The impact of hearing loss on cognitive outcomes among children treated with radiation therapy for ependymoma.

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Learn more: PMC Disclaimer | PMC Copyright Notice Neuro Oncol . 2026 Feb 16;28(6):1517–1526. doi: 10.1093/neuonc/noag029 The impact of hearing loss on cognitive outcomes among children treated with radiation therapy for ependymoma Jeanelle S Ali 1, 2 , Johnnie K Bass 3 , Fang Wang 4 , Xiaomeng Yuan 5 , Haitao Pan 6 , Jason M Ashford 7 , Niki Jurbergs 8 , Nicole Salman 9 , Thomas E Merchant 10 , Heather M Conklin 11, ✉ Author information Article notes Copyright and License information 1 Mental Health Neuropsychology Program, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada 2 Department of Psychology and Biobehavioral Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA 3 Department of Rehabilitation Services, St. Jude Children's Research Hospital, Memphis, Tennessee, USA 4 Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA 5 Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA 6 Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA 7 Department of Psychology and Biobehavioral Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA 8 Department of Psychology and Biobehavioral Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA 9 Department of Psychology and Biobehavioral Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA 10 Department of Radiation Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA 11 Department of Psychology and Biobehavioral Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA ✉ Corresponding Author: Heather M. Conklin, PhD, Department of Psychology and Biobehavioral Sciences, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Mail Stop 740, Memphis, TN 38105-3678, USA ( heather.conklin@stjude.org ). Received 2025 Sep 5; Accepted 2026 Feb 5; Collection date 2026 Jun. © The Author(s) 2026. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( https://creativecommons.org/licenses/by-nc/4.0/ ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. PMC Copyright notice PMCID: PMC13231161  PMID: 41698849 Abstract Background Sensorineural hearing loss (SNHL) is a common adverse treatment effect among pediatric brain tumor survivors. Neurocognitive functioning among children for whom radiation therapy (RT) is the primary SNHL risk factor has received limited attention. Accordingly, this study investigated neurocognitive outcomes as a function of SNHL among children treated for ependymoma with RT. Methods Prospective, serial, neurocognitive, and audiology assessments were conducted with 145 children diagnosed with ependymoma and enrolled on a Phase II trial of conformal photon RT ( NCT00187226 ; 53% female; 83% White; mean age at RT = 5.04 ± 4.47 years). SNHL was dichotomized as normal/mild-to-moderate or severe (Chang grade <2b vs. ≥2b). Cognitive risk was assessed for participants with severe SNHL in either ear who completed neurocognitive assessments at least one year after hearing loss (n = 50). Results At pre-RT baseline, full scale IQ (FSIQ), verbal learning, and communication were lower than normative expectations ( P < .05), with a significant decline in FSIQ, estimated IQ (EIQ), reading, and communication over time. FSIQ and communication skills were worse among children with severe SNHL across all time points ( P < .05). EIQ showed greater decline over time in those with severe SNHL ( P < .0005), even after accounting for age at RT and pre-RT chemotherapy. Conclusions Severe SNHL was associated with worse intellectual functioning and communication skills across time points among pediatric ependymoma survivors. The decline in EIQ suggests increased risk related specifically to hearing loss. Severe SNHL following RT for ependymoma, even if only in 1 ear, is a cognitive risk factor requiring monitoring and intervention. Keywords: cognitive late effects, pediatric ependymoma, radiation therapy, ­sensorineural hearing loss Key Points. Radiation therapy is a risk factor for SNHL in children treated for ependymoma. Intellectual functioning and communication are worse for children with severe SNHL across time. Severe SNHL increases risk for intellectual decline irrespective of age at treatment and chemotherapy. Importance of the Study Despite documentation of significant declines in cognitive and academic functioning for children treated for brain tumors, longitudinal research exploring the incidence and neurocognitive impact of SNHL is limited. Our findings indicate children diagnosed with ependymoma demonstrated performance lower than normative expectations on measures of intellectual function, verbal learning, and communication skills prior to treatment. Performance declined over time following treatment with conformal photon RT and was worse among children with severe SNHL. Severe SNHL following RT for ependymoma, even if only in 1 ear, is a cognitive risk factor requiring monitoring and intervention. These findings can be used to inform modifications in cancer-directed treatment (eg cochlear-sparing irradiation and use of otoprotectants), develop monitoring guidelines, educate caregivers regarding risk, and develop targeted interventions (eg improving hearing aid adherence, teaching visual phonics). Successful management of pediatric brain tumors often requires aggressive treatment, including surgical resection, radiation therapy (RT), and chemotherapy. 1 , 2 Sensorineural hearing loss (SNHL) is a common adverse effect of these life-saving treatments. Rates of SNHL vary across studies of children treated for brain tumors and can range from 0% to 54%, with increased rates noted at long-term follow-up. 3-5 SNHL can be long-lasting and progressive and may continue to deteriorate following pediatric brain tumor care. 3 Treatment with platinum-based chemotherapy, 5 younger age at treatment, 3 and infratentorial tumor location increase SNHL risk. 6 The use of RT as the primary treatment modality for pediatric brain tumors is also associated with risk for SNHL. Otologic structures reside in the temporal bone. As such, the risk and severity of SNHL increase when a greater radiation dose is administered to surrounding brain regions due to potential cochlear damage. 3 , 7 A 14% prevalence rate of SNHL was reported in a prior study examining a large group of pediatric patients who were treated with conformal or intensity-modulated photon RT for localized primary brain tumors, 39% of this sample was diagnosed with ependymoma and they were the most likely of the tumor types to experience SNHL. 8 Children treated for brain tumors are also at risk for neurocognitive and academic deficits due to their disease and treatment. 9 Younger age at treatment, lower socioeconomic status (SES), female biological sex, and greater time elapsed since treatment are established factors related to increased cognitive risk. 10 , 11 Higher RT dose and larger field size are also associated with increased neurocognitive risk among children treated with RT. 12 Specifically, difficulties with communication skills, attention regulation, working memory, and decreased processing speed have been reported among children treated with RT. 13 , 14 Children who experience SNHL due to their treatment may be at increased neurocognitive risk. Hearing loss during critical periods of development may adversely impact acquisition of key communication and academic skills. 15 This may occur because language development plays a key role in the consolidation of memories and development of cognitive skills, such as numeracy. 16 Children who experience severe SNHL after treatment with both craniospinal RT and chemotherapy for medulloblastoma demonstrate greater intellectual and academic declines, with specific difficulties identified in reading-based skills, working memory, and processing speed. 4 , 17 Importantly, these studies examined the impact of hearing loss following multimodal treatments for pediatric brain tumors, which makes it difficult to isolate separate contributions of individual treatment elements. Despite the aforementioned risk factors, there has been limited investigation of neurocognitive and academic outcomes among children treated for brain tumors for whom RT is the primary SNHL risk factor. Of note, ependymoma, the third most common central nervous system (CNS) tumor of childhood that arises from the ependyma in the brain or spinal cord with 3-year progression-free survival rates as high as 75%, is often diagnosed in very young children, with predominantly infratentorial tumor location, and RT as preferred treatment modality. Thus, childhood ependymoma is a high-risk group for SNHL despite the majority not receiving platinum-based chemotherapy. Accordingly, this study investigated neurocognitive outcomes as a function of SNHL among children treated for ependymoma with RT. We hypothesized that children with severe SNHL in either ear would display decreased performance across measures of neurocognitive functioning. We also hypothesized that SES would be associated with neurocognitive and adaptive changes over time, with children in higher SES groups displaying fewer cognitive declines over time. Methods Patients Prospective, serial, neurocognitive, and audiology assessments were conducted with 145 children diagnosed with ependymoma and enrolled on an institutional Phase II trial of conformal photon RT (CRT; RT1, NCT00187226 ). Institutional Review Board approval was granted. Study enrollment was from July 1997 through June of 2007, and survivors were followed at least 10 years. Caregivers provided informed consent to participate prior to study enrollment. Eligible participants were diagnosed with intracranial ependymoma, low-grade glioma, or craniopharyngioma; however, given elevated SNHL risk, only participants diagnosed with ependymoma were included in the current study. Patients were required to be English-speaking to participate in neurocognitive assessments. See Bass et al 8 for additional information about the study procedures that are summarized here. Patients received CRT, including intensity-modulated photon radiation therapy, over 6 to 7 weeks using conventional fractionation (1.8 Gy per day) with a prescribed dose of 59.4 Gy. Children younger than 18 months received 54.0 Gy. The irradiated clinical target volume included a 10-mm margin surrounding the tumor, tumor bed, or both, in order to treat subclinical microscopic disease. An additional 3 to 5 mm, expanded in three dimensions, was included to account for uncertainty in image registration and patient positioning. Cochlea were contoured on the treatment planning CT, and doses were kept as low as reasonably achievable without compromising the target volume. Patients who did not experience hearing loss and those who experienced hearing loss and had one or more cognitive assessments at least 1 year after hearing loss was detected were included in the analyses (4 removed: 1 due to missing audiology and 3 missing cognitive assessments after SNHL; final N = 145). Serial neurocognitive assessments were discontinued if tumor recurrence or progression required additional cancer-directed therapy. Of the 145 participants included in the analysis, the Barratt Simplified Measure of Social Status (BSMSS), 18 a measure of SES, was gathered for 99 patients. Analyses that include BSMSS were modeled on these 99 patients. Audiology Assessment Participants completed hearing assessments with a certified, licensed audiologist at several timepoints, including pre-RT (baseline), every 6 months for 5 years following RT, and annually subsequently for at least 5 years. Audiological data gathered were assigned a grade based on the Chang Ototoxicity Grading Scale. 19 SNHL was dichotomized as normal/mild-to-moderate or severe (Chang grade <2b vs ≥2b). For these analyses we focused on children acquiring severe SNHL (n = 50), as Chang grades of 2b and above are considered significant enough to warrant hearing aids. Final Chang grades used in analyses were based on the ear with SNHL in children with unilateral loss and the better ear for children with bilateral loss. Neurocognitive Testing Neurocognitive measures included in this study were selected from the larger RT1 cognitive battery based on the hearing loss literature. 4 , 17 Measures that were anticipated to be most sensitive to hearing loss in pediatric brain tumor survivors were chosen a priori based on previous studies about the functional impact of hearing loss in children treated for embryonal tumors with multimodal therapy. 4 , 17 Assessments were serially administered before RT, 6 months later, annually for 5 years, either year 7 or 8, and year 10. Cognitive measures included assessments of intellectual functioning (Wechsler Estimated IQ [EIQ] and Full Scale IQ [FSIQ]), reading skills (Wechsler Individual Achievement Test; WIAT), verbal learning (California Verbal Learning Test; CVLT), parent ratings of internalizing problems (Child Behavior Checklist; CBCL), communication skills (Vineland Adaptive Behavior Scales; VABS), and SES (BSMSS). This study alternated administration of EIQ and FSIQ, which are highly correlated ( r = 0.93), at differ time points (FSIQ at years 2, 5, 7 or 8, and 10) to balance the larger set of information captured in FSIQ with the shorter time burden of EIQ, while still having an index of global cognitive abilities for longitudinal analyses. Assessments were administered in a standardized manner, one-on-one in a quiet exam room with limited background noise to optimize sound perception. In order to account for the potential impact of hearing loss on standardized assessment procedures, clinicians completed standard behavior observation forms that determined performance validity, including the inability to adequately hear examiner-provided information, as well as reasons for missing data. Measures completed by parents (eg to assess internalizing problems and communication skills) are valid for children with hearing loss and were gathered for all participants. Intellectual Quotient FSIQ or EIQ was derived from the age-appropriate Wechsler scales-WISC-III, 20 WPPSI-R, 21 and WAIS-III 22 that were administered based on relevant timepoint. EIQ was calculated using scaled scores from the Block Design, Information, and Similarities subtests. There is a longstanding precedent in the literature of using this subtest combination to estimate IQ in documenting cognitive late effects following treatment for childhood brain tumors, 9 and these 3 subtests have been shown to be one of the most reliable and valid IQ estimates. 23 Age-based standardized scores (Mean = 100, Standard Deviation [SD]  = 15) were calculated by comparing participants to representative normative samples for these correlated measures. 23 , 24 Scores from this technique for estimating IQ and IQ scores garnered from full test administration are highly correlated ( r = 0.93). 24 In particular, Palmer and colleagues demonstrated strong and statistically significant correlations of EIQ and FSIQ ( r = 0.91) among pediatric brain tumor survivors. 25 Reading Skills and Verbal Learning Reading skills were evaluated using the WIAT Basic Reading scale. 26 The WIAT is a well-established measure of academic skills. 27 Reading skills, including the identification of lower-case letters, production of rhyming words, comparison of phonetic sounds, and ability to decode simple words, were examined using this measure. Age-based standardized scores (Mean = 100, SD = 15) were calculated and higher scores indicate better performance. Verbal learning and memory were assessed using the age-appropriate version of the CVLT. 28 The CVLT has well-established reliability and validity 28 and is considered a useful measure of rote verbal learning and memory when information is presented in the form of a word list. Age-based z-scores were calculated for each participant (Mean = 0, SD = 1). Emotional and Adaptive Functioning Parent ratings of internalizing problems (eg anxiety and depression, social withdrawal) were assessed using the CBCL. 29 The CBCL has established reliability and validity with mean alpha coefficients ranging from 0.89 to 0.96 for the Internalizing scale. This measure consists of 113 items with each item rated on a scale from 0 (Not True) to 2 (Very True or Often True). Age-standardized T-scores (Mean = 50, SD = 10) were derived; we included the Internalizing subscale for the purposes of the current study as the existing literature indicates the childhood cancer survivorship population is at greater risk for internalizing as compared to externalizing problems. Higher scores are indicative of increased parental concerns. Communication skills were assessed using the Communication subscale of the VABS. 30 The VABS is a well-known measure of adaptive skills with established reliability and validity. 30 The Communication domain was administered as a semi-structured interview that assessed receptive, expressive, and written communication skills based on parent report. Age-based standardized scores (Mean = 100, SD = 15) were calculated, 30 with higher scores indicating better performance. Socioeconomic Status Baseline SES data were gathered through retrospective record review. The BSMSS 18 is based on Hollingshead’s Four Factor Index of Social Status. 31 Scores were calculated using parental occupation and level of education along with marital status. Occupations were coded based on the BSMSS classification system that is thought to be indicative of skill, power, and social position of the family in society (eg higher executives and owners of large businesses were placed in the highest category while service workers such as dishwashers were placed in the lowest category). Education was accounted for using level of school completed with 7th grade and below receiving the lowest score and graduate degree or professional school beyond college receiving the highest scores. For families headed with a single parent, or with multiple caregivers, scores were adjusted accordingly. Composite scores range from 8 to 66 with higher scores indicative of higher SES. Statistical Analyses Qualitative statistics were conducted to characterize the sample and compare those with normal/mild-to-moderate hearing loss (Chang grade < 2b) to severe hearing loss (Chang grade ≥ 2b) using Pearson’s Chi-squared, Exact, or Kruskal-Wallis tests, as appropriate. The random coefficient linear mixed effect model with patient-specific intercepts and slopes, and unstructured variance-covariance, was used to model the trend of the neurocognitive scores over time. Univariate models were conducted for each cognitive outcome that included an intercept, time, SNHL (Chang grade < 2b vs ≥2b) and the interaction of SNHL and time. Subsequently, multivariate models were conducted that included demographic and clinical variables that were significant in univariate models (eg age at RT, pre-RT chemotherapy, race, and SES) entered simultaneously with time. The general model can be written as: cognitive score = intercept + covariates + SNHL + time + SNHL*time. Results Tables 1 and 2 display demographic and clinical characteristics of the sample. Participants were 53% female and 83% White. The mean age at diagnosis was 4.59 ± 4.48 years (range = 0.01-22.75) and mean age at RT = 5.04 ± 4.47 years. All participants received focal RT and 30 participants (20.7%) were administered pre-RT chemotherapy, prior to trial enrollment. Pre-irradiation chemotherapy regimens in this cohort relied on a backbone of vincristine, cyclophosphamide, etoposide, and either cisplatin or carboplatin. Most received platinum-based agents, including cisplatin and carboplatin (n = 1), carboplatin (n = 10), cisplatin (n = 16), and neither carboplatin nor cisplatin (n = 3). Ninety-seven participants (66.9%) had hydrocephalus at diagnosis. All participants required at least 1 surgery. Forty-four participants (30.3%) required 2 surgeries and 13 (9.0%) required 3 or more surgeries. The average SES score for the total sample was in the middle range (BSMSS Mean = 37.88; SD = 13.2; range = 9-61). Table 1. Age and Socioeconomic Status for the Entire Sample and SNHL Groups Group N Mean SD Median Min Max P -value Age at diagnosis All 145 4.59 4.48 2.62 0.01 22.75 .0059 * <2B Chang Score 95 5.22 5.02 2.82 0.19 22.75 ≥2B Chang Score 50 3.38 2.91 2.27 0.01 13.55 Age at irradiation All 145 5.04 4.47 3.03 1.02 22.92 .0413 * <2B Chang Score 95 5.52 4.98 3.28 1.02 22.92 ≥2B Chang Score 50 4.12 3.16 2.84 1.06 13.65 BSMSS All 99 37.88 13.20 38 9 61 .7348 <2B Chang Score 64 38.22 12.38 38 12 61 ≥2B Chang Score 35 37.27 14.77 37.5 9 61 Open in a new tab P -value based on Fisher’s Exact Test. Abbreviation: BSMSS = Barratt Simplified Measure of Social Status, range 8-66. * P < .05. Table 2. Additional Demographic and Clinical Characteristics for Entire Sample and SNHL Groups Hearing loss status Total sample < 2B Chang Score ≥ 2B Chang Score P -value Sex (n, %) Female 68 46.9 44 46.3 24 48.0 0.8628 Male 77 53.1 51 53.7 26 52.0 Race (n, %) White 120 82.8 83 87.4 37 74.0 0.1075 Black 18 12.4 9 9.5 9 18.0 Asian 2 1.4 1 1.1 1 2.0 Hispanic 1 0.7 1 1.1 0.0 0.0 Other 4 2.8 1 1.1 3 6.0 Hydrocephalus (n, %) Yes 97 66.9 58 61.1 39 78.0 0.0430 * No 48 33.1 37 39.0 11 22.0 Extent of resection GTR 122 84.1 85 89.5 37 74.0 0.0293 * <GTR 23 15.9 10 10.5 13 26.0 Number of surgeries One 88 60.7 64 67.4 24 48.0 0.0038 * Two 44 30.3 28 29.5 16 32.0 Three 10 6.9 2 2.1 8 16.0 Four 3 2.1 1 1.1 2 4.0 Open in a new tab P -value based on Fisher’s Exact Test. Abbreviation: GTR = gross total resection. * P < .05. Comparisons of Demographic and Clinical Characteristics by Hearing Loss Status Thirty-four percent of the participants had severe SNHL (n = 50). Sixty-three percent of participants had no hearing loss (n = 91), 2% had mild hearing loss (n = 3), and less than 1% had moderate hearing loss (n = 1). Severe SNHL was not associated with biological sex, race, or SES ( P > .10). However, severe SNHL was associated with presence of hydrocephalus ( P = .04), less extensive surgical resection ( P = .03), and a greater number of surgeries ( P < .01). Pre-RT chemotherapy was also associated with severe SNHL ( P < .01). Age at diagnosis and age of RT differed across SNHL groups. Those with severe SNHL had a younger age at diagnosis (mean age = 3.38 vs. 5.22 years; P < .01) and a younger average age of RT (mean age = 4.12 vs. 5.53 years; P = .04). Longitudinal Neurocognitive Patterns Univariate LMM Univariate LMMs ( Supplementary Table S1 ) revealed baseline (pre-RT) IQ (FSIQ), verbal learning and memory (CVLT), and communication skills (VABS Communication) were lower than normative expectations ( P < .05). There was a significant decline in IQ (FSIQ and EIQ), reading skills (WIAT Reading), and communication skills (VABS Communication) over time ( P < .05). In contrast, verbal learning and memory (CVLT) and internalizing problems (CBCL) remained stable over time. Among SNHL groups, IQ (FSIQ) and communication skills (VABS Communication) were worse among those children with severe SNHL across all time points (main effect; P < .05; Figure 1 ). IQ (EIQ) showed a greater decline over time in those children with severe SNHL (interaction; P < .0005; Figure 2 ). There was also a trend for a greater decline in FSIQ over time among those with severe hearing loss (interaction; P = .06). Figure 1. Open in a new tab Change in FSIQ and VABS over time as a function of sensorineural hearing loss. Abbreviations: FSIQ, full scale intelligence quotient; VABS, Vineland Adaptive Behavior Scales. Figure 2. Open in a new tab Change in estimated IQ over time as a function of sensorineural hearing loss. Abbreviation: EIQ, estimated intelligence quotient. Multivariate LMM All clinical/demographic covariates were tested in univariate models first. Covariates that were significantly associated with neurocognitive scores were considered as potential covariates for multivariate models; significant covariates were added to models simultaneously with time. A backward elimination approach guided by the Akaike information criterion and Bayesian information criterion was used to simplify models by removing nonsignificant variables. Given their established importance to cognitive outcomes following treatment for brain tumors in the literature, and the focus of this study, age at RT and SNHL were included as covariates in multivariate models even if not significant. Results from multivariate LMMs ( Supplementary Table S2 ) for IQ including age at RT, SNHL, race, and SES indicated EIQ and FSIQ remained lower at baseline (prior to RT). There was a trend for a decline in EIQ over time ( P = .07). Severe SNHL remained associated with a greater decline in EIQ over time ( P < .005). Verbal learning and memory (CVLT) with age at RT, SNHL, and race in the model was within age normative expectations at baseline but declined over time ( P < .01). Reading skills also declined over time ( P < .0001); however, this decline was not related to SNHL. Communication skills from the VABS with age at RT, SNHL, biological sex, and SES in the model remained lower than expectations at baseline ( P < .0001). Importantly, communication skills were lower over time among participants with severe SNHL ( P = .04). Internalizing behaviors (CBCL) with age at RT, SNHL, and extent of resection in the model were within normative expectations at baseline and remained stable over time. Internalizing behaviors were not associated with SNHL. Pre-RT chemotherapy Based on the established importance of pre-RT chemotherapy as a predictor of both SNHL and neurocognitive outcomes, univariate LMMs were conducted to investigate the impact of pre-RT chemotherapy on all 6 cognitive outcomes (EIQ, FSIQ, WIAT-Reading, CVLT, VABS Communication, and CBCL-Internalizing). Chi-squared test revealed pre-RT chemotherapy was significantly associated with SNHL ( P < .0005). Pre-RT chemotherapy was significantly associated with lower IQ (FSIQ [ P < .005] and EIQ [ P < .05]) and communication skills (VABS Communication [ P < .005]) but not reading (WIAT), learning and memory (CVLT), or internalizing behaviors (CBCL). Importantly, when multivariate models for IQ (FSIQ and EIQ) and communication skills (VABS Communication) included pre-RT chemotherapy with age at RT, SNHL, race, and SES, severe SNHL remained predictive of greater decline in EIQ over time ( P < .005). Discussion Findings from this prospective clinical trial with serial surveillance of hearing status and neurocognition indicate that severe SNHL following RT for ependymoma is a cognitive risk factor requiring monitoring and intervention. Prior to RT, IQ, verbal learning and memory, and communication skills were lower than normative expectations. This finding is consistent with the literature 10 , 32 and likely reflects the negative impact of tumor mass effect and surgical resection. Cognitive deficits associated with brain tumors prior to adjuvant therapy have been shown in young children 10 as well as those with infratentorial tumors, 4 in accordance with the demographic and clinical characteristics of the current study sample. IQ, reading, and communication skills further declined over time after RT, consistent with the literature that shows cognitive declines following photon radiotherapy. 33 , 34 Children with severe SNHL demonstrated worse intellectual functioning and communication skills across assessment time points. Severe SNHL was associated with hydrocephalus, multiple surgeries, pre-RT chemotherapy, and young age at RT. As such, it is possible that lower IQ and communication skills could reflect cognitive risk shared among these established risk factors. 12 Severe SNHL was not associated with demographic factors, including biological sex, race, or SES. Estimated IQ showed a greater decline in those with severe SNHL, even after accounting for age at RT and pre-RT chemotherapy, established risk factors for both SNHL and cognitive late effects. 35 , 36 This is one of the only studies to demonstrate that RT, in the absence of platinum-based chemotherapy, is a significant contributor to SNHL in children treated for brain tumors. 37 It is the first study to demonstrate severe SNHL related to RT uniquely impacts cognitive outcomes. Among non-oncology populations, hearing loss at young ages is associated with delayed milestones and reduced quality of life, 38 including delayed language development, academic and social issues, social isolation, and employment challenges as adults. 39 Given treatment-related ototoxicity can sometimes be avoided (eg with newer treatment modalities such as volumetric arc therapy using photons, intensity-modulated proton therapy, and use of smaller clinical target volumes that reduce cochlear radiation dose exposure, particularly for tumors in the posterior fossa) or its impact mitigated (eg with early identification and hearing interventions), these findings have important implications for audiology monitoring and hearing intervention guidelines following RT for brain tumors. They also have important implications for future trial designs including the reduced use of platinum-based chemotherapy as adjuvant therapy unless there is evidence these agents improve progression-free or overall survival when administered before or after radiotherapy. It is somewhat unexpected that estimated IQ declined more in those with severe SNHL when reading did not. It is possible that participants with severe SNHL were able to master single-word decoding early on (prior to RT based on the average age in this sample) with reading comprehension, language processing, and organization more impacted over time thus reflected in preserved single-word decoding and weaker verbal reasoning and academic skills. Further, estimated IQ, as measured in this study, is weighted toward vocabulary knowledge and academically acquired information that can be significantly impacted by decreased access to sound and information presented orally in the school setting. Verbal learning and memory remained stable over time. These findings are consistent with previous research that did not show decline over time on measures of verbal or visual-auditory learning after RT among children with ependymoma. 40 Consistent with current findings, prior research indicates learning and memory are impacted at baseline due to mass effect of the tumor and/or hydrocephalus and remain relatively stable over time when conformal RT approaches are used for infratentorial tumors. 40 Internalizing symptoms, such as anxiety, depressed mood, and social withdrawal, also remained stable over time. Although previous research indicates that those with infratentorial brain tumors score higher on measures of internalizing behaviors, 41 possibly due to the impact of their illness and treatment on daily living activities and peer socialization, it may be that the timing of our follow-up did not allow for capture of potential changes in internalizing behaviors that may be seen at longer-term follow-up. 42 That said, these findings are consistent with previous studies, which suggest that children with cancer tend to be resilient and well-adjusted. 43 This work has many strengths, including a large sample size, protocol-prescribed treatment, prospective/longitudinal cognitive assessments with an expansive cognitive battery, frequent audiological monitoring, and access to SES data. However, there are limitations that suggest areas for future study. Although the novel finding of a decline in EIQ adds to our knowledge about cognitive trajectories among this population, EIQ can underestimate declines in FSIQ in children treated with RT. 44 EIQ minimizes the impact of working memory and processing speed on FSIQ, areas that tend to be affected among children treated with RT. 45 That said, other research indicates that FSIQ and EIQ are highly correlated in brain tumor survivors, 23 have similar slopes in longitudinal analysis, 25 and FSIQ was at the trend level for greater declines in those children with severe SNHL. A further limitation is that a subset of participants received platinum-based chemotherapy prior to RT, which is an established risk for ototoxicity. 46 Encouragingly, this was a small subset of the sample (20.7%) and the findings related to greater EIQ changes in children with severe SNHL remained when accounting for pre-RT chemotherapy. Information regarding frequency of hearing aid use was not available and should be evaluated in future studies as a potential mitigator of hearing loss-related cognitive declines. Additionally, SES data were only gathered at baseline. As such, change to SES over time was not available for analysis. Though study enrollment ended in 2007 (with potential follow-up until 2017), the findings remain relevant as ototoxicity prevention therapies are in the early stages of research. Further, there are many survivors and newly diagnosed children treated with conformal photon irradiation for ependymoma for whom these findings are relevant. For patients who may be treated with proton therapy, cochlear-sparing irradiation and/or with otoprotectants, cognitive risk may be mitigated. However, there is no evidence that otoprotectants are beneficial to patients with SNHL risk associated with irradiation only and cochlear-sparing irradiation may be infeasible or contraindicated. Finally, given the small number of participants with severe bilateral SNHL, this study focused on those with hearing loss in either ear. This methodology has been used in previous studies of children treated for cancer and current study findings highlight the negative impact of SNHL, even if only in 1 ear. These findings have important clinical implications for the standard of care for young children treated for ependymoma. Given the significant neurocognitive impacts described in this study, it is imperative that clinicians consider otoprotectant use (such as, amifostine or sodium thiosulfate) to mitigate cisplatin-induced toxicity when available. 47 Current findings indicating SNHL-risk based on RT alone warrants early and frequent audiology assessments for children treated for brain tumors, even if they have not received platinum-based chemotherapy. These findings also highlight opportunities for intervention and rehabilitation that may have been overlooked. For example, cochlear-sparing irradiation approaches should be considered when appropriate. Additionally, the use of hearing aids or cochlear implants 48 in young children with SNHL can lead to better cognitive and language development. 48 Given the expanding candidacy for use of cochlear implants and development of MRI-compatible implants, it will be important to conduct research with children who are brain tumor survivors with cochlear implants. In line with this, there is encouraging data among non-BT survivors regarding the impact of early intervention programs focused on auditory-verbal therapy on language growth 49 and linguistic skills among children with cochlear implants. 50 Following the identification of hearing changes, clinicians may consider incorporating a multi-modal approach for children with SNHL (such as, hearing aids, cochlear implants, audio-verbal therapy (AVT), and targeted interventions to improve hearing aid adherence). Educating caregivers about the risk for SNHL and potential cognitive impact may also increase adherence with audiology assessment and hearing interventions. Future research should focus on the evaluation of downstream neurodevelopmental changes in regions of the brain supporting auditory processing in children with treatment-related ototoxicity as well as the relationship between hearing aid adherence and cognitive outcomes. It is also imperative for future research to consider the role that SES may play in the implementation of the aforementioned interventions considering the findings that SES is a predictor of cognitive performance before and after RT. Future research should also investigate the cognitive impact of mild/moderate SNHL relative to severe SNHL to see if children with mild SNHL would also benefit from intervention. Taken together, these results should inform modifications in cancer-directed treatment, development of audiology monitoring guidelines, education of caregivers regarding risk, and development of targeted interventions with the overarching goal of mitigating SNHL and its impact on quality of life among this vulnerable population. Supplementary Material noag029_Supplementary_Data noag029_supplementary_data.docx (48KB, docx) Acknowledgments The authors thank the patients and their families who volunteered their time to participate in neurocognitive assessments during their enrollment on the RT1 protocol. We also thank our psychological examiners and supervising clinical psychologists for their valuable contributions to this work. Portions of this manuscript were presented at the annual meeting of the International Neuropsychological Society, San Diego, CA (virtual), February 2021. Contributor Information Jeanelle S Ali, Mental Health Neuropsychology Program, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Department of Psychology and Biobehavioral Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Johnnie K Bass, Department of Rehabilitation Services, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Fang Wang, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Xiaomeng Yuan, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Haitao Pan, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Jason M Ashford, Department of Psychology and Biobehavioral Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Niki Jurbergs, Department of Psychology and Biobehavioral Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Nicole Salman, Department of Psychology and Biobehavioral Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Thomas E Merchant, Department of Radiation Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA. Heather M Conklin, Department of Psychology and Biobehavioral Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. Supplementary Material Supplementary material is available online at Neuro-Oncology ( https://academic.oup.com/neuro-oncology ). Author Contributions Acquired study data and provided valuable insight into interpretation of results: J.K.B., N.J., and T.E.M. Originally conceived the idea for the study: H.M.C. and J.K.B. Involved in all aspects of the present study including design of the work, data analysis, interpretation, and final manuscript preparation: J.S.A., J.K.B., and H.M.C. Substantially contributed to analysis and interpretation of data for the work: F.W., X.Y., H.P., J.S.A., and H.M.C. Prepared figures and tables: J.S.A., J.M.A., and H.M.C. Contributed to writing and editing the final manuscript and have read and approved final version of this manuscript: J.S.A., J.K.A., F.W., X.Y., H.P., J.M.A., N.J., N.S., T.E.M., and H.M.C. Conflict of Interest Statement The authors declare that there is no conflict of interest. J.K.B. discloses honoraria for convention presentation. Funding This work was supported by the National Cancer Institute (St. Jude Cancer Center Support [CORE] Grant [P30 CA21765]); and the American Lebanese Syrian Associated Charities (ALSAC). Data Availability Original data will be made available upon reasonable request. Correspondence can be directed to Dr. Heather Conklin at heather.conklin@stjude.org . References 1. 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