Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children's Cancer Group study.

PURPOSE: To investigate the intellectual outcomes of children with medulloblastomas/primitive neuroectodermal tumors (MB/PNET) treated with reduced-dose craniospinal radiotherapy (RT) plus adjuvant chemotherapy. PATIENTS AND METHODS: Forty-three children with average-risk posterior fossa MB/PNETs underwent longitudinal intelligence testing. All had been treated with a reduced-dose craniospinal RT regimen (23.4 Gy to the neuraxis, 32.4-Gy boost to the posterior fossa) and adjuvant chemotherapy. RESULTS: The estimated rate of change from baseline was significant for Full Scale Intelligence Quotient (FSIQ), Verbal IQ (VIQ), and Nonverbal IQ (NVIQ) (P <.001 for all three outcomes). The rate of change was estimated to be -4.3 FSIQ points per year, -4.2 VIQ points per year, and -4.0 NVIQ points per year. Females were more subject to VIQ decline than were males (P =.008), and young children (< 7 years of age) were more negatively affected than were older children, with a significant decline in NVIQ (P =.016). Finally, patients with higher baseline evaluations suffered greater declines in IQ than did those with lower baseline scores. CONCLUSION: This study represents the largest series of patients with average-risk MB/PNETs treated with a combination of reduced-dose RT and adjuvant chemotherapy whose intellectual development has been followed prospectively. Intellectual loss was substantial but suggestive of some degree of intellectual preservation compared with effects associated with conventional RT doses. However, this conclusion remains provisional, pending further research.

Neuropsychological functioning of youths with sickle cell disease: comparison with non-chronically ill peers.

OBJECTIVE: To compare the neuropsychological functioning of children with sickle cell disease (SCD) with no evidence of overt clinical stroke to that of classmates without a chronic illness matched on gender, race, and age. We examined both overall level of performance and patterns of performance utilizing empirically derived construct scores of key domains of neurocognitive functioning. METHODS: An abbreviated neuropsychological battery of tests was given to 31 children with SCD and 31 case controls. Empirically derived construct scores were developed for primary analyses. RESULTS: Children with SCD had significantly lower scores on three level-of-performance construct scores: total, verbal, and attention/memory. Mean scores for children with SCD were lower than those for case controls on every level-of-performance construct score and every standardized test score. However, pattern-of-performance construct scores were not significantly different. CONCLUSIONS: Children with SCD without overt stroke demonstrate significant deficits in neurocognitive functioning compared to classroom case controls. These findings highlight the impact of SCD on general neurocognitive functioning and suggest that routine screening of cognitive functioning should be a requisite element of comprehensive care for children with SCD. Within the context of documented physical limitations, we conclude that children with SCD are at very high risk for impaired psychosocial outcomes.

Early exposure to lead and juvenile delinquency.

Cross-sectional studies have reported an association between lead (Pb) levels in bone and delinquent behavior in later childhood and adolescence. This is the first prospective longitudinal study of Pb and child development to address this question with comprehensive assessments of toxicant exposure and other developmental cofactors. A prospective longitudinal birth cohort of 195 urban, inner-city adolescents recruited between 1979 and 1985 was examined. Relationships between prenatal and postnatal exposure to Pb (serial blood Pb determinations) and antisocial and delinquent behaviors (self- and parental reports) were examined. Prenatal exposure to Pb was significantly associated with a covariate-adjusted increase in the frequency of parent-reported delinquent and antisocial behaviors, while prenatal and postnatal exposure to Pb was significantly associated with a covariate-adjusted increase in frequency of self-reported delinquent and antisocial behaviors, including marijuana use. Use of marijuana itself by Cincinnati Lead Study (CLS) teens was strongly associated with all measures of delinquent and antisocial behavior. This prospective longitudinal study confirmed earlier clinical observations and recent retrospective studies that have linked Pb exposure with antisocial behavior in children and adolescents. Both prenatal and postnatal exposure to Pb were associated with reported antisocial acts and may play a measurable role in the epigenesis of behavioral problems independent of the other social and biomedical cofactors assessed in this study.

The relationship between CVLT-C process scores and measures of executive functioning: lack of support among community-dwelling adolescents.

In an effort to characterize how a child goes about learning and recalling information, the developers of the California Verbal Learning Test for Children (CVLT-C) provided normative data related to both learning outcome and learning process. The present study examined the assertion that CVLT-C process indices relate to executive functioning in a sample of community-dwelling adolescents. Contrary to predictions, measures of executive functioning typically correlated poorly with measures of learning process, despite displaying significant correlations with measures of learning outcome. Although further research is recommended, these findings do not support the clinical interpretation of CVLT-C process indices as reflections of executive functioning.

Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study.

PURPOSE: Medulloblastoma is the most common malignant brain tumor of childhood. After treatment with surgery and radiation therapy, approximately 60% of children with medulloblastoma are alive and free of progressive disease 5 years after diagnosis, but many have significant neurocognitive sequelae. This study was undertaken to determine the feasibility and efficacy of treating children with nondisseminated medulloblastoma with reduced-dose craniospinal radiotherapy plus adjuvant chemotherapy. PATIENTS AND METHODS: Over a 3-year period, 65 children between 3 and 10 years of age with nondisseminated medulloblastoma were treated with postoperative, reduced-dose craniospinal radiation therapy (23.4 Gy) and 55.8 Gy of local radiation therapy. Adjuvant vincristine chemotherapy was administered during radiotherapy, and lomustine, vincristine, and cisplatin chemotherapy was administered during and after radiation. RESULTS: Progression-free survival was 86% +/- 4% at 3 years and 79% +/- 7% at 5 years. Sites of relapse for the 14 patients who developed progressive disease included the local tumor site alone in two patients, local tumor site and disseminated disease in nine, and nonprimary sites in three. Brainstem involvement did not adversely affect outcome. Therapy was relatively well tolerated; however, the dose of cisplatin had to be modified in more than 50% of patients before the completion of treatment. One child died of pneumonitis and sepsis during treatment. CONCLUSION: These overall survival rates compare favorably to those obtained in studies using full-dose radiation therapy alone or radiation therapy plus chemotherapy. The results suggest that reduced-dose craniospinal radiation therapy and adjuvant chemotherapy during and after radiation is a feasible approach for children with nondisseminated medulloblastoma.

Neurologic validity of the Wisconsin Card Sorting Test with a pediatric population.

This study investigated the neurologic validity of the Wisconsin Card Sorting Test (WCST) with a pediatric population; that is, the ability of the test to detect dysfunction in the frontal lobes. Fifty children with diverse etiologies of brain dysfunction were classified via EEG, MRI, or CT as having left hemisphere, right hemisphere, or bilateral frontal, extrafrontal, or multifocal/diffuse regions of brain dysfunction. Findings failed to support the hypotheses that WCST performance is more impaired in frontal lesions than extrafrontal or multifocal/diffuse lesions, or that WCST performance is more impaired in left hemisphere lesions than right. Although the WCST is not helpful in localizing cerebral area of dysfunction, it may still be a clinically useful test for examining processes that children use to solve complex problems.

Recovery in pediatric brain injury: is psychostimulant medication beneficial?

OBJECTIVE: To assess the effects of methylphenidate on attention, memory, behavior, processing speed, and psychomotor skills of children with closed head injuries. DESIGN: Double-blind, placebo-controlled, crossover design. SETTING: An outpatient facility of a children's hospital medical center. PATIENTS: Ten pediatric subjects identified through chart review. Subjects met baseline scores for hyperactivity (Conner's Hyperactivity Index greater than or equal to 60) and intellectual functioning (Verbal Intelligence Quotient greather than or equal to 70) and achieved minimal scores on two psychometric tests. All subjects evidenced head injury by focal lesions on computed tomography scan and/or sequelae reported at the time of injury. Severity of injury ranged from mild to severe. All subjects were medically stable at the time of testing. Mean time post injury was 2 years, 8 months. INTERVENTION: Administration of methylphenidate and placebo. MAIN OUTCOME MEASURES: Percentage change in scores was calculated to assess differences between baseline and end of methylphenidate/placebo trials. RESULTS: No significant differences between methylphenidate and placebo on measures assessing behavior, attention, memory, and processing speed. CONCLUSIONS: The results of the study call into question the effectiveness of methylphenidate in the pediatric head injury population.

Adult psychosocial outcome in early-treated phenylketonuria.

Concerns about the psychosocial risk of adults with early-treated phenylketonuria (ETPKU) are predicated on four sources of scientific data: (1) consistent documentation of increased behavioural risk in children with ETPKU; (2) recent evidence of neurocognitive impairment in adults with ETPKU; (3) reports of neuroimaging abnormalities in adults with ETPKU; and (4) preliminary evidence of increased rates of psychiatric disturbance in this population. We studied the psychosocial adjustment of 25 patients, aged 18 years and older, with ETPKU. On most psychosocial outcome measures, patients were indistinguishable from 15 sibling controls. However, on a self-report inventory of psychiatric symptoms, 20% of the patients demonstrated significant morbidity. Psychosocial outcome of these patients was unrelated to concurrent or historical biological dietary disease factors, unlike neurocognitive outcome. A strong relationship was demonstrated, however, between neurocognitive measures and psychosocial morbidity. These findings indicate that a significant minority of patients with ETPKU develop psychosocial difficulties with multiple clinical elevations on a psychiatric inventory. However, most adults with ETPKU cope with the challenges of young adulthood with the same degree of success as their unaffected siblings. Neuropsychological surveillance during childhood and adolescence is important in identifying patients at risk for both neurocognitive and psychosocial morbidity.

Mood and global-local visual processing.

Testing hypotheses derived from neuropsychological models of mood, as well as the association of mood states and personality characteristics with global-local visual processing, were examined. Fifty-nine men completed measures associated with depression and positive mood, and were administered a brief perceptual judgment task that assessed global-local visual processing biases. Additionally, 19 of these 59 subjects were administered measures of anxiety and optimism-pessimism and completed an expanded judgment task. Affective and personality variables were then correlated with judgment task performances. Consistent with predictions, positive mood and optimism were directly associated with a global bias and inversely related to a local bias. A converse pattern of findings was obtained with depression and trait anxiety. Implications for research concerning other aspects of visual processing are discussed.

Pre- and post-stroke MRI and neuropsychological studies in sickle cell disease: a case study.

The case of a patient with sickle cell disease is presented in which neuropsychological and magnetic resonance imaging studies were completed prior to and after a right hemispheric stroke. The contribution of a new MR perfusion technique in understanding the neurological complications in this patient is discussed. This case illustrates the complex pathophysiology of neuropsychological deficits in SCD and underscores the need to develop models that better reflect this complexity.

Bone marrow transplantation in a young child with sickle cell anemia.

Bone marrow transplantation (BMT) is the only curative therapy available for hemoglobinopathies. BMT was performed on a young child with sickle cell anemia (SCA) after approximately 9 months of transfusion therapy following her initial stroke. The patient received a matched sibling donor (sickle trait) BMT. The conditioning regimen consisted of busulfan 4 mg/kg/day x 4, cyclophosphamide 50 mg/kg/day x 4. Graft vs. host disease prophylaxis was daily cyclosporine for 6 months. There were no significant complications during BMT. Engraftment occurred on day +17 and the patient was transfusion independent since day +45. Pre-BMT cerebral arteriography showed multiple stenotic cerebral vessels and a moya-moya pattern. Perfusion MRI demonstrated reduced capillary perfusion. Approximately 170 days after BMT the patient experienced episodes of transient left-sided weakness and speech problems. Neuroimaging revealed progression of large vessel pathology by angiography despite significant improvement in cortical perfusion (MR perfusion scan). Molecular analysis by PCR and DNA fingerprinting confirmed absence of mixed mosaicism. Rheologic evaluation showed normal corrected bulk viscosity. It is possible that progression of large vessel pathology and return of clinical symptoms in the face of normal rheologic parameters may be due to worsening of the already damaged cerebral vessels by the BMT conditioning regimen. Further evaluations of patients with SCA undergoing BMT after a stroke are needed to answer this question.

Early-treated phenylketonuria: adult neuropsychologic outcome.

Twenty-five adults with phenylketonuria that was treated early were compared with 15 unaffected control siblings with respect to intellectual and neuropsychologic measures. Patients were found to have normal intelligence but were significantly lower than their control siblings on measures of intelligence, attention, and complex visuoconstructional ability. Stepwise multiple regression analyses found the patients' intellectual outcome to be best predicted by indexes reflecting early insult to the brain, whereas performance on a measure of novel problem solving was best predicted by concurrent serum phenylalanine level. Different pathophysiologic mechanisms may thus account for cognitive deficits in this population. These results provide further evidence of continuing benefits of dietary adherence into adulthood.

Long-term neurobehavioral outcome in pediatric brain-tumor patients: review and methodological critique.

This paper provides an overview of pediatric brain tumors and reviews the literature on long-term neurobehavioral outcomes for these children. Progress in this area has been slow due to numerous methodological and practical complications. While some general conclusions can be drawn, the development of comprehensive models awaits more research into the multiplicity of biological and nonbiological events, and their interactions, potentially affecting outcome. Increased theoretical and methodological sophistication will be needed to address this complex classification of diseases. Barriers to research in this area are enumerated as are suggestions for future efforts.

Social interactions between children with cancer or sickle cell disease and their peers: teacher ratings.

We evaluated the social reputation of children with cancer (nonprimary brain tumors) (n = 26) children with a primary malignancy involving the central nervous system (n = 15), and children with sickle cell disease (SCD) (n = 33) using a standardized measure of social reputation, the Revised Class Play (RCP). Each child's classroom teacher completed the RCP, an instrument designed to assess sociability-leadership, aggressive-disruptive, and sensitive-isolated interpersonal qualities. Matched-pairs analyses comparing the child with chronic illness to one peer in each class who was the same gender/race and the closest date of birth showed children with cancer were nominated more often for sociability-leadership roles and less often for aggressive-disruptive roles. Brain tumor survivors were nominated more often for sensitive-isolated roles. Children with SCD were not significantly different from peers. Findings suggest that the stressful life events associated with cancer or SCD did not have a significant negative impact on social adjustment for school-aged children with these diseases. The data demonstrate the critical need for appropriate controls when evaluating psychosocial morbidity and chronic illness. Better understanding of the processes of resilience for these children who are routinely exposed to heightened stress provides an opportunity to improve the competence of other high-risk youth.