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Purpose Children with brain tumors experience cognitive late effects, often related to cranial radiation. We sought to determine differential effects of surgery and chemotherapy on brain structure and neuropsychological outcomes in children who did not receive cranial radiation therapy (CRT). Methods Twenty-eight children with a history of posterior fossa tumor (17 treated with surgery, 11 treated with surgery and chemotherapy) underwent neuroimaging and neuropsychological assessment a mean of 4.5 years (surgery group) to 9 years (surgery + chemotherapy group) posttreatment, along with 18 healthy sibling controls. Psychometric measures assessed IQ, language, executive functions, processing speed, memory, and social-emotional functioning. Group differences and correlations between diffusion tensor imaging findings and psychometric scores were examined. Results The z-score mapping demonstrated fractional anisotropy (FA) values were ≥2 standard deviations lower in white matter tracts, prefrontal cortex gray matter, hippocampus, thalamus, basal ganglia, and pons between patient groups, indicating microstructural damage associated with chemotherapy. Patients scored lower than controls on visuoconstructional reasoning and memory (P ≤ .02). Lower FA in the uncinate fasciculus (R = -0.82 to -0.91) and higher FA in the thalamus (R = 0.73-0.91) associated with higher IQ scores, and higher FA in the thalamus associated with higher scores on spatial working memory (R = 0.82). Conclusions Posterior fossa brain tumor treatment with surgery and chemotherapy affects brain microstructure and neuropsychological functioning years into survivorship, with spatial processes the most vulnerable. Biomarkers indicating cellular changes in the thalamus, hippocampus, pons, prefrontal cortex, and white matter tracts associate with lower psychometric scores.

Background “Head Start” III, was a prospective clinical trial using intensive induction followed by myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR) to either avoid or reduce the dose/volume of irradiation in young children with medulloblastoma. Methods Following surgery, patients received 5 cycles of induction followed by myeloablative chemotherapy using carboplatin, thiotepa, and etoposide with AuHCR. Irradiation was reserved for children >6 years old at diagnosis or with residual tumor post-induction. Results Between 2003 and 2009, 92 children Conclusion We report excellent survival and preservation of mean IQ and memory for young children with ND medulloblastoma using high-dose chemotherapy, with most patients surviving without irradiation.

Severe chronic anemia is an independent predictor of overt stroke, white matter damage, and cognitive dysfunction in the elderly. Severe anemia also predisposes to white matter strokes in young children, independent of the anemia subtype. We previously demonstrated symmetrically decreased white matter (WM) volumes in patients with sickle cell disease (SCD). In the current study, we investigated whether patients with non-sickle anemia also have lower WM volumes and cognitive dysfunction. Magnetic Resonance Imaging was performed on 52 clinically asymptomatic SCD patients (age = 21.4 ± 7.7; F = 27, M = 25; hemoglobin = 9.6 ± 1.6 g/dL), 26 non-sickle anemic patients (age = 23.9 ± 7.9; F = 14, M = 12; hemoglobin = 10.8 ± 2.5 g/dL) and 40 control subjects (age = 27.7 ± 11.3; F = 28, M = 12; hemoglobin = 13.4 ± 1.3 g/dL). Voxel-wise changes in WM brain volumes were compared to hemoglobin levels to identify brain regions that are vulnerable to anemia. White matter volume was diffusely lower in deep, watershed areas proportionally to anemia severity. After controlling for age, sex, and hemoglobin level, brain volumes were independent of disease. WM volume loss was associated with lower Full Scale Intelligence Quotient (FSIQ; P = .0048; r(2) = .18) and an abnormal burden of silent cerebral infarctions (P = .029) in males, but not in females. Hemoglobin count and cognitive measures were similar between subjects with and with-out white-matter hyperintensities. The spatial distribution of volume loss suggests chronic hypoxic cerebrovascular injury, despite compensatory hyperemia. Neurocognitive consequences of WM volume changes and silent cerebral infarction were strongly sexually dimorphic. Understanding the possible neurological consequences of chronic anemia may help inform our current clinical practices.

Patients with congenital heart disease (CHD) demonstrate multidomain cognitive delays. Cingulo-opercular and cerebellar brain networks are critical to language functions. This is a description of our initial experience aiming to identify an anatomic correlate for CHD patients with expressive language delays. Fetal CHD patients, prospectively enrolled, underwent serial fetal (1.5T), postnatal pre- and postoperative (3T) MRI. Non-CHD patients were enrolled retrospectively from the same epoch. Comparable fetal and neonatal T2 contrast was used for manual linear cross-sectional measurement. Multivariable analysis was used for adjustments and curve fitting. Neurodevelopment was assessed with Battelle Developmental Inventory, 2nd ed. between 9 and 36 months of age. This interim analysis included patients from our longitudinal CHD study who had fetal, postnatal imaging and neurodevelopmental data—yielding a total of 62 mothers (11 CHD fetuses and 51 non-CHD fetuses). Altered brain trajectories were seen in selected cerebellar and opercular measurements in CHD patients compared with the non-CHD group. Smaller inferior cerebellar vermis measurements were associated with multiple communication-related abnormalities. Altered early structural development of the cerebellum and operculum is present in patients with CHD, which correlates with specific neurodevelopmental abnormalities.

BACKGROUND Few neuroimaging studies of children with brain tumors treated with chemotherapy without radiation exist, and the neuropsychological effects of chemotherapy remain unclear. We aimed to differentiate the effects of surgery and chemotherapy on brain microstructure and cognition. METHODS Twenty-eight children with a history of posterior fossa tumor (17 treated with surgery alone; 11 treated with surgery + chemotherapy), and 21 sibling controls (n= 49) underwent diffusion tensor imaging (DTI) and neuropsychological assessment a mean of 4.5 (surgery group) to 9 years (surgery + chemotherapy group) after treatment. Psychometric measures focused on general intelligence, executive functions, processing speed, learning and memory, and social-emotional functioning. Age at diagnosis and time since diagnosis were covariates in the analyses. Group differences in DTI findings and psychometric scores, and correlations between psychometric scores and DTI results were examined. RESULTS Mean fractional anisotropy (FA) in the prefrontal cortex, white matter tracts, hippocampus, putamen, globus pallidus, thalamus, and pons were significantly (z≥ 2SD) lower in children treated with surgery + chemotherapy compared to those treated with surgery alone. In neuropsychological evaluation, the patient groups differed only in receptive vocabulary (p= 0.05), with children treated with surgery + chemotherapy scoring lower. Both patient groups scored lower than healthy sibling controls on measures of visuoconstructional reasoning (p= 0.02) and delayed visual (p= 0.02) and spatial memory (p= 0.01). Lower FA in the uncinate fasciculus and higher FA in the right thalamus associated with higher scores on general intelligence (p= 0.003, p= 0.002), and higher FA in the right thalamus associated with higher scores on spatial learning (p= 0.01) and memory (p= 0.01) in children treated with surgery + chemotherapy. CONCLUSIONS Chemotherapy is associated with injury to the microstructure of white and gray matter and neuropsychological deficits not seen in children with posterior fossa tumors treated with surgery alone.

Children ages 9–12 years face increasing social and academic expectations that require mastery of their thoughts, emotions, and behavior. Little is known about the development of neural pathways integral to these improving capacities during the transition from childhood to adolescence. Among 234 healthy, inner-city male and female youth (speciesHomo sapiens) 9–12 years of age followed by the Columbia Center for Children's Environmental Health, we acquired diffusion tensor imaging, multiplanar chemical shift imaging, and cognitive measures requiring self-regulation. We found that increasing age was associated with increased fractional anisotropy and decreased apparent diffusion coefficient, most prominently in the frontal and cingulate cortices, striatum, thalamus, deep white matter, and cerebellum. Additionally, we found increasing age was associated with increasedN-acetyl-l-aspartate (NAA) in the anterior cingulate and insular cortices, and decreased NAA in posterior cingulate and parietal cortices. Age-associated changes in microstructure and neurometabolite concentrations partially mediated age-related improvements in performance on executive function tests. Together, these findings suggest that maturation of key regions within cortico-striatal-thalamo-cortical circuits subserve the emergence of improved self-regulatory capacities during the transition from childhood to adolescence.SIGNIFICANCE STATEMENTFew imaging studies of normal brain development have focused on a population of inner-city, racial/ethnic minority youth during the transition from childhood to adolescence, a period when self-regulatory capacities rapidly improve. We used DTI and MPCSI to provide unique windows into brain maturation during this developmental epoch, assessing its mediating influences on age-related improvement in performance on self-regulatory tasks. Our findings suggest that rapid maturation of cortico-striato-thalamo-cortical circuits, represented as progressive white-matter maturation (increasing FA and increasing NAA, Ch, Cr concentrations accompanying advancing age) in frontal regions and related subcortical projections and synaptic pruning (decreasing NAA, Ch, Cr, Glx) in posterior regions, support age-related improvements in executive functioning and self-regulatory capacities in youth 9–12 years of age.

Background Intensified therapy with platinum-based regimens for pediatric brain tumors has dramatically increased the number of pediatric brain tumor survivors (PBTS) but frequently causes permanent sensorineural hearing loss (SNHL). Although neurocognitive decline in PBTS is known to be associated with radiation therapy (RT), SNHL represents a potential additional contributor whose long-term impact has yet to be fully determined. Methods The neurocognitive impact of significant SNHL (Chang scale ≥ 2b) in PBTS was assessed through a retrospective cohort study of audiograms and neurocognitive testing. Scores for neurocognitive domains and subtest task performance were analyzed to identify specific strengths and weakness for PBTS with SNHL. Results In a cohort of PBTS (n = 58) treated with platinum therapy, significant SNHL was identified in more than half (55%, n = 32/58), of which the majority required hearing aids (72%, 23/32). RT exposure was approximately evenly divided between those with and without SNHL. PBTS were 6.7 ± 0.6 and 11.3 ± 0.7 years old at diagnosis and neurocognitive testing, respectively. In multivariate analyses adjusted for RT dose, SNHL was independently associated with deficits in intelligence, executive function, and verbal reasoning skills. Subtests revealed PBTS with SNHL to have poor learning efficiency but intact memory and information acquisition. Conclusions SNHL in PBTS increases the risk for severe therapy-related intellectual and neurocognitive deficits. Additional prospective investigation in malignant brain tumors is necessary to validate these findings through integration of audiology and neurocognitive assessments and to identify appropriate strategies for neurocognitive screening and rehabilitation specific to PBTS with and without SNHL.

Background. Childhood brain tumor survivors (CBTS) often experience treatment-related neurocognitive deficits affecting quality of life (QOL), but systemic chemotherapy contributions to outcomes are unclear. Our objective was to relate brain tissue changes to neurocognitive and QOL effects after systemic myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue in CBTS. Procedure. Regional brain volumes and diffusion tensor indices were correlated with neurocognitive, behavioral, and QOL measures, and compared between 8 CBTS (mean age 8.5 years, mean age at diagnosis 32 months), and 9 healthy controls (mean 9.3 years). Results. Overall QOL, school, and psychosocial functioning were significantly lower in patients ( P < .05). Most patients scored within normative ranges on neurocognitive and behavioral assessment. Elevated mean diffusivity and decreased fractional anisotropy, indicating gray and white matter injury, respectively, appeared in memory and executive functioning areas. Low scores on Inhibition on the Neuropsychological Assessment–II were correlated with elevated mean diffusivity in prefrontal cortex. Conclusions. Brain injury, decreased QOL, and to a lesser extent, executive functioning deficits appear in CBTS treated with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue. Early cognitive and psychological assessment and intervention are warranted in this population.

Opsoclonus myoclonus syndrome (OMS) produces long-term cognitive, behavioral, and motor deficits. Objective was to see if more aggressive treatment improved outcome. Assessment included opsoclonus myoclonus syndrome rating, developmental/cognitive and motor assessment, and adaptive behavior. Fourteen subjects completed testing. Nine had neuroblastoma. Onset was at 10 to 35 months; onset to diagnosis: 2 days to 14 months, and onset to first treatment: 5 days to 15 months. Initial treatment was corticotropin (12), oral steroids (3), plus intravenous immunoglobulin in all. Ten received rituximab, 5 cyclophosphamide. Age at testing ranged from 2.5 to 10.3 years. Adaptive Behavior Score (11 subjects), mean 93.5; estimated Intelligence Quotient/Developmental Quotient mean 93.5; Motor: mean 92.8. Residual opsoclonus myoclonus syndrome symptoms at the time of the evaluation were generally minor; opsoclonus myoclonus syndrome scores ranged from 0 to 6. Comparison to previously reported opsoclonus myoclonus syndrome subjects showed improved outcomes: Adaptive behavior, cognitive and motor scores were significantly higher ( P < .001) in new subjects. Outcomes have improved with more aggressive immunosuppression, with most opsoclonus myoclonus syndrome survivors now functioning at or near normal.

Introduction: We used MR imaging techniques to investigate the neurological consequences of chronic anemia in human patients with sickle cell disease, non-sickle anemic syndromes (called anemic-controls) and non-anemic controls. We previously demonstrated that hemoglobin level is an independent predictor of white matter volume (WMV) in brain as well as cognitive performance. Importantly, WMV was independent of genotype (sickle vs non-sickle), treatment type, HgB S%, fetal HgB level, Lactate dehydrogenase (LDH) and presence of silent strokes. We also demonstrated that low hemoglobin is associated with abnormal brain functional connectivity and iron levels in select brain regions. In the present study, we examine the effects of anemia on brain integrity using apparent diffusion coefficient (ADC) calculated from diffusion weighted imaging (DWI). ADC measures the magnitude of the motion of water in tissue and can be used to imply tissue damage, making it highly sensitive to neuropathology as altered tissue integrity and loss of cellular structures can change the diffusivity of water. We then explore the associations between ADC, local brain volume, functional connectivity, iron and cognitive performance. Methods: MRI data, CBC and neuropsychological testing results were obtained from 26 sickle cell disease (age = 20.9 ± 11.3, F:M = 13:13, HgB = 9.7 ± 2.1), 20 anemic-control (age = 25.9 ± 11.3, F:M = 10:10, HgB = 10.9 ± 0.5) and 25 control subjects (age = 23.1 ± 8.4, F:M = 16:9, HgB = 13.2 ± 1.2). (Recruited with informed consent or assent; IRB: CHLA CCI#11-00083). DWI (TE = 86ms; TR = 6700ms; resolution=2.5mm3; 30 directions; bvalue=1000m/s2; reverse-gradient b=0) were acquired on a 3T Philips Achieva (v.3.2.1) using an 8-channel head coil. Images were corrected for motion and distortion then voxel-wise calculations of ADC were computed then transferred to a common atlas space. (brainsuite.org, v18). 3D T1 weighted, quantitative susceptibility mapping, and functional MRI (fMRI) images were collected using our previously published protocols. After regressing out age and sex, we determined the effect of hemoglobin level at each voxel of the brain on ADC then corrected for multiple comparison (BH FDR α=0.1). Significant regions were retained, (p Results: Hemoglobin level significantly correlated with ADC throughout the brain, but most strongly in deep white matter and subcortex, followed by the occipital lobe and cerebellum (Figure 1). The scatterplot between mean ADC and hemoglobin showed no discernable differentiation between anemia subtypes (Figure 2). Mean ADC and our previously developed markers of disease correlated well with each other showing that the severity of anemia correlates with higher ADC, lower white matter volume (WMV), abnormal functional connectivity (CDI), higher brain iron and lower Matrix Reasoning scores (males only; Table 1). Conclusion: Increased ADC, correlating with anemia severity, was observed in subcortical structures of an anemic population at risk for white matter shrinkage and cognitive dysfunction. ADC (but not WMV) correlated with brain iron which is known to accumulate in the presence of cerebral hypoxia. ADC and WMV changes were comparable in males and females but only males showed lower fluid reasoning. This data shows that anemia and brain iron are associated with brain tissue disruption and function. Disclosures Coates: vifor: Consultancy, Honoraria; celgene: Consultancy, Honoraria, Other: steering committee of clinical study; agios pharma: Consultancy, Honoraria; apo pharma: Consultancy, Honoraria, Speakers Bureau. Wood:BiomedInformatics: Consultancy; Imago Biosciences: Consultancy; National Institutes of Health: Research Funding; Apopharma: Consultancy; WorldcareClinical: Consultancy; Philips Healthcare: Research Funding; BluebirdBio: Consultancy; Celgene: Consultancy.

International audience; Sickle cell disease (SCD) is a chronic blood disorder that is often associated with acute and chronic cerebrovascular complications, including strokes and impaired cognition. Using functional resting state magnetic resonance images, we performed whole-brain analysis of the amplitude of low frequency fluctuations (ALFF), to detect areas of spontaneous blood oxygenation level dependent signal across brain regions. We compared the ALFF of 20 SCD patients to that observed in 19 healthy, age and ethnicity-matched, control subjects. Significant differences were found in several brain regions, including the insula, precuneus, anterior cingulate cortex and medial superior frontal gyrus. To identify the ALFF differences resulting from anemia alone, we also compared the ALFF of SCD patients to that observed in 12 patients having comparable hemoglobin levels but lacking sickle hemoglobin. Increased ALFF in the orbitofrontal cortex and the anterior and posterior cingulate cortex and decreased ALFF in the frontal pole, cerebellum and medial superior frontal gyrus persisted after accounting for the effect of anemia. The presence of white matter hyperintensities was associated with depressed frontal and medial superior frontal gyri activity in the SCD subjects. Decreased ALFF in the frontal lobe was correlated with decreased verbal fluency and cognitive flexibility. These findings may lead to a better understanding of the pathophysiology of SCD.

Sickle cell disease (SCD) is a genetic hematological disease in which the hemoglobin molecule in red blood cells is abnormal. It is closely associated with many symptoms, including pain, anemia, chest syndrome and neurocognitive impairment. One of the most debilitating symptoms is elevated risk for cerebro-vascular accidents. The corpus callosum (CC), as the largest and most prominent white matter (WM) structure in the brain, can reflect the chronic cerebrovascular damage resulting from silent strokes or infarctions in asymptomatic SCD patients. While a lot of studies have reported WM alterations in this cohort, little is known about the shape deformation of the CC. Here we perform the first surface morphometry analysis of the CC in SCD patients using four different shape metrics on T1-weighted magnetic resonance images. We detect regional surface morphological differences in the CC between 11 patients and 10 healthy control subjects. Differences are located in the genu, posterior midbody and splenium, potentially casting light on the anatomical substrates underlying neuropsychological test differences between the SCD and control groups.

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. ClinicalTrials.gov 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.

The posterior fossa syndrome (PFS) is common after cerebellar tumor resection in pediatric patients. It is characterized by postoperative mutism and ataxia and associated with persistent abnormalities in mood and cognition. Method: A 2-year prospective study of children and adolescents with cerebellar tumors identified by neuroimaging was performed at the Children’s Hospital Los Angeles. Results: There were 8 girls and 14 boys in the study, aged 14 months to 17 years. The tumor sizes ranged from 2 to 6.5 cm in diameter. The patients presented with ataxia, headache, vomiting, depressed or irritable mood and inattention. Symptoms of PFS were present postoperatively in all except for the 2 patients with lateral tumors. The symptoms began before resection, were most prominent immediately after surgery, and improved over time. Neuropsychological assessment of 10 patients documented a persistent cognitive decrement. Conclusion: This small, descriptive study provides information on the natural history of pediatric posterior fossa tumors from before surgery through the postoperative period.

Background Evaluation of neurocognitive outcomes after a treatment strategy of chemotherapy followed by reduced-dose and volume irradiation for primary central nervous system (CNS) germinoma. Methods Neuropsychological evaluations including measures of verbal and nonverbal intellectual functioning, working memory, processing speed, verbal and nonverbal memory, executive functioning, depression, anxiety, and social functioning were analyzed for all patients (N = 20) with histologically diagnosed CNS germinoma diagnosed at our institution between 2003 and 2009. All 20 patients underwent at least one neuropsychological evaluation, 14 patients had at least two evaluations, 7 patients had at least three, and 2 had four, generating a total of 43 test batteries at a mean of 3.0 years from diagnosis. Results The 20 patients performed as a group in the average range on all neurocognitive measures administered when compared to the nonmedical normative group. No decline over time was indicated on any of the neurocognitive measures. An improvement over time was indicated for nonverbal reasoning, nonverbal memory, processing speed, working memory, response inhibition, and cognitive flexibility. No significant differences were found by tumor location, age at diagnosis, or hydrocephalus at presentation. Conclusions For pediatric and adolescent patients with newly diagnosed CNS germinoma, modest chemotherapy followed by reduced dose ventricular field irradiation with simultaneous integrated boost to the primary site, is associated with preservation of neurocognitive, social and emotional functioning. Pediatr Blood Cancer 2011; 57: 669–673. © 2011 Wiley-Liss, Inc.

Background The standard treatment for ependymoma is surgical resection followed by postoperative irradiation to the local site. The role of radiation therapy in completely resected supratentorial ependymoma has been questioned over the past two decades. Procedure Retrospective review of the medical records of all consecutively diagnosed supratentorial ependymoma patients at Children's Hospital Los Angeles between January 1999 and December 2009. Results Ten patients (three females) were included. The median age at presentation was 5.6 years (range 1.8–15.6 years). Reviewed histology was anaplastic ependymoma in seven patients and cellular ependymoma in three patients. Gross total resection was achieved in six patients; five were observed and one received chemotherapy. In the four patients who underwent subtotal resection, one was observed, two received local irradiation and one received irradiation and chemotherapy. The median length of follow up was 43 (range 22–81) months. Four relapses were observed; two patients who underwent initial gross total resection. All patients who underwent gross total resection were alive at the time of preparation of this article. The 5-year progression-free and overall survival rates were 53 ± 19% and 86 ± 13% respectively. Conclusions Radiation therapy was avoided in five patients following gross total resection, four of whom had anaplastic histology. In some children with completely resected supratentorial ependymoma, surgery alone may be an acceptable treatment option. Pediatr Blood Cancer 2012; 58: 380–383. © 2011 Wiley Periodicals, Inc.

Background The purpose of this study is to evaluate the relationship between brain tumour location and core areas of cognitive and behavioural functioning for paediatric brain tumour survivors. The extant literature both supports and refutes an association between paediatric brain tumour location and neurocognitive outcomes. We examined neuropsychological test data to identify any differences in neurocognitive and behavioural profile associated with supratentorial versus infratentorial tumour location. Methods Following Institutional Review Board approval, the medical records and neuropsychological test data collected between 1997 and 2002 for 70 children treated for brain tumour at Children's Hospital Los Angeles were reviewed. Fifty-one per cent of the participants had tumours located in the supratentorial regions of the brain, whereas 49% had infratentorial tumours. Primary medical treatments involved tumour resection (90%), cranial radiation therapy (76%), chemotherapy (71%), and 59% all three medical procedures. The two tumour location groups did not differ significantly in the cumulative treatment dose of irradiation to the tumour bed or in the dose delivered to the whole brain. Neuropsychological test data included measures of verbal and non-verbal intellectual functioning, attention/working memory, processing speed, verbal and visual memory, fine motor skills, visual–motor integration, academic achievement, and social–emotional functioning. Differences between the two groups were evaluated using anova, t-tests and chi-squared statistical tests. Results The supratentorial and infratentorial tumour location groups did not differ on measures of intellectual functioning. However, survivors of infratentorial tumours performed more poorly on selected measures of more specific cognitive functions and on parent-report of social–emotional functioning relative to survivors of supratentorial tumours, even when age at diagnosis was held as a covariate. Higher frequency of auditory deficits was noted in the infratentorial tumour group and was associated with lowered academic achievement scores. Conclusions The differences by location found in more specific neurocognitive and social–emotional variables, after controlling for age at diagnosis, may possibly reflect tumour location-specific effects. However, this interpretation remains tentative given the limitations in our study and inability to control for the range of medical and treatment-related factors that may have contributed towards the outcomes observed in our sample. At the same time, most of our findings appear consistent with reports from recent studies in this area.

Children with brain tumors treated with cranial irradiation experience significant cognitive late effects. Cranial irradiation followed by posterior fossa boost results in high doses of radiation to the thalamus, hippocampus and putamen, structures critical to cognitive functioning. Twenty-three children (mean 12 years of age) with a history of posterior fossa tumor (13 treated with surgery, chemotherapy and cranial irradiation; 10 treated with surgery and chemotherapy) underwent neuroimaging, neurocognitive and psychosocial assessment 3.7 to 8.8 years after treatment. The putamen, thalamus and hippocampus were manually segmented in the radiation treatment group and the dose to each structure was calculated. Differences in patient demographics and medical history among patients in each treatment group were evaluated using the χ(2) test (for categorical variables) and t-test (for continuous variables). Linear regression was utilized to examine differences in neuropsychological test scores and QOL measures among the two treatment groups. Time off treatment was a significant predictor of verbal comprehension standard index score and BRIEF(®) metacognition index for survivors in both treatment groups, before correction for multiple comparisons. There were no significant differences on psychometric scores between the two groups after Bonferroni correction, and no significant correlation of structural radiation dose to scores; however, there was wide range of abilities from impaired to superior in both groups in this small sample.

Introduction: Mutant mouse models with congenital heart disease (CHD) were observed to have distinct brain dysplasia, prompting an assessment for brain anomalies in CHD patients. CHD infants with brain magnetic resonance imaging (MRI) assessments were recruited and scored using a novel brain dysplasia index. Validation was conducted with parallel brain connectome analysis and neurodevelopment outcome assessments. Methods: The Ohia mutant mouse line and others were analyzed for brain defects using 3D episcopic confocal histopathology. In parallel, we recruited 220 CHD neonates with MRI scans from two large centers. This included pre and postoperative conventional MRI sequences and diffusion tensor imaging (DTI). Brain connectivity measurements with DTI-graph analysis and neurodevelopmental testing at 18 months of age (Battelle Developmental Inventory) were obtained. Results: The CHD mouse mutant analysis revealed high prevalence of brain dysplasia involving the olfactory bulb, cerebellum, hippocampus, corpus callosum and choroid plexus. Based on these findings, a brain dysplasia index (BDI) was developed for clinical assessment of CHD patients, with one point for abnormality in any of these structures right or left and for presence of extra-axial cerebral spinal fluid. Analysis of 220 CHD neonates yielded BDI scores ranging from 1 to 17, with average score of 4.1. An elevated BDI score was seen across a spectrum of cardiac lesions, and was similar pre-op and post-op. DTI graph connectivity measurements (reduced nodal efficiency) correlated with high BDI score (p Conclusion: A brain dysplasia index was developed based on brain anomalies seen in CHD mutant mouse models. Infants with CHD of a broad spectrum with high BDI score showed abnormal brain connectivity and poor neurodevelopmental outcome. These findings suggest the poor neurodevelopmental outcome associated with CHD may involve subtle brain dysplasia with a shared developmental etiology with the structural heart disease.

Objectives: Term congenital heart disease (CHD) neonates demonstrate pre-operative (op) abnormal brain metabolism (reduced N-acetylaspartate (NAA), elevated lactate) on long echo MR spectroscopy (MRS). We sought to delineate associations between serial brain metabolism and patient and perioperative clinical factors in term neonates with CHD using short echo MRS. We measured NAA and lactate as well as other metabolites important for brain connectivity such as neurotransmitters glutamate/glutamine and GABA. Methods: Subjects were prospectively enrolled to undergo pre and post-op 3T short echo single voxel MRS of parietal white matter with absolute quantitation of 15 metabolites using LCModel. Neurodevelopment (ND) was assessed via 18 month Battelle Developmental Inventory. Linear and logistic regression with false discovery rate correction was used for statistical analysis. Results: Eighty subjects were enrolled 2009-2015 and 21 term CHD infants underwent both pre and post-op MRS. Eight infants had at least one MRS and ND. NAA and glutamate were significantly decreased post-op compared to pre-op (p Conclusion: In term CHD neonates, serial brain metabolism by MRS demonstrates alterations beyond NAA, including neurotransmitters GABA and glutamate/glutamine. These abnormalities are associated with multiple clinical pre and post-op factors and also predict prolonged hospital stay and 18 month ND.

To determine associations between patient and clinical factors with postnatal brain metabolism in term neonates with congenital heart disease (CHD) via the use of quantitative magnetic resonance spectroscopy.Neonates with CHD were enrolled prospectively to undergo pre- and postoperative 3T brain magnetic resonance imaging. Short-echo single-voxel magnetic resonance spectroscopy of parietal white matter was used to quantify metabolites related to brain maturation (n-acetyl aspartate, choline, myo- inositol), neurotransmitters (glutamate and gamma-aminobutyric acid), energy metabolism (glutamine, citrate, glucose, and phosphocreatine), and injury/apoptosis (lactate and lipids). Multivariable regression was performed to search for associations between (1) patient-specific/prenatal/preoperative factors with concurrent brain metabolism and (2) intraoperative and postoperative factors with postoperative brain metabolism.A total of 83 magnetic resonance images were obtained on 55 subjects. No patient-specific, prenatal, or preoperative factors associated with concurrent metabolic brain dysmaturation or elevated lactate could be identified. Chromosome 22q11 microdeletion and age at surgery were predictive of altered concurrent white matter phosphocreatine (P .0055). The only significant intraoperative association found was increased deep hypothermic circulatory arrest time with reduced postoperative white matter glutamate and gamma-aminobutyric acid (P .0072). Multiple postoperative factors, including increased number of extracorporeal membrane oxygenation days (P .0067), intensive care unit, length of stay (P .0047), seizures in the intensive care unit (P .0009), and home antiepileptic use (P .0002), were associated with reduced postoperative white matter n-acetyl aspartate.Multiple postoperative factors were found to be associated with altered brain metabolism in term infants with CHD, but not patient-specific, preoperative, or intraoperative factors.

Purpose High-grade gliomas of the CNS are characterized by poor treatment response and prognosis for long-term survival. The Children's Oncology Group (COG) L991 study investigated the neuropsychological, behavioral, and quality of life (QoL) outcomes after treatment on the Children's Cancer Group (CCG) trial for high-grade gliomas (CCG-945). Patients and Methods Fifty-four patients (29 males, 25 females) with a median age of 8.8 years at diagnosis (range, 0.2 to 19.5 years) were enrolled at 25 institutions in North America, representing 81% of available survivors; median length of follow-up was 15.1 years (range, 9.5 to 19.2 years), and median age at study evaluation was 23.6 years (range, 11.3 to 36 years). Standardized tests of neuropsychological functioning and QoL were performed. Descriptive statistics summarized principal findings, and one-way analysis of variance identified potential predictors of outcomes. Results With an average follow-up time of 15 years, survivors demonstrated intellectual functioning within the low-average range. Executive functioning and verbal memory were between the low-average and borderline ranges. In contrast, visual memory and psychomotor processing speed were between the borderline and impaired ranges, respectively. Approximately 75% of patient reported overall QoL within or above normal limits for both physical and psychosocial domains. Nonhemispheric tumor location (midline or cerebellum), female sex, and younger age at treatment emerged as independent risk factors. Conclusion These results serve as a benchmark for comparison with future pediatric high-grade glioma studies, in addition to identifying at-risk cohorts that warrant further research and proactive interventions to minimize late effects while striving to ensure survival.

Background The purpose of this study was to evaluate a reduced irradiation dose strategy for newly diagnosed primary central nervous system (CNS) germinomas. Methods Twenty patients with histologically diagnosed localized pure germinoma (n = 19) or germinoma with a mature teratoma component (n = 1) received four cycles of carboplatin and etoposide at 3-week intervals. In 18 patients, chemotherapy was followed by whole ventricular irradiation to 21.6–25.5 Gy with a simultaneous integrated or sequential primary site boost to 30–30.6 Gy. Initial tumor markers for beta-human chorionic gonadotrophin (HCGβ) and alpha-fetoprotein (AFP) were evaluated in serum and lumbar cerebrospinal fluid (CSF). Endoscopic biopsies were performed in 12 patients and partial resections in the remaining 8 patients at diagnosis. Neurocognitive function was evaluated periodically following treatment. Results Eighteen of 20 patients are without evidence of residual or recurrent tumor. Both relapsing patients were subsequently determined to harbor malignant non-germinomatous germ cell tumor (NGGCT). This retrospective study shows that the Kaplan–Meier estimates of event-free survival (EFS) and overall survival (OS) at 3 years for all 20 patients were 89.5 ± 7.1% and 100%, respectively. Neurocognitive function was well preserved in all 19 evaluable patients. Conclusion Chemotherapy followed by reduced dose whole ventricular and local boost irradiation appears to be effective in patients with localized pure CNS germinoma with evidence of preservation of neurocognitive function. Pediatr Blood Cancer 2010;55:42–46. © 2010 Wiley-Liss, Inc.

BACKGROUND: Mitigating long-term treatment-related effects in survivors of pediatric brain tumors is hampered, in part, by a long clinical prodrome, ill-defined diagnostic criteria, and reliance on indirect observations of the brain. Recently, oxidative stress has been associated with several forms of brain injury. The brain's response to increased oxidative stress includes, in part, a shift from oxidative phosphorylation to glycolysis for its ATP production. We investigated if lactate, a product of glycolysis, was increased in the brain of a patient with treatment-related brain injury via magnetic resonance spectroscopy (MRS). METHODS: A 24 year-old patient treated for a mixed germ cell tumor at the age of 17 with a standard protocol including high-dose chemotherapy, hematopoietic progenitor cell rescue, and irradiation developed evidence of treatment-related brain injury 6 years later. MRS was performed on abnormal-appearing white matter before and serially over 100 minutes after oral administration of 13Carbon-labeled glucose. RESULTS: MRS of abnormal-appearing parietal white matter demonstrated inverted choline:creatine ratio, decreased levels of N-acetyl aspartate, and elevated levels of lactate when compared to historical age-matched controls. Subsequent spectra obtained over the course of 100 minutes following administration of 13Carbon-labeled glucose demonstrated a linear decrease in the concentration of native 12Carbon lactate (slope = -0.003, R2 = 0.51, p = 0.006). CONCLUSIONS: The metabolite profile of the abnormal white matter was not consistent with a non-metabolically active pool or necrosis. The real-time decrease of observed 12Carbon lactate indicated the active production of 13Carbon lactate following oral 13Carbon-labeled glucose administration. To our knowledge, this is the most direct evidence of active glycolysis in the abnormal-appearing white matter in a survivor of a pediatric brain tumor with treatment-related brain injury. Thus, the detection of active glycolysis by increased concentrations of lactate may indicate a compensatory mechanism of neurons under increased oxidative stress and serve as a potential biomarker for this injury.