Neurocognitive development of children after a cerebellar tumor in infancy: A longitudinal study.

PURPOSE: To assess the long-term neuropsychologic effects experienced by children who have tumors in the cerebellum that are diagnosed and treated during infancy. PATIENTS AND METHODS: Twenty-seven children with posterior fossa tumors diagnosed at less than 36 months of age were assessed prospectively with a comprehensive set of age-appropriate tests. Group means and SDs are reported for assessments conducted at diagnosis (analysis 1) and at the most recent follow-up appointment (analysis 2). Cognitive developmental growth curves were derived from the prospective data (analysis 3) using mixed model regression analyses and controlling for age at diagnosis and socioeconomic status. RESULTS: In the first analysis, eight of 11 infants at diagnosis scored within normal limits on all neuropsychologic domains, except for motor skills, which were impaired. In the second analysis, mean scores at the most recent follow-up of 21 of 27 patients were mostly in the normal range; however, group comparisons between those who had (n = 7) and had not (n = 14) been treated with cranial radiation therapy (CRT) showed that patients in the irradiated (CRT) group scored significantly lower than those in the nonirradiated (No-CRT) group on verbal intelligence quotient (IQ) and in the motor domain. In the third analysis (growth curves of CRT and No-CRT groups), statistically significant differences in slope were found on verbal IQ, performance IQ, perceptual-motor skills, language, and attention/executive skills. Slopes on the fine-motor domain were similar; both groups declined at approximately the same rate. CONCLUSION: Neurocognitive development and outcome of children with cerebellar tumors diagnosed in infancy is very positive among those who were treated with surgery and chemotherapy. Declines in performance across time were minimal, and scores tended to remain within normal limits. By itself, a cerebellar tumor in infancy does not seem to have a significant impact on children. However, those who received CRT as part of their treatment are likely to have neurocognitive and psychosocial deficits that require remediational interventions.

Brain tumors in children with neurofibromatosis: additional neuropsychological morbidity?

Neurofibromatosis type 1 is a common autosomal dominant genetic disorder associated with numerous physical anomalies and an increased incidence of neuropsychological impairment. Tumors of the CNS occur in approximately 15% of children with neurofibromatosis, presenting additional risk for cognitive impairment. This study examines the impact of an additional diagnosis of brain tumor on the cognitive profile of children with neurofibromatosis. A comprehensive battery of neuropsychological tests was administered to 149 children with neurofibromatosis. Thirty-six of these children had a codiagnosis of brain tumor. A subset of 36 children with neurofibromatosis alone was matched with the group of children diagnosed with neurofibromatosis and brain tumor. Although mean scores of the neurofibromatosis plus brain tumor group were, in general, lower than those of the neurofibromatosis alone group, these differences were not statistically significant. Children in the neurofibromatosis plus brain tumor group who received cranial irradiation (n = 9) demonstrated weaker academic abilities than did children with brain tumor who had not received that treatment. These results suggest that neurofibromatosis is associated with impairments in cognitive functioning, but the severity of the problems is not significantly exacerbated by the codiagnosis of a brain tumor unless treatment includes cranial irradiation.

Sibling Adaptation to Childhood Cancer Collaborative Study: the association of sibling adaptation with maternal well-being, physical health, and resource use.

This multi-institutional study investigated the association of behavioral/emotional adaptation among siblings of children with cancer with maternal general well-being, physical health, and resource use. One hundred seventy siblings and mothers completed standardized interviews and self-report measures 6 to 42 months after the cancer was diagnosed. As a group, mothers of children with cancer reported significantly lower levels of well-being than matched controls. When stratified according to the level of the sibling's behavioral/emotional adaptation, mothers of siblings in the Dysfunctional group (1) reported the lowest levels of well-being; (2) during the preceding year, were more likely to have sought professional services than mothers of children in the Resilient group; and (3) were least likely to have found social support helpful. Our results support an association between maternal well-being and sibling adjustment but show it is unlikely that nonspecific social support will improve adjustment. The rationale for problem-solving training for mothers is provided.

MOPP chemotherapy without irradiation as primary postsurgical therapy for brain tumors in infants and young children.

Infants and young children who have brain tumors have a poor rate of survival and high treatment associated morbidity. A trial of mechlorethamine, vincristine (oncovin), procarbazine, and prednisone (MOPP) was performed to test the hypothesis that replacing radiotherapy with chemotherapy would improve survival and decrease long term morbidity of infants who have brain tumors. Between 1976 and 1988, 17 consecutive children less than 36 months old when diagnosed with medulloblastoma or ependymoma were treated with MOPP chemotherapy as primary therapy following surgical excision or biopsy of the tumor. Radiotherapy was reserved for recurrent disease. Ten of 17 children have survived without evidence of disease: medulloblastoma eight of 12 with median survival time of 10.6 years (range, 6.2 to 15.2 yrs); and ependymoma, 2 of 5 (at 13.0 and 16.0 yrs). Four of the 10 children with medulloblastoma and ependymoma who relapsed are now disease free at 7.5, 11.7, 12.2 and 13.5 yrs post relapse after receiving salvage therapy with cisplatin (n = 1) or irradiation (n = 3). All relapses occurred within 26 months of diagnosis. Data on growth demonstrated height less than the 5th percentile in all children who received cranial irradiation compared to 25 to 95th percentile for nonirradiated children. Intellectual ability for the group who did not require radiation was within normal range (mean IQ 100.1) and stable across annual assessments. Those who required radiation had lower IOs which continued to decline over time (mean IQ 85 at mean age of 5.8 years, declining to 63 at 10 years). In young children with brain tumors, primary chemotherapy with MOPP, omitting radiotherapy, provides improved neurodevelopmental outcome and survival.

Correlation of medical and neurosurgical events with neuropsychological status in children at diagnosis of astrocytoma: utilization of a neurological severity score.

Neuropsychological studies of children who have brain tumors have yielded diverse results with respect to identifying factors that contribute to poor intellectual outcome. The purpose of this study was to evaluate the relationship between pre- and perioperative events, tumor-related factors, and the neuropsychological status of children diagnosed with astrocytoma. Events that could potentially be detrimental to neuropsychological outcome were quantified utilizing a new "neurological severity score." The Neurological Severity Score was developed as a research tool to test our hypothesis that ultimate intellectual outcome is a result of cumulative, interactive insults on the central nervous system. This study constitutes a first step in examining the predictive value of the Neurological Severity Score by evaluating its correlation with baseline neuropsychological status. Fifty-nine children who had astrocytoma (36 supratentorial and 23 infratentorial) received complete neurological and neuropsychological evaluations within 3 months of diagnosis. Each child's neurological history and examination results were scored by an independent observer using the Neurological Severity Score. Neuroimages obtained at diagnosis and at the time of neuropsychological testing were evaluated as well. For the group as a whole, memory, attention, and motor abilities were significantly below age-appropriate norms, whereas intelligence, language, and academic skills were preserved. Patterns of deficits were identified and related to tumor site. There were no significant differences in mean neuropsychological domain scores between groups based on gender, pre-versus post-operative status, ethnicity, tumor grade, or abnormalities on magnetic resonance imaging (MRI). The Neurological Severity Score was significantly inversely correlated with visual-spatial skills, memory, attention, performance IQ, and global IQ. In conclusion, among all the medical and neurological factors present at diagnosis, the neurological severity score had the highest correlation with neuropsychological scores. This instrument has promise as a research tool in investigations of the psychological effects of cancer and its treatment on children.

Neuropsychologic effects of chemotherapy on children with cancer: a longitudinal study.

PURPOSE: A prospective study was conducted to assess the effects of chemotherapy for cancer on children's long-term neuropsychologic status. PATIENTS AND METHODS: Ninety-nine children who received no cranial radiation therapy (CRT) completed four annual neuropsychologic assessments. Fifty-one patients received intrathecal (IT) chemotherapy (ITC); 48 received no CNS treatment. These two groups were compared using repeated-measures analysis of variance on IQ, memory, language, freedom from distractibility, academic achievement, executive functions, and fine-motor, perceptual-motor, and tactile-spatial skills. In addition, 51 of the sample of 99 patients had been examined 5 to 11 years after diagnosis. Their data were analyzed to evaluate the longer-term effects of chemotherapy. The predictability of demographic and medical variables on neuropsychologic outcome at 3-year and long-term follow-up study were assessed using multiple regression techniques. RESULTS: Overall, the effects of chemotherapy in the absence of CRT appear to be slight. Patients who received ITC and intravenous (IV) methotrexate declined slightly on perceptual-motor skills, but were still well within the normal range. Both groups, regardless of treatment, declined on academic achievement tests, although not to a statistically significant degree. Age effects were found on performance IQ (PIQ) and perceptual-motor skills. Socioeconomic status (SES) correlated with a large number of variables. Sex effects were not significant. CONCLUSION: The present results are largely consistent with previous findings for nonirradiated groups. Treatment effects from ITC are slightly more apparent 5 to 11 years after diagnosis than at 3-year follow-up evaluation but this does not constitute a clinically meaningful difference. More noticeable are academic declines among all groups, regardless of treatment.

Sibling adaptation to childhood cancer collaborative study: health outcomes of siblings of children with cancer.

OBJECTIVE: This seven-site study examined the overall health status, healthcare utilization, somatization, and health-risk behaviors of siblings of children with cancer compared to these factors in matched controls or normative data. The study also examined whether informants (i.e., siblings, parents, physicians) differed in their assessments of the above health domains. DESIGN: Subjects were 254 siblings of children with cancer from seven different pediatric oncology treatment centers that participated in the Sibling Adaptation to Childhood Cancer Collaborative study group. Predictors of the siblings' health status, healthcare utilization, somatization, and health-risk behaviors were identified, and the relationship between these health domains and the siblings' resiliency vs. dysfunctionality were explored via interviews. RESULTS: Overall, siblings were found to be moderately healthy, although siblings report significant problems with sleeping and eating. Healthcare utilization appears to be reduced for siblings. Most importantly, the parents of these siblings are less likely to seek medical help for a variety of conditions for which parents of control children would bring their children to a doctor. A pattern emerged of parental underreporting of sibling health variables when compared to what the siblings themselves reported. When the relationship between health outcomes and the siblings' adaptation to their sick sibling's illness was examined, the resilient and dysfunctional groups significantly differed from each other. It appears that health outcomes are related to sibling adaptation to the changes brought about by their sick sibling's cancer diagnosis and treatment. CONCLUSIONS: The focus of care for families of children with cancer is often limited to the child with cancer. As indicated in this study, the "healthy" siblings may be overlooked in the process. While parents appear to recognize that their "healthy" children are complaining more about aches and pains, they may have little energy or time to attend to the needs of these other family members. It is the intent of this study to document what clinicians may expect and to highlight the need for evaluation of this otherwise neglected group.

Sibling adaptation to childhood cancer collaborative study: siblings' perceptions of the cancer experience.

Investigated responses of siblings (N = 254) of children with cancer to structured interviews designed to elicit thoughts and feelings about effects of cancer on self and family. Siblings indicated distress about family separations and disruptions, lack of attention, focus of family on the ill child, negative feelings in themselves and family members, cancer treatments and their effects, and fear of death. Siblings also reported becoming more compassionate, families becoming closer, and having experiences they otherwise would not have had. Age and gender differences in responses indicated distinctive perceptions of and vulnerability to the cancer experience. Older siblings were far more likely to report positive effects than younger siblings suggesting that level of maturity can moderate the stress of an ill child within the family.

Neuropsychological profile of children with neurofibromatosis, brain tumor, or both.

Neurofibromatosis type 1, a common autosomal dominant genetic disorder, is associated with numerous physical and medical anomalies as well as an increased incidence of learning disability. Tumors of the central nervous system have been estimated to occur in 15%, but their contribution to neuropsychological status is unknown. This study examines the relative contribution of neurofibromatosis and brain tumor to the cognitive profile of children with neurofibromatosis. A comprehensive battery of neuropsychological and behavioral tests was administered to a group of 65 children with neurofibromatosis type 1. Fourteen were then matched on demographic variables with two other groups of children who had either a brain tumor in addition to neurofibromatosis or a brain tumor alone. The two brain tumor groups were also matched on tumor type, location, and therapy. Mean scores of the neurofibromatosis-brain tumor group were generally the lowest of the three groups; those of the brain tumor group were highest, and performance of the neurofibromatosis group was generally between the other two groups. These results suggest that neurofibromatosis is, by itself, associated with significant cognitive morbidity, but that the severity of the problems is increased somewhat if a brain tumor is also present.

Sibling adaptation to childhood cancer collaborative study: prevalence of sibling distress and definition of adaptation levels.

A multisite collaborative study assessed the frequency and intensity of emotional/behavioral distress in siblings of children with cancer. A sample of 254 siblings, aged 4 to 18 years, and their parents completed interviews and self-report measures 6 to 42 (average 22.5) months after diagnosis of cancer in a brother or sister. Matched controls were obtained from respondents to the Child Health Supplement of the National Health Interview Survey administered in 1988 (CHS88). Before diagnosis, the prevalence of parent-reported emotional/behavioral problems among siblings was similar to that in the general population (7.7% vs 6.3%; p = not significant). After diagnosis, prevalence rose to 18% among siblings. When siblings were grouped according to the presence or absence of problems exacerbated by and/or arising after diagnosis, four levels of adaptation, consistent with scores on the Behavior Problem Scales from the CHS88, emerged. This differentiation may help explain inconsistencies in sibling response reported previously and provides a framework for investigating factors that enhance adaptation.

Neuropsychological changes in children with cancer: the treatment of missing data in longitudinal studies.

Researchers conducting longitudinal studies with children or adults are inevitably confronted with problems of attrition and missing data. Missing data in longitudinal studies is frequently handled by excluding from analyses those cases for whom data are incomplete. This approach to missing data is not optimal. On the one hand, if data are missing at random, then dropping incomplete cases ignores information collected on those cases that could be used to improve estimates of population parameters (e.g., means, variances, covariances, and growth rates) and improve the power of significance tests of statistical hypotheses. On the other hand, if data are not missing at random, then dropping incomplete cases leads to biased parameter estimates and hypothesis tests that may be internally and externally invalid. This study uses three years of follow-up data from a longitudinal investigation of neuropsychological outcomes of cancer in children to demonstrate the problems presented by missing data in repeated measures designs and some solutions. In evaluating potential biasing effects of attrition, the study extends previous research on neuropsychological outcomes in pediatric cancer by inclusion of patients whose disease had relapsed, and by comparison of surviving and nonsurviving patients. Although the data presented have specific relevance to the study of neuropsychological outcome in pediatric cancer, the problems of missing data and the solutions presented are relevant to a wide variety of diseases and conditions of interest to researchers in child and adult neuropsychology.

Neuropsychological effects of central nervous system prophylactic treatment in childhood leukemia: methodological considerations.

Reviewed 53 studies on the effects of central nervous system prophylactic treatment (CNSPT) on cognition and neuropsychological functioning. CNSPT involves irradiation and/or chemotherapy directed to the brain, and is frequently administered to children who have leukemia. The effects of CNSPT on neuropsychological functioning in long-term cancer survivors remains controversial. A number of studies failed to identify any neuropsychological impact secondary to CNSPT, whereas others reported deficits that appear to be a function of CNSPT. Several methodological issues that make it difficult to draw meaningful conclusions from this research literature are identified and discussed. Specific recommendations are made for improvements in research on CNSPT in children.

Neurophysiological basis of cognitive deficits in long-term survivors of childhood cancer.

Thirty-three survivors of childhood cancer were tested with event-related potentials (P300), motor reaction time tests, and neuropsychological tests to assess the underlying physiological basis of treatment-related cognitive sequelae. Thirteen patients had received intrathecal chemotherapy, 11 had received intrathecal chemotherapy plus cranial radiotherapy, and nine had been treated without any form of central nervous system therapy. Neuropsychological performance of the groups treated without cranial radiotherapy was normal, but the group given cranial radiotherapy was significantly impaired. Mean reaction time and P300 latency were somewhat slower in the group given intrathecal chemotherapy relative to the group given no central nervous system treatment, but were significantly delayed in the group given cranial radiotherapy. Correlations of reaction time and P300 latency with neuropsychological test scores were also obtained. Results suggest that slowing of cortical activity secondary to white-matter damage may underlie cognitive decline in children treated with intensive central nervous system therapies, especially cranial radiotherapy.

Improved neuropsychological outcome in children with brain tumors diagnosed during infancy and treated without cranial irradiation.

Neuropsychological outcome of 28 patients with brain tumors diagnosed before the age of 36 months (mean, 19 months) was assessed using a comprehensive battery of tests. Elapsed time between diagnosis and testing averaged 6.2 years. Half the patients had received cranial radiation therapy and surgery, with and without chemotherapy, whereas the rest had received only surgery, with or without chemotherapy. Groups were comparable with respect to tumor diagnosis and location, age at diagnosis, race, and sex. Intellectual functioning was significantly lower in children whose treatment included cranial irradiation than in those treated without cranial irradiation, and this effect was more pronounced in nonverbal than in verbal intellectual abilities. Mean scores for the radiation group were lower than for the no-radiation group in all areas assessed and were significantly below age-based normative means in five of the eight cognitive areas: intellectual, memory, attention, motor, and visual-spatial skills. Mean scores for children in the no-radiation group were generally within the average range in all cognitive areas except visual-spatial skills, which were significantly below age-based normative means. Endocrine deficiencies and growth retardation were much more prevalent in patients treated with cranial irradiation. Because the immature brain is susceptible to treatment-related pathologic changes, infants are at greater risk than older children for significant, long-term neuropsychological, endocrine, and growth sequelae. In children treated without cranial irradiation, morbidity was minimized without an increased rate of mortality.

Psychosocial adjustment among pediatric cancer patients: a multidimensional assessment.

Identified types and frequencies of psychological difficulties manifested by pediatric oncology patients and child-, family-, and illness-related correlates of adjustment. Parents of 48 children with cancer, 4 to 17 years of age, completed the Personality Inventory for Children (PIC). Analysis of mean PIC scores indicated that the children had a high frequency of somatic concerns and problems in academic functioning. Similar mean PIC profiles were obtained for children across gender, age, and diagnostic groups. Overall, 52% of the children had profiles with two or more clinically significant problem areas. Children's adjustment was associated with gender, social competence, and parental coping. Boys exhibited significantly more problems than did girls. Children whom teachers rated as less socially competent and whose parents reported few effective coping responses exhibited greater difficulties in adjustment.

Absence of synergistic effects of CNS treatments on neuropsychologic test performance among children.

Three hypotheses are proposed to account for neurobehavioral impairments following treatment with cranial radiation therapy (CRT) and intrathecal (IT) chemotherapy: CNS treatments exert a synergistic effect (A x B), an additive effect (A + B), or a single-agent effect (A or B). Eighty-five long-term survivors of non-CNS cancers aged 6 to 16 years were classified into groups on the basis of CNS treatments: CRT-IT (n = 25), CRT-No IT (n = 11), No CRT-IT (n = 24), and No CRT-No IT (n = 25). Study I findings did not provide support for synergistic mechanisms; nonorthogonal analysis of variance showed interaction effects (CRT x IT) restricted to tactile-perceptual speed. However, main effects were significant for a single agent (CRT) across a wide range of measures. General intelligence, academic achievement, verbal knowledge and reasoning, and perceptual-motor abilities were found to be significantly lower among CRT-treated groups. Study II findings provided additional support for the role of CRT; Pearson correlations within the CRT-No IT group indicated significant negative associations between CRT dose estimates for cortical regions and perceptual-motor abilities.

Pretreatment neuropsychological status and associated factors in children with primary brain tumors.

We report on the neuropsychological status of 31 children with primary brain tumors who underwent assessment before receiving therapy. Overall, the children performed within normal limits in all test areas. The exception was the group with anterior hemispheric tumors who demonstrated deficits in executive cognitive functions. Also, when compared according to tumor type, children with midline tumors and hydrocephalus performed more poorly than others on measures of intelligence, executive abilities, visual-motor skills, and fine-motor functions. Although one-half to two-thirds of the children with supratentorial midline and infratentorial tumors had cranial nerve, oculomotor, or cerebellar deficits, only the latter were associated with specific neuropsychological deficits (poorer performance on fine-motor and visual-motor tests). Age did not appear to be a factor in these children's neuropsychological test performances.

Neurobehavioral effects of central nervous system prophylactic treatment of cancer in children.

This article reviews 41 studies of the effects of prophylactic CNS treatment on the neurobehavioral development of children with cancer. This research is classified according to studies of (a) children in treatment; (b) long-term survivors; and (c) longitudinal follow-ups of children from the time of diagnosis. Studies vary considerably in design, sample, and outcome variables, so firm conclusions regarding the morbidity of CNS prophylaxis are not currently possible. However, the studies do suggest that CNS prophylaxis does impair cognitive development, particularly when cranial radiation therapy is part of the treatment. There is also evidence of greater impairment in younger children and some suggestion of more frequent impairment of non-language skills relative to language skills. The possible relationships among age, radiation, and non-language cognitive skills may be linked to disruption of white matter CNS structures apparent on autopsy and cerebral tomography following treatment.