Establishing multifactorial risk factors for adult-onset hearing loss: A systematic review with topic modelling and synthesis of epidemiological evidence.

BACKGROUND: This systematic review explores the multifaceted nature of risk factors contributing to adult-onset HL. The objective was to synthesise the most recent epidemiological evidence to generate pooled proportional incidences for the identified risk factors. METHODS: We conducted an extensive search of electronic databases (MEDLINE, EMBASE, and psychINFO) for studies providing epidemiological evidence of risk factors associated with hearing loss. Topic modelling using Latent Dirichlet Allocation (LDA) was first conducted to determine how many risk factor themes were available from the papers. Data were analysed by calculating the pooled proportional incidence using a meta-analysis of proportions. RESULTS: From the 72 studies reviewed, six key risk factor themes emerged through LDA topic modelling. The review identified ototoxicity, primarily caused by cancer treatments and antibiotics, infectious diseases like COVID-19, occupational noise exposure, lifestyle factors, health conditions, biological responses, and age progression as significant risk factors for HL. The highest proportional incidence was found with cancer-related ototoxicity at 55.4% (95%CI: 39.0-70.7), followed closely by ototoxicity from infectious diseases at 50.0% (95%CI: 28.5-71.5). This high proportional incidence suggests the need to explore less destructive therapies and proactively monitor hearing function during treatments. CONCLUSIONS: The findings of this review, combined with the synthesis of epidemiological evidence, enhance our understanding of hearing loss (HL) pathogenesis and highlight potential areas for intervention, thereby paving the way for more effective prevention and management of adult-onset hearing loss in our ageing global population.

Effects on hearing after long-term use of iron chelators in beta-thalassemia: Over twenty years of longitudinal follow-up.

OBJECTIVE: The role of iron chelation in causing hearing loss (HL) is still unclear. The present study assessed the prevalence of HL among transfusion-dependent thalassemia (TDT) patients who underwent audiological follow-up over a 20-year period. METHODS: We retrospectively analyzed clinical records and audiological tests from January 1990 (T0) to December 2022 (T22) of a group of TDT patients who received iron chelation therapy with deferoxamine (DFO), deferiprone (DFP) or deferasirox (DFX), in monotherapy or as part of combination therapy. RESULTS: A total of 42 adult TDT patients (18 male, 24 female; age range: 41-55 years; mean age: 49.2 ± 3.7 years) were included in the study. At the T22 assessment, the overall prevalence of sensorineural HL was 23.8 % (10/42). When patients were stratified into two groups, with and without ototoxicity, no differences were observed for sex, age, BMI, creatinine level, pre-transfusional hemoglobin, start of transfusions, cardiac or hepatic T2 MRI; only ferritin serum values and duration of chelation were significantly higher (p = 0.02 and p = 0.01, respectively) in patients with hearing impairment in comparison to those with normal hearing. CONCLUSION: This study with long-term follow-up suggests that iron chelation therapy might induce ototoxicity; therefore, a long and accurate audiological follow-up should be performed in TDT patients.

Intraarticular vancomycin decreased the risk of acute postoperative periprosthetic joint infection without increasing complication in primary total joint arthroplasty-a prospective study.

OBJECTIVES: To investigate the preventive effect of intraarticularly administered vancomycin on acute postoperative periprosthetic joint infection (PJI) in total joint arthroplasty (TJA). METHODS: Consecutive patients who underwent unilateral primary TJA were prospectively enrolled. The patients were divided into vancomycin group and control group according to whether 1 g of vancomycin powder suspended in 30 ml normal saline was intraarticularly administered after arthrotomy closure. Acute postoperative PJI and aseptic wound complication were evaluated within 3 months postoperatively. Vancomycin-associated toxicity including acute renal failure, ototoxicity and anaphylaxis was also evaluated. RESULTS: In terms of demographic parameters and comorbidities, no significant difference was found between the two groups. Intra-articular vancomycin significantly lowered the risk of acute postoperative PJI after primary TJA (P = 0.015) and primary total knee arthroplasty (P = 0.031). However, for patients who underwent total hip arthroplasty, the PJI rate was comparable between the two groups. Overall, the risk of aseptic wound complication between the two groups was also similar. Vancomycin-associated acute renal injury, ototoxicity, or anaphylaxis was not observed. CONCLUSIONS: Intra-articular injection of 1 g of vancomycin suspension after arthrotomy closure during TJA lowered the risk of acute postoperative PJI without increasing the risk of aseptic wound complication and vancomycin-associated systemic toxicity.

The relevance of ototoxicity induced by radiotherapy.

BACKGROUND: The risk of ototoxicity, characterized by hearing impairment, tinnitus, or middle ear inflammation, is elevated in both child and adult cancer survivors who have undergone head-neck or brain radiation, or a combination of the two. To provide optimal care for these cancer survivors and minimize subsequent complications, it is crucial to comprehend the relationship between radiotherapy and ototoxicity. METHODS: A comprehensive search of databases, including the Cochrane Library, PubMed, Embase, and Web of Science, was conducted from the inception of the knowledge base up until January 2023. The metafor-package was employed to compare ototoxicity rates in individuals receiving radiotherapy. Two independent assessors extracted data and analyzed targets using a random-effects model. RESULTS: Out of the 28 randomized controlled trials (RCTs) included in the analysis, 25 were prospective RCTs. Subgroup analysis revealed that mean cochlear radiation dose, primary tumor location, radiotherapy modality, and patient age significantly influenced total hearing impairment. Intensity-modulated radiotherapy was associated with less ototoxicity than 2D conventional radiotherapy (OR, 0.53; 95% CI, 0.47-0.60; P = 0.73; I2 = 0%). Stereotactic radiotherapy appeared to be a superior option for hearing preservation compared to radiosurgery (OR, 1.44; 95% CI, 1.00-2.07; P = 0.69; I2 = 0%). Children demonstrated a higher risk of hearing impairment than adults. More than 50% of patients with vestibular neuroadenoma experienced hearing impairment following radiation therapy. A strong association was observed between the average cochlear radiation dose and hearing impairment. Increased cochlear radiation doses may result in a heightened risk of hearing impairment. CONCLUSION: Several risk factors for radiation-induced hearing impairment were identified in this study. High cochlear radiation doses were found to exacerbate the risk of hearing impairment resulting from radiation therapy.

Novel teprotumumab treatment of severe thyroid dermopathy; ototoxicity as an adverse side effect.

Pretibial myxedema, more generally thyroid dermopathy, results from mucopolysaccharide accumulation in the dermis, typically between the knee and dorsal foot. Thyroid dermopathy presents in Graves disease, but can occur in Hashimoto thyroiditis, primary hypothyroidism, and euthyroid patients. Treatment of thyroid eye disease with teprotumumab is established in the literature, with few case reports also showing improvement in pretibial myxedema. Reported is a 76-year-old man with thyroid eye disease and pretibial myxedema treated with teprotumumab; improvement was demonstrated in both conditions. He developed "muffled" hearing as an adverse effect, a complication not widely published in the dermatology literature. At 18 months post-treatment, his symptoms are stable without recurrence, but hypoacusis persists. Given the long-term efficacy and side-effects, dermatologists should recognize the potential benefits and risks of using teprotumumab for thyroid dermopathy. A baseline audiogram may be considered prior to therapy. Additionally, longitudinal data is needed to document the benefits and risks of this novel therapy.

OTOTOXICITY OF ANTIMYCOBACTERIAL THERAPY: MANIFESTATIONS, MECHANISMS OF MANAGEMENT AND CONTROL.

OBJECTIVE: The aim: To study the nature and incidence of hearing loss related to tuberculosis (TB) or resulting from antimycobacterial therapy, and its impact on treatment outcomes in patients with multidrug-resistant TB (MDR-TB). PATIENTS AND METHODS: Materials and methods: An analysis of reports on adverse reactions, medical records and electronic database of the register of TB patients was made. The pathogen was microbiologically verified in all the patients. Patients underwent clinical and laboratory, instrumental, microbiological (BACTEC), molecular genetic (Xpert® MTB/RIF® Ultra, Xpert® MTB/XDR, GenoType® MTBDRplus/sl) examinations. To prevent the development of complications and to control adverse effects, alongside with the determination of the corrected QT interval, visual acuity, and color vision, brief peripheral neuropathy screen and audiometry were performed. RESULTS: Results: During MDR-TB treatment with aminoglycosides, therapy was more commonly interrupted during the second episode of therapy (p=0,051), while treatment failure, longer treatment duration, and hearing impairment were almost equally observed in both groups (р=0,431, р=0,432, р=0,69). Treatment success was more commonly observed among patients receiving the first course of therapy. Some patients undergoing repeated antimycobacterial therapy were transferred to palliative care (p=0,13). The short-term treatment regimen effectively prevented ototoxicity. CONCLUSION: Conclusions: Novel antimycobacterial agents and short-term TB treatment regimens increased patient compliance with treatment and reduced the incidence of certain adverse effects due to their monitoring and prevention. Due to the transition to mainly drug therapy, adverse effects such as ototoxicity were completely eliminated. This was due to personalized treatment selection, its monitoring, and assessing the outcomes.

Identification of Perinatal Risk Factors for Auditory Neuropathy Spectrum Disorder.

OBJECTIVES/HYPOTHESIS: To identify medical risk factors associated with auditory neuropathy spectrum disorder (ANSD). STUDY DESIGN: Retrospective case-control study. METHODS: During a 2-year period (2013-2014) patients with newly diagnosed ANSD were identified at a tertiary care facility. Twenty-two patients (n = 22) were identified aged 0.5 to 8.1 years. There were 15 males and seven females. Sixteen had bilateral, four had left-sided, and two had right-sided ANSD. Two age-matched, side-matched, and gender-matched control groups were then collected. The first group was 22 normal-hearing children (n = 22). The second was 22 children with sensorineural hearing loss (SNHL) (n = 22) who did not meet the criteria for ANSD. The chart of each subject was reviewed for the following five-predictor variables: prematurity, low birth weight, jaundice, use of mechanical ventilation, and administration of ototoxic medications. Analysis of variance was performed to analyze the prevalence of perinatal risk factors among the three groups. Multivariate linear regression was then applied. RESULTS: When comparing the ANSD group to both the normal-hearing and SNHL groups, the subjects with ANSD had statistically significant higher rates of prematurity, low birth weight, jaundice, and mechanical ventilation. Multiple regression analysis was performed to identify predictors of ANSD compared to each control group individually. Jaundice in the first month of life approached significance when comparing the ANSD group to the normal-hearing group, and was the only medical risk factor found to be statistically significant when comparing the ANSD group to the SNHL group. CONCLUSIONS: A history of neonatal hyperbilirubinemia was significantly more common in children with ANSD compared to children with severe SNHL. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:671-674, 2021.

Otoprotective Effect of 2,3,4',5-Tetrahydroxystilbene-2-O-ß-d-Glucoside on Gentamicin-Induced Apoptosis in Mouse Cochlear UB/OC-2 Cells.

Excessive levels of reactive oxygen species (ROS) lead to mitochondrial damage and apoptotic cell death in gentamicin-induced ototoxicity. 2,3,4',5-Tetrahydroxystilbene-2-O-ß-d-glucoside (THSG), a bioactive constituent, isolated from Polygonum multiflorum Thunb., exhibits numerous biological benefits in treating aging-related diseases by suppressing oxidative damage. However, its protective effect on gentamicin-induced ototoxicity remains unexplored. Therefore, here, we aimed to investigate the otoprotective effect of THSG on gentamicin-induced apoptosis in mouse cochlear UB/OC-2 cells. We evaluated the effect of gentamicin and THSG on the ROS level, superoxide dismutase (SOD) activity, mitochondrial membrane potential, nuclear condensation, and lactate dehydrogenase (LDH) release, and the expression of apoptosis-related proteins was assessed to understand the molecular mechanisms underlying its preventive effects. The findings demonstrated that gentamicin increased ROS generation, LDH release, and promoted apoptotic cell death in UB/OC-2 cells. However, THSG treatment reversed these effects by suppressing ROS production and downregulating the mitochondrial-dependent apoptotic pathway. Additionally, it increased the SOD activity, decreased the expression of apoptosis-related proteins, alleviated the levels of the apoptotic cells, and impaired cytotoxicity. To the best of our knowledge, this is the first study to demonstrate that THSG could be a potential therapeutic option to attenuate gentamicin-induced ototoxicity.

Clinical Implications of Chloroquine and Hydroxychloroquine Ototoxicity for COVID-19 Treatment: A Mini-Review.

At this time of the COVID-19 pandemic, potentially effective treatments are currently under urgent investigation. Benefits of chloroquine and hydroxychloroquine for the treatment of COVID-19 infection have been proposed and clinical trials are underway. Chloroquine and hydroxychloroquine, typically used for the treatment of malaria and autoimmune diseases, have been considered for off-label use in several countries. In the literature, there are reports of ototoxic effects of the drugs causing damage to the inner ear structures, which then result in hearing loss, tinnitus, and/or imbalance. This mini-review represents a summary of the findings from a systematic search regarding ototoxicity of chloroquine and hydroxychloroquine in the published literature. The characteristics of sensorineural hearing loss and/or tinnitus after chloroquine or hydroxychloroquine treatment can be temporary but reports of persistent auditory and vestibular dysfunction exist. These are not frequent, but the impact can be substantial. Additionally, abnormal cochleovestibular development in the newborn was also reported after chloroquine treatment in pregnant women. The suggested dose of chloroquine for COVID-19 infection is considerably higher than the usual dosage for malaria treatment; therefore, it is plausible that the ototoxic effects will be greater. There are potential implications from this review for survivors of COVID-19 treated with chloroquine or hydroxychloroquine. Patient reports of hearing loss, tinnitus, or imbalance should be noted. Those with troublesome hearing loss, tinnitus and/or imbalance are encouraged to be referred for hearing evaluation and interventions once they are stable. Clinical trials of chloroquine or hydroxychloroquine should also consider including audiological monitoring in the protocol.

The Contribution of Ototoxic Medications to Hearing Loss Among Older Adults.

BACKGROUND: Ototoxicity may interact with the effects of aging, leading to a more severe hearing loss than that associated with age alone. The purpose of this study was to explore the associations between ototoxic medication use and the incidence and progression of hearing loss in older adults with a population-based longitudinal study. METHODS: Epidemiology of Hearing Loss Study participants (n = 3,753) were examined. Medication use was assessed using a standardized questionnaire by the examiners at each examination every 5 year. The ototoxic medications include loop diuretics, nonsteroidal anti-inflammatory drugs, antibiotics, chemotherapeutic agents, quinine, and acetaminophen in this study. Generalized estimating equations model was used as a proportional hazard discrete time analysis. RESULTS: Number of ototoxic medications was associated with the risk of developing hearing loss during the 10-year follow-up period (hazard ratio [HR] = 1.15, 95% confidence interval [CI] = 1.06, 1.25) after adjusting for age, sex, smoking, and body mass index. Loop diuretics (HR = 1.40, 95% CI = 1.05, 1.87) were associated with the 10-year incidence of hearing loss. Nonsteroidal anti-inflammatory drugs (HR = 1.45, 95% CI = 1.22, 1.72) and loop diuretics (HR = 1.33 95% CI = 1.08, 1.63) were associated with risk of progressive hearing loss over 10 years. CONCLUSION: These ototoxic medications are commonly used in older adults and should be considered as potentially modifiable contributors to the incidence and severity of age-related hearing loss.

GSTA4 mediates reduction of cisplatin ototoxicity in female mice.

Cisplatin is one of the most widely used chemotherapeutic drugs for the treatment of cancer. Unfortunately, one of its major side effects is permanent hearing loss. Here, we show that glutathione transferase α4 (GSTA4), a member of the Phase II detoxifying enzyme superfamily, mediates reduction of cisplatin ototoxicity by removing 4-hydroxynonenal (4-HNE) in the inner ears of female mice. Under cisplatin treatment, loss of Gsta4 results in more profound hearing loss in female mice compared to male mice. Cisplatin stimulates GSTA4 activity in the inner ear of female wild-type, but not male wild-type mice. In female Gsta4-/- mice, cisplatin treatment results in increased levels of 4-HNE in cochlear neurons compared to male Gsta4-/- mice. In CBA/CaJ mice, ovariectomy decreases mRNA expression of Gsta4, and the levels of GSTA4 protein in the inner ears. Thus, our findings suggest that GSTA4-dependent detoxification may play a role in estrogen-mediated neuroprotection.

Auditory and Histopathological Effects of Topical Mercurochrome Treatment in Rats with Tympanic Membrane Perforation.

OBJECTIVES: Topical treatment is first choice in the treatment of uncomplicated chronic otitis media. It was intended to assess auditory and histopathological safety of ototopical use of mercurochrome solution in rats with induced tympanic membrane perforation. MATERIALS AND METHODS: The study was conducted on 21 female Wistar-Albino rats which were randomly assigned into 3 groups. In all rats, perforation was performed at right tympanic membrane. Distortion product otoacoustic emissions (DPOAEs) measurements were performed at frequencies of 2000, 3000 and 4000 Hz (with L1/L2: 70 /70 dB at 2f1-f2 frequency; f2/f1 ratio: 1:22) before recovery from anesthesia and signal-to-noise ratio (SNR) were recorded. Normal saline, 2% mercurochrome and gentamicin were given to group 1, 2 and 3 twice daily over a week, respectively. Rats were sacrificed after DPOAE measurements on day 14. Right temporal bone specimens were examined under light microscope after processing. RESULTS: Based on DPOAE results, there was no significant difference among groups before treatment. On day 14, significant differences were found in DPOAE measurements at 3000 and 4000 Hz, and in mean SNR values in 2% mercurochrome and gentamicin groups when compared to normal saline group while no significant difference was detected at 2000 Hz among groups. In addition, significant degeneration was detected in Corti organs, spiral ganglions and stria vascularis in groups 2 and 3. CONCLUSION: In this study, it was observed that mercurochrome use in external otitis and otitis media with tympanic membrane perforation could cause ototoxicity and concluded that the solution should be used cautiously.