Cognitive Implications of Ototoxicity in Pediatric Patients With Embryonal Brain Tumors.

PURPOSE: Sensorineural hearing loss (SNHL) is associated with intellectual and academic declines in children treated for embryonal brain tumors. This study expands upon existing research by examining core neurocognitive processes that may result in reading difficulties in children with treatment-related ototoxicity. PATIENTS AND METHODS: Prospectively gathered, serial, neuropsychological and audiology data for 260 children and young adults age 3 to 21 years (mean, 9.15 years) enrolled in a multisite research and treatment protocol, which included surgery, risk-adapted craniospinal irradiation (average risk, n = 186; high risk, n = 74), and chemotherapy, were analyzed using linear mixed models. Participants were assessed at baseline and up to 5 years after diagnosis and grouped according to degree of SNHL. Included were 196 children with intact hearing or mild to moderate SNHL (Chang grade 0, 1a, 1b, or 2a) and 64 children with severe SNHL (Chang grade 2b or greater). Performance on eight neurocognitive variables targeting reading outcomes (eg, phonemics, fluency, comprehension) and contributory cognitive processes (eg, working memory, processing speed) was analyzed. RESULTS: Participants with severe SNHL performed significantly worse on all variables compared with children with normal or mild to moderate SNHL (P ≤ .05), except for tasks assessing awareness of sounds and working memory. Controlling for age at diagnosis and risk-adapted craniospinal irradiation dose, performance on the following four variables remained significantly lower for children with severe SNHL: phonemic skills, phonetic decoding, reading comprehension, and speed of information processing (P ≤ .05). CONCLUSION: Children with severe SNHL exhibit greater reading difficulties over time. Specifically, they seem to struggle most with phonological skills and processing speed, which affect higher level skills such as reading comprehension.

Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1.

OBJECTIVE: To assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1). METHODS: A multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8-15 years were screened for visuospatial learning or attention deficits (n = 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n = 74; 40 mg/d) or placebo (n = 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population. RESULTS: Lovastatin had no significant effect on primary outcomes after 16 weeks of treatment: visuospatial learning (Cohen d = -0.15, 95% confidence interval -0.47 to 0.18) or sustained attention (Cohen d = 0.19, 95% confidence interval -0.14 to 0.53). Lovastatin was well tolerated, with no increase in reported adverse events compared to placebo. CONCLUSIONS: Lovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population. CLINICALTRIALSGOV IDENTIFIER: This study was registered at ClinicalTrials.gov (NCT00853580) and Australian New Zealand Clinical Trials Registry (ACTRN12607000560493). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for children with NF1, lovastatin does not improve visuospatial learning or attention deficits.

Neuroplastic Response After Radiation Therapy for Pediatric Brain Tumors: A Pilot Study.

PURPOSE: Clinically effective measurement of cognitive toxicity from photon radiation therapy (XRT) should be accurate, sensitive, and specific. This pilot study tested translational findings on phasic changes in children's memory systems that are sensitive and insensitive to toxic XRT effects to identify a possible neuroplastic effect. METHODS AND MATERIALS: Memory processes were prospectively tested before XRT and at 3 later time points up to 2 years in 35 children with mixed primary brain tumors who had not experienced recurrence. Memory processes were verbal-semantic, visual-semantic, and visual-perceptual, including accuracy, speed to recall, encoding, retrieval, and recognition. The mixed-effects model included time (to estimate slope), covariates (age, tumor locus, XRT field, and medications) as fixed effects, and individual random intercepts. A sensitivity analysis examined the influence of XRT dose to the hippocampi on memory. RESULTS: Retrieval from long-term verbal-semantic memory declined 2 months after completing XRT, as seen in adults, and was lowest at 1 year, which was delayed in comparison with adults. Double dissociation from visual-perceptual memory at baseline and 2 months was found, consistent with adults. Recovery was demonstrated 2 years after XRT. Patterns were unchanged when dose to hippocampus was included in the model. CONCLUSIONS: Verbal and semantic long-term retrieval is specifically sensitive to XRT-related cognitive dysfunction, without effect on visual-perceptual memory. Children reached nadir in XRT-sensitive memory 1 year after XRT and recovered by 2 years, which is later than that observed in adults. The protracted period of post-XRT injury may represent the maturation of the human hippocampus and white matter into late adolescence.

Working memory abilities among children treated for medulloblastoma: parent report and child performance.

OBJECTIVE: We investigated the 5-year postsurgical developmental trajectory of working memory (WM) in children with medulloblastoma using parent and performance-based measures. METHOD: This study included 167 patients treated for medulloblastoma. Serial assessments of WM occurred at predetermined time points for 5 years. RESULTS: There was a subtle, statistically significant increase in parental concern about WM, coupled with a statistically significant decrease in age-standardized scores on performance-based measures. However, whole-group mean scores on both parent and performance-based measures remained in the age-expected range. Posterior fossa syndrome was consistently associated with poorer WM. Younger age at treatment and higher treatment intensity were associated with greater negative change in WM performance only. CONCLUSIONS: Most children treated for medulloblastoma display WM within the age-appropriate range according to parent report and performance. However, the subtle negative changes over time and identified subgroups at increased risk highlight the need for ongoing monitoring of this population.

Examination of risk factors for intellectual and academic outcomes following treatment for pediatric medulloblastoma.

BACKGROUND: The aim of this study was to prospectively examine the effects of hearing loss and posterior fossa syndrome (PFS), in addition to age at diagnosis and disease risk status, on change in intellectual and academic outcomes following diagnosis and treatment in a large sample of medulloblastoma patients. METHODS: Data from at least 2 cognitive and academic assessments were available from 165 patients (ages 3-21 years) treated with surgery, risk-adapted craniospinal irradiation, and 4 courses of chemotherapy with stem cell support. Patients underwent serial evaluation of cognitive and academic functioning from baseline up to 5 years post diagnosis. RESULTS: Serious hearing loss, PFS, younger age at diagnosis, and high-risk status were all significant risk factors for decline in intellectual and academic skills. Serious hearing loss and PFS independently predicted below-average estimated mean intellectual ability at 5 years post diagnosis. Patients with high-risk medulloblastoma and young age at diagnosis (<7 years) exhibited the largest drop in mean scores for intellectual and academic outcomes. CONCLUSIONS: Despite a significant decline over time, intellectual and academic outcomes remained within the average range at 5 years post diagnosis for the majority of patients. Future studies should determine if scores remain within the average range at time points further out from treatment. Patients at heightened risk should be closely monitored and provided with recommendations for appropriate interventions.

Neural substrates for heightened anxiety in children with brain tumors.

This study investigated anxiety symptoms' associations with cognitive functioning and tumor locus in pediatric brain tumor patients. Data from 91 patients were collected as part of a neuropsychological assessment. Significant relationships were found between anxiety symptoms and mental set shifting (Wisconsin Card Sorting). Analyses revealed patients with right cortical tumors or left cerebellar tumors had significantly greater anxiety than those with midline/bilateral tumor and those with left cortical or right cerebellar tumors. Results support the specific risk of anxiety with right cortical and left cerebellar tumors. Results highlight the association of anxiety and one important element of executive functioning.

Parent-reported social outcomes after treatment for pediatric embryonal tumors: a prospective longitudinal study.

PURPOSE: To examine longitudinal parent-reported social outcomes for children treated for pediatric embryonal brain tumors. PATIENTS AND METHODS: Patients (N=220) were enrolled onto a multisite clinical treatment protocol. Parents completed the Child Behavior Checklist/6-18 at the time of their child's diagnosis and yearly thereafter. A generalized linear mixed effects model regression approach was used to examine longitudinal changes in parent ratings of social competence, social problems, and withdrawn/depressed behaviors with demographic and treatment factors as covariates. RESULTS: During the 5-year period following diagnosis and treatment, few patients were reported to have clinically elevated scores on measures of social functioning. Mean scores differed significantly from population norms, yet remained within the average range. Several factors associated with unfavorable patterns of change in social functioning were identified. Patients with high-risk treatment status had a greater increase in parent-reported social problems (P=.001) and withdrawn/depressed behaviors (P=.01) over time compared with average-risk patients. Patients with posterior fossa syndrome had greater parent-reported social problems over time (P=.03). Female patients showed higher withdrawn/depressed scores over time compared with male patients (P<.001). Patient intelligence, age at diagnosis, and parent education level also contributed to parent report of social functioning. CONCLUSION: Results of this study largely suggest positive social adjustment several years after diagnosis and treatment of a pediatric embryonal tumor. However, several factors, including treatment risk status and posterior fossa syndrome, may be important precursors of long-term social outcomes. Future research is needed to elucidate the trajectory of social functioning as these patients transition into adulthood.

Phase measurement of cognitive impairment specific to radiotherapy.

PURPOSE: Memory impairment is an early-delayed effect of radiotherapy (RT). The prospective longitudinal measurement of the cognitive phase effects from RT was conducted on treated and untreated brain tumor patients. The study design investigated semantic vs. perceptual and visual vs. verbal memory to determine the most disease-specific measure of RT-related changes and understanding of the neurotoxicity from RT to the brain. METHODS AND MATERIALS: Tests of memory that had previously shown RT-related phasic changes were compared with experimental tests of memory to test hypotheses about cognition targeted to the neural toxicity of RT. The results from 41 irradiated and 29 nonirradiated patients with low-grade, supratentorial tumors were analyzed. The methods controlled for comorbid white matter risk, recurrence, interval after treatment, and age (18-69 years). The effects were examined before RT and at three points after RT to 1 year using a mixed effects model that included interval, group, surgical status, medication use, practice, and individual random effects. Four new tests of memory and other candidate cognitive tests were investigated, and a post hoc analysis of a comprehensive battery of tests was performed to identify the cognitive processes most specific to RT. RESULTS: The RT effects on memory were identified in the treated group only; among the new tests of memory and the complete neurocognitive battery, the RT effects were significant only for delayed recall (p < 0.009) and interval to recognize (p < 0.002). Tumor location was not related to the treatment effect. Memory decline was specific to retrieval of semantic memories; a double dissociation of semantic from perceptual visual memory was demonstrated in the RT group. CONCLUSIONS: These results implicate memory dependent on the semantic cortex and the hippocampal memory system. A cognitive measurement that is brief but specific to neural mechanisms is effective and feasible for studies of RT damage.

How parents cope with their child's diagnosis and treatment of an embryonal tumor: results of a prospective and longitudinal study.

The current study reports longitudinal coping responses among parents of children diagnosed with an embryonal brain tumor. Patients (n = 219) were enrolled on a treatment protocol for a pediatric embryonal brain tumor. Their parents (n = 251) completed the Coping Response Inventory at time of their child's diagnosis and yearly thereafter, resulting in 502 observations. Outcomes were examined with patient and parent age at diagnosis, patient risk, parent gender and education as covariates. At the time of diagnosis, the highest observed coping method was seeking guidance with well above average scores (T = 61.6). Over time, younger parents were found to seek guidance at a significantly higher rate than older parents (P = .016) and the use of acceptance resignation and seeking alternative results by all parents significantly increased (P = .011 and P < .0001 respectively). The use of emotional discharge was also observed above average at time of diagnosis (T = 55.4) with younger fathers being more likely to exhibit emotional discharge than older fathers (P = .002). Differences in coping according to age of the patient and parent education level are also discussed. Results show a high need for guidance, and above average emotional discharge, especially among younger parents. It is imperative for the healthcare team to lead with accurate information so that these parents may make informed decisions about the care of their child. This need remains high years after diagnosis. Therefore it is critical to continue a consistent level of effective communication and support, even following treatment.

Mechanisms of compartmental purkinje cell death and survival in the lurcher mutant mouse.

The Lurcher mutant mouse is characterized by its ataxic gait and loss of cerebellar Purkinje cells and their afferents, granule cells and olivary neurons, during the first weeks of postnatal development. For the 50 years since its discovery, the heterozygous Lurcher mutant has served as an important model system for studying neuron-target interactions in the developing cerebellum and cerebellar function. The identification of the Lurcher (Lc) gene over 10 years ago as a gain-of-function mutation in the δ2 glutamate receptor (GluRδ2) led to extensive studies of cell death mechanisms in the Lc/+ cerebellum. The advantage of this model system is that GluRδ2(+) receptors and GluRδ2(Lc) channels are expressed predominantly in Purkinje cells, making it possible to study the effects of a well-characterized leak current in a well-defined cell type during a critical phase of neuronal development. Yet there is still controversy surrounding the mechanisms of neuronal death in Lc/+ Purkinje cells with competing hypotheses for necrotic, apoptotic, and autophagic cell death pathways as a consequence of the excitotoxic stress caused by the GluRδ2(Lc) leak current. The goal of this review is to summarize recent studies that critically test the role of various cell death pathways in Lc/+ Purkinje cell degeneration with respect to evidence for the molecular heterogeneity of Purkinje cells. We propose that the expression of putative survival factors, such as heat shock proteins, in a subset of cerebellar Purkinje cells may affect cell death pathways and account for the pattern and diverse mechanisms of Lc/+ Purkinje degeneration.

Tumor locus moderates anxiety symptoms in a pediatric neuro-oncologic sample.

Despite the prevalence of pediatric Central Nervous System (CNS) solid tumors, little is understood about patients' disease-related anxiety experience. Data from 25 remitted pediatric CNS tumor patients posttreatment were collected. Significant symptoms of anxiety were reported by 32% of patients. MRI studies showed all anxious patients had right cortical tumors or left cerebellar tumors. Confound analyses suggest these results are not better accounted for by demographic, disease, or treatment variables. These results evidence the risk some pediatric neuro-oncologic patients face for developing significant anxiety symptoms.

Development of Hsp25 expression compartments is not constrained by Purkinje cell defects in the Lurcher mouse mutant.

Four transverse zones can be distinguished in the adult mouse cerebellar cortex based on differential expression of cell-specific antigens, termination patterns of mossy fiber afferents, and phenotypes of mouse mutants with cerebellar defects: the anterior zone (AZ), central zone (CZ), posterior zone (PZ), and nodular zone (NZ). In the heterozygous Lurcher (Lc/+) mouse a zonally restricted abnormality in Purkinje cell development is seen. The Purkinje cell-specific antigen zebrin II is normally differentially expressed in all four zones of the adult cerebellum, but in the Lc/+ mutant is confined to the PZ and NZ, caudal to a transverse boundary in the dorsal aspect of lobule VIII. In this study we wanted to understand why zebrin II expression is arrested at this boundary and whether the Lc mutation affects the differentiation of additional Purkinje cell antigens in a similar manner. To determine this, we took advantage of the dynamic developmental timetable of another Purkinje cell antigen, the small heat shock protein Hsp25. Using immunohistochemistry we demonstrate that cerebellar maturation anterior to the CZ/PZ transverse boundary appears to be unaffected by the Lc allele, in that initial progression of Hsp25 expression in the Lc/+ cerebellum was similar to controls. Double-labeling experiments with anti-Hsp25 and anti-calbindin suggest that characteristic banding patterns of Hsp25 in Lc/+ cerebellum develop and are preserved despite cell loss. Thus, since simple temporal or spatial models cannot account for the zonal restriction seen during Lc/+ cerebellar development, the abnormality may be zebrin II-specific.

MRI changes due to early-delayed conformal radiotherapy and postsurgical effects in patients with brain tumors.

PURPOSE: Discernment of radiotherapy (XRT) effects vs. tumor activity is difficult in brain tumor patients during the months after XRT when white matter hyperintensities sometimes emerge. We examined brain scans in XRT-treated vs. untreated patients for early-delayed post-XRT effects. METHODS AND MATERIALS: Brain regions susceptible to XRT injury were examined on magnetic resonance imaging (MRI) for T2-weighted hyperintensities and atrophy in 37 adults with low-grade primary brain tumors (13 nonirradiated and 24 irradiated). Cases evidencing recurrence/growth over the study period were censored. Interactions with age, mood, fatigue, medications, tumor type and grade, extent of resection, and laterality of MRI changes were examined. RESULTS: Hyperintensity and atrophy ratings over time for the treated and untreated groups were not significantly different. White matter atrophy increased unrelated to XRT. In all patients combined, white matter atrophy and hyperintensities were greater at all time points and more lateralized in surgically treated patients. CONCLUSIONS: Radiotherapy status was not related to changes in MRI ratings during the weeks/months after XRT. Findings contradict assumptions about radiographically evidenced early-delayed XRT effects. Increases in T2-weighted hyperintensities during the 1-6-month period post-conformal radiotherapy for low-grade tumors are likely not related to early-delayed XRT effects.

The impact of low-grade brain tumors on verbal fluency performance.

Verbal fluency has traditionally represented left hemispheric function, based on large acquired lesion studies. However, recent functional imaging studies have demonstrated bilateral hemispheric activation during phonemic and semantic word generation tasks. We examined 25 left hemisphere (LH) and 26 right hemisphere (RH) low-grade brain tumor patients on semantic and phonemic fluency. Patients were also assigned to a combined posterior (left and right) group (n = 26) or a combined posterior (left and right) group (n = 20) and compared with normal controls (NC; n = 57). We hypothesized that there would be greater left than right hemispheric phonemic and semantic fluency impairments. We also hypothesized that there would be greater anterior, specifically left anterior, than posterior impairments on phonemic fluency given their respective retrieval and initiation requirements. Finally, it was predicted that the LH patients, particularly the left posterior group, would exhibit the greatest semantic fluency impairments. Results indicated that on semantic fluency, the LH group produced significantly fewer semantic fluency responses compared to the RH group, but the expected left posterior and left frontal group differences were not found. There were no significant patient group differences associated with phonemic fluency. While we encountered semantic fluency impairments in this brain tumor population, we did not find the extensive deficits associated with the distinct or localized brain regions previously reported in the literature.

A critical review of the clinical effects of therapeutic irradiation damage to the brain: the roots of controversy.

We critically examined the damaging affects of therapeutic irradiation by comparing results from cross-disciplinary studies of early- and late-delayed radiotherapy effects. Focus is attained by concentrating on clinical treatment issues (volume of brain, dose, timing of effects, age, modality types, and stereotactic treatment techniques), rather than on methodological means or problems, which is necessary to understand the mechanisms and characteristics of radiotherapy-induced behavioral dysfunction including cognition. We make observations and hypotheses about the actual risks from radiotherapy that could be informative in the treatment decision process, and which may lessen the concerns of some patients and their families about the risks they take when receiving radiation. Conditions that predispose to radiation injury are reviewed: (1) higher doses even to part of the brain versus lower doses to the whole brain, (2) combined treatment modalities, (3) malignancy itself, (4) radiation early during postnatal brain development, and (5) late-delayed effects (more than 3 years posttreatment). Current neurocognitive frameworks for understanding cognitive change over time in children and adults are summarized, along with the literature on effects of brain tumors and treatment on depression. No studies have as yet identified candidate brain regions that are more sensitive to radiotherapy. Two studies have provided early, preliminary evidence for a specific vulnerability of visual attention/memory to the early stage of late radiation damage. Furthermore, radiation effects appear severe only in a minority of patients. Risk is related to direct and indirect effects of cancer type, concurrent clinical factors, and premorbid risk factors.

The impact of frontal and non-frontal brain tumor lesions on Wisconsin Card Sorting Test performance.

Several lesion and imaging studies have suggested that the Wisconsin Card Sorting Test (WCST) is a measure of executive dysfunction. However, some studies have reported that this measure has poor anatomical specificity because patients with either frontal or non-frontal focal lesions exhibit similar performance. This study examined 25 frontal, 20 non-frontal low-grade brain tumor patients, and 63 normal controls (NC) on the WCST. The frontal patients were also assigned to either a left frontal (n=10) group or a right frontal group (n=15) and compared with the non-frontal group and NC. It was hypothesized that the frontal brain tumor patients would display greater deficits on categories achieved and a higher number of perseverative errors than non-frontal brain tumor patients on the WCST. Finally, it was predicted that right frontal brain tumors would result in greater executive functioning deficits than left frontal or non-frontal brain tumors. Results indicated that the left frontal group achieved the fewest categories and committed the most perseverative errors compared to the other patient and normal control groups. In addition, the left frontal group committed significantly more perseverative errors than the right frontal group. These results suggest that the WCST is sensitive to the effects of low-grade brain tumors on executive functioning.

The impact of left and right intracranial tumors on picture and word recognition memory.

This study investigated the effects of left and right intracranial tumors on picture and word recognition memory. We hypothesized that left hemispheric (LH) patients would exhibit greater word recognition memory impairment than right hemispheric (RH) patients, with no significant hemispheric group picture recognition memory differences. The LH patient group obtained a significantly slower mean picture recognition reaction time than the RH group. The LH group had a higher proportion of tumors extending into the temporal lobes, possibly accounting for their greater pictorial processing impairments. Dual coding and enhanced visual imagery may have contributed to the patient groups' similar performance on the remainder of the measures.

Attention in adult intracranial tumors patients.

This study investigated the neuropsychological effects of intracranial tumors on attention, prior to irradiation and chemotherapy. Subjects (n = 55) being treated for low-grade, supratentorial brain tumors were administered tests of attention and working memory. We divided the tumor patients into a "superficial" regional group (e.g., gliomas that infiltrate white matter and meningiomas attached to the cortical surface) and classified them into four brain regions: anterior left side, anterior right side, posterior left side, posterior right side. The groups were also classified into either a combined anterior group or combined posterior group, and either a combined left hemispheric group or combined right hemispheric group. All groups were compared to deep tumor (DT) patients (e.g., pituitary and pineal tumors) and a demographically normal control (NC) group (n = 63). While the NC group primarily outperformed the brain tumor groups on the neuropsychological measures, there were instances where the individual brain tumor groups demonstrated higher scores than the NC group. Significant differences among the brain tumor groups were only found on Digits Forward. The DT group performed significantly worse than the superficial regional groups and the combined anterior and combined posterior groups on Digits Forward. The DT group was also worse than the combined left hemispheric and right hemispheric groups on Digits Forward. The fact that the DT group performed similarly to the other patient groups on the remaining attention measures suggests that these tumors are associated with especially poor attentional performance.

The predictive value of longitudinal neuropsychologic assessment in the early detection of brain tumor recurrence.

BACKGROUND: Neuropsychologic tests are widely used to predict the course of progressive neurologic diseases, and recent research has demonstrated the specificity of cognitive measures, even in relatively diffuse diseases. However, the cognitive effects of brain tumors of similar histology and location are known to be highly variable. The authors used the specificity of cognitive function principle to compare two models for the early detection of low-grade brain tumor recurrence prior to detection with clinically scheduled neuroimaging. METHODS: To test the feasibility of these prediction models, 34 patients with supratentorial, low-grade brain tumors prospectively were administered serial comprehensive neuropsychologic examinations; 11 patients developed recurrent tumors during the series and 23 patients did not. A general model based on tests sensitive to malignancy and white matter disease was compared with a tumor-specific model based on indices related to each patient's tumor locus. A Cox proportional hazards model was used to identify the predictor variables that significantly changed immediately prior to recurrence. RESULTS: Only the tumor-specific model achieved statistical significance (P < 0.02). A tumor-specific index decline of 1 standard deviation indicated a 5-fold increase in the probability of tumor recurrence. CONCLUSIONS: Although this method needs to be tested with more frequent and regular observations and with a larger sample, these results provide evidence of the feasibility of the subject-specific model as a predictor of recurrence. The evidence of the predictive value of a tumor-specific model is consistent with studies that identify only limited, brain structure-specific cognitive decline from broad neuropsychologic batteries.