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Otoacoustic emission testing is a recording of sounds generated within the cochlea (Prieve & Fitzgerald, 2002). OAEs are generally used as they can detect minor changes in cochlear function prior to changes in thresholds on either the conventional audiogram or UHFA (Guthrie, 2008). DPOAEs allow for information pertaining to the integrity of the cochlea to be obtained, therefore contributing to the differential diagnosis linked to auditory functioning at this level of the auditory system (Prieve & Fitzgerald, 2002). OAEs are physiological assessments of cochlear function and are extremely sensitive measures

(Guthrie, 2008). As ototoxicity manifests in the outer hair cells initially (Durrant et al., 2009), it is a useful measure in patients receiving ototoxic medication. OAEs are classified

according to the stimulus that elicits the emission, namely spontaneous and evoked OAEs

(Hall, 2000). In this assessment, coherent acoustic reflections and acoustic distortion products are measured in the external auditory meatus. These acoustic occurrences are obtained by specific stimulus frequencies or bandwidths via a transducer positioned close to the tympanic membrane and acoustically coupled to the external auditory meatus. The emissions generated are dependent on the homeostasis of outer hair cells electromechanical and mechanoelectrical transduction processes (Guthrie, 2008). The mechanoelectrical process involves the OAEs arising from a nonlinear electromechanical distortion within the human cochlear. This distortion is turn creates a source of energy in the outer ear which is then measured as the emission (Gorga et al., 1997).

Evoked OAEs require a stimulus, while spontaneous OAEs require no such stimulus.

Spontaneous OAEs have little clinical value (Hall, 2000). Evoked OAEs includes into three types, namely TEOAEs, Stimulus Frequency OAEs (SFOAEs) and DPOAEs. These types require different stimuli to elicit the emissions, being a click stimulus, a continuous pure tone stimulus and two pure tones as the stimulus respectively (Martin, Jassir, Stagner, Whitehead

& Lonsbury-Martin, 1998). TEOAEs and DPOAEs, however, remain the most useful in clinical practice. The presence of OAEs with normal middle ear functioning implies hearing within reasonable limits, while the reduction or absence of OAEs indicates reduced outer hair cell functioning and thus implies hearing loss. TEOAEs have been shown to measure a hearing loss up to 30 dB, yet when the hearing loss is greater, the TEOAEs are shown to be absent. DPOAEs, in contrast, the measure can still be measured when a hearing loss is between 50-70 dBHL (Gorga et al., 1997). As hearing loss resulting from ototoxicity may result in a moderate-severe or severe hearing loss (Sagwa et al., 2015), DPOAEs are likely more useful for this population.

Also, despite the clinical utility of behavioural hearing thresholds being primarily explored, it is well established that these measures are influenced by factors such as attention,

motivation, and patient compliance. Objective measures, such as DPOAEs, show clinical relevance and may be one of the only other practical ways to evaluate children and adults unable to respond behaviuorally. DPOAEs are a convenient and non-invasive means to detect an ototoxic change in outer hair cell function, which is the area affected explicitly by initial ototoxicity. Distortion generated in the cochlea in response to the two simultaneous pure tones (ƒ1 and ƒ2, ƒ1<ƒ2) can be recorded in the ear canal at frequencies mathematically linked to the stimulus frequencies. The most comprehensively studied and clinically used is the DPOAE at the frequency 2ƒ1-ƒ2. Compared to normal-hearing ears, DPOAE levels are reduced with mild to moderate hearing losses and are rarely present when hearing thresholds exceed 60 dB HL (Poling, Lee, Siegel & Dahr et al., 2012).

Gender has shown to impact DPOAEs where females tend to have larger emissions when elicited with a low-frequency stimulus (Dunckley & Dreisbach, 2004), while males lose more DPOAE amplitude with a hearing loss that is proportional in females (Cilento, Norton

& Gates, 2003). Age also shows the impact on DPOAEs; as age increases, DPOAE

amplitudes decreases (Dorn, Piskorski, Keefe, Neely & Gorga, 1998). Ethnicity has shown to impact of TEOAEs, yet not on DPOAEs (Hall, 2000).

Interpretation of DPOAEs relies on a few factors, such as low environmental ambient noise levels, repeated replicated reading that confirms the results and the assurance of no middle ear pathologies that could affect the readings (Hall, 2000). The ambient noise level in the DPOAE is regarded at the noise floor, whereas the Declustering Potential is the emission level. The signal to noise ratio is the difference between the noise floor and Declustering Potential, and acceptance of the response is dependent on this (Hall, 2000). The ratio of 10 dB sound pressure level (SPL) or greater is accepted widely, as this is a clear indication of a cochlear response and that ambient noise levels have not interfered in the reading. However,

other studies have shown a 6 dB SPL, or even 3 dB SPL signal to noise ratio is acceptable (Chan, Wong & McPherson, 2004).

Determining effective ototoxicity detection and monitoring strategies using objective measures such as DPOAEs is an active area of research. However, there currently are no accepted protocols or criteria for ototoxic change using DPOAEs (Durrant et al., 2009). Most reports in patients receiving ototoxic drugs which have utilised objective measures such as DPOAEs, in which sensitivity was defined as a clinically significant change in the value of the objective measure (Konrad-Martin et al., 2005). Stavroulaki et al. (2002) reported that a significant change could be 2.4 dB. Cunningham (2011) however discusses that from clinical experience changes of 3-6 dB SPL from one test session to the next (while all other test parameters are held constant, or an attempt at that occurs) are accepted as significant and indicate a change in cochlear function. Opinions vary, and there are no agreed-upon decisions of a universal dB SPL amount that indicates a "significant change" from one test session to the next (Cunningham, 2011).

Therefore, for this current study, a clinically significant change attributed to

ototoxicity is defined 6 dB or more at or above 2 kHz at one or more frequency unilaterally or bilaterally. A clinically significant change can be classified as 6 dB sound pressure level (SPL) or higher, as adapted from Cunningham (2011). Therefore, variability in detection threshold or standard deviation is from 0 to 5 dB SPL (Roede, Harris, Probst & Xu, 1993).

The grading systems below also only take PTA into account, and no grading system has been developed to grade OAEs.

Screening with DPOAEs may be enhanced by testing only in the 3- to the 5.2-kHz range, thus decreasing testing time. Higher time averages to increase the signal-to-noise ratio and use of this narrower bandwidth might also allow for accurate bedside testing (Ress et al.,

1999). There are thus various considerations to consider when monitoring ototoxicity;

including the population under investigation and resources available.

Both PTA (including UHFA) and DPOAE measures can complement each other. PTA is a psycho-physical measurement of hearing with the aim of getting complete knowledge of an individual’s ability to interpret various kinds of acoustic stimuli (Huizing, 1951), whereas DPOAE have higher sensitivity than PTA in the monitoring of cochlear function (Sakashita et al., 1998), but not interpretation. OAEs can detect minor changes accounting from ototoxicity before they are evident on the audiogram (Guthrie, 2008). As DPOAEs do not require an individual to respond physically, this can occur when patients are too weak to participate in PTA. PTA is measured by placing earphones on an individual while the

clinician presents different pure tones with various frequencies to each ear via the earphones.

Whereas, with DPOAEs, the clinician places a probe in an individual’s ear. This probe emits the stimulus of two ‘primary tones’ that vary in frequency, and the cochlea responds by producing sounds. The microphone then picks these miniature sounds/emissions on the probe, and this is a measurement of cochlear functioning, and not hearing, as hearing extends beyond the cochlea to the temporal lobe (Martin & Clark, 2003). Therefore, this study

utilised both DPOAEs, PTA, and UHFA to allow for a comprehensive overview of the participants audiological functioning.

Despite the beneficial clinical utility of these DPOAEs, the correlation between DPOAEs and audiometric thresholds has been a topic of investigation. Varying degrees of correlation has been observed when comparing DPOAE to PTA as well as UHFA. These investigations are important as they allow the determination whether PTA, UHFA as well as DPOAEs need to be conducted, or whether the DPOAEs can be conducted instead of PTA of UHFA to save time.

Correlation was noted between DPOAEs (up to 8 kHz) and UHFA (up to 20 kHz) when used to detect ototoxicity in cisplatin patients. Results showed that they both detected the same ototoxicity; five of the ten patients (Yu et al., 2014). Correlation was further noted between DPOAEs and PTA in individuals with normal hearing (2 to 6 kHz). Moreover, extended high frequency (EHF) PTA (PTA) (up to 20 kHz) and DPOAEs (up to 8 kHz) were compared in patients receiving cisplatin. Although both EHF-PTA and DPOAE showed the same sensitivity in detecting ototoxicity, they did not produce the same results in all patients, and so perhaps the two tests can complement each other, not outweigh each other (Yu et al., 2014). A positive correlation was further noted in ordinary hearing persons between PTA and DPOAE at 2, 3, 4, 6 kHz (Campos & Carvalho, 2011).

However, weak correlation between DPOAEs and PTA was observed in the industrial setting. This study stated that there is no relevant predictive relationship between DPOAEs and PTA to monitor noise-induced hearing loss (Wooles, Mulheran, Bray, Brewster &

Banerjee, 2015). Also, DPOAEs were shown to detect more hearing loss than PTA at 8.9,10 kHz (Daud, Mohamadi, Haron & Rahman, 2014), showing a reduced correlation between DPOAEs and UHFA.

In summary, both DPOAEs and PTA, specifically UHFA have a place in ototoxicity monitoring. Although there is a correspondence between the DPOAEs and PTA; the

relationship is not always consistent. This translates into the need for both DPOAEs and PTA, specifically UHFA to complement each other, instead of their use in isolation.