissions, and a decrease in highfrequency emissions. However, generalisation of results to the general population was not possible in view of the small sample size. The present study also investigates the patterns of DPOAE changes in young children with confirmed hearing loss due to ototoxicity. However, this study uses a larger sample size and compares multiple DPOAE results during and after the course of anticancer chemotherapy for each participant. METHOD Participants
Two participant groups were studied: Control group. The participants were 15 children (6 males and 9 females) aged between 3 and 12 years (mean age = 7.9 years, Standard Deviation [SD] = 2.8 years) with hearing thresholds less than 25 dB HL from 250 Hz to 8 kHz, and good general
DPOAE CHANGES IN YOUNG CHILDREN
health. Children in the control group were also required to have normal middle ear function as judged by tympanometry results (static compliance between 0.3 and 1.6 cm 3 and middle ear pressure between +100 and –150 daPa). This pressure range was extended from the standard > –100 daPa of Jerger’s (1970) classification system to accommodate peak pressure fluctuations common in children’s ears that do not develop middle ear disease (ASHA, 1998). For three participants, only one ear was used due to middle ear dysfunction in the other ear. Experimental group. Participants were 7 paediatric oncology patients. The characteristics of participants (A–G) including age and diagnosis are listed in Table 1. The participants were selected on the basis that they were undergoing treatment with at least one major dose of cisplatin or carboplatin, and their initial hearing assessments were within normal limits. None of the experimental participants were treated with radiation prior to or during their audiological assessments for this study. Audiological findings were excluded from the study if the participant failed tympanometry (defined as per control group with the exception of the static compliance lower cut off being to 0.18 to allow for children under 3 years of age) on the day of testing. The participants were included in the study if a significant decrease in pure tone sensitivity, consistent with ototoxicity as defined by ASHA (1994), was found after the beginning of chemotherapy. ASHA (1994) TABLE 1 Age and Diagnosis of Experimental Participants Participant
Age (years)
Diagnosis
A
2
Neuroblastoma
B
4
Neuroblastoma
C
5
Ganglioglioma
D
11
E
2
Neuroblastoma
F
1
Neuroblastoma
G
13
Hepatoblastoma
Perisellar germ cell tumour (brain)
defines ototoxicity as either an increase in pure tone threshold of greater than or equal to 20 dB HL at any one test frequency or greater than or equal to 10 dB HL at any two adjacent test frequencies when compared to previous test results. Procedure
Participants were assessed using otoscopy, pure tone audiometry, tympanometry and DPOAEs. Otoscopy involved examining the participants’ ears for any abnormalities, occlusion or collapsing ear canals. Tympanometry was performed using the Madsen Zodiac 901 Middle Ear Analyser. A probe tone of 226 Hz was delivered to the child’s ear while the pressure was varied from +200 to -400 daPa with a pump speed of 200 daPa/sec. An Interacoustics AC30 audiometer and standard supra-aural TDH39 headphones were used in a soundproof booth for pure tone audiometry assessments. Hearing thresholds at .25 kHz, .5 kHz, 1 kHz, 2 kHz, 3 kHz, 4 kHz, 6 kHz, and 8 kHz were obtained using the Hughson-Westlake procedure. If an experimental group subject was unwell, as many frequencies as possible were obtained before the participant tired. To ensure hearing losses were sensorineural, bone conduction was performed if a hearing loss was noted on pure tone audiometry. If pure tone testing could not be performed due to child’s age, then visual reinforcement orientation audiometry (VROA) using warble tones was performed. VROA was conducted using a Madsen Midimate audiometer with a Yamaha speaker system. DPOAE testing was performed in a quiet clinic room using the IL096 system (Otodynamics Ltd) and recorded as a distortion product (DP) gram (a plot of DPOAE amplitude/noise against frequency). DPOAE data were collected at 3 points per octave for 3 sweeps of the frequency range per test. The ratio of the frequencies of the primaries (f 1 /f 2 ) was set at 1.22 to ensure optimal DPOAE responses (Harris et al., 1989). The frequency of f 2 was varied in 1/ 3 octave steps from 1 kHz to 6.3 kHz. The DP-grams 93
NUALA BEAHAN ET AL.
were obtained by sweeping two primary tones at frequencies f 1 and f 2 with corresponding stimulus intensity levels of L1 = 65 dB SPL and L2 = 55 dB SPL respectively. DPOAE amplitudes at a frequency of 2f1-f2 were measured. The 65/55 level advocated by Stover et al. (1996) was selected as it was found to yield optimal DPOAE results. The resulting data consisted of distortion product and noise floor amplitudes in seven frequency bands (1.6 kHz, 2 kHz, 2.5 kHz, 3.2 kHz, 4 kHz, 5 kHz, and 6.3 kHz). DPOAEs at 1 kHz and 1.3 kHz were not included in the analysis due to noise contamination under standard test conditions (Gorga et al., 1993). Data Collection and Analysis
Any data contaminated by middle ear involvement (as defined above) was excluded from analysis. Control group. DPOAE testing was conducted twice within the same testing session to estimate normal variability in DPOAE testing. After the first test, the probe was removed and reinserted into the ear canal for the second test. The data collected from the second test was then subtracted from the first test, yielding the difference in DPOAE amplitude for each frequency band in dB SPL, expressed in absolute (i.e., positive) values. The mean and SD of these absolute values at each frequency were calculated. Experimental group. The difference in DPOAE amplitude before and after drug treatment was established by subtracting the
postdrug from the predrug DPOAE amplitude at each frequency. A change in DPOAEs was considered significant for individual ears if the change in DPOAE amplitude exceeded the mean change plus 2 SD absolute difference value of the control group at each frequency. That change was then considered to be significant at the 0.05 significance level. Changes in DPOAE amplitude also were considered significant if the emissions were present predrug and became absent postdrug, or vice versa. In the literature, the criterion for the presence of DPOAEs has varied, but generally, the emission amplitude should be at least 3 dB to 9 dB above the mean noise floor (e.g., Musiek & Baran, 1997). In the present study, DPOAEs were considered present if the emission amplitude was 3 dB greater than the mean plus 1 SD noise level (Nicholas, Kei, Woodyatt, & McPherson, 1999). RESULTS Control group. The mean, SD and mean + 2 SD of the difference in DPOAE amplitudes for control group ears at each test frequency were calculated as shown in Table 2. From Table 2, DPOAE amplitudes at 5 kHz and 6.3 kHz showed the greatest variability between tests with a SD of 4.09 dB and 5.13 dB respectively. The average variation was approximately 2 dB between tests for other frequencies. Experimental group. Chemotherapy regimes, doses of additional potentially ototoxic antibiotics, and levels of hearing loss varied widely between experimental participants. Table 3 displays a summary of ages, treat-
TABLE 2 Mean Differences in DPOAE Amplitudes (Expressed in Absolute Values in dB SPL) Obtained From Two DP-Grams With Primaries at 65/55 dB SPL From 15 Control Participants Frequency (kHz) 1.6 N (ears)
94
27
2 27
2.5 27
3.2 27
4 27
5 27
6.3 27
Mean (dB)
1.78
1.6
2.43
2.13
1.48
3.27
SD (dB)
2.62
1.6
3.45
2.35
1.87
4.09
3.12 5.13
Mean + 2SD
7.01
4.8
9.32
6.83
5.21
11.46
13.39
DPOAE CHANGES IN YOUNG CHILDREN
TABLE 3 Summary of Age, Treatment Days, and Doses of Potentially Ototoxic Agents Administered to Participants A–G at the Time of Most Significant Hearing Changes Participant A A A
Age
Day Count
2.4
97
2.5 2.6
126 158
B
4.2
22
B
4.3
58
B B B B C C C C D D E E E F F F
4.4 4.5 4.6 4.7 5.3 5.3 5.7 5.8 12 12.2 2.6 2.8 2.8 1.9 2 2.1
92 127 155 211 44 83 222 251 28 93 243 315 357 223 264 297
Cisplatin Carboplatin Gentamicin Vincristine Vancomycin Bleomycin 200.00
0.00
1150.00
1.60
5625.00
0.00
200.00
0.00
2816.67
4.55
5976.56
0.00
98.36
0.00
377.05
0.00
0.00
0.00
298.36
0.00
3193.72
4.55
5976.56
0.00
0.00
0.00
754.10
1.62
0.00
0.00
298.36
0.00
3947.81
6.18
5976.56
0.00
86.96
0.00
956.52
3.48
5326.09
0.00
86.96
0.00
956.52
3.48
5326.09
0.00
80.60
0.00
820.90
3.58
0.00
0.00
167.55
0.00
1777.42
7.06
5326.09
0.00
78.79
0.00
606.06
3.64
4363.64
0.00
246.34
0.00
2383.48
10.70
9689.72
0.00
82.09
0.00
880.60
0.00
1373.13
0.00
328.43
0.00
3264.07
10.70
11062.86
0.00
80.30
0.00
848.49
0.00
5666.67
0.00
408.73
0.00
4112.56
10.70
16729.52
0.00
0.00
1500.00
2086.96
0.00
13391.30
0.00
408.73
1500.00
6199.52
10.70
30120.83
0.00
0.00
0.00
182.93
0.00
0.00
0.00
0.00
0.00
730.60
6.66
792.21
0.00
104.88
0.00
365.85
1.63
0.00
0.00
104.88
0.00
1096.45
8.29
792.21
0.00
100.00
0.00
200.00
11.51
400.00
0.00
204.88
0.00
1296.45
19.80
1192.21
0.00
104.88
0.00
0.00
0.00
0.00
0.00
309.76
0.00
1296.45
19.80
1192.21
0.00
105.00
0.00
0.00
0.00
0.00
15.00
105.00
0.00
0.00
0.00
0.00
15.00
105.50
1000.00
0.00
0.00
0.00
30.05
210.50
1000.00
0.00
0.00
0.00
45.05
200.00
0.00
327.87
0.00
0.00
0.00
200.00
0.00
3878.27
3.15
33325.60
0.00
200.00
0.00
1808.33
3.12
0.00
0.00
400.00
0.00
5686.61
6.27
33325.60
0.00
203.17
0.00
2928.96
0.00
12923.50
0.00
603.17
0.00
8615.57
6.27
46249.10
0.00
100.00
0.00
486.67
1.44
333.33
0.00
380.00
0.00
5931.70
5.78
13110.82
0.00
100.39
0.00
176.47
0.00
352.94
0.00
480.39
0.00
6108.17
5.78
13463.76
0.00
100.39
0.00
882.35
0.00
0.00
0.00
580.78
0.00
6990.53
5.78
13463.76
0.00
95
NUALA BEAHAN ET AL.
TABLE 3 (CONTINUED) Summary of Age, Treatment Days, and Doses of Potentially Ototoxic Agents Administered to Participants A–G at the Time of Most Significant Hearing Changes Participant G G G G G
Age
Day Count
13.3
62
13.3 13.4 13.6 13.8
88 138 188 251
Cisplatin Carboplatin Gentamicin Vincristine Vancomycin Bleomycin 159.72
500.00
0.00
0.00
0.00
0.00
239.86
996.45
0.00
0.00
0.00
0.00
0.00
500.00
0.00
0.00
0.00
0.00
239.86
1496.45
0.00
0.00
0.00
0.00
79.86
500.00
170.14
0.00
0.00
0.00
319.72
1996.45
170.14
0.00
0.00
0.00
80.00
500.00
0.00
0.00
0.00
0.00
399.72
2496.45
170.14
0.00
0.00
0.00
80.00
0.00
0.00
0.00
0.00
0.00
479.72
2496.45
170.14
0.00
0.00
0.00
Note: Drug doses are reported in mg/m2 and include cumulative dose since last hearing test and cumulative dose (in italics) since the beginning of chemotherapy.
ment days, and potentially ototoxic chemotherapy doses (dose since last hearing test and cumulative dose) for each participant of the experimental group. The day counter values created for this study vary widely between participants. The day counter was started on the first day that the participant received potentially ototoxic medications, or the day of their initial hearing assessment, whichever came first. In most instances, potentially ototoxic medications occurred first as the participants were treated with aminoglycosides prior to starting anticancer chemotherapy. Figure 1 outlines the final hearing thresholds in the better ear of all experimental participants. Participant E ultimately showed the most severe hearing loss of all participants, with frequencies as low as 500 Hz showing ototoxic changes. Participant E also had the highest cumulative doses of cisplatin (603.17 mg/m 2 ), gentamicin (8615.57 mg/m 2 ), and vancomycin (46249.10 mg/m 2 ). While no participants were treated solely with carboplatin, Participant G received the highest cumulative carboplatin dose of 2496.45 mg/m 2 . Participant C received the highest cumulative vincristine dose of 19.80 mg/m2. 96
Three major patterns of DPOAE change were identified in the experimental participants: (1) Concurrent decreases in DPOAEs that matched pure tone threshold changes at approximately the same frequencies, (2) DPOAE changes prior to PTT change and (3) DPOAE and PTT changes not related in terms of test frequency and direction of change. The results of three of the experimental participants that exemplify these patterns are detailed below. For brevity, only the test results with significant hearing or DPOAE changes are discussed. For behavioural hearing thresholds, all changes described met the ASHA (1994) criteria for significant ototoxic change as defined earlier. For DPOAE results, all changes met the criteria of significant changes as outlined in the method section. For some participants, their first audiogram showing likely ototoxic hearing loss coincided with middle ear dysfunction. Hence, this data was excluded from the study due to the potential of middle ear dysfunction to confound other data collected. Therefore, the significant hearing changes reported in this study do not necessarily include the participant’s first significant hearing change.
dB HL
DPOAE CHANGES IN YOUNG CHILDREN
100 90 80 70 60 50 40 30 20 10 0 -10 0.5
1
2
4
8
Frequency (k Hz) Participant A - Binaural - Day 158 Participant B - Right ear - Day 211 Participant C - Right ear - Day 359 Participant D - Left ear - Day 93 Participant E - Binaural - Day 357 Participant F - Binaural - Day 297 Participant G - Left ear - Day 251
FIGURE 1 Experimental participant’s final hearing thresholds for the better ear.
Pattern 1: Concurrent Decreases in DPOAES That Matched PTT Changes at Approximately the Same Frequencies
emissions remaining absent at 3.2kHz to 6.3 kHz were noted for the right ear.
This pattern of change was noted in every experimental participant, although not in every test for every experimental participant. In particular, Participant F’s test results have been selected for detailed description of this pattern. For Participant F the Day 223 to 264 comparison showed a 25 dB and 55 dB drop at 4 kHz and 6 kHz respectively, using VROA testing (see Figure 2a), but the threshold at 8 kHz could not be tested at this time. DPOAE testing showed a decrease at 3.2 kHz, newly absent emissions at 4 kHz, and emissions remaining absent at 5 kHz and 6.3 kHz in the left ear (see Figure 2b). The right ear exhibited a newly absent emission at 3.2 kHz and emissions remaining absent at 4kHz to 6.3 kHz (see Figure 2c). The day 264 to 297 comparison showed a 40 dB decrease in hearing thresholds at 3 kHz and a 15 dB decrease at 4 kHz. DPOAEs decreased at 2.5 kHz, became absent at 3.2 kHz and remained absent at 4 kHz to 6.3 kHz for the left ear, and a decrease at 2.5 kHz, and
Pattern 2: DPOAE Changes Prior to PTT Change
Preemptive DPOAE changes were noted in participants as either a significant decrease or increase in emissions at a frequency lower than any frequency currently showing significant PTT changes. Participants A, B, C, D, and E showed this pattern in at least one of the test-to-test comparisons that were recorded. A detailed description of PTT and DPOAE changes for participant C has been selected as an example of pre-emptive DPOAE changes noted in this study. For Participant C five test-to-test comparisons were examined in each ear. The first comparison shows the first significant change in thresholds that occurred. Figure 3 presents PTT and DPOAE changes over time for Participant C. The day 83 test for the left ear shows the 8 kHz PTT dropped by a significant 45 dB (see Figure 3a). The 6 kHz threshold at this time was 25 dB. DPOAEs showed a significant 97
NUALA BEAHAN ET AL.
dB HL
(a) VROA thre sholds 100 90 80 70 60 50 40 30 20 10 0 -10
Day 223 Day 264 Day 297
0.5
1
2
3
4
6
8
Fr eque ncy (k Hz)
(b) DP amplitude and noise leve ls - Le ft ear 25 15 Day 223 DP
dB SPL
5
Day 223 N Day 264 DP
-5
Day 264 N Day 297 DP
-15
Day 297 N
-25 -35 1.6
2.0
2.5
3.2
4.0
5.0
6.3
Fr eque ncy (k Hz)
(c) DP amplit ude and noi se le vel s - Right ear 25 15 Day 223 DP
dB SPL
5
Day 223 N Day 264 DP
-5
Day 264 N Day 297 DP
-15
Day 297 N
-25 -35 1.6
2.0
2.5
3.2
4.0
5.0
6.3
Fr eque ncy (k Hz)
FIGURE 2 Participant F: VROA and DPOAEs showing the most significant changes. (DP = DPOAE amplitude, N = DP noise floor + 1 SD).
98
DPOAE CHANGES IN YOUNG CHILDREN
(a) PTA Left ear
(c) PTA Right ear
100 90 80 70 60 50 40 30 20 10 0 -10
100 90 80 70 60 50 40 30 20 10 0 -10
Day 44 Day 222 Day 251 Day 289 Day 359
0.25
0.5
1
2 3 Frequency (kHz)
4
6
Day 44 Day 83
dB HL
dB H L
Day 83
Day 222 Day 251 Day 289 Day 359
0.25
8
0.5
1
2
3
4
6
8
Frequency (kHz)
(b) DP amplitude and noise levels - Left ear
25
Day 44 DP Day 44 N
15
Day 83 DP Day 83 N
dB SPL
5
Day 222 DP Day 222 N
-5
Day 251 DP Day 251 N
-15
Day 289 DP Day 289 N
-25
Day 359 DP Day 359 N
-35 1.6
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FIGURE 3 Participant C: PTA and DPOAEs showing the most significant changes. (DP = DPOAE amplitude, N = DP noise floor + 1 SD).
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increase at 2 kHz and a decrease at 4 kHz only (see Figure 3b). Day 83 to 222 saw PTTs decline from 4 kHz to 8 kHz and DPOAEs concurrently became absent at these frequencies. Day 222 to 251 showed no significant changes in PTTs; however, DPOAEs at this time declined at 2 kHz and became absent at 3.2 kHz. Unfortunately, 3 kHz was unable to be tested on pure tone audiometry. Day 251 to 289 showed a decrease in 3 kHz and 4 kHz pure tone thresholds. DPOAEs indicated absent emissions from 2.5 kHz to 6.3 kHz. The final comparison for the left ear from day 289 to 359 showed a decline in thresholds from 2 kHz to 4 kHz and all DPOAEs now absent. Although the 2 kHz threshold declined, the PTT stayed within normal limits at 15 dB HL. Between days 44 and 83, the PTT in the right ear declined by 35 dB at 8 kHz (see Figure 3c). DPOAEs showed a decrease at 3.2 kHz and became absent at 6.3 kHz with noise floors showing little change between tests (see Figure 3d). The subsequent comparison between days 83 and 222 showed a decline in PTTs between 4 kHz and 8 kHz. DPOAEs increased at 3.2
kHz, declined at 4 kHz and were absent 5 kHz to 6.3 kHz. Between days 222 to 251 the PTT at 4 kHz declined further and DPOAEs declined at 3.2 kHz and 4 kHz. DPOAEs at 2 kHz increased in amplitude, as did the noise floor reading between these tests. Between days 251 and 289, PTTs did not change significantly, although the 4 kHz DPOAE progressed from severely reduced to absent. Potentially ototoxic drugs administered since the last audiological evaluation consisted only of vincristine (5.09 mg/m2). From day 289 to 359, PTTs declined slightly at 2 kHz and declined dramatically at 3 kHz. DPOAEs reduced at 2.5 kHz and became absent at 3.2 kHz. Pattern 3: DPOAE and PTT Changes Not Related in Terms of Test Frequency and Direction of Change
This pattern was identified as a result of the DPOAE and PTT findings for a single participant — Participant G. Day 138 to 188, the left ear showed no significant changes in PTT and no significant change in DPOAEs. Between day 188 and
(c) PTA Right ear
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FIGURE 4 Participant G: PTA and DPOAEs showing the most significant changes. (DP = DPOAE amplitude, N = DP noise floor + 1 SD).
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251 hearing thresholds dropped to a mild hearing loss from 4 kHz to 8 kHz (see Figure 4a). DPOAEs at this time showed no significant change from the previous test. However, a trend of emission decrease was noted from 4 kHz to 8 kHz (see Figure 4b). Day 62 to 88 showed no significant PTT change in the right ear, but an absent emission at 6.3 kHz occurred (see Figures 4c and 4d). At the day 88 to 138 comparison, the 6.3 kHz emission became present again at a slightly reduced level from the day 62 recording. At this time, the emission level at 2 kHz increased and hearing thresholds dropped by 10 dB and 20 dB at 6 kHz and 8 kHz respectively. The final comparison between days 138 to 188 showed a further decline in hearing thresholds from 4 kHz to 8 kHz. Emissions at this time decreased in amplitude at 2 kHz and 6.3 kHz, but remained present above the noise floor. Participant G showed pure tone changes least typical of those commonly noted with ototoxic hearing loss. Test results showed significant fluctuations in DPOAE amplitude at 1.6 kHz, 2 kHz, and 6.3 kHz. At the final hearing test for this study (day 304), all DPOAEs were present from 1.6 kHz to 6.3 kHz bilaterally. However, a mild hearing loss remained in the frequency range of 4 kHz to 8 kHz bilaterally. DISCUSSION The results showed that the degree of ototoxic hearing loss varied widely in the experimental group. Some participants experienced only mild hearing losses while others experienced at least a moderately-severe hearing loss. Given the varying susceptibility to ototoxic drugs, and the differences among drug regimens, this was not a surprising finding. In general, such a varied pattern of hearing loss results are in agreement with studies such as Freilich, Kraus, Budnick, Bayer, and Finlay (1996), Hale et al. (1999), and Pasic and Dobie (1991). The present study was aimed at investigating the pattern of DPOAE changes in children with confirmed hearing losses due to
ototoxicity. The findings of this study showed no perfect match between PTT and DPOAE results with respect to frequency and pattern of changes (decrease/increase). Nevertheless, three patterns of DPOAE change with progressive ototoxicity were identified. The most common pattern for DPOAE change was for DPOAEs and PTT results to show concurrent deterioration at approximately the same frequencies. As noted in the Results section, this pattern was found in all experimental participants, although not in every test performed on the participants. However, there were exceptions to this finding. For example, Participants A, B, D, and G showed instances of DPOAEs remaining present (although often at reduced amplitudes) after a significant hearing loss occurred at the same frequency. Participant G’s overall pattern of results was quite unusual (discussed further below). However, these less common DPOAE findings for Participants A, B and D stand as an important reminder that DPOAEs are not a test of hearing sensitivity, but of OHC function. Hence the common pattern of DPOAE reduction or absence in the presence of hearing loss was a strong but not universal finding in this study. The present study also revealed patterns of DPOAE change prior to PTT change, suggesting possible predictive power in DPOAE testing. Participant C demonstrated a pattern of pre-emptive DPOAE decreases and absences at frequencies where PTT deterioration was about to occur. Participant C also demonstrated emission increases at frequencies lower than that at which subsequent PTT decreases were noted, as per the animal studies conducted by Brown et al. (1989) and Kakigi et al. (1998). Participants B and D also showed low frequency DPOAE increases. However, unlike Participant C, these were in the presence of significant noise floor differences between tests. Hence noise floor fluctuation, a significant confounding variable in the paediatric population, made analysis of DPOAE changes difficult. There is also a concern that at small signal-to-noise ratios, background noise may result in the overestimation of 101
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DPOAE amplitudes (Whitehead, LonsburyMartin, & Martin, 1993). A potential way to overcome these issues may be to focus on frequencies above 2 kHz where ambient noise impact is minimal (Lee & Kim, 1999). The final pattern identified in the present study was that the DPOAE and PTT changes were not related in terms of test frequency and direction of change (see Figure 4). Although DPOAEs showed significant changes for Participant G, ultimately all DPOAEs were present while hearing sensitivity was reduced. Participant G received the highest cumulative dose of carboplatin of all the experimental participants. Given that the participant responses were repeatable and accurate on audiometry, there would appear to be three possible explanations for these observations: (1) The findings are an example of DPOAEs showing poor sensitivity to cochlear hearing loss of up to a moderate level (< 50 dB HL); or (2) a result of a central pathology, such as cisplatin slowing brainstem conduction times on auditory brainstem response (ABR) assessment (Hansen, 1992); or (3) although very unlikely in humans, the finding may be similar to the animal studies of Takeno et al. (1994), Wake et al. (1994) and Wang et al. (1997), where carboplatin caused mild IHC damage creating decreased hearing sensitivity but leaving the OHCs intact and, hence, no changes in DPOAEs. A firm opinion regarding the nature and cause of the hearing loss cannot be made as Participant G was treated concurrently with cisplatin, carboplatin, and gentamicin. In this case, conclusions as to the role of carboplatin in ototoxic hearing loss are problematic, as with studies by Parsons et al. (1998) and Freilich et al. (1996). Several limitations have been identified in this study which might have affected interpretation of the results. For example, the protocol did not allow for group comparisons as the participants in the experimental group were heterogeneous with respect to age, gender, diagnosis, prognosis, treatment regimes, drug dosages, schedule of audiological testing and severity of hearing loss. A larger control group would have contributed a more sensitive set of 102
DPOAE test–retest reliability data, allowing more effective analysis and interpretation of the experimental group data. Other limitations of this study were mostly related to the nature of the experimental group of paediatric oncology patients. First, concurrent treatment with several potentially ototoxic agents made it difficult to differentiate the effect of one drug from another. Second, although regular audiological evaluation was included as part of the care of this patient group, an exact time schedule for testing was unrealistic. Hence, a more naturalistic approach to researching in this area is required, and some desirable opportunities for DPOAE collection must be forgone. Third, and most unfortunately, hearing loss progressed so quickly for some patients that DPOAEs from the damaged cochlea were completely absent by the second audiological evaluation. This restricted the observation of subtle cochlear changes which affected DPOAE results. If it had been possible to use extended high frequency audiometry with this subject group, it may have created a larger time window to observe DPOAE changes with progressive cochlear damage and allowed more substantial correlation studies. Fourth, this patient group experienced more middle ear and eustachian tube dysfunction than healthy children of the same age. Hence, some otherwise useful data was discarded due to contamination from potential middle ear pathology. It is important to note when researching in this area that developmental changes in OAEs occur as children grow and the physical properties of the ear may change with age. In general, OAE amplitudes are thought to decrease with age. Kon, Inagaki, and Kaga’s (2000) developmental OAE study reports that noise floor gradually decreases with age, becoming asymptotic at 6 years of age. They also report that DPOAEs generated with an f2 frequency of 5042 Hz show the least developmental change, and that DPOAEs generated with an f 2 frequency of 3174 Hz rapidly decrease until 6 years of age and then gradually decrease hereafter. Kon et al. (2000)
DPOAE CHANGES IN YOUNG CHILDREN
generally consider 6 years of age to be a turning point as to age-dependant DPOAE changes. Within this study, the ranges for monitoring hearing were over a period of months, so developmental changes are unlikely to play a significant role in DPOAE changes. However, studies over a longer period of time or comparing patients of different ages should account for this possible confounding variable. In conclusion, the present study has found DPOAEs useful in monitoring for potential ototoxicity in the paediatric oncology population. The dominating pattern of DPOAE changes was concurrent decreases in DPOAEs that matched PTT changes at approximately the same frequencies. However, DPOAEs were not proven to exceed the reliability of behavioural assessments in this population unlike adult studies such as Ress et al. (1999). Monitoring ototoxicity using DPOAEs is vital in patients who cannot be assessed behaviourally, but this does not mean that DPOAEs are a suitable replacement for behavioural testing in children. However, the present study did identify some encouraging findings of preemptive DPOAE changes prior to PTT shifts when noise floor readings remained constant. Perhaps a similar study concentrating on older children where internal and external noise could be more easily controlled would find more consistent patterns of pre-emptive DPOAE change. Furthermore, testing an older paediatric population would allow for more detailed audiological assessments. An expansion of testing into the extended high frequency (9 kHz–16 kHz) range may allow for more detailed research into the function of the basal region of the cochlea. This extended high frequency testing may then facilitate in further delineating the relationship between DPOAE and audiometry results. REFERENCES American Speech–Language–Hearing Association. (1988). Tutorial: Tympanometry. Journal of Speech and Hearing Disorders, 53, 354–377. American Speech–Language–Hearing Association. (1994). Guidelines for the audiologic management
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