Postirradiation Treatment Outcomes for Children with Acute Lymphocytic Leukemia: Clarification of Risks

Developmental and educational consequences of treatment foracute lymphocytic leukemia (ALL) were examined in a group of26 elementary school children who were survivors of the disease.All of the survivors had received cranial irradiation as partof their treatment. Risks were assessed by comparing each ALLsurvivor to one normal sibling on a comprehensive battery oftests and on measures of behavior and school performance. Consistentwith previous findings, the ALL group performed less well thantheir siblings on tests of IQ, neuropsychological skills, andacademic achievement. Analysis of ratings by parents and teachersrevealed that the ALL group was less able to meet the academicdemands of school but did not differ from the sibling groupin behavioral adjustment. A greater number of children fromthe ALL group obtained borderline to low-average full-scaleIQ scores; and more received special educational assistanceat school. However, none of these children met criteria formental retardation. The present findings help to clarify therisks associated with treatment protocols that include prophylactic irradiation.     

Neuropsychological sequelae of central nervous system prophylaxis in survivors of childhood acute lymphoblastic leukemia

We assessed neuropsychologically 106 children with acute lymphoblastic leukemia (ALL) who had all received cranial irradiation for the prevention of central nervous system (CNS) leukemia 1-13 years previously. Children were assessed for adverse late effects of their therapy, using age-appropriate Wechsler measures of overall intellectual ability and supplementary tests. Forty-five siblings near in age to the patients were tested as controls. The patients who had had the most intensive central nervous system (CNS) prophylaxis were found to have a WISC-R Full Scale IQ 17 points lower than the sibling control group. Performance IQ was more affected than verbal IQ. The patients were more easily distracted and less able to concentrate. The severity of the aftereffects was related to younger age at the time of CNS prophylaxis and to a higher dose of cranial irradiation but not to time since CNS prophylaxis. CNS prophylaxis using a combination of cranial irradiation and intrathecal methotrexate has lowered the incidence of CNS relapse in childhood ALL but is associated with considerable long-term morbidity in survivors.     

Processing speed, working memory, and IQ: a developmental model of cognitive deficits following cranial radiation therapy

IQ decrements following cranial radiation therapy (CRT) for acute lymphoblastic leukemia (ALL) are most apparent years after treatment. The authors examined a developmental model for delayed deficits by evaluating the relationship between processing speed, working memory, and IQ in long-term survivors of childhood ALL (n = 27) compared with demographically matched controls (n = 27). The ALL group treated with CRT showed deficits in IQ, working memory, and processing speed relative to controls. Differences in IQ between the CRT group and controls were mediated by differences in working memory. Processing speed did not fully account for the working memory deficit in the CRT group. Participants with ALL treated only with chemotherapy showed similar working memory and processing speed as matched controls. Data suggest that deficits in processing speed and working memory following CRT may underlie declines in IQ.     

Intellectual, neuropsychological, and academic functioning in long-term survivors of leukemia

OBJECTIVE: To assess the effects of treatment for acute lymphoblastic leukemia (ALL) on children's cognitive functioning. METHOD: Participants were long-term survivors of ALL treated with cranial irradiation and central nervous system (CNS) chemotherapy (n = 20), or CNS chemotherapy only (n = 21), healthy children (n = 21), and children with chronic asthma (n = 21). The groups were compared on measures of intellectual, neuropsychological, and academic functioning. RESULTS: CNS chemotherapy, with and without cranial irradiation, was associated with significantly lower levels of intellectual and academic functioning. Children with chronic asthma obtained lower scores than healthy controls, but these differences were not significant. Tests of neuropsychological functioning did not consistently separate the groups. CONCLUSIONS: CNS chemotherapy and, to a lesser extent, chronic illness both contribute to the poorer performance of long-term survivors of ALL on measures of intellectual and academic functioning.     

Cognitive and Academic Late Effects Among Children Previously Treated for Acute Lymphocytic Leukemia Receiving Chemotherapy as CNS Prophylaxis

Objective: Examine cognitive and academic late effects amongchildren and adolescents who had received central nervous system(CNS) prophylactic chemotherapy alone for acute lymphocyticleukemia (ALL); none had received whole brain radiation therapy(RT). Method: Subjects included 47 children and adolescents from 5to 22 years of age who were treated on the same protocol andhad been off treatment from 2 to 7 years at the time of assessment. Results: As a group the survivors displayed generally averageperformance on measures of cognitive and academic abilities,although they differed from normative means on tests of nonverbalskills. Girls performed more poorly than the normative sampleon nonverbal tasks, while no differences were found for boys.Age at diagnosis and time off treatment were not significantlyassociated with cognitive and academic functioning for survivorsof this particular chemotherapy-only protocol. Conclusions: Data were interpreted to support generally modestpotential late effects in specific areas for children and adolescentssurviving ALL. These findings suggest a need for monitoringnonverbal cognitive skills for childhood survivors of ALL, particularlyfor girls.     

Internalizing Behavior Problems and Scholastic Achievement in Children: Cognitive and Behavioral Pathways as Mediators of Outcome

Examined a conceptual model in which dual developmental pathways (behavioral and cognitive) are hypothesized to account for the relation among internalizing behavior problems, intelligence, and later scholastic achievement using a cross-sectional sample of 325 children. Classroom behavior and select aspects of cognitive functioning (vigilance, short-term memory) were hypothesized to mediate the relations among internalizing problems, IQ, and long-term scholastic achievement. Hierarchical tests applied to a nested series of models demonstrated that (a) individual differences in measured intelligence among children are associated with variations in classroom performance and cognitive functioning, (b) classroom performance and cognitive functioning make unique contributions to prediction of later achievement over and above the influence of intelligence, (c) anxious/depressive features are correlated but separable constructs, and (d) anxiety/depression and withdrawal contribute to prediction of classroom performance and cognitive functioning over and above the effects of intelligence. Classroom performance and cognitive functioning thus appear to mediate the effects of internalizing behaviors as well as intelligence. Particular attention to the presence and potential impact of social withdrawal on children's functioning, both alone and concomitant with anxiety/depression, appears warranted during the course of clinical evaluations owing to the strong continuity among these variables.     

Age of onset and behavioral manifestations in Huntington's disease: An Enroll‐HD cohort analysis

Huntington's disease is associated with motor, cognitive and behavioral dysfunction. Behavioral symptoms may present before, after, or simultaneously with clinical disease manifestation. The relationship between age of onset and behavioral symptom presentation and severity was explored using the Enroll‐HD database. Manifest individuals (n = 4469) were initially divided into three groups for preliminary analysis: early onset (<30 years; n = 479); mid‐adult onset (30‐59 years; n = 3478); and late onset (>59 years; n = 512). Incidence of behavioral symptoms reported at onset was highest in those with early onset symptoms at 26% (n = 126), compared with 19% (n = 678) for mid‐adult onset and 11% (n = 56) for late onset (P < 0.0001). Refined analysis, looking across the continuum of ages rather than between categorical subgroups found that a one‐year increase in age of onset was associated with a 5.6% decrease in the odds of behavioral symptoms being retrospectively reported as the presenting symptom (P < 0.0001). By the time of study enrollment, the odds of reporting severe behavioral symptoms decreased by 5.5% for each one‐year increase in reported age of onset. Exploring environmental, genetic and epigenetic factors that affect age of onset and further characterizing types and severity of behavioral symptoms may improve treatment and understanding of Huntington's disease's impact on affected individuals.     

Cognitive effects of childhood leukemia therapy: a case for four specific deficits

Prophylactic treatment of the central nervous system (CNS) with cranial irradiation and antineoplastic drugs has made childhood acute lymphoblastic leukemia (ALL) a survivable disease, but at the same time there have been many reports of iatrogenic effects, including deficits in cognitive functioning. Previous research suggests a particular effect on the Freedom from Distractibility factor of the WISC-R, memory, and attention. These particular abilities are tested in a group of 43 ALL survivors, with comparisons against solid tumor as well as sibling controls. The results indicate that four cognitive processes are affected by CNS prophylaxis for ALL: short-term memory, speed of processing, visuomotor coordination, and sequencing ability. Younger children have a more severe speed of processing deficit and children treated with a less rigorous protocol appear to be slightly less affected generally. The specific cognitive deficits found are related to neurological evidence on both theoretical and empirical grounds. Results suggest that children who have received CNS prophylaxis are able to learn, but may be slower to acquire new material and may benefit from bimodal presentation.     

Comparison of Learned Helplessness Cognitions and Behavior in Children With High and Low Scores on the Children's Depression Inventory

We examined the relationship between depressive symptoms and the cognitive and behavioral deficits associated with learned helplessness in 50 elementary school children using self-report, parent report, and behavioral data. We compared children with high and low scores on the Children's Depression Inventory on attributional style, locus of control, social desirability responding, the Child Behavior Checklist, intelligence, demographic characteristics, academic achievement, and learned helplessness behaviors. Results supported previous findings that children with depressive symptoms demonstrate an attributional style similar to that of depressed adults. They were found to attribute bad outcomes to internal, stable, and global factors and good outcomes to external, unstable, and specific factors. We did not find children with depressive symptoms to display significantly more helpless behavior than nondepressed children. However, problems in the behavioral measure of learned helplessness were evident. Therapeutic and research implications are discussed.     

Decreased serum testosterone levels in long-term adult survivors with fatty liver after childhood stem cell transplantation

Fatty liver and male gonadal dysfunction are potential late effects of therapy in adult survivors treated with stem cell transplantation (SCT) in childhood. Obesity and metabolic syndrome also are associated with low serum testosterone levels in the general population. However, the relationship between the degree of fatty liver and changes in serum testosterone levels in adult survivors has not been fully studied. We reviewed the clinical records of 34 male patients who received allogeneic SCT in childhood or adolescence. The median age at SCT was 10.0 years, and the median follow-up after SCT was 15.9 years. All but one patient showed no tendency toward overweight/obesity during the follow-up period. Fatty liver was diagnosed by ultrasound in 15 patients at 4 to 20 years after SCT. Patients who received cranial radiation therapy before SCT were more likely to develop fatty liver and insulin resistance. Moreover, fatty liver was statistically associated with decreased serum testosterone levels, whereas nonfatty liver was not (median, 527 ng/dL [range, 168-944 ng/dL] versus 302 ng/dL [165-698 ng/dL]; P < .0001). Changes in testosterone levels after SCT are affected not only by primary gonadal dysfunction but also by subsequent development or exacerbation of fatty liver.     

Neurocognitive interventions for children and adolescents surviving cancer

BACKGROUND: It is well recognized that many cures for childhood leukemia and brain tumors entail some relatively permanent neurocognitive and psychological costs to the patient and family. As cure rates have improved over the past three decades, increasing efforts have been directed toward reducing treatment-related late effects. OBJECTIVE: The particular focus of this review will be on interventions for the neuropsychological late effects associated with the treatment of acute lymphoblastic leukemia (ALL) and malignant brain tumors. SUMMARY: We will first briefly review current approaches to the medical treatment of ALL and brain tumors to provide an appreciation of potential sources of brain injury. We will then summarize the existing literature on types of neuropsychological deficits found among survivors, with special attention to variables that place some children at greater risk. Then, there will be a discussion of approaches to intervention for these deficits-specifically, cognitive remediation, pharmacology, and ecological alterations in the classroom. Finally, we will present directions for future research in the field.     

Understanding the cognitive impact on children who are treated for medulloblastoma

OBJECTIVE: Risk-adapted treatment approaches employed within contemporary medulloblastoma treatment protocols aim to reduce the neurotoxicity directed at the central nervous system. Despite these important steps to reduce radiation dose exposure, an overwhelming majority of medulloblastoma survivors continue to experience academic failure and significant learning delays. METHODS: A review of the current literature is presented. RESULTS: Deficits in intellectual function, academic achievement, memory, attention, and processing speed are reported. Finally, intervention programs, including pharmacotherapy and experimental cognitive intervention studies, are discussed. A review of neuroimaging studies shows changes in brain tissue following chemotherapy and radiation treatment. CONCLUSIONS: Declining IQ and academic struggles may be predated by difficulties with attention, memory, and processing speed. More clinical trials directed at treating and preventing neurocognitive late effects through cognitive rehabilitation are needed.     

Acute neurocognitive response to methylphenidate among survivors of childhood cancer: a randomized, double-blind, cross-over trial

OBJECTIVE: To investigate the acute efficacy and adverse side effects of methylphenidate (MPH) among survivors of childhood cancer [acute lymphoblastic leukemia (ALL) or brain tumor (BT)] with learning impairments. METHODS: Participants (N = 122) completed a two-day, in-clinic, double-blind, cross-over trial during which they received MPH (0.60 mg/kg of body weight) and placebo that were randomized in administration order across participants. Performance was evaluated using measures of attention, memory, and academic achievement. RESULTS: A significant MPH versus placebo effect was revealed on a measure of attention, cognitive flexibility, and processing speed (Stroop Word-Color Association Test). Male gender, older age at treatment, and higher intelligence were predictive of better medication response. No significant differences were found for number or severity of adverse side effects as a function of active medication. CONCLUSIONS: MPH shows some neurocognitive benefit and is well tolerated by the majority of children surviving ALL and BT.     

Sex differences in cognitive processing in children treated with CNS prophylaxis for acute lymphoblastic leukemia

Evaluated cognitive processing in 51 children (27 female, 24 male) who had been treated for acute lymphoblastic leukemia (ALL) with CNS prophylaxis (cranial radiation in combination with intrathecal chemotherapy) and were continuously disease-free for 5 to 12 years. The control group comprised 15 children treated for Wilm's tumor. Functions assessed included visuoperceptual skills, generation of organizational strategies, sensitivity to organizational structure, and attention. The ALL group showed performance deficits relative to the solid tumor controls in appreciating the organization inherent in complex visuospatial material and alertness, with females more severely affected than males. Sex differences favoring males on IQ and academic achievement were related to these cognitive processes.     

Achievement and Intelligence Test-Retest Performance in Pediatric Cancer Patients at Diagnosis and One Year Later

Intellectual, achievement, and behavior evaluations were completedat diagnosis and 1 year later on 16 leukemic (ALL) and 17 solidtumor (ST) patients between 5 and 16 years of age at diagnosis.Rank order correlations between change in psychometric performanceand amount of chemotherapy received were computed for the ALLand ST groups separately. The number of significant correlationsbetween chemotherapy and change in psychometric data did notexceed chance expectations. There were no significant changesin behavior ratings over time for either the ALL or ST patients.Children with ALL younger than 8 years when diagnosed declinedin word recognition, Performance IQ and Full-scale IQ. Similarbut nonsignificant declines were observed in five young ST patients.Both ALL and ST patients over age 8 years when diagnosed hadnonsignificant changes in achievement and IQ performance. Largenegative V-P scores were noted in younger ST patients and ALLpatients of all ages both at diagnosis and 1 year later.     

Relationship between intelligence and the size and composition of the corpus callosum

We investigated the relationship between the morphology of the corpus callosum (CC) and IQ in a healthy sample of individuals in their late teens and early twenties. The relationship between the area of the CC, measured at the midline, and IQ showed regional differences. We observed that a higher estimated performance IQ was associated with smaller area in the posterior regions of the CC, a finding that differs from a positive association previously observed in a somewhat older adult sample. In contrast, higher estimated verbal IQ was associated with decreased fractional anisotropy of the genu, an anterior portion of the CC. Age effects were also observed such that older age was associated with larger CC area. Our results suggest that CC morphology is related to cognitive performance, which may have implications for clinical populations in whom CC morphology is atypical.     

Scholarly literature review: management of neurocognitive late effects with stimulant medication

OBJECTIVE: To examine the extant literature on stimulant drug therapy for survivors of childhood cancer during the late-effects period. METHODS: A review of literature is provided on the mechanism of and cognitive toxicities for children and adolescents treated for acute lymphoblastic leukemia (ALL) and malignant brain tumors (BT) as well as the pharmacotherapy of stimulant medications, with a specific review of literature on the efficacy and safety of the stimulants for children with ALL and BT. RESULTS: Only four studies were found that have examined the effects of stimulant medication on the cognitive toxicities of childhood survivors of cancer during the late-effects period and only two of these investigations were controlled clinical trials. Findings suggest efficacy of the stimulants on parent and teacher ratings of attention and putative tasks of attention and executive functioning. CONCLUSIONS: Although there is some preliminary support for the efficacy and safety of the stimulants for survivors of ALL and BT, more research is needed concerning the long-term effects of the stimulants among cancer survivors.     

Predictors of Response to Behavioral Treatments Among Children With ADHD-Inattentive Type

The goal of the study was to examine baseline characteristics—child gender, IQ, age, internalizing problems, symptoms of hyperactivity/impulsivity (HI), oppositional defiant disorder, and sluggish cognitive tempo, and parent income, education, attention deficit/hyperactivity disorder (ADHD) severity, and anxiety/depression (A/D)—associated with response to behavioral treatments for ADHD, predominantly inattentive type. We employed data from 148 children (M = 8.7 years), 58% male, and 57% Caucasian in a randomized clinical trial. Positive treatment response was defined as (a) 5 or fewer inattentive symptoms and (b) a decrease of at least 3 inattentive symptoms from baseline to posttreatment. Child HI, parental A/D, and child IQ were associated with positive response, as follows: Child HI had a main effect in which it was negatively associated with treatment response (36% with 2 or more HI symptoms were positive responders vs. 59% of those with 1 or no symptoms) that was qualified by parental A/D and child IQ. When children had 2 or more symptoms of HI and higher parental A/D, positive response rate was low at 25%; when children had 2 or more symptoms of HI, low parental A/D, and an IQ of 105 or higher, positive response rate was 85%. Furthermore, the group with the poorest response rate (25%) had parents who self-reported greater ADHD severity, and the group with a relatively good rate of positive response (59%) had the lowest number of oppositional defiant disorder symptoms. Likelihood of positive response to our behavioral treatment for ADHD-I is dependent on child and parent factors.     

Factors related to changes in cognitive, educational and visual motor integration in children who undergo hematopoietic stem cell transplant

OBJECTIVES: Investigate cognitive, educational, and perceptual motor skills up to 2 years posttransplant of pediatric hematopoietic progenitor cell transplantation (HPCT) survivors and their correlates. METHODS: Survivors were assessed at baseline, 12, and 24 months after transplant. RESULTS: Performance IQ improved over time and was negatively related to maternal depression. Full IQ and educational outcomes were positively related to child's age and mother's age. Low depression scores were associated with high Verbal IQ one and 2 years post-HPCT, and with high visual motor scores 2 years post-HPCT. Poor educational outcomes were related to increased time since diagnosis. Two years post-HPCT, Performance IQ and Processing Speed were above the norm values whereas arithmetic and motor scores were below. CONCLUSIONS: Pediatric HPCT survivors do better cognitively than educationally. Maternal age and depression, child's age, and time since diagnosis are critical factors for these outcomes.     

Motor and perceptual timing deficits among survivors of childhood leukemia

OBJECTIVE: There is growing evidence of cerebellar-frontal system change in children treated for leukemia with chemotherapy alone (Lesnik et al., 1998). METHODS: We compared 22 long-term survivors of acute lymphoblastic leukemia (ALL), aged 8-18, to 22 age- and gender-matched controls on tasks emphasizing cerebellar-frontal functioning including judgment of time duration and motor timing. Groups were also compared on a judgment of pitch task, used as a control measure. Children with ALL were at least 5 years from diagnosis, treated with intrathecal chemotherapy (methotrexate in all, hydrocortisone and cytarabine in 20/22), but not radiation therapy, and free from recurrence of disease. RESULTS: After controlling for IQ, the ALL group had poorer performance than controls on judgment of long duration and motor timing, but not judgment of pitch. CONCLUSIONS: Treatment with intrathecal and infusional chemotherapy for childhood ALL may be associated with skill deficits comparable to those seen in individuals with cerebellar-frontal abnormalities.