Episodes of acute methotrexate-related neurotoxicity linked to compromised long-term neurocognitive function.

Methotrexate is a critical component of curative chemotherapy for pediatric acute lymphoblastic leukemia (ALL), but is associated with neurotoxicity. Information on long-term outcomes following an acute neurotoxic event is limited. Therefore, this report compares neurocognitive performance more than 12 months post diagnosis (mean = 4 years) between ALL patients with (n = 25) and without (n = 146) a history of acute neurotoxicity. Compared to children with no documented on-treatment neurotoxic event, children who experienced a neurotoxic event during treatment exhibited poorer performance on measures of fine motor function (p = .02) and attention (p = .02). Children with ALL who experience acute neurotoxicity may be candidates for early neuropsychological screening and intervention.

Adaptive, behavioral, and emotional outcomes following postoperative pediatric cerebellar mutism syndrome in survivors treated for medulloblastoma.

OBJECTIVE: Patients who experience postoperative pediatric cerebellar mutism syndrome (CMS) during treatment for medulloblastoma have long-term deficits in neurocognitive functioning; however, the consequences on functional or adaptive outcomes are unknown. The purpose of the present study was to compare adaptive, behavioral, and emotional functioning between survivors with and those without a history of CMS. METHODS: The authors examined outcomes in 45 survivors (15 with CMS and 30 without CMS). Comprehensive neuropsychological evaluations, which included parent-report measures of adaptive, behavioral, and emotional functioning, were completed at a median of 2.90 years following craniospinal irradiation. RESULTS: Adaptive functioning was significantly worse in the CMS group for practical and general adaptive skills compared with the group without CMS. Rates of impairment in practical, conceptual, and general adaptive skills in the CMS group exceeded expected rates in the general population. Despite having lower overall intellectual functioning, working memory, and processing speed, IQ and related cognitive processes were uncorrelated with adaptive outcomes in the CMS group. No significant group differences or increased rates of impairment were observed for behavioral and emotional outcomes. CONCLUSIONS: Survivors with CMS, compared with those without CMS, are rated as having significant deficits in overall or general adaptive functioning, with specific weakness in practical skills several years posttreatment. Findings from this study demonstrate the high risk for ongoing functional deficits despite acute recovery from symptoms of CMS, highlighting the need for intervention to mitigate such risk.

Genetic susceptibility to cognitive decline following craniospinal irradiation for pediatric central nervous system tumors.

BACKGROUND: Survivors of pediatric central nervous system (CNS) tumors treated with craniospinal irradiation (CSI) exhibit long-term cognitive difficulties. Goals of this study were to evaluate longitudinal effects of candidate and novel genetic variants on cognitive decline following CSI. METHODS: Intelligence quotient (IQ), working memory (WM), and processing speed (PS) were longitudinally collected from patients treated with CSI (n = 241). Genotype-by-time interactions were evaluated using mixed-effects linear regression to identify common variants (minor allele frequency > 1%) associated with cognitive performance change. Novel variants associated with cognitive decline (P < 5 × 10-5) in individuals of European ancestry (n = 163) were considered replicated if they demonstrated consistent genotype-by-time interactions (P < .05) in individuals of non-European ancestries (n = 78) and achieved genome-wide statistical significance (P < 5 × 10-8) in a meta-analysis across ancestry groups. RESULTS: Participants were mostly males (65%) diagnosed with embryonal tumors (98%) at a median age of 8.3 years. Overall, 1150 neurocognitive evaluations were obtained (median = 5, range: 2-10 per participant). One of the five loci previously associated with cognitive outcomes in pediatric CNS tumors survivors demonstrated significant time-dependent IQ declines (PPARA rs6008197, P = .004). Two variants associated with IQ in the general population were associated with declines in IQ after Bonferroni correction (rs9348721, P = 1.7 × 10-5; rs31771, P = 7.8 × 10-4). In genome-wide analyses, we identified novel loci associated with accelerated declines in IQ (rs116595313, meta-P = 9.4 × 10-9), WM (rs17774009, meta-P = 4.2 × 10-9), and PS (rs77467524, meta-P = 1.5 × 10-8; rs17630683, meta-P = 2.0 × 10-8; rs73249323, meta-P = 3.1 × 10-8). CONCLUSIONS: Inherited genetic variants involved in baseline cognitive functioning and novel susceptibility loci jointly influence the degree of treatment-associated cognitive decline in pediatric CNS tumor survivors.

Cognitive Sparing in Proton versus Photon Radiotherapy for Pediatric Brain Tumor Is Associated with White Matter Integrity: An Exploratory Study.

Radiotherapy for pediatric brain tumors is associated with reduced white matter structural integrity and neurocognitive decline. Superior cognitive outcomes have been reported following proton radiotherapy (PRT) compared to photon radiotherapy (XRT), presumably due to improved sparing of normal brain tissue. This exploratory study examined the relationship between white matter change and late cognitive effects in pediatric brain tumor survivors treated with XRT versus PRT. Pediatric brain tumor survivors treated with XRT (n = 10) or PRT (n = 12) underwent neuropsychological testing and diffusion weighted imaging >7 years post-radiotherapy. A healthy comparison group (n = 23) was also recruited. Participants completed age-appropriate measures of intellectual functioning, visual-motor integration, and motor coordination. Tractography was conducted using automated fiber quantification (AFQ). Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were extracted from 12 tracts of interest. Overall, both white matter integrity (FA) and neuropsychological performance were lower in XRT patients while PRT patients were similar to healthy control participants with respect to both FA and cognitive functioning. These findings support improved long-term outcomes in PRT versus XRT. This exploratory study is the first to directly support for white matter integrity as a mechanism of cognitive sparing in PRT.

Superior verbal learning and memory in pediatric brain tumor survivors treated with proton versus photon radiotherapy.

OBJECTIVE: Radiotherapy for pediatric brain tumor has been associated with late cognitive effects. Compared to conventional photon radiotherapy (XRT), proton radiotherapy (PRT) delivers lower doses of radiation to healthy brain tissue. PRT has been associated with improved long-term cognitive outcomes compared to XRT. However, there is limited research comparing the effects of XRT and PRT on verbal memory. METHOD: Survivors of pediatric brain tumor treated with either XRT (n = 29) or PRT (n = 51) completed neuropsychological testing > 1 year following radiotherapy. Performance on neuropsychological measures was compared between treatment groups using analysis of covariance. Chi-squared tests of independence were used to compare the frequency of encoding, retrieval, and intact memory profiles between treatment groups. Associations between memory performance and other neurobehavioral measures were examined using Pearson correlation. RESULTS: Overall, patients receiving PRT demonstrated superior verbal learning and recall compared to those treated with XRT. Encoding and retrieval deficits were more common in the XRT group than the PRT group, with encoding problems being most prevalent. The PRT group was more likely to engage in semantic clustering strategies, which predicted better encoding and retrieval. Encoding ability was associated with higher intellectual and adaptive functioning, and fewer parent-reported concerns about day-to-day attention and cognitive regulation. CONCLUSION: Results suggest that PRT is associated with verbal memory sparing, driven by effective encoding and use of learning strategies. Future work may help to clarify underlying neural mechanisms associated with verbal memory decline, which will better inform treatment approaches. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A Prospective Evaluation of Fatigue in Pediatric Brain Tumor Patients Treated With Radiation Therapy.

Background: Fatigue is a well-established consequence of cranial radiotherapy in survivors of pediatric brain tumor, but less is known about acute fatigue during radiotherapy treatment. This study aimed to longitudinally evaluate fatigue in newly diagnosed pediatric patients with brain tumors during treatment. Methods: Primary caregivers of pediatric patients with brain tumors completed the proxy-reported Parent Fatigue Scale assessments prior to radiotherapy and weekly during radiotherapy treatment. The association between clinical factors and fatigue at each assessment was evaluated with multiple linear regressions. A comparison of fatigue between radiation modalities was also analyzed. Results: A total of 33 caregivers completed pre-radiation fatigue assessments, with 29 reporting fatigue during radiotherapy. Patients were aged 3 to 16 years (M = 8.32) at diagnosis and diagnosed with medulloblastoma (n = 23), primitive neuroectodermal tumor (n = 2), ependymoma (n = 1), germ cell tumor (n = 1), pineoblastoma (n = 1), atypical teratoid rhabdoid (n = 1), and other unspecific tumors (n = 3). Moderate-to-severe fatigue was reported for the majority of patients (31/33; 94%) during treatment. Craniospinal irradiation dose was the only significant predictor of fatigue (p < .05), but this association was restricted to the first week of therapy and was attenuated by therapy completion. Discussion: Although fatigue is often considered a long-term consequence of cranial radiotherapy, this pilot study demonstrates that moderate-to-severe fatigue is pervasive prior to radiotherapy and persists throughout treatment in pediatric patients with brain tumors, regardless of radiation modality or clinical factors. Additional research is warranted to establish a link between acute and long-term fatigue and develop interventions to mitigate this adverse outcome.

Longitudinal investigation of suicidal ideation and associated factors during pediatric acute lymphoblastic leukemia chemotherapy.

OBJECTIVE: This study describes the prevalence of suicidal ideation (SI) during acute lymphoblastic leukemia (ALL) therapy and investigates the influence of clinical factors and physical symptoms on SI. METHODS: The Children's Depressive Inventory (CDI-2) was administered to ALL patients (diagnosed 2012-2017) at start of consolidation, delayed intensification (DI), maintenance cycle 1 (MC1), and maintenance cycle 2 (MC2) in a multi-site study. SI was present if patients endorsed the item "I want to kill myself." Logistic regression models evaluated associations between SI and sociodemographic factors; depressive symptoms; and below average, average, and above average symptom clusters identified using latent class analysis of pain, nausea, fatigue, and sleep. RESULTS: Participants (n = 175) were 51% male, 75% high-/very high-risk disease, with a median age of 11.2 years at diagnosis (range: 7-18 years). Overall, 14.9% of patients (75% under age 12 years) endorsed SI during treatment, including 4% at start of consolidation, 9% at DI, 8% at MC1, and 4% at MC2. Non-Hispanic Other patients were 10.9-times (95% CI: 2.30-53.40) more likely than non-Hispanic Whites to endorse SI (p = 0.003). The frequency of SI was higher in patients experiencing above average (53.3%) compared to below average (4.1%, p = 0.003) symptoms. Depressive symptoms were consistently associated with SI. CONCLUSIONS: SI during the initial year of childhood ALL was more prevalent in children under the age of 12 years, from ethnic groups not typically associated with increased risk, and who endorsed increased physical and depressive symptoms. Findings highlight the need for improved screening of mental health problems to mitigate symptoms of distress.

Predicting neurocognitive function in pediatric brain tumor early survivorship: The neurological predictor scale and the incremental validity of tumor size.

BACKGROUND: The Neurological Predictor Scale (NPS) quantifies cumulative exposure to conventional treatment-related neurological risks but does not capture potential risks posed by tumors themselves. This study evaluated the predictive validity of the NPS, and the incremental value of tumor location and size, for neurocognitive outcomes in early survivorship following contemporary therapies for pediatric brain tumors. PROCEDURE: Survivors (N = 69) diagnosed from 2010 to 2016 were administered age-appropriate versions of the Wechsler Intelligence Scales. Hierarchical multiple regressions examined the predictive and incremental validity of NPS score, tumor location, and tumor size. RESULTS: Participants (51% female) aged 6-20 years (M = 13.22, SD = 4.09) completed neurocognitive evaluations 5.16 years (SD = 1.29) postdiagnosis. The NPS significantly predicted Full-Scale Intelligence Quotient (FSIQ; ΔR2  = .079), Verbal Comprehension Index (VCI; ΔR2  = 0.051), Perceptual Reasoning Index (PRI; ΔR2  = 0.065), and Processing Speed Index (PSI; ΔR2  = 0.049) performance after controlling for sex, age at diagnosis, and maternal education. Tumor size alone accounted for a significant amount of unique variance in FSIQ (ΔR2  = 0.065), PRI (ΔR2  = 0.076), and PSI (ΔR2  = 0.080), beyond that captured by the NPS and relevant covariates. Within the full model, the NPS remained a significant independent predictor of FSIQ (ß = -0.249, P = 0.016), VCI (ß = -0.223, P = 0.048), and PRI (ß = -0.229, P = 0.037). CONCLUSIONS: Tumor size emerged as an independent predictor of neurocognitive functioning and added incrementally to the predictive utility of the NPS. Pretreatment disease burden may provide one of the earliest markers of neurocognitive risk following contemporary treatments. With perpetual treatment advances, measures quantifying treatment-related risk may need to be updated and revalidated to maintain their clinical utility.

Cerebellar Mutism Syndrome in Pediatric Neuro-oncology: A Multidisciplinary Perspective and Call for Research Priorities.

Cerebellar mutism syndrome (CMS), also known as posterior fossa syndrome, occurs in a subset of children after posterior fossa tumor resection, most commonly medulloblastoma. Patients with this syndrome exhibit often transient, although protracted, symptoms of language impairment, emotional lability, cerebellar, and brainstem dysfunction. However, many patients experience persistent neurological deficits and lasting neurocognitive impairment. Historically, research and clinical care were hindered by inconsistent nomenclature, poorly defined diagnostic criteria, and uncertainty surrounding risk factors and etiology. Proposed diagnostic criteria include two major symptoms, language impairment and emotional lability, as proposed by the international Board of the Posterior Fossa Society in their consensus statement as well as other experts in this field. Risk factors most commonly associated with development of CMS include midline tumor location, diagnosis of medulloblastoma and specific tumor subtype, younger age at diagnosis, and preoperative language impairment. A proposed etiology of CMS includes disruption of the cerebellar outflow tracts, the cerebellar nuclei, and their efferent projections through the superior cerebellar peduncle. Treatment for CMS remains supportive. Herein, we present a comprehensive overview of CMS etiology, diagnosis, risk factors, clinical presentation, and clinical management. In addition, we identify essential multidisciplinary research priorities to advance diagnostics, prevention, and intervention efforts for patients with, or at risk for, development of CMS.

Cognitive predictors of social adjustment in pediatric brain tumor survivors treated with photon versus proton radiation therapy.

BACKGROUND: Pediatric brain tumor survivors are at risk for poor social outcomes. It remains unknown whether cognitive sparing with proton radiotherapy (PRT) supports better social outcomes relative to photon radiotherapy (XRT). We hypothesized that survivors treated with PRT would outperform those treated with XRT on measures of cognitive and social outcomes. Further, we hypothesized that cognitive performance would predict survivor social outcomes. PROCEDURE: Survivors who underwent PRT (n = 38) or XRT (n = 20) participated in a neurocognitive evaluation >1 year post radiotherapy. Group differences in cognitive and social functioning were assessed using analysis of covariance (ANCOVA). Regression analyses examined predictors of peer relations and social skills. RESULTS: Age at evaluation, radiation dose, tumor diameter, and sex did not differ between groups (all p > .05). XRT participants were younger at diagnosis (XRT M = 5.0 years, PRT M = 7.6 years) and further out from radiotherapy (XRT M = 8.7 years, PRT M = 4.6 years). The XRT group performed worse than the PRT group on measures of processing speed (p = .01) and verbal memory (p < .01); however, social outcomes did not differ by radiation type. The proportion of survivors with impairment in peer relations and social skills exceeded expectation; χ2 (1) = 38.67, p < .001; χ2 (1) = 5.63, p < .05. Household poverty predicted peer relation difficulties (t = 2.18, p < .05), and verbal memory approached significance (t = -1.99, p = .05). Tumor diameter predicted social skills (t = -2.07, p < .05). CONCLUSIONS: Regardless of radiation modality, survivors are at risk for social challenges. Deficits in verbal memory may place survivors at particular risk. Results support monitoring of cognitive and social functioning throughout survivorship, as well as consideration of sociodemographic risk factors.

Association between fatigue and sleep disturbances during treatment for pediatric acute lymphoblastic leukemia and posttreatment neurocognitive performance.

BACKGROUND: Survivors of pediatric acute lymphoblastic leukemia (ALL) are at increased risk of neurocognitive weakness in the areas of attention, executive function, and processing speed. Although fatigue and sleep disturbances are frequent complications of ALL therapy and associated with cognitive functions, the impact of fatigue and sleep profiles during active ALL treatment on posttreatment neurocognitive performance has received limited attention. METHODS: Pediatric patients (n = 120) with ALL (diagnosed 2011-2016) who completed fatigue and sleep questionnaires at four time points during active treatment were enrolled in a study of neurocognitive performance. Latent class growth analysis identified subgroups of patients with similar sleep and fatigue profiles during treatment. Neurocognitive performance collected >6 months post treatment on 40 participants was compared between latent classes using multivariable linear regression models. RESULTS: Participants (57.5% male and 79.1% Hispanic or non-Hispanic White) were classified into one of two fatigue and sleep profiles: Class 1 characterized by mild fatigue and sleep disturbances during treatment (50.8%), and Class 2 characterized by higher levels of fatigue and sleep disturbances (49.2%). Posttreatment cognitive performance was in the normal range for most measures, but significantly below normative means for executive function, verbal short-term memory, attention, and distractability measures. Compared to Class 1, Class 2 demonstrated significantly (p < .05) poorer posttreatment neurocognitive performance, particularly in measures of attention. CONCLUSIONS: Our findings indicate that fatigue and sleep disturbances during the first year of pediatric ALL therapy may impact long-term neurocognitive performance. Sleep and fatigue may be targets for intervention to preserve cognitive functioning in survivors.

Treatment age and neurocognitive outcomes following proton beam radiotherapy for pediatric low- and intermediate-grade gliomas.

The relationship between age and neurocognitive functioning following proton beam radiotherapy (PRT) in low- and intermediate-grade gliomas (LIGG) has yet to be examined. Eighteen LIGG patients treated with PRT were prospectively enrolled and received annual neurocognitive evaluations of perceptual/verbal reasoning, working memory, and processing speed postradiotherapy. The median age at diagnosis was 8.2 years (range 1.0-14.7) and the median age at PRT was 9.9 years (range 4.2-17.0). Patients' neurocognitive performance did not change on any measure following PRT (p ≥ .142). We did not observe significant changes in cognitive function over time among a small group of LIGG patients treated with PRT.

Prospective patient-reported symptom profiles associated with pediatric acute lymphoblastic leukemia relapse.

PURPOSE: Despite improvements in frontline pediatric acute lymphoblastic leukemia (ALL) treatment, relapse remains a concern. Research in adult cancer patients suggests that patient-reported symptoms may predict survival, but the relationship between symptoms and relapse for pediatric ALL has received little attention. METHODS: Pediatric patients with ALL (age 2-18 years) and/or their primary caregivers completed symptom surveys at the end of induction, start of delayed intensification (DI), start of maintenance cycle 1 (MC1), and start of maintenance cycle 2 (MC2). Symptom clusters for co-occurring fatigue, pain, sleep disruptions, and nausea were defined using latent profile analysis. Hazard ratios (HR) and 95% confidence intervals (CI) for the association between symptom clusters, individual symptoms, and subsequent relapse were calculated using multivariable Cox proportional hazards models, adjusting for clinical and demographic factors. RESULTS: Eligible patients (n = 208) were followed an average of 2.6 years for the incidence of relapse (n = 22). Associations between relapse and symptoms were identified for fatigue at DI (HR = 1.83, 95%CI 1.23-2.73) and MC1 (HR = 2.14, 95%CI 1.62-2.84), pain at DI (HR = 1.80, 95%CI 1.19-2.72), nausea at the end of induction (HR = 1.19, 95%CI 1.01-1.39), and sleep disturbances at the end of induction (HR = 2.00, 95%CI 1.11-3.62), DI (HR = 1.73, 95%CI 1.01-2.96), and MC1 (HR = 2.19, 95%CI 1.10-4.35). Symptom clusters comprised of individuals with a higher average symptom burden at DI were significantly (p < 0.05) associated with relapse. CONCLUSION: Patient-reported symptoms may provide prognostic information to aid in the identification of pediatric ALL patients at increased risk of relapse.

Cerebrospinal Fluid Metabolomic Profiles Associated With Fatigue During Treatment for Pediatric Acute Lymphoblastic Leukemia.

CONTEXT: Cancer-related fatigue (CRF) is one of the most distressing and persistent symptoms reported during pediatric acute lymphoblastic leukemia (ALL) therapy; however, information on the pathways underlying CRF severity is limited. OBJECTIVES: We conducted global metabolomics profiling of cerebrospinal fluid (CSF) samples to provide insight into the underlying mechanisms of CRF. METHODS: Fatigue in pediatric ALL patients (2012-2017) was assessed during postinduction therapy approximately six months after diagnosis. Postinduction CSF was collected from 171 participants, comprising discovery (n = 86) and replication (n = 85) cohorts. We also conducted secondary validation using diagnostic CSF from 48 replication cohort participants. CSF metabolomic profiling was performed using gas chromatography-mass spectrometry (MS) and liquid chromatography-MS/MS. Kendall's rank correlation was used to evaluate associations between metabolite abundance and CRF. False discovery rate was used to account for multiple comparisons. RESULTS: Participants were 56% males and 59% Hispanic with a mean age at diagnosis of 8.5 years. A total of 274 CSF-derived metabolites were common to the discovery and replication cohorts. Eight metabolites were significantly associated with fatigue in the discovery cohort (P < 0.05), of which three were significant in the replication cohort, including false discovery rate-corrected associations with gamma-glutamylglutamine (Pcombined = 6.2E-6) and asparagine (Pcombined = 3.5E-4). Notably, the abundance of gamma-glutamylglutamine in diagnostic CSF samples was also significantly associated with fatigue (P = 0.0062). CONCLUSION: The metabolites identified in our assessment have been implicated in neurotransmitter transportation and glutathione recycling, suggesting that glutamatergic pathways or oxidative stress may contribute to ALL-associated CRF. This information could inform targeted therapies for reducing CRF in at-risk individuals.

The relationship between chronic health conditions and cognitive deficits in children, adolescents, and young adults with down syndrome: A systematic review.

BACKGROUND: Individuals with Down syndrome are predisposed to a number of chronic health conditions, but the relationship between these conditions and cognitive ability is not clear. The primary objective of this systematic review is to assess this relationship by evaluating studies that measure cognitive performance in the context of Down syndrome-associated chronic health conditions. METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Studies included in this review (1) included children, adolescent, and young adult participants with Down syndrome and one or more co-occurring health conditions; (2) were quantitative; and (3) reported outcomes related to both chronic health conditions and cognitive performance. A set of predetermined chronic health conditions that are common in Down syndrome (e.g. sleep disorders, congenital heart disease, thyroid disease, seizure disorders, and pulmonary hypertension) were selected based on prevalence rates in Down syndrome. RESULTS: Fifteen studies met inclusion criteria. The majority these of studies assessed cognitive performance in association with sleep disorders (47%) and congenital heart disease (47%). Fewer studies reported on the effect of thyroid disease (7%) and seizure disorders (7%) on cognitive ability. None of the studies reported cognitive outcomes related to pulmonary hypertension. Of the chronic health conditions evaluated, associations between sleep disorders and cognitive dysfunction were most common among individuals with Down syndrome. CONCLUSIONS: Individuals with Down syndrome exhibit deficits in cognitive ability, particularly related to attention, executive function and verbal processing. These deficits may be further exacerbated by the presence of chronic health conditions, particularly sleep disorders. Individuals with Down syndrome and co-occurring sleep disorders may benefit from early interventions to mitigate their risk for adverse cognitive outcomes.

Facilitating Transitions to Adulthood in Pediatric Brain Tumor Patients: the Role of Neuropsychology.

PURPOSE OF REVIEW: Transition-age patients with history of a pediatric brain tumor are at significant risk for difficulties transitioning to adulthood. We review current transition models and the potential role of neuropsychology in the transition process for adolescent and young adult brain tumor survivors. RECENT FINDINGS: Several recently developed healthcare transition models include consideration of patients' cognitive and functional capacities, yet currently available transition readiness tools are limited in scope and do not possess adequate normative data across pediatric medical populations. We explore the potential utility and added benefit of systematically incorporating neuropsychology in the transition process for pediatric brain tumor survivors. The literature supports increased evaluation and intervention targeted at psychosocial barriers to transition. Based on these findings, we propose a family-centered and multidisciplinary care model that promotes both medical and broader psychosocial transition processes. Neuropsychology is ideally suited to assess the wide-ranging areas encompassed in transition readiness and to facilitate the transition process.

Premorbid functioning as a predictor of outcome in pediatric brain tumor: An initial examination of the normalcy assumption.

BACKGROUND: Research on neurodevelopmental outcome in survivors of pediatric brain tumor (BT) is often based on the assumption of normal development up to the onset of overt symptoms. We sought to verify the "normalcy assumption" and to investigate corollary issues including challenges inherent to the measurement of premorbid neurobehavioral functioning. PROCEDURE: The Brain Radiation Investigative Study Consortium (BRISC) is a prospective longitudinal multisite study of 58 children diagnosed with BT. Premorbid functioning was assessed via retrospective parent report on standardized rating scales and detailed questionnaires. Findings were examined for the sample as a whole and in patients grouped by tumor histology (embryonal and non-embryonal). RESULTS: Mean age at diagnosis was 9.84 years (range, 3-16). The overall sample showed low proportions of pre/postnatal risk factors and delays in development. The proportion of children with clinically significant premorbid attention (18%) problems based on the BASC-2 exceeded expectation of that in healthy children (6.68%). Similar findings were obtained for somatization (18%) and anxiety (14%). Delays in talking were significantly more common in children with embryonal than non-embryonal tumors (P = 0.02). The non-embryonal tumor group had significantly higher overall rates of premorbid psychosocial problems than the embryonal tumor group (P < 0.001). CONCLUSIONS: We describe a rigorous approach to estimating premorbid developmental status in pediatric BT. The findings suggest mixed support for the "normalcy assumption" and highlight the complexity of this concept and need for further investigation. Our results also suggest the need for further study of potential premorbid correlates with tumor histology.

[Formula: see text] Reliable change in pediatric brain tumor: A preliminary investigation.

Children treated for brain tumor show evidence of declines in general intellectual abilities (i.e., IQ). Group-level data indicate subtle declines over time on average, but no study has utilized a clinical criterion to identify and describe a reliable change in survivors of pediatric brain tumor (PBT). In this study, we discuss the utility of reliable change index (RCI) methodology to supplement group-level analysis (e.g., repeated measures ANOVA). This pilot sample consisted of 22 children (M age = 10.47 years) treated for PBT who completed initial and follow-up assessments (M interval = 23.58 months). Cognitive data included composite scores from the WISC-IV. An RCI z-score was calculated for each participant on each composite score based on two different test-retest reliability coefficients. As a group, survivors of PBT did not demonstrate a statistically significant change from initial to follow-up on any WISC-IV composite score. When RCI was calculated based on reliability coefficients with shorter test-retest intervals provided by the test publisher, 77% of survivors demonstrated a reliable change in performance on at least one measure. The frequency of RCI decreases in working memory was significantly higher than expected. In contrast, only 32% of survivors showed reliable changes on at least one measure when RCI was based on a reliability coefficient derived from a clinical sample with a longer retest interval. This study demonstrates that highly divergent results may be obtained with RCI and the importance of the source of reliability estimates.

Effect of sensorineural hearing loss on neurocognitive and adaptive functioning in survivors of pediatric embryonal brain tumor.

PURPOSE: Survivors of pediatric embryonal brain tumors (BT) are at high risk for sensorineural hearing loss (SNHL) associated with neurocognitive decline. However, previous studies have not assessed the relationship between SNHL and adaptive functioning. We examined neurocognitive and adaptive functioning in patients with and without SNHL. METHODS: Participants included 36 patients treated for an embryonal BT with craniospinal irradiation (CSI) and cisplatin chemotherapy who were assessed 6.7 years post-treatment on average. The impact of SNHL on neurocognitive performance and parent-rated adaptive functioning was assessed in univariate and multivariate analyses. RESULTS: There were 17 cases with SNHL (mean age at evaluation = 14.4) and 19 cases with NH (mean age at evaluation = 13.8). After accounting for age at diagnosis and additional covariates in multivariable analyses, SNHL was associated with worse overall intellectual functioning (p = 0.027) and perceptual reasoning (p = 0.016) performance. There was no effect of SNHL on adaptive functioning in multivariable models. Age at diagnosis and sex were associated with performance on neurocognitive measures. CONCLUSIONS: SNHL in pediatric embryonal BT is associated with increased risk for neurocognitive deficits in conjunction with other demographic and treatment-related factors.

Neuropsychological functioning following surgery for pediatric low-grade glioma: a prospective longitudinal study.

OBJECTIVE: High survival rates have led to an increased emphasis on the functional outcomes of children diagnosed with low-grade glioma. Most outcomes research has focused on risks associated with radiotherapy, but less is known about neuropsychological risks for patients treated with surgery alone. Here, the authors sought to examine the neuropsychological trajectories of children diagnosed with a low-grade glioma and monitored up to 6 years postsurgery. Secondarily, they explored demographic and clinical predictors of neuropsychological performance. METHODS: The neuropsychological functioning of 32 patients (median age at diagnosis 10.0 years) was prospectively assessed annually for up to 6 years after surgery (median days from surgery at baseline = 72). Tumor location was predominately supratentorial (65.6%). A combination of performance-based and parent-reported measures was used to assess intelligence, memory, executive functioning, and fine motor control in all patients. RESULTS: Binomial tests at the postoperative baseline revealed that the proportion of children falling below the average range (< 16th percentile) was significantly higher than the rate expected among healthy peers on measures of verbal memory, processing speed, executive functioning, and fine motor control (p < 0.05). Even so, linear mixed models indicated that neuropsychological functioning at the postoperative baseline did not significantly change over time for up to 6 years after surgery across all domains. A larger tumor size was associated with a slower reaction time (p < 0.01). A supratentorial tumor location and history of seizures were associated with more parent-reported executive difficulties (p < 0.01). CONCLUSIONS: While radiotherapy is a known risk factor for neuropsychological deficits in pediatric brain tumor patients, findings in this study indicate that children treated for low-grade glioma with surgery alone (without radiotherapy or chemotherapy) remain susceptible to difficulties with memory, executive functioning, and motor functioning that persist over time. Over half of the children in the study sample required school support services to address neuropsychological weaknesses. Although low-grade glioma is often conceptualized as a benign tumor, children treated for this lesion require ongoing monitoring and intervention to address neuropsychological weaknesses resulting from the tumor itself as well as the surgery.