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1.  Alterations in Evoked Otoacoustic Emissions by the Use of Meglumine Antimoniate in American Tegumentary Leishmaniasis Patients 
PLoS ONE  2017;12(1):e0168492.
Tegumentary Leishmaniasis (TL) is a neglected, non-contagious, infectious disease, caused by different protozoa species of the Leishmania genus that affects skin and mucous membranes. Meglumine Antimoniate (MA), the first drug of choice for TL treatment in Brazil, has already been associated with cochlear toxicity, which is defined as damages of the cochlea caused by exposure to chemical substances, resulting in reversible or irreversible hearing loss. Auditory monitoring for cochlear toxicity aims at the early detection of auditory disorders, enabling, when possible, hearing to be preserved or an early auditory rehabilitation. Although otoacoustic emissions (OAEs) are used in this monitoring, there is no consensus on the criteria that define cochlear toxicity by this examination. The objective of this study was to describe the characteristics of the OAEs in cochlear toxicity monitoring in TL patients using MA.
Prospective and longitudinal study of auditory monitoring of 35 patients with parasitological diagnosis of TL, with liminal tonal audiometry, high frequency audiometry, immitanciometry, distortion product evoked otoacoustic emissions (DPEOAEs) and transient evoked otoacoustic emissions (TEOAEs) before treatment, at the end of treatment, one month after the end of treatment and two months after the end of treatment.
80% male, with median age of 44 years (IIQ: 22–59). In the pre-treatment evaluation: 11.4% complained of hearing loss and 20% of tinnitus, 48.6% presented auditory alterations in liminal tonal audiometry (LTA, 65.2% in high frequency audiometry (HFA), 26.6% in DPEOAE and 51.4% in TEOAE. No association was verified between genre and alterations in the EOAE examinations. We observed that patients that presented disorders in DPEOAE examinations were 17 years older than those without alterations and that patients that showed disorders in TEOAEO examinations were 34 years older than those without disorders. The presence of alterations in DPEOAE and TEOAE before beginning treatment was associated with each other and with the presence of alterations in LTA and HFA, and only DPEOAE was associated with hearing loss. We observed a significantly higher number of alterations of DPEOAE at the end of treatment than during pre-treatment and values of the ratio signal/noise significantly smaller at the end of treatment than during pre-treatment in the frequencies of 2 kHz (difference of 1.7dB; p = 0.016) and 4 kHz (difference of 2.45dB; p = 0.016) in DPEOAE and in the range 1.75/2.5 kHz in TEOAE (difference of 2.9dB; p = 0.039).
The ototoxic signals observed in our study using EOAE indicated that both, DPEOAE and TEOAE are adequate and sensitive techniques for clinical monitoring of ototoxicity by MA. Their application is very simple, and their results help the physician to take the most adequate steps for each patient, thus avoiding permanent hearing damage.
PMCID: PMC5207536  PMID: 28045920
2.  Comparison of the Effectiveness of Monitoring Cisplatin-Induced Ototoxicity with Extended High-Frequency Pure-Tone Audiometry or Distortion-Product Otoacoustic Emission 
Korean Journal of Audiology  2014;18(2):58-68.
Background and Objectives
To compare the effectiveness of monitoring cisplatin-induced ototoxicity in adult patients using extended high-frequency pure-tone audiometry (EHF-PTA) or distortion-product otoacoustic emission (DP-OAE) and to evaluate the concurrence of ototoxicity and nephrotoxicity in cisplatin-treated patients.
Subjects and Methods
EHF-PTA was measured at frequencies of 0.25, 0.5, 1, 2, 3, 4, 6, 8, 9, 11.2, 12.5, 14, 16, 18, and 20 kHz and DP-OAE at frequencies of 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8 kHz in cisplatin-treated patients (n=10). Baseline evaluations were made immediately before chemotherapy and additional tests were performed before each of six cycles of cisplatin treatment. Laboratory tests to monitor nephrotoxicity were included before every cycle of chemotherapy.
Four of 10 patients showed threshold changes on EHF-PTA. Five of 10 patients showed reductions in DP-OAE, but one was a false-positive result. The results of EHF-PTA and DP-OAE were consistent in two patients. Only one patient displayed nephrotoxicity on laboratory tests after the third cycle.
In our study, the incidence rate of cisplatin-induced ototoxicity was 40% with EHF-PTA or DP-OAE. Although both EHF-PTA and DP-OAE showed the same sensitivity in detecting ototoxicity, they did not produce the same results in all patients. These two hearing tests could be used to complement one another. Clinicians should use both tests simultaneously in every cycle of chemotherapy to ensure the detection of ototoxicity.
PMCID: PMC4181054  PMID: 25279227
Cisplatin; Ototoxicity; Otoacoustic emission; Pure-tone audiometry
3.  Group-Wide, Prospective Study of Ototoxicity Assessment in Children Receiving Cisplatin Chemotherapy (ACCL05C1): A Report From the Children’s Oncology Group 
Journal of Clinical Oncology  2016;35(4):440-445.
Optimal assessment methods and criteria for reporting hearing outcomes in children who receive treatment with cisplatin are uncertain. The objectives of our study were to compare different ototoxicity classification systems, to evaluate the feasibility of including otoacoustic emissions and extended high frequency audiometry, and to evaluate a central review mechanism for audiologic results for cisplatin-treated children in the cooperative group setting.
Patients and Methods
Eligible participants were 1 to 30 years, with planned cisplatin-containing treatment. Hearing evaluations were conducted at baseline, before each cisplatin cycle, and at the end of therapy. Audiologic results were assessed and graded by the testing audiologist and by two central review audiologists using the American Speech-Language-Hearing Association Ototoxicity Criteria (ASHA), Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE), and Brock Ototoxicity Grades (Brock). One central reviewer also used the International Society of Pediatric Oncology Ototoxicity Scale (SIOP).
At the end of treatment, the prevalence of any degree of ototoxicity ranged from 40% to 56%, and severe ototoxicity ranged from 7% to 22%. Compared with CTCAE, SIOP detected significantly more ototoxicity (P = .004), whereas Brock criteria detected significantly fewer patients with any or severe ototoxicity (P < .001 for both). SIOP detected ototoxicity earlier than did the other scales. Agreement between the central reviewers and the institutional audiologist was almost perfect for ASHA and Brock, whereas the poorest agreement occurred with CTCAE.
The SIOP scale may be superior to ASHA, Brock, and CTCAE scales for classifying ototoxicity in pediatric patients who were treated with cisplatin. Future studies should evaluate inter-rater reliability of the SIOP scale.
PMCID: PMC5455699  PMID: 27937095
4.  Ototoxicity of artemether/lumefantrine in the treatment of falciparum malaria: a randomized trial 
Malaria Journal  2008;7:179.
Due to increasing drug resistance, artemisinin-based combination chemotherapy (ACT) has become the first-line treatment of falciparum malaria in many endemic countries. However, irreversible ototoxicity associated with artemether/lumefantrine (AL) has been reported recently and suggested to be a serious limitation in the use of ACT. The aim of the study was to compare ototoxicity, tolerability, and efficacy of ACT with that of quinine and atovaquone/proguanil in the treatment of uncomplicated falciparum malaria.
Ninety-seven patients in south-west Ethiopia with slide-confirmed malaria were randomly assigned to receive either artemether/lumefantrine or quinine or atovaquone/proguanil and followed-up for 90 days. Comprehensive audiovestibular testing by pure tone audiometry (PTA), transitory evoked (TE) and distortion product (DP) otoacoustic emissions (OAE) and brain stem evoked response audiometry (BERA) was done before enrolment and after seven, 28 and 90 days.
PTA and DP-OAE levels revealed transient significant cochlear hearing loss in patients treated with quinine but not in those treated with artemether/lumefantrine or atovaquone/proguanil. TE-OAE could be elicited in all examinations, except for three patients in the Q group on day 7, who suffered a transient hearing loss greater than 30 dB. There was no evidence of drug-induced brain stem lesions by BERA measurements.
There was no detrimental effect of a standard oral regimen of artemether/lumefantrine on peripheral hearing or brainstem auditory pathways in patients with uncomplicated falciparum malaria. In contrast, transient hearing loss is common after quinine therapy and due to temporary outer hair cell dysfunction.
PMCID: PMC2559845  PMID: 18796142
5.  COAST (Cisplatin ototoxicity attenuated by aspirin trial): A phase II double-blind, randomised controlled trial to establish if aspirin reduces cisplatin induced hearing-loss 
European Journal of Cancer  2017;87:75-83.
Cisplatin is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Cisplatin and gentamicin are thought to damage hearing through a common mechanism, involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin-induced ototoxicity. We, therefore, tested the hypothesis that aspirin could also reduce ototoxicity from cisplatin-based chemotherapy.
A total of 94 patients receiving cisplatin-based chemotherapy for multiple cancer types were recruited into a phase II, double-blind, placebo-controlled trial and randomised in a ratio of 1:1 to receive aspirin 975 mg tid and omeprazole 20 mg od, or matched placebos from the day before, to 2 days after, their cisplatin dose(s), for each treatment cycle. Patients underwent pure tone audiometry before and at 7 and 90 days after their final cisplatin dose. The primary end-point was combined hearing loss (cHL), the summed hearing loss at 6 kHz and 8 kHz, in both ears.
Although aspirin was well tolerated, it did not protect hearing in patients receiving cisplatin (p-value = 0.233, 20% one-sided level of significance). In the aspirin arm, patients demonstrated mean cHL of 49 dB (standard deviation [SD] 61.41) following cisplatin compared with placebo patients who demonstrated mean cHL of 36 dB (SD 50.85). Women had greater average hearing loss than men, and patients treated for head and neck malignancy experienced the greatest cHL.
Aspirin did not protect from cisplatin-related ototoxicity. Cisplatin and gentamicin may therefore have distinct ototoxic mechanisms, or cisplatin-induced ototoxicity may be refractory to the aspirin regimen used here.
•Aspirin was well tolerated.•Aspirin did not protect hearing at the doses and in the schedule investigated here.•Cisplatin and gentamicin may have distinct ototoxic mechanisms.•Qualitative data suggest protective aspirin effect but low power for hypothesis.•Cisplatin-induced ototoxicity results in significant morbidity.
PMCID: PMC5729023  PMID: 29128692
Cisplatin; Chemotherapy; Aspirin; Ototoxicity; Hearing
6.  The relationship between ultra-high frequency thresholds and transient evoked otoacoustic emissions in adults with tinnitus 
Background: The possible role of cochlear function in tinnitus generation is still a matter of debate. To assess the role of outer hair cell dysfunction in tinnitus and its possible relationship with ultra-high frequency (UHF) hearing sensitivity, transient evoked otoacoustic emissions (TEOAE) and UHF hearing thresholds were investigated in normal hearing individuals with and without tinnitus.
Methods: Eighteen individuals with tinnitus and 22 without tinnitus participated in this study. TEOAE was recorded with click stimulus at 80 dBpeSPL. UHF pure tone audiometry was performed at 10, 12.5, 16, and 18 kHz.
Results: TEOAE was significantly abnormal in 72.2% of the tinnitus, and 18.2% of the control groups (p=0.001). The individuals with tinnitus had significantly poorer UHF hearing sensitivity compared to the control group at 12.5 and 18 kHz (p≤0.048). There was a stronger correlation between increasing UHFs hearing threshold and decreasing SNRs of TEOAEs in the tinnitus group compared to the controls.
Conclusion: Our study revealed poorer UHF hearing thresholds and more TEOAE abnormalities in normal hearing individuals with tinnitus compared to the controls. Perhaps the alterations in the basal cochlea, following a decrease in UHF hearing sensitivity, affect OAEs that are originated from more apical cochlear parts in tinnitus ears more than non-tinnitus ears.
PMCID: PMC5307623  PMID: 28210614
Tinnitus; Otoacoustic Emissions; Ultra-High Frequency Thresholds
7.  The Incidence of Amikacin Ototoxicity in Multidrug-ResistantTuberculosis Patients 
Amikacin has been shown to irreversibly suppressCochlear activity.The aim of this study is to assess the incidence of amikacinototoxicity in multidrug-resistant tuberculosis patients and riskfactors associated withthis ototoxicity.In this cross-sectional study, 41 patientswith multidrug-resistant tuberculosis (MDR-TB) were included.All patients received fixed dose of intravenous amikacin(500 mg/day) and anti-TB medications for six months. Baseline Pure-Tone Audiometry (PTA) was performed on all patients,before and during the drug treatment with the frequency range between 250 Hz and 8000 Hz. Patients were closely observed for the occurrence of symptomatic ototoxicity using a questionnaire .To find an association between the incidence of cochlear damage and patients’ demographics, all patients’ data were recorded.
A total of 29 patients suffered from hearing loss (70.1%) (Male: n = 18; Female: n = 20).Using logistic regression, the incidence ofamikacinototoxicity was higher in men than in women. There was a negative correlation between the duration of the amikacin treatment and the difference in hearing thresholds(r = -0.34, p = 0.03). The mean of hearing threshold was significantly increased before and after the amikacin treatment((23.68 ± 19.26 vs. 38.93 ± 22.80) (p < 0.0001)). The incidence of hearing loss was remarkable in MDR-TB patients treating with amikacin. However, risk factors’ determination and monitoring of audiometric result variations could haveinfluenced the incidence of the amikacin ototoxicity.
PMCID: PMC3813070  PMID: 24250429
Ototoxicity; Amikacin; Multidrug-resistant tuberculosis; Pure-tone audiometry
8.  Analysis of risk factors for cisplatin-induced ototoxicity in patients with testicular cancer. 
British Journal of Cancer  1998;77(8):1355-1362.
This study evaluates the degree and relevance of persisting ototoxicity after cisplatin-based standard-dose chemotherapy for testicular cancer, with emphasis on identification of potential factors for an increased risk of this late sequel. Hearing thresholds of 86 patients with a median age of 31 years (range 21-53 years) and a median follow-up time of 58 months (range 15-159 months) were assessed by conventional pure-tone audiometry. Interviews were conducted evaluating the patients' history with special regard to audiological risk factors, as well as circumstances of ototoxic symptoms. Details concerning treatment and patient variables were extracted retrospectively from the patients' charts. An additional screening programme assessed current body functions, blood parameters and other late toxicities. Symptomatic ototoxicity persisted in 20% of patients (59% tinnitus, 18% hearing loss, 23% both), while 10% had experienced completely reversible ototoxic symptoms for a duration of 1-18 months after treatment. Symptoms were bilateral in 81% of patients. Hearing thresholds were compatible with cisplatin-induced hearing loss in 42% of audiograms performed. Subjective (history) and objective (audiogram) findings were not always consistent. The following statistically significant risk factors for ototoxicity were established: high cumulative dose of cisplatin (P < 0.0001); history of noise exposure (P = 0.006). Additionally, high doses of vincristine (P = 0.001) seemed to result in reversible ototoxic symptoms. No other independent risk factors were identified. In conclusion, persisting ototoxicity represents a clinical sequel for approximately 20% of testicular cancer patients treated at standard dose but may affect more than 50% of patients receiving cumulative doses of cisplatin > 400 mg m(-2). Previous noise exposure may also result in a threefold increased risk for cisplatin ototoxicity. Future studies should use these risk factors as important stratification criteria for trials aiming at the evaluation and prevention of cisplatin-induced ototoxicity.
PMCID: PMC2150148  PMID: 9579846
9.  Assessment of aminoglycoside-induced hearing impairment in hospitalized neonates by TEOAE 
Aminoglycosides, as potent bactericidal antibiotics against aerobic gram-negative infections, is still widely used, especially in NICU patients, despite their known potential ototoxic effects.
To evaluate the potential of transient evoked otoacoustic emissions (TEOAEs) in early identification of decreased hearing sensitivity in hospitalized neonates receiving aminoglycosides for severe gram-negative infections.
Materials and Methods
Fifty (50) neonates treated with intravenous gentamicin (5 mg/kg/day) or amikacin (15 mg/kg/day) were tested with TEOAE in the beginning and the end of aminoglycoside therapeutic course. There were 23 males and 27 females, ranging from 29 to 40 weeks (mean: 36 weeks). The treatment duration was 3–30 days (in 26 neonates up to 7 days — group A, and in 24 neonates higher than 7 days — group B).
In group A, no statistically significant difference in the mean response level was found between the onset and the end of treatment course (p > 0.001).
In group B, a statistically significant difference in the mean response level was found between the onset and the end of treatment course, especially at high frequency region (p < 0.001).
TEOAE is sensitive enough to detect early aminoglycoside ototoxicity. As this test is simple to perform, non-invasive and reliable, so we suggest that TEOAE test should be performed in NICU as routine for monitoring cochlear function to prevent permanent hearing loss especially in those who are receiving aminoglycoside for more than 7 days.
PMCID: PMC3450078  PMID: 23120646
Neonates; NICU; TEOAE; Aminoglycoside; Ototoxicity
10.  Distortion-Product Otoacoustic Emission Test Performance for Ototoxicity Monitoring 
Ear and hearing  2011;32(1):61-74.
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.
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.
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.
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.
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.
PMCID: PMC5588870  PMID: 20625302
11.  Hydrogen Inhalation Protects against Ototoxicity Induced by Intravenous Cisplatin in the Guinea Pig 
Introduction: Permanent hearing loss and tinnitus as side-effects from treatment with the anticancer drug cisplatin is a clinical problem. Ototoxicity may be reduced by co-administration of an otoprotective agent, but the results in humans have so far been modest.
Aim: The present preclinical in vivo study aimed to explore the protective efficacy of hydrogen (H2) inhalation on ototoxicity induced by intravenous cisplatin.
Materials and Methods: Albino guinea pigs were divided into four groups. The Cispt (n = 11) and Cispt+H2 (n = 11) groups were given intravenous cisplatin (8 mg/kg b.w., injection rate 0.2 ml/min). Immediately after, the Cispt+H2 group also received gaseous H2 (2% in air, 60 min). The H2 group (n = 5) received only H2 and the Control group (n = 7) received neither cisplatin nor H2. Ototoxicity was assessed by measuring frequency specific ABR thresholds before and 96 h after treatment, loss of inner (IHCs) and outer (OHCs) hair cells, and by performing densitometry-based immunohistochemistry analysis of cochlear synaptophysin, organic transporter 2 (OCT2), and copper transporter 1 (CTR1) at 12 and 7 mm from the round window. By utilizing metabolomics analysis of perilymph the change of metabolites in the perilymph was assessed.
Results: Cisplatin induced electrophysiological threshold shifts, hair cell loss, and reduced synaptophysin immunoreactivity in the synapse area around the IHCs and OHCs. H2 inhalation mitigated all these effects. Cisplatin also reduced the OCT2 intensity in the inner and outer pillar cells and in the stria vascularis as well as the CTR1 intensity in the synapse area around the IHCs, the Deiters' cells, and the stria vascularis. H2 prevented the majority of these effects.
Conclusion: H2 inhalation can reduce cisplatin-induced ototoxicity on functional, cellular, and subcellular levels. It is proposed that synaptopathy may serve as a marker for cisplatin ototoxicity. The effect of H2 on the antineoplastic activity of cisplatin needs to be further explored.
PMCID: PMC5601388
ABR; inner hair cells; outer hair cells; synaptophysin; organic cation transporter 2; copper transporter 1; perilymph metabolomics; in vivo
12.  Time-Frequency Analysis of Transient-Evoked Otoacoustic Emissions in Children exposed to Carboplatin Chemotherapy 
Audiology & neuro-otology  2012;18(2):71-82.
The aims of this study were to characterize and quantify time-frequency changes in transient-evoked otoacoustic emissions (TEOAEs) recorded in children diagnosed with retinoblastoma who were receiving carboplatin chemotherapy. A signal processing technique, the wavelet transform (WT), was used to analyze TEOAE waveforms in narrow-band frequency components. Ten children (aged 3–72 months) diagnosed with unilateral or bilateral retinoblastoma were enrolled in the study. TEOAEs were acquired from the children with linear sequences of 70 dB peSPL clicks. After WT analysis, TEOAE energy, latency, and normalized energy in the narrow-band frequency components were compared before and during carboplatin (average dose 1693 mg/m2) chemotherapy treatment. On a group basis, no significant differences (p>0.05) in pre- and post-carboplatin TEOAE energy, latency, or normalized energy were observed. There were decreases in normalized energy on an individual basis in 10/18 ears in the sample. Exposure to carboplatin chemotherapy did not cause significant changes in TEOAE energy, latency, and normalized energy during treatment. However, long-term monitoring of hearing with measurements of TEOAEs is warranted given the risks of delayed hearing loss in some children receiving carboplatin chemotherapy.
PMCID: PMC3777667  PMID: 23147804
Carboplatin; Children; Cochlea; Ototoxicity; TEOAE; Wavelet
13.  Audiological Evaluation of Patients Taking Kanamycin for Multidrug Resistant Tuberculosis 
The incidence of multidrug resistant tuberculosis is increasing in developing countries. Aminoglycosides are an integral part of second-line drugs, however ototoxicity is a major limitation for their use. This study aims to determine the extent of hearing loss in patients taking one of the commonly prescribed drugs for Multidrug resistant tuberculosis (MDR-TB), Kanamycin, at a Government Medical College, Patiala, Punjab, India, which is a 1200 bed tertiary care hospital.
Materials and Methods:
A total of 100 patients (68 males and 32 females) with confirmed diagnosis of MDR-TB were included in this study conducted between January 2012 and February 2014. Subjects were between 15 to 60 years of age, with a mean age of 37.46 ± 10.1. Pure tone audiometry (PTA) was performed before the start of the therapy, as a baseline, and was repeated after 1 week and 6 weeks of Kanamycin use to assess hearing loss as an effect of therapy.
Of the 100 patients examined, ototoxicity was found in 18 subjects post therapy. Incidence of high frequency hearing loss was 2% at week 1, and 12% after 6 weeks of follow up. However, 4% of the cases developed flat loss at week 6. The hearing loss was bilateral in 13 patients and unilateral in 5 patients. Ototoxicity was more common in males (66.67%) compared to females (33.3%). Maximum cases were found in the age group of 36 to 45 years (36.8%), the majority being from a rural background (83.3%). The association with socioeconomic status (P=0.024) and co-morbid conditions like diabetes and hypertension (P=0.001) reached statistical significance.
Lack of specific guidelines to monitor patients taking aminoglycosides makes ototoxicity a major adverse effect of their use in MDR-TB. More studies are mandated to study the risk factors associated with the development of ototoxicity and for the development of alternate drugs for the treatment of MDR-TB.
PMCID: PMC4930843  PMID: 27429949
Co-morbidity; Kanamycin; Ototoxicity; MDR-TB; Pure tone audiometry; Socioeconomic status
14.  The Specificity and Sensitivity of Transient Otoacustic Emission in Neonatal Hearing Screening Compared with Diagnostic Test of Auditory Brain Stem Response in Tehran Hospitals 
Iranian Journal of Pediatrics  2013;23(2):199-204.
Since early detection (specially before 6 months of age) of deaf people leads to better hearing and speech outcome after treatment, several clinical trials have been performed in order to find a cost effective, short duration screening test for diagnosis of neonatal hearing impairment. The aim of this study was to assess the sensitivity and specificity of Transient Otoacustic Emission (TEOAE) test in newborns comparing with auditory brain stem response (ABR) in the age of 3 months and to analyze the association between risk factors and hearing loss in neonates.
A cross-sectional study was conducted January2008 - May 2009 in Tehran. 1000 newborns (526 boys and 474 girls) were assessed. First, all of neonates were evaluated by TEOAE 24h after birth. If responses of OAE were failing, they were retested 10 to 15 days after birth by TEOAE. Also, All Neonates were assessed by ABR in the age of 3 months. Descriptive Statistics was used to analyze data.
Eighteen out of 1000 neonates failed double–checked TEOAE tests, of which 6 were confirmed by ABR test (12 false positive results). Nine out of 1000 neonates had impaired ABR tests, from these patients, 6 had failed OAE as well, but 3 had normal OAE (3 false negative results). From these 9 patients 2 had profound hearing loss and received cochlear implantation. We found that OAE has 66.7% sensitivity and 98.8% specificity in diagnosis of neonatal hearing impairment. Its positive and negative predictive value was 33.3% and 99.7% respectively. Also we did not find statistically significant relationship between hearing loss and risk factors.
TEOAE as a simple, non-invasive, short duration and cost effective method, is a suitable test for neonatal hearing screening. Even though only two thirds of patients were detected by this method, 99.7% negative predictive value makes it a good screening test. We recommend OAE as a suitable primary neonatal hearing screening all over the country.
PMCID: PMC3663313  PMID: 23724183
Hearing Loss; Sensitivity; Specificity; Auditory Brain Stem Response; Otoacustic Emission
15.  Gentamicin-Induced Ototoxicity and Nephrotoxicity Vary with Circadian Time of Treatment and Entail Separate Mechanisms 
Chronobiology international  2015;32(9):1223-1232.
The aminoglycoside antibiotic gentamicin can cause both ototoxicity and nephrotoxicity, the severity of which varies with circadian time of daily treatment. However, it is not yet resolved if such drug-induced adverse effects are independent or dependent phenomena. Two groups of 9 female Sprague-Dawley rats (200-250 g), each housed separately, entrained to a 12h light (06:00 to 18:00h)-12h dark cycle, received a daily subcutaneous injection of 100 mg/kg gentamicin. One group was treated at the beginning of the activity span, 2 HALO (Hours After Lights On), and the other at the beginning of the rest span, 14 HALO. Global toxicity was gauged both by body weight loss relative to the pre-treatment baseline and number of deaths. Ototoxicity, i.e., hearing loss, was assessed by changes in Auditory Brainstem Responses (ABR) for pure tone stimuli of 8, 16, 24, and 32 kHz before and after 2 and 4 weeks of gentamicin treatment. Renal toxicity was evaluated by changes in urinary N-acetyl-β-glucosaminidase (NAG)/creatinine (CR) concentration ratio before and after each week of treatment. In a complementary substudy of separate but comparable 2 and 14 HALO groups of rats, blood samples were obtained before and 30, 60, 120, and 240-mins post-subcutaneous injection of 100 mg/kg gentamicin. Number of animal deaths was greater in the 2 (4 deaths) than 14 HALO (1 death) group, mirroring more severe initial (1st 2 weeks of treatment) body weight losses from baseline, being more than 2-fold greater in animals of the 2 than 14 HALO group. Ototoxicity progressively worsened during treatment; although, the extent of hearing loss varied according to circadian time of treatment across all frequencies (p<0.05), particularly the 24 and 32 kHz ones (both p<0.005), both at the 2 and 4 week assessments. At 32 kHz after 4 weeks of gentamicin dosing, the 2 HALO group showed an average 42 dB hearing loss, while the 14 HALO group exhibited only an average 10 dB loss. ABR response latencies were longer for the 2 than 14 HALO rats. The time course of nephrotoxicity differed from that of ototoxicity. The mean urinary NAG/CR ratio peaked after the 1st week of treatment, averaging 13.64-fold greater than baseline for the 2 HALO-treated animals compared to 7.38-fold greater than baseline for the 14 HALO-treated ones. Ratio values declined thereafter; although even after the 2nd week of dosing, they remained greater in the 2 than 14 HALO group (averaging 8.15-fold greater and 2.23-fold greater than baseline, respectively). Pharmacokinetic analysis of the blood gentamicin values revealed slower clearance, on average by ∼25% (p<0.001), in the rats of the 14 than 2 HALO group (x̄ ± S.E.: 3.22 ± 0.49 and 4.53 ± 0.63 mL/min/kg, respectively). The study findings indicate robust difference of the time course in rats of both treatment groups of gentamicin-induced ototoxicity and nephrotoxicity, supporting the hypothesis these organ toxicities are independent of one another, and further suggest the observed treatment-time differences in gentamicin adverse effects may be more dependent on local cell, tissue, or organ circadian (chrono)pharmacodynamic than (chrono)pharmacokinetic mechanisms.
PMCID: PMC5013539  PMID: 26506922
Ototoxicity; Nephrotoxicity; Gentamicin; Circadian Rhythm; Aminoglycosides; Chronopharmacology; Chronotoxicity
16.  Development and Validation of a Cisplatin Dose-Ototoxicity Model 
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.
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.
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.
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.
PMCID: PMC5549622  PMID: 22992258
Cisplatin; ototoxicity; ototoxicity monitoring; Veterans
17.  Study of streptomycin-induced ototoxicity: protocol for a longitudinal study 
SpringerPlus  2016;5(1):758.
Hearing impairment is due to various causes including ototoxicity from aminoglycosides. The susceptibility to aminoglycosides increases in the presence of certain mitochondria gene mutations. There is unrestrained use of aminoglycosides in many developing nations which may worsen the burden of hearing impairment in these countries but there is lack of data to drive required policy changes. Streptomycin (an aminoglycoside) is part of the drug regimen in re-treatment of tuberculosis. Exploring the impact of streptomycin ototoxicity in tuberculosis patients provides a unique opportunity to study aminoglycoside ototoxicity within the population thus providing data that can inform policy. Also, since streptomycin ototoxicity could adversely affect treatment adherence in tuberculosis patients this study could enable better pre-treatment counseling with subsequent better treatment adherence. Patients on tuberculosis re-treatment will be recruited longitudinally from Direct Observation Therapy-Short course centers. A baseline full audiologic assessment will be done before commencement of treatment and after completion of treatment. Early detection of ototoxicity will be determined using the American Speech and Hearing Association criteria and genetic analysis to determine relevant mitochondria gene mutations will be done. The incidence of ototoxicity in the cohort will be analyzed. Both Kaplan–Meier survival curve and Cox proportional hazards tests will be utilized to determine factors associated with development of ototoxicity and to examine association between genotype status and ototoxicity. This study will provide data on the burden and associated predictors of developing aminoglycoside induced ototoxicity. This will inform public health strategies to regulate aminoglycoside usage and optimization of treatment adherence and the management of drug-induced ototoxicity among TB patients. Furthermore the study will describe mitochondrial gene mutations associated with ototoxicity in the African population.
Electronic supplementary material
The online version of this article (doi:10.1186/s40064-016-2429-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4912548  PMID: 27386243
Ototoxicity; Streptomycin; Tuberculosis; Aminoglycosides; Africa; Drug-induced hearing loss
18.  The Profile of Otoacoustic Emissions and Multifrequency Tympanometry in Otosclerotic Patients Undergoing Two Types of Stapes Surgery: Small Fenestra and Microtraumatic Stapedotomy 
Otoacoustic emissions (OAEs) are influenced in otosclerosis. The aim of the current study was to investigate the profile of transient evoked (TEOAEs) and distortion product otoacoustic emissions (DPOAEs) in association with multifrequency tympanometry measures in otosclerotic patients undergoing 2 types of stapes surgery: small fenestra and microtraumatic stapedotomy.
A retrospective analysis of prospectively collected data was conducted evaluating 51 otosclerotic patients and 50 normal hearing subjects. Small fenestra and microtraumatic stapedotomy were performed in 27 and 24 patients, respectively. Pure tone audiometry (PTA) was always measured. Detection of TEOAEs and DPOAEs at 5 frequency steps (1, 1.4, 2, 2.8, and 4 kHz) preoperatively and at 2 and 5 months postoperatively, stratified by the type of surgery, represented the main goal of the study. Resonant frequency derived by multifrequency tympanometry was also evaluated.
All patients demonstrated improvement in hearing level postoperatively, with significant closure of air-bone gap on PTA. Resonant frequency values returned to normal after microtraumatic stapedotomy but were exceedingly decreased following the small fenestra technique. The detection of both TEOAEs and DPOAEs was improved, but when the detection was stratified by the tested frequencies, significant increase in the number of patients with detectable OAEs was observed, mainly during testing at 1 and 1.4 kHz.
Otosclerotic patients exhibited improvement in the detection of OAEs, particularly at low frequencies, after both procedures. Resonant frequency was normalized following the microtraumatic stapedotomy, whereas it is over-decreased after the small fenestra technique.
PMCID: PMC4167506  PMID: 25205087
Audiometry; Hearing Loss; Conductive; Otosclerosis; Stapes Surgery
19.  Analysis of Cisplatin-Induced Ototoxicity Risk Factors in Iranian Patients with Solid Tumors: a Cohort, Prospective and Single Institute Study 
Cisplatin has been associated with irreversible hearing damage. Up to now, there is no therapeutic intervention showing benefit in preventing Cisplatin-induced ototoxicity. The aim of this study was to determine risk factors contributing to hearing impairment after cisplatin administration in Iranian patients.
Hearing thresholds of 124 patients before and after cisplatin administration were assessed with reference to pure-tone audiometry averages at several frequencies from 2006 to 2010. Mean values were calculated at each tested frequency in each ear at baseline and subsequent follow-up audiometry. Hearing impairment was assessed with the Münster score.
The mean age at diagnosis and the median cumulative Cisplatin dose were 47.3 years and 453.8 milligrams, respectively. Bilateral hearing loss, mostly of grade 1, and tinnitus were detected in 26% and 3.2% of patients. Logistic regression analysis showed that a high cumulative dose of cisplatin was the most important risk factor for developing hearing damage (P=0.034). The most significant changes in the status of the auditory system and the most severe threshold shift from base line (35 dB) were observed at a frequency of 8 kHz. Also, patients who received higher individual doses of Cisplatin showed significantly more tinnitus (P=0.002).
The results are testament to benefits of routine audiometric monitoring program during cisplatin-based chemotherapy. Further research should be performed to understand other risk factors, such as genetic predictors of Cisplatin-induced ototoxicity.
PMCID: PMC5464495  PMID: 28441710
Cisplatin; hearing loss; risk factors; cancer
20.  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 χ2 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.
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.
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.
PMCID: PMC5590654  PMID: 20701838
Ototoxicity; ototoxicity monitoring; tinnitus; veterans
21.  Mercury Exposure in a Riverside Amazon Population, Brazil: A Study of the Ototoxicity of Methylmercury 
Introduction Mercury poisoning causes hearing loss in humans and animals. Acute and long-term exposures produce irreversible peripheral and central auditory system damage, and mercury in its various forms of presentation in the environment is ototoxic.
Objective We investigated the otoacoustic emissions responses in a riverside population exposed to environmental mercury by analyzing the inhibitory effect of the medial olivocochlear system (MOCS) on transient otoacoustic emissions (TEOAE).
Methods The purpose of the research was to evaluate the entire community independently of variables of sex and age. All of the participants were born and lived in a riverside community. After otolaryngologic evaluation, participants were received tympanometry, evaluation of contralateral acoustic reflexes, pure tone audiometry, and recording of TEOAEs with nonlinear click stimulation. Hair samples were collect to measure mercury levels.
Results There was no significant correlation between the inhibitory effect of the MOCS, age, and the level of mercury in the hair.
Conclusions The pathophysiological effects of chronic exposure may be subtle and nonspecific and can have a long period of latency; therefore, it will be important to monitor the effects of mercury exposure in the central auditory system of the Amazon population over time. Longitudinal studies should be performed to determine whether the inhibitory effect of the MOCS on otoacoustic emissions can be an evaluation method and diagnostic tool in populations exposed to mercury.
PMCID: PMC4399177  PMID: 25992169
mercury; methylmercury compounds; auditory pathways; medial olivocochlear system; otoacoustic emissions; ototoxicity
22.  Research protocol: Cisplatin-associated ototoxicity amongst patients receiving cancer chemotherapy and the feasibility of an audiological monitoring program 
BMC Women's Health  2017;17:129.
Cisplatin is an anti-cancer chemotherapy drug classified as an alkylating agent. It is used for the treatment of a variety of cancers such as cervical, breast, stomach, prostate, bladder and oesophageal, to name a few. However due to its expansive toxicity profile, patients receiving cisplatin can experience high frequency hearing loss, a side effect known as ototoxicity. The dearth of information on the extent and severity of cisplatin-associated ototoxicity in South Africa prevents the implementation of a context-specific audiological monitoring programme.
This study aims to determine the extent and severity of ototoxicity amongst patients with cervical cancer, receiving cisplatin-based chemotherapy and hence the feasibility of an ototoxicity monitoring program in the province of KwaZulu-Natal, South Africa. A concurrent mixed methods design will be employed in the study. This longitudinal study will involve interviewing oncology nurses, oncologists, pharmacists and audiologists to assess the level of awareness to ototoxicity, as well as conducting diagnostic audiological evaluations at regular intervals on 78 patients with cervical cancer to ascertain the progression of hearing loss during and after chemotherapy. The feasibility of the monitoring program will be assessed as a parallel process to the audiological evaluations, where patient outcomes and cost implications to the patient and the health sector will be considered. Data will be subjected to statistical analyses so as to strengthen knowledge in the field and inform appropriate policies, and healthcare providers.
This study is the first longitudinal study in South Africa to determine the ototoxic effects of cisplatin therapy on patients diagnosed with cervical cancer. Thus, the results generated from this study is likely to bring novel information to the fore using an evidence-based approach that will influence policy and clinical practice which can vastly improve the quality of life of patients undergoing chemotherapy. Mitigation of any further loss in the quality of life of affected patients is of paramount importance and the data generated from this project can lay the basis for further effective dialogue towards policy formulation on an ototoxic monitoring programme and the resultant strengthening of health systems in limited resource settings.
Electronic supplementary material
The online version of this article (10.1186/s12905-017-0486-8) contains supplementary material, which is available to authorized users.
PMCID: PMC5725900  PMID: 29228931
Cervical cancer; Cisplatin; Ototoxicity; Hearing loss; Quality of life; Audiology
23.  Monitoring carboplatin ototoxicity with distortion-product otoacoustic emissions in children with retinoblastoma 
Carboplatin is a common chemotherapy agent with potential ototoxic side effects that is used to treat a variety of pediatric cancers, including retinoblastoma. Retinoblastoma is a malignant tumor of the retina that is usually diagnosed in young children. Distortion-product otoacoustic emission tests offer an effective method of monitoring for ototoxicity in young children. This study was designed to compare measurements of distortion-product otoacoustic emissions obtained before and after several courses of carboplatin chemotherapy in order to examine if (a) mean distortion-product otoacoustic emission levels were significantly different; and (b) if criterion reductions in distortion-product otoacoustic emission levels were observed in individual children.
A prospective repeated measures study. Ten children with a median age of 7.6 months (range, 3–72 months) diagnosed with unilateral or bilateral retinoblastoma were examined. Distortion-product otoacoustic emissions were acquired from both ears of the children with 65/55 dB SPL primary tones (f2= 793–7996 Hz) and a frequency resolution of 3 points/octave. Distortion-product otoacoustic emission levels in dB SPL were measured before chemotherapy treatment (baseline measurement) and after 3–4 courses of chemotherapy (interim measurement). Comparisons were made between baseline and interim distortion-product otoacoustic emission levels (collapsed across ears). Evidence of ototoxicity was based on criterion reductions (≥ 6 dB) in distortion-product otoacoustic emission levels.
Significant differences between baseline and interim mean distortion-product otoacoustic emission levels were only observed at f2=7996 Hz. Four children exhibited criterion reductions in distortion-product otoacoustic emission levels.
Mean distortion-product otoacoustic emission levels at most frequencies were not changed following 3–4 courses of carboplatin chemotherapy in children with retinoblastoma. However, on an individual basis, children receiving higher doses of carboplatin exhibited criterion reductions in distortion-product otoacoustic emission level at several frequencies. These findings suggest that higher doses of carboplatin affect outer hair cell function, and distortion-product otoacoustic emission tests can provide useful information when monitoring children at risk of developing carboplatin ototoxicity.
PMCID: PMC4787621  PMID: 20667604
Carboplatin; Child; Cochlea; Hearing; Retinoblastoma
24.  Ototoxicity of Amikacin 
Amikacin was used in 77 treatment courses at a dosage of ≥7.5 mg/kg every 8 h, and patients were monitored for ototoxicity by following serial audiograms, serum creatinine, and amikacin blood levels. Patients were leukopenic (58), were infected by gentamicin-resistant organisms (11), or had cystic fibrosis (8). Three patients developed tinnitus, but none had vertigo or nystagmus. Of 55 courses with pre- and post-treatment audiogram, 13 (24%) were associated with development of high-frequency hearing loss, which was usually bilateral. No patient had conversational hearing loss, and audiograms reverted to normal in three patients. Onset of cochlear damage occurred in one patient after therapy was stopped. The group with high-tone hearing loss, in comparison to the group without audiographic changes, received a larger mean total dose (24 versus 9.6 g), were treated for a longer duration (19 versus 9 days), and more frequently had previous aminoglycosides. Fifty-seven percent of patients with a “peak” serum level exceeding 32 μg/ml and 55% of patients with “trough” levels exceeding 10 μg/ml developed cochlear damage. There was no difference between the groups in age, body weight, previous cochlear damage, renal disease before or during therapy, or average daily dose. Both monitoring of blood levels and limiting duration of therapy may prevent amikacin ototoxicity.
PMCID: PMC429657  PMID: 938024
25.  A Randomised, Double Blind Trial of N-Acetylcysteine for Hearing Protection during Stapes Surgery 
PLoS ONE  2015;10(3):e0115657.
Otosclerosis is a disorder that impairs middle ear function, leading to conductive hearing loss. Surgical treatment results in large improvement of hearing at low sound frequencies, but high-frequency hearing often suffers. A likely reason for this is that inner ear sensory cells are damaged by surgical trauma and loud sounds generated during the operation. Animal studies have shown that antioxidants such as N-Acetylcysteine can protect the inner ear from noise, surgical trauma, and some ototoxic substances, but it is not known if this works in humans. This trial was performed to determine whether antioxidants improve surgical results at high frequencies.
We performed a randomized, double-blind and placebo-controlled parallel group clinical trial at three Swedish university clinics. Using block-stratified randomization, 156 adult patients undergoing stapedotomy were assigned to intravenous N-Acetylcysteine (150 mg/kg body weight) or matching placebo (1:1 ratio), starting one hour before surgery. The primary outcome was the hearing threshold at 6 and 8 kHz; secondary outcomes included the severity of tinnitus and vertigo.
One year after surgery, high-frequency hearing had improved 2.7 ± 3.8 dB in the placebo group (67 patients analysed) and 2.4 ± 3.7 dB in the treated group (72 patients; means ± 95% confidence interval, p = 0.54; linear mixed model). Surgery improved tinnitus, but there was no significant intergroup difference. Post-operative balance disturbance was common but improved during the first year, without significant difference between groups. Four patients receiving N-Acetylcysteine experienced mild side effects such as nausea and vomiting.
N-Acetylcysteine has no effect on hearing thresholds, tinnitus, or balance disturbance after stapedotomy.
Trial Registration NCT00525551
PMCID: PMC4357436  PMID: 25763866

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