Patterns of intellectual development among survivors of pediatric medulloblastoma: a longitudinal analysis.

PURPOSE: To examine two competing hypotheses relating to intellectual loss among children treated for medulloblastoma (MB): Children with MB either: (1) lose previously learned skills and information; or (2) acquire new skills and information but at a rate slower than expected compared with healthy same-age peers. PATIENTS AND METHODS: Forty-four pediatric MB patients were evaluated who were treated with postoperative radiation therapy (XRT) with or without chemotherapy. After completion of XRT, a total of 150 examinations were conducted by use of the child version of the Wechsler Intelligence SCALES: These evaluations provided a measure of intellectual functioning called the estimated full-scale intelligence quotient (FSIQ). Changes in patient performance corrected for age (scaled scores) as well as the uncorrected performance (raw scores) were analyzed. RESULTS: At the time of the most recent examination, the obtained mean estimated FSIQ of 83.57 was more than one SD below expected population norms. A significant decline in cognitive performance during the time since XRT was demonstrated, with a mean loss of 2.55 estimated FSIQ points per year (P =.0001). An analysis for the basis of the intelligence quotient (IQ) loss revealed that subtest raw score values increased significantly over time since XRT, but the rate of increase was less than normally expected, which resulted in decreased IQ scores. CONCLUSION: These results support the hypothesis that MB patients demonstrate a decline in IQ values because of an inability to acquire new skills and information at a rate comparable to their healthy same-age peers, as opposed to a loss of previously acquired information and skills.

Immediate neurocognitive effects of methylphenidate on learning-impaired survivors of childhood cancer.

PURPOSE: To test if methylphenidate (MPH) has an objective beneficial effect on immediate performance on tests of neurocognitive functions among learning-impaired survivors of childhood acute lymphoblastic leukemia (ALL) and malignant brain tumors (BT). PATIENTS AND METHODS: From July 1, 1997 through December 31, 1998, 104 long-term survivors of childhood ALL or a malignant BT completed neurocognitive screening for learning impairments and concurrent problems with sustained attention. Eligibility criteria for the MPH trial included an estimated intelligence quotient greater than 50, academic achievement in the 16(th) percentile or lower for age in reading, math, or spelling, and an ability to sustain attention on a computerized version of the Conners' Continuous Performance Test (CPT) in the 16(th) percentile or lower for age and sex. Of the 104, 32 (BT, n = 25; ALL, n = 7) were eligible on the basis of these a priori criteria for a randomized, double-blinded, placebo-controlled trial of MPH. The patients ingested a placebo (lactose) or MPH (0.6 mg/kg; 20 mg maximum) and repeated selected portions of the screening battery 90 minutes later. RESULTS: Compared to the 17 patients randomized to the placebo group, the 15 patients randomized to the MPH group had a significantly greater improvement on the CPT for sustained attention (errors of omission, P =.015) and overall index (P =.008) but not for errors of commission (indicative of impulsiveness) nor reaction times. A trend for greater improvement in the MPH group on a measure of verbal memory failed to reach statistical significance. No trend was observed for MPH effectiveness in improving learning of a word association task. No significant side effects from MPH were observed. CONCLUSION: MPH resulted in a statistically significant improvement on measures of attention abilities that cannot be explained by placebo or practice effects.

Risks of young age for selected neurocognitive deficits in medulloblastoma are associated with white matter loss.

PURPOSE: To test the hypothesis that inadequate development of normal-appearing white matter (NAWM) is associated with the relationship between young age at the time of craniospinal irradiation (CRT) and deficient neurocognitive performance in survivors of childhood medulloblastoma. PATIENTS AND METHODS: Forty-two patients treated since 1985 participated in this cross-sectional study. All had been treated with CRT with or without chemotherapy and had survived 1 or more years after treatment. Neurocognitive evaluations were conducted with tests of intellect (intelligent quotient; IQ), verbal memory, and sustained attention. Quantitative magnetic resonance imaging, using a hybrid neural network, assessed the volume of NAWM. RESULTS: Neurocognitive test results were below normal expectations for age at the time of testing. A young age at CRT was significantly associated with worse performance on all neurocognitive tests except that of verbal memory. An increased time from completion of CRT was significantly associated with worse performance on all neurocognitive tests except that of sustained attention. After statistically controlling for the effects of time from CRT, we examined the association of NAWM with neurocognitive test results. These analyses revealed that NAWM accounted for a significant amount of the association between age at CRT and IQ, factual knowledge, and verbal and nonverbal thinking, but not sustained attention or verbal memory. CONCLUSION: The present results suggest that, at least for some cognitive functions, deficient development and/or loss of NAWM after CRT may provide a neuroanatomical substrate for the adverse impact of a young age at the time of CRT.

Effect of ionizing radiation on the human brain: white matter and gray matter T1 in pediatric brain tumor patients treated with conformal radiation therapy.

OBJECTIVE: To test a hypothesis that fractionated radiation therapy (RT) to less than 60 Gy is associated with a dose-related change in the spin-lattice relaxation time (T1) of normal brain tissue, and that such changes are detectable by quantitative MRI (qMRI). METHODS: Each of 21 patients received a qMRI examination before treatment, and at several time points during and after RT. A map of brain T1 was calculated and segmented into white matter and gray matter at each time point. The RT isodose contours were then superimposed upon the T1 map, and changes in brain tissue T1 were analyzed as a function of radiation dose and time following treatment. We used a mixed-model analysis to analyze the longitudinal trend in brain T1 from the start of RT to 1 year later. Predictive factors evaluated included patient age and clinical variables, such as RT dose, time since treatment, and the use of an imaging contrast agent. RESULTS: In white matter (WM), a dose level of greater than 20 Gy was associated with a dose-dependent decrease in T1 over time, which became significant about 3 months following treatment. In gray matter (GM), there was no significant change in T1 over time, as a function of RT doses < 60 Gy. However, GM in close proximity to the tumor had an inherently lower T1 before therapy. Neither use of a contrast agent nor a combination of chemotherapy plus steroids had a significant effect on brain T1. CONCLUSION: Results suggest that T1 mapping may be sensitive to radiation-related changes in human brain tissue T1. WM T1 appears to be unaffected by RT at doses less than approximately 20 Gy; GM T1 does not change at doses less than 60 Gy. However, tumor appears to have an effect upon adjacent GM, even before treatment. Conformal RT may offer a substantial benefit to the patient, by minimizing the volume of normal brain exposed to greater than 20 Gy.

Subtle white matter volume differences in children treated for medulloblastoma with conventional or reduced dose craniospinal irradiation.

Medulloblastoma is the most common malignant brain tumor in children, and approximately seventy percent of average-risk patients will achieve long-term survival. Craniospinal irradiation (CSI), combined with chemotherapy and surgery, is currently the mainstay of treatment but places children who survive at risk for serious neurocognitive sequelae. These sequelae are intensified with a younger age at treatment, greater elapsed time following treatment, and an increased radiation dose. Many newer treatment approaches have attempted to address this problem by reducing the dose of the CSI component of radiation therapy while maintaining the current survival rates. This study evaluates longitudinal MR imaging during therapy to assess the impact of the two CSI doses (conventional [36 Gy] and reduced [23.4 Gy]) on normal appearing white matter volumes (NAWMV) evaluated in a single index slice. Twenty-six children and young adults at least three years of age enrolled on an institutional protocol for newly diagnosed, previously untreated primary medulloblastoma had at least four MR examinations over a minimum nine month period following CSI. These serial volumes were evaluated as a function of time since CSI in three analyses: 1) all subjects, 2) subjects stratified by age at CSI, and 3) subjects stratified by CSI dose. The first analysis demonstrated that medulloblastoma patients treated with CSI have a significant loss of NAWMV in contradistiction to normally expected maturation. Stratifying the patients by age at CSI found no significant differences in the rate of NAWMV loss. The final analysis stratified the patients by CSI dose and revealed that the rate of NAWMV loss was 23% slower in children receiving reduced-dose. Serial quantitative MR measures of NAWMV may provide a neuroanatomical substrate for assessing functional impact of CSI on normal brain function following treatment for medulloblastoma.

Guidelines for the recognition, prevention, and remediation of burnout in health care professionals participating in the care of children with cancer: report of the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology.

This is the eighth official document of the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology, instituted in 1991. It deals with a topic discussed and approved by the SIOP Committee; namely, "Recognition, prevention, and remediation of burnout in health care professionals participating in the care of children with cancer." It is addressed to the Pediatric Oncology community and outlines: 1) the general definition of burnout as mental and physical exhaustion, indifference, sense of failure as a professional, and sense of failure as a person; 2) the causes of burnout from the nature of the work itself, the work environment, and the characteristics of the individual; 3) the prevention of burnout, changing the detrimental aspects of one's work environment and modifying one's own behavior; and accepting methods to remediate burnout when it occurs.

Cognitive and academic functioning in survivors of pediatric bone marrow transplantation.

PURPOSE: To evaluate cognitive and academic functioning in survivors of pediatric bone marrow transplants (BMTs) at 1 and 3 years after a BMT. PATIENTS AND METHODS: In a prospective, longitudinal design, patients underwent a comprehensive battery of neurocognitive measures before admission for transplantation and at 1, 3, and 5 years after a BMT. This article describes a cohort of 102 survivors with follow-up data available for 1 year after a BMT, including 54 survivors with follow-up available for 3 years. This represents the largest cohort of pediatric BMT survivors yet reported in a prospective study. RESULTS: In the cohort as a whole, there were no significant changes on global measures of intelligence (intelligence quotient [IQ]) and academic achievement at either 1 or 3 years after a BMT, despite adequate power to detect an IQ change of three points or greater. Likewise, performance on specific tests of neuropsychologic function remained stable. No significant differences were observed between patients whose conditioning regimen included total-body irradiation (TBI) and those whose did not. The primary predictor of neurocognitive outcome was patient age, with younger patients more likely to show declines over time. The subset of patients who were less than 3 years of age at the time of transplantation seemed to be particularly vulnerable to cognitive sequelae. CONCLUSION: The use of BMTs with or without TBI entails minimal risk of late neurocognitive sequelae in patients who are 6 years of age or older at the time of transplantation. However, patients who are less than 6 years of age at the time of transplantation, and particularly those less than 3 years of age, seem to be at some risk of cognitive declines.

CNS germinoma: disease control and long-term functional outcome for 12 children treated with craniospinal irradiation.

PURPOSE: To provide evidence that radiation therapy alone in the form of craniospinal irradiation (CSI) and a boost to the primary site of disease provides effective disease control and limited additional morbidity for patients with CNS germinoma. METHODS AND MATERIALS: Twelve patients with a median age of 12 years (range 9-16 years) with CNS germinoma were treated with CSI (median 25.6 Gy, range 23.4-32 Gy) and a boost to the primary site of disease (50.4 Gy, range 45-54 Gy) between January 1987 and June 1998. All patients were biopsied prior to radiation therapy and none received chemotherapy. No patients were lost to follow-up and the majority had long-term (> 45 month) pre- and postirradiation endocrine and psychology assessment. RESULTS: All 12 patients are alive and no failures have occurred with a median follow-up of 69 months (range 14-143 months). Preirradiation endocrine deficiencies were present in 6 of 6 suprasellar tumors and 1 of 6 pineal tumors; with follow-up there was no substantial difference between age and gender adjusted pre- and postirradiation stature and weight. With long-term follow-up, there were no significant differences between pre- and postirradiation full-scale, verbal, and performance IQ scores. CONCLUSIONS: This study confirms the ability of radiation therapy alone to achieve disease control with a high rate of success in pediatric patients and demonstrates that the treatment toxicity faced by these patients may be less than anticipated. Because these patients present with substantial preexisting morbidity at diagnosis and may be of an age where the potential for radiation-related side effects is relatively small, the superiority of treatment alternatives may be difficult to prove.

Neurocognitive deficits in medulloblastoma survivors and white matter loss.

Although previous studies have documented a significant risk of intellectual loss after treatment for childhood medulloblastoma (MED), the pathophysiology underlying this process is poorly understood. The purpose of this study was to test the hypotheses that (1) patients treated for MED in childhood have reduced volumes of normal white matter (NWM) related to their treatment with craniospinal irradiation with or without chemotherapy, and (2) deficits in NWM among patients surviving MED can at least partially explain deficits in their intellectual performance. Eighteen pediatric patients previously treated for MED were matched on the basis of age at the time of evaluation to 18 patients previously treated for low-grade posterior fossa tumors with surgery alone (mean difference, 3.7 months). Evaluations were conducted with age-appropriate neurocognitive testing and quantitative magnetic resonance imaging by using a novel automated segmentation and classification algorithm constructed from a hybrid neural network. Patients treated for MED had significantly less NWM (p < 0.01) and significantly lower Full-Scale IQ values than those treated for low-grade tumors (mean, 82.1 vs 92.9). In addition, NWM had a positive and statistically significant association with Full-Scale IQ among the patients treated for MED. We conclude that irradiation- or chemotherapy-induced destruction of NWM can at least partially explain intellectual and academic achievement deficits among MED survivors.

Survival and neurodevelopmental outcome of young children with medulloblastoma at St Jude Children's Research Hospital.

PURPOSE: Young children treated for medulloblastoma are at especially high risk for morbidity and mortality from their disease and therapy. This study sought to assess the relationship, if any, between patient outcome and M stage. Neuropsychologic and endocrine outcomes were also assessed. PATIENTS AND METHODS: Twenty-nine consecutively diagnosed infants and young children were treated for medulloblastoma at St Jude Children's Research Hospital between November 1984 and December 1995. All patients were treated with the intent of using postoperative chemotherapy to delay planned irradiation. RESULTS: The median age at diagnosis was 2.6 years. Six patients completed planned chemotherapy without progressive disease and underwent irradiation at completion of chemotherapy. Twenty-three children experienced disease progression during chemotherapy and underwent irradiation at the time of progression. The 5-year overall survival rate for the entire cohort was 51% +/- 10%. The 5-year progression-free survival rate was 21% +/- 8%. M stage did not impact survival. All patients lost cognitive function during and after therapy at a rate of -3.9 intelligence quotient points per year (P =.0028). Sensory functions declined significantly after therapy (P =.007). All long-term survivors required hormone replacement therapy and had growth abnormalities. CONCLUSION: The majority of infants treated for medulloblastoma experienced disease progression during initial chemotherapy. However, more than half of these patients can be cured with salvage radiation therapy, regardless of M stage. The presence of metastatic disease did not increase the risk of dying from medulloblastoma. All patients treated in this fashion have significant neuropsychologic deficits. Our experience demonstrates that medulloblastoma in infancy is a curable disease, albeit at a significant cost.

Subtle brain abnormalities in children with sickle cell disease: relationship to blood hematocrit.

Our objective was to test a hypothesis that subtle brain abnormality can be present in pediatric sickle cell disease (SCD) patients who are clinically free of stroke. We prospectively compared 50 patients with 52 healthy age-similar controls, using quantitative magnetic resonance imaging. A previously validated precise and accurate inversion-recovery method was used to measure T1 in a slice at the basal ganglia. We also used the Wechsler test to measure intelligence quotient (IQ) in a randomly selected subset of 27 patients. Brain T1 was significantly lower in patients in every gray matter structure evaluated but in none of the white matter structures. Regression suggests that T1 in caudate, nucleus pulvinares, and cerebral cortex was abnormal by age 4 years. Psychometric testing showed that 33% of patients were functioning in the range of mild mental deficiency (IQ, 50-70), compared with a published prevalence of 1.45% in inner-city black children. Thus, in our patients, SCD was associated with a 23-fold increase in the risk of mild mental deficiency. Full-scale IQ of SCD patients was a function of hematocrit (Hct), and when Hct was used to stratify patients, those with an Hct of less than 27% had significantly lower psychometric test scores, and significantly lower gray matter T1, than those with an Hct of 27 or more. Both cognitive deficits and subtle T1 abnormalities were associated with a low Hct, and both could be present when conventional magnetic resonance imaging findings were normal. Our findings suggest that chronic hypoxia of brain tissue can occur in SCD patients free of clinical stroke.

Guidelines for assistance to terminally ill children with cancer: a report of the SIOP Working Committee on psychosocial issues in pediatric oncology.

This, the sixth official document of the SIOP Working Committee on psychosocial issues in pediatric oncology, develops another important and especially difficult topic: assistance for terminally ill children with cancer. This is provided for the pediatric oncology community as a useful set of guidelines. It should be always possible for a declining child to die without unnecessary physical pain, fear, or anxiety. It is essential that he or she receive adequate medical, spiritual, and psychological support, and that the child at no point feels abandoned. Palliative care, in the terminal phase of cancer, should be tailored to the different needs and desires of the child and the family, with the goal of providing the best possible quality of life for the days that remain.

Health status and health-related quality of life in long-term adult survivors of pediatric solid tumors.

We have examined the influence of selected factors (gender, marital status, socio-economic status, co-morbid conditions, access to medical care, age at diagnosis, intensity of therapy and time since diagnosis) on subsequent health status and health-related quality of life (HRQL) of long-term survivors of pediatric solid tumors. Two hundred and twenty individuals who had survived a pediatric solid tumor 15 years or longer completed telephone and written assessments of their current status. Health status was assessed using the Late Effects of Normal Tissues toxicity scale. HRQL was investigated using the Ferrans and Powers Quality of Life Index-Cancer (QLIC) and the EORTC Quality of Life Questionnaire C30 (QLQ-C30). Results indicated that health status and HRQL were better in survivors treated with low-intensity therapy. One hundred and thirty respondents (59.1%) reported at least 1 serious toxicity. Dyspnea and fatigue were commonly reported in survivors of Hodgkin's disease. Correlational analyses showed that predictors of health status included socio-economic status, marital status and the presence of co-morbid factors. Mean HRQL scores for the 4 domains of the Ferrans and Powers QLIC and the functional scales of the EORTC QLQ-C30 indicated that most of the survivors were experiencing moderately good to excellent HRQL. One-third of survivors reported that their history of cancer had an adverse impact on their current financial status. Prediction models constructed for 3 of the domains from the 2 HRQL instruments are presented (health and functioning, global HRQL and financial impact). Within these 3 models, consistent predictors of HRQL outcomes included health status, presence of dyspnea or pain, marital status and socio-economic status.

Correlation of the Health Utilities Index Mark 2 cognition scale and neuropsychological functioning among survivors of childhood medulloblastoma.

Children surviving medulloblastoma have a high risk for chronic, treatment-related neurocognitive deficits. Neuropsychological testing provides important data regarding the comparative toxicities of various therapeutic approaches. However, such testing can be expensive and logistically difficult, especially if a consulting psychologist is not readily available at the treating institution. Our purpose was to investigate the usefulness of a health-related quality of life inventory that does not require a psychologist for completion. We assessed the concurrent validity of traditional intelligence (IQ) testing and levels on the Cognition attribute of the multi-attribute Health Utilities Index Mark 2 (HUI 2) in estimating academic achievement scores of 22 patients treated for medulloblastoma with craniospinal irradiation following surgical resection. The results demonstrated that the Cognition utility scores were significantly lower than scores from the other components of the HUI 2 (Sensation, Mobility, Emotion, Self-Care, Pain). Cognition scores were also significantly positively correlated with IQ and achievement scores. Furthermore, Cognition scores were significantly lower among children who had received special educational services when compared with those who had not received such services. Our results provide preliminary evidence of the potential usefulness of the HUI 2 Cognition attribute in estimating IQ, achievement and the likelihood of the need for special educational services among children treated for medulloblastoma.

A hybrid neural network analysis of subtle brain volume differences in children surviving brain tumors.

In the treatment of children with brain tumors, balancing the efficacy of treatment against commonly observed side effects is difficult because of a lack of quantitative measures of brain damage that can be correlated with the intensity of treatment. We quantitatively assessed volumes of brain parenchyma on magnetic resonance (MR) images using a hybrid combination of the Kohonen self-organizing map for segmentation and a multilayer backpropagation neural network for tissue classification. Initially, we analyzed the relationship between volumetric differences and radiologists' grading of atrophy in 80 subjects. This investigation revealed that brain parenchyma and white matter volumes significantly decreased as atrophy increased, whereas gray matter volumes had no relationship with atrophy. Next, we compared 37 medulloblastoma patients treated with surgery, irradiation, and chemotherapy to 19 patients treated with surgery and irradiation alone. This study demonstrated that, in these patients, chemotherapy had no significant effect on brain parenchyma, white matter, or gray matter volumes. We then investigated volumetric differences due to cranial irradiation in 15 medulloblastoma patients treated with surgery and radiation therapy, and compared these with a group of 15 age-matched patients with low-grade astrocytoma treated with surgery alone. With a minimum follow-up of one year after irradiation, all radiation-treated patients demonstrated significantly reduced white matter volumes, whereas gray matter volumes were relatively unchanged compared with those of age-matched patients treated with surgery alone. These results indicate that reductions in cerebral white matter: 1) are correlated significantly with atrophy; 2) are not related to chemotherapy; and 3) are correlated significantly with irradiation. This hybrid neural network analysis of subtle brain volume differences with magnetic resonance may constitute a direct measure of treatment-induced brain damage.

Quantitative MRI of the brain in children with sickle cell disease reveals abnormalities unseen by conventional MRI.

Conventional MRI (cMRI) has shown that brain abnormalities without clinical stroke can manifest in patients with sickle cell disease (SCD). We used quantitative MRI (qMRI) and psychometric testing to determine whether brain abnormalities can also be present in patients with SCD who appear normal on cMRI. Patients 4 years of age and older with no clinical evidence of stroke were stratified by cMRI as normal (n = 17) or abnormal (n = 13). Spin-lattice relaxation time (T1) of gray and white matter structures was measured by the precise and accurate inversion recovery (PAIR) qMRI method. Patient cognitive ability was assessed with a standard psychometric instrument (WISC-III or WISC-R). In all 30 patients with SCD, qMRI T1 was lower than in 24 age- and race-matched controls, in cortical gray matter (P < .0006) and caudate (P < .0009), as well as in the ratio of gray-to-white matter T1 (P < .008). In the 17 patients who were shown to be normal by cMRI, qMRI T1 was still lower than in controls, in both cortical gray matter (P < .02) and caudate (P < .004). Histograms of voxel T1 show that the proportion of voxels with T1 values intermediate between gray and white matter (ie, consistent with encephalomalacia) was 9% higher than controls in patients shown to be normal by cMRI (P < .05) and 15% higher than controls in patients shown to be abnormal by cMRI (P < .0005). The full scale intelligence quotient (FSIQ) of all patients with SCD was 75, compared to the FSIQ of 88 in a historical control group of patient siblings (P < .001). The FSIQ of patients shown to be normal by cMRI was 79, significantly lower than the FSIQ of patient siblings (P < .04). The FSIQ of 71 in patients shown to be abnormal by cMRI was significantly lower than both the patient siblings (P < .005) and the patients shown to be normal by cMRI (P < .04). Patients shown to be abnormal by cMRI scored lower than patients shown to be normal by cMRI, specifically on the subtests of vocabulary (P = .003) and information (P = .03). Cognitive impairment is thus significant, even in patients with SCD who were shown to be normal by cMRI, suggesting that cMRI may be insensitive to subtle neurologic damage that can be detected by qMRI. Because cognitive impairment can occur in children normal by cMRI, our findings imply that prophylactic therapy may be needed earlier in the course of SCD to mitigate neurologic damage.

Abnormalities of the central nervous system in very young children with sickle cell anemia.

OBJECTIVE: To determine whether abnormalities of the CNS are present in very young children with sickle cell anemia. STUDY DESIGN: Thirty-nine children with hemoglobin SS between the ages of 7 and 48 months were examined with magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). No child had a history of clinical stroke, although 3 had a history of seizures (2 neonatal). Twenty-one patients underwent developmental testing with the Bayley or McCarthy Scales. RESULTS: The overall prevalence of CNS abnormalities in asymptomatic children was 4 of 36 (11%, confidence interval 3, 26%). One patient had a silent infarct observed on MRI and a stenotic lesion on MRA; 3 other patients had stenotic lesions on MRA. The 3 patients who had a history of seizures all had lesions consistent with infarcts on MRI. Of the asymptomatic patients who had psychometric testing, 1 of 18 was developmentally delayed. One of 3 with a history of seizures had mild developmental delay. CONCLUSIONS: Very young children with sickle cell anemia (and no history of clinical stroke) have infarction in the brain and/or stenosis of major cerebral arteries, similar to those reported in older children. These findings indicate a need for larger studies to define the incidence of CNS lesions in this age group and to determine the need for early therapeutic intervention to prevent CNS sequelae of sickle cell disease.