Neuropsychologic assessment of long-term survivors of childhood leukemia

Thirty-two long-term survivors of childhood leukemia who were followed up at the University of Texas M. D. Anderson Hospital were evaluated with a battery of 17 neuropsychologic tests. These tests were selected to assess the development of cognitive skills and functions associated with brain impairment in children. Statistically significant differences were found between the group of children given CNS irradiation and the nonirradiated group on full-scale IQ and verbal IQ scores, mathematics skills, constructional skills, and memory for spatial material. Of particular interest was the absence of differences in language-based measures of verbal memory and the presence of group differences on measures of memory for spatial material. While the sample size was small, the findings delineate specific areas likely to be affected. These results indicate the need for caution when including cranial irradiation in CNS prophylaxis. When any CNS treatment is given, it seems appropriate that provisions be made for assessment and remediation of affected skills.     

Cognitive functioning in long-term survivors of childhood leukemia: a prospective analysis

Treatment-related cognitive impairments have been reported for survivors of childhood leukemia following prophylactic central nervous system (CNS) treatment with 2400 cGy craniospinal irradiation and intrathecal chemotherapy. The present study was designed to prospectively evaluate cognitive functioning of 24 children prior to CNS prophylaxis of 1800 cGy of craniospinal irradiation and intrathecal drugs, and at intervals of 1 and 4-5 years. At diagnosis, prior to CNS treatment, all 24 subjects performed in the average range of intelligence, as measured by the Wechsler Intelligence Scales. Subjects continued to perform in the average range with no significant declines at the 1-year follow-up. Significant declines in cognitive functioning, however, were found at the 4- to 5-year follow-up period, with five subjects (21%) performing in the low average or borderline levels of intelligence. Of the 19 subjects performing in the average range, five showed significant discrepancies between Verbal and Performance IQ scores. Nine subjects exhibited poor performance on a subtest cluster assessing perceptual and attentional processes. With regard to school experiences, 50% of the subjects had received some type of special education services. The findings indicate the need for annual evaluations of cognitive functioning in long-term survivors of childhood leukemia who received 1800 cGy craniospinal irradiation, to identify potential cognitive late effects of treatment requiring appropriate special education services.     

Intellectual, educational, and behavioural sequelae after cranial irradiation and chemotherapy.

Cognitive and educational sequelae are inconsistently reported in children treated with cranial irradiation for acute lymphoblastic leukaemia. This study investigated differences in these skills after cranial irradiation, controlling the effects of chemotherapy and psychosocial factors. Three groups were evaluated: 100 children diagnosed with acute lymphoblastic leukaemia and treated with cranial irradiation and chemotherapy; 50 children diagnosed with acute lymphoblastic leukaemia or other cancers and treated with chemotherapy alone; and a healthy control group of 100 children. Children in the clinical groups stopped treatment at least two years before evaluation and had no history of relapse. Children were aged between 7 and 16 at the time of assessment. Evaluation included cognitive, educational, and behavioural measures. Analyses found that children receiving cranial irradiation and chemotherapy performed more poorly than non-irradiated groups on intellectual and educational tests, with verbal and attentional deficits most pronounced. Children receiving chemotherapy alone performed similarly to controls, suggesting such treatment is not associated with adverse neurobehavioural sequelae.     

Intellectual, educational, and behavioural sequelae after cranial irradiation and chemotherapy

Cognitive and educational sequelae are inconsistently reported in children treated with cranial irradiation for acute lymphoblastic leukaemia. This study investigated differences in these skills after cranial irradiation, controlling the effects of chemotherapy and psychosocial factors. Three groups were evaluated: 100 children diagnosed with acute lymphoblastic leukaemia and treated with cranial irradiation and chemotherapy; 50 children diagnosed with acute lymphoblastic leukaemia or other cancers and treated with chemotherapy alone; and a healthy control group of 100 children. Children in the clinical groups stopped treatment at least two years before evaluation and had no history of relapse. Children were aged between 7 and 16 at the time of assessment. Evaluation included cognitive, educational, and behavioural measures. Analyses found that children receiving cranial irradiation and chemotherapy performed more poorly than non-irradiated groups on intellectual and educational tests, with verbal and attentional deficits most pronounced. Children receiving chemotherapy alone performed similarly to controls, suggesting such treatment is not associated with adverse neurobehavioural sequelae.     

Feasibility of neuropsychological assessment in leukaemia patients shortly after diagnosis: directions for future prospective research.

AIMS: To study neuropsychological functioning of newly diagnosed children with acute lymphoblastic leukaemia (ALL) within two weeks after diagnosis in order to determine the feasibility of a sibling controlled prospective study design. METHODS: Fifty consecutive patients (median age at testing 6.6 years, range 4-12) were included in a prospective, longitudinal, nationwide study. Treatment would include intrathecal and systemic chemotherapy according to the DCLSG ALL-9 protocol. Children were evaluated with an extensive neuropsychological battery including measures of intelligence, memory, attention, language, visual-constructive function, and fine-motor abilities within two weeks after start of the chemotherapy. The control group consisted of 29 healthy siblings (median age at testing 8.2 years, range 4-12), who were tested <4 weeks after the patients' assessment. RESULTS: Mean scores on Wechsler Intelligence Scales did not differ significantly between patients and siblings; mean IQ scores for both the patients and the controls were high average. To examine specific neuropsychological functions, norm scores based on the exact age were acquired by fitting procedures, but no significant differences were found. CONCLUSIONS: Neuropsychological assessment of patients during early hospitalisation is feasible. The results indicate no adverse effect of illness and psychological factors on IQ and neuropsychological functioning of patients with recently diagnosed ALL. The prospective design of this study of cognitive late effects of chemotherapy will allow discrimination between adverse sequelae of disease and treatment.     

Impact of age and diagnosis on waiting times between important healthcare events among children 0 to 19 years cared for in pediatric units: the Canadian Childhood Cancer Surveillance and Control Program

BACKGROUND: The objectives were to describe and compare waiting times to diagnosis and treatment of children and adolescents who accessed pediatric oncology centers in Canada for healthcare, and to assess the effects and relative contributions of age, sex, and diagnosis to waiting times. METHODS: Waiting times were assessed for 2,365 children (0 to 14 y) and 375 adolescents (15 to 19 y) diagnosed with cancer between 1995 and 2000 inclusive and followed by the Treatment and Outcome Surveillance system of the Canadian Children's Cancer Surveillance and Control Program. Differences were assessed using the chi2 test, Fisher exact test, and Wilcoxon test statistic. RESULTS: Median waiting times between first assessment by treating oncologist or surgeon and definitive diagnostic procedure, and the subsequent interval to first therapeutic event, were 2 days each. Significant variation existed in both periods when stratified by age and diagnosis but not sex. The most significant differences between age groups were eliminated when stratified by diagnosis. INTERPRETATION: This analysis suggests that once they enter the healthcare system, children and adolescents treated in pediatric centers in Canada experience short waiting times to key diagnostic and treatment events. Differences in wait times between the 2 age groups are not clinically significant and can be attributed to the differences in the types of cancer experienced by adolescents compared with children.     

Psychological functioning in children with cyanotic heart defects

The relationship between congenital heart disease (CHD) and psychological functioning was studied in 63 children with transposition of the great arteries (TGA) and 77 children with tetralogy of Fallot (TF). These youngsters were compared with a group of 36 children originally diagnosed with CHD, but who spontaneously recovered (SR) without medical intervention. All children were under one year of age when diagnosed and were given psychological testing between 5.5 and 6.3 years. Children with TGA and TF had poorer overall psychological functioning and significantly greater central nervous system (CNS) impairment than the SR children. However when the effects of IQ and CNS impairment were controlled, there were no differences between groups. The diagnosis of a severe cyanotic heart defect does not appear to make a child more likely to have emotional disorder in the absence of other factors.     

Feasibility of neuropsychological assessment in leukaemia patients shortly after diagnosis: directions for future prospective research

Aims: To study neuropsychological functioning of newly diagnosed children with acute lymphoblastic leukaemia (ALL) within two weeks after diagnosis in order to determine the feasibility of a sibling controlled prospective study design. Methods: Fifty consecutive patients (median age at testing 6.6 years, range 4–12) were included in a prospective, longitudinal, nationwide study. Treatment would include intrathecal and systemic chemotherapy according to the DCLSG ALL-9 protocol. Children were evaluated with an extensive neuropsychological battery including measures of intelligence, memory, attention, language, visual-constructive function, and fine-motor abilities within two weeks after start of the chemotherapy. The control group consisted of 29 healthy siblings (median age at testing 8.2 years, range 4–12), who were tested <4 weeks after the patients'' assessment. Results: Mean scores on Wechsler Intelligence Scales did not differ significantly between patients and siblings; mean IQ scores for both the patients and the controls were high average. To examine specific neuropsychological functions, norm scores based on the exact age were acquired by fitting procedures, but no significant differences were found. Conclusions: Neuropsychological assessment of patients during early hospitalisation is feasible. The results indicate no adverse effect of illness and psychological factors on IQ and neuropsychological functioning of patients with recently diagnosed ALL. The prospective design of this study of cognitive late effects of chemotherapy will allow discrimination between adverse sequelae of disease and treatment.     

Intelligence,motor skills and behaviour at 5 years in early-treated congenital hypothyroidism

The cognitive functioning, motor skills and behaviour of 5-year-old children with early-treated congenital hypothyroidism was assessed. The study group was 57 children with congenital hypothyroidism (CH) diagnosed by neonatal screening in N.E. and N.W. Thames regions between 1978 and 1981 along with 51 non-affected controls matched for age, sex, social class and language background. Small differences in I.Q. and behaviour between the patients and the controls were not statistically significant. However, children with CH showed significant deficits in motor skills (M 79.9 SE 3.7) compared to the controls (M 99.8 SE 4.0) (P=0.0003). Deficits were particularly marked for balance. In addition, children with more severe hypothyroidism at diagnosis (Plasma thyroxine <20 nmol/l) did significantly less well in respect to I.Q. and motor skills than those with less severe hypothyroidism (plasma thyroxine >60 nmol/l). These findings provide further evidence for the importance of the severity of hypothyroidism in determining the outcome for intelligence and motor skills in children with early-treated congenital hypothyroidism. Deficits in motor skills, particularly in relation to balance, suggest that early impairment of the vestibular system may occur despite early treatment.     

Intellectual function in long-term survivors of childhood acute lymphoblastic leukemia: protective effect of pre-irradiation methotrexate? A Childrens Cancer Study Group study

Having demonstrated in a laboratory model that the neurotoxicity of CNS irradiation can be ameliorated with pre-irradiation methotrexate, we retrospectively compared two methods of CNS prophylaxis in childhood acute lymphoblastic leukemia which differed only in the timing of intrathecal methotrexate and radiotherapy. The results of standard IQ tests conducted 2-11 years after 24 Gy of cranial radiotherapy were obtained in 72 patients, of whom 27 had pre-irradiation methotrexate and 45 did not (control group). The two groups were otherwise comparable. In girls, the full-, performance-, and verbal-scale IQ scores were consistently higher in the pre-irradiation methotrexate group than in the corresponding control group (P less than 0.025). Among girls less than 5 years of age when irradiated, the mean IQ scores were 25-29 points higher after pre-irradiation methotrexate than after the control treatment (P less than 0.0007). These results suggest that pre-irradiation methotrexate may help prevent CNS radiotoxicity in children, and that the benefit is dependent on patient age and gender.     

Cancer Incidence and Survival Among Infants in Israel, 1998–2007

Cancer during the first year of life is relatively rare and often has clinical and biological properties different from those of the same histologic type of cancer occurring in older children. The aim of this study was to find differences in epidemiology and survival between infants and older children and to compare the percentage of distribution of infant cancer types in Israel with that reported in the United States. We collected infant <1 year of age cases diagnosed between 1998 and 2007 as having cancer from the database of the Israel National Cancer Registry, a total of 309 cases with an incidence rate of 228.5 cases per million. The largest group was diagnosed with neuroblastoma (35%) with an incident rate of 80 per million, followed by leukemia (15.9%), with acute lymphoid leukemia and acute myeloid leukemia accounting for most of this group and central nervous system malignancies comprised 10.7% of infant cancer. One hundred and fifty four new cases of infant girls was diagnosed compared to 155 infant boys with an incidence rates of 234 cases per million for girls and 224.7 for boys, not statistically significant (F:M rate ratio of 1.04). The 5-year survival rates seen in the different groups were leukemia: 55.3%, lymphoma: 71%, CNS tumors: 53.3%, neuroblastoma: 93.4%, retinoblastoma: 94.7% renal tumors: 90.9%, hepatic tumors: 63.3%, soft tissue sarcoma: 76.2%, germ cell neoplasms: 83.3%, and other epithelial neoplasms: 100%. Our study did not find survival differences with statistical significance upon comparing survival rates between different genders and ethnic groups.     

Adjustment and vocational satisfaction of patients treated during childhood or adolescence for acute lymphoblastic leukemia

This investigation evaluated the psychosocial consequences of the diagnosis and treatment of acute lymphoblastic leukemia (ALL) on the long-term adjustment of a sample of 46 patients less than 20 years of age at diagnosis (mean age: 7.46 years). Subjects were followed up for an average of 15.4 years after diagnosis and were a mean of 22.87 years old at assessment. A sample of Hodgkin's disease and non-Hodgkin's lymphoma survivors served as a comparison group. Patients completed standardized measures of well-being, stress reaction, vocational satisfaction, and a questionnaire assessing defensiveness regarding their history of cancer treatment, experienced job discrimination, and social involvement. Overall, the subjects appeared to be well-adjusted; female subjects, however, exhibited an increased tendency to experience anxiety in stressful situations. Vocational discrimination did not appear to be a significant problem for this group of survivors, and subjects exhibited levels of vocational satisfaction that did not differ from population norms. Greater defensiveness regarding a history of cancer treatment was associated with lower levels of well-being and heightened stress reaction. Survivors who received CNS prophylaxis that included cranial irradiation had lower well-being scores than did those survivors receiving only intrathecal methotrexate.     

A two-year prospective follow-up study of community-based early intensive behavioural intervention and specialist nursery provision for children with autism spectrum disorders

BACKGROUND: This prospective study compared outcome for pre-school children with autism spectrum disorders (ASD) receiving autism-specific nursery provision or home-based Early Intensive Behavioural Interventions (EIBI) in a community setting. METHODS: Forty-four 23- to 53-month-old children with ASD participated (28 in EIBI home-based programmes; 16 in autism-specific nurseries). Cognitive, language, play, adaptive behaviour skills and severity of autism were assessed at intake and 2 years later. RESULTS: Both groups showed improvements in age equivalent scores but standard scores changed little over time. At follow-up, there were no significant group differences in cognitive ability, language, play or severity of autism. The only difference approaching significance (p = .06), in favour of the EIBI group, was for Vineland Daily Living Skills standard scores. However, there were large individual differences in progress, with intake IQ and language level best predicting overall progress. CONCLUSIONS: Home-based EIBI, as implemented in the community, and autism-specific nursery provision produced comparable outcomes after two years of intervention.     

Central nervous system prophylaxis. Studies showing impairment in verbal skills and academic achievement

School attendance and school achievement were the parameters studied to assess the pediatric cancer patient's ability to learn and keep pace with their peers. Effects of CNS prophylaxis, as either intrathecal methotrexate (IT) alone or intrathecal methotrexate given in addition to cranial radiation (CRT), were studied in two groups. A third group of cancer patients who received no CNS prophylaxis, and two comparison groups, siblings and a matched sample of children, also participated in the study. Impairment in central nervous system function was measured by means of psychological testing, neurological examination, and computer-assisted tomography. Patients who received central nervous system prophylactic treatments at an early age had poorer performance on verbal IQ scores, with comprehension and arithmetic subscores being most affected. Patients who received both cranial radiotherapy plus intrathecal methotrexate showed a decrease in six out of seven categories of instruction when grades from the year prior to diagnosis were compared to those obtained 3 years after diagnosis. The combined groups of patients with leukemia had a lower grade point average and poorer school attendance than did the comparison groups.     

Cognitive profiles and social-communicative functioning in children with autism spectrum disorder

BACKGROUND: Whether there is an unusual degree of unevenness in the cognitive abilities of children with autism spectrum disorder (ASD) and whether different cognitive profiles among children with ASD might index etiologically significant subgroups are questions of continued debate in autism research. METHOD: The Differential Ability Scales (DAS) and the Autism Diagnostic Observation Schedule (ADOS) were used to examine profiles of verbal and nonverbal abilities and their relationship to autistic symptomatology in 120 relatively high-functioning children with ADI-confirmed diagnoses of autism. RESULTS: Discrepancies between verbal and nonverbal ability scores occurred at a significantly higher rate than in the DAS normative sample (30%) in both a younger group of 73 children (56%) with a mean age of 5;5 and an older group of 47 children (62%) with a mean age of 8;11. Discrepancies were mainly in favor of nonverbal ability in the younger group, but occurred equally in favor of verbal and nonverbal abilities in the older group. Comparison of the two age groups suggested a growing dissociation between verbal and nonverbal (and particularly visual processing) skills with age. In the older group, children with discrepantly higher nonverbal abilities demonstrated significantly greater impairment in social functioning, as measured on the ADOS, independent of absolute level of verbal and overall ability. CONCLUSIONS: These findings demonstrate a high rate of uneven cognitive development in children with ASD. Indications of a dissociation between verbal and visual-perceptual skills among the older children, and the specific association of discrepantly high nonverbal skills with increased social symptoms suggest that the nonverbal > verbal profile may index an etiologically significant subtype of autism.     

The prognosis and survival of childhood acute lymphoblastic leukemia with central nervous system relapse

Central nervous system (CNS) relapse in childhood acute lymphoblastic leukemia (ALL) has been overcome by sensitive therapeutic approachs. This study was planned to present the development of CNS relapse and survival in newly diagnosed 190 ALL patients whose cases were followed in the authors' unit between March 1991 and May 2002. St. Jude Study XI protocol was given to the patients who applied between March 1991 and March 1997 (group A) (n = 122), and St. Jude Study XIII protocol was given to the patients who applied between March 1997 and May 2002 (group B) (n = 68). The patients having isolated CNS relapse in group A received craniospinal irradiation (CSI) median 3.5 months after CNS relapse (range 2-6 months), a short time after reinduction, and 2 cures of consolidation. In group B, patients having isolated CNS relapse received IT once a month and a high-dose methotrexate treatment once every 8 weeks and 3 or 4, cures later therapy CSI median 7 months after CNS relapse (range 6-8 months) was given. When the overall survival rates of the 2 groups are compared, a statistically significant higher survival rate at 5 years was determined in group B than in group A (respectively, 82.3%, 58.4%) (p < .05). When subgroups of the patients (that is, those with no relapse, isolated CNS or BM relapse, or CNS + BM relapse) were compared in both groups, it was found that survival was much higher for the ones with no relapse and with isolated CNS relapse (respectively, 87.9%, 72.7%) compared to isolated BM or CNS + BM relapse groups (respectively, 10%, 13.3%) (p < .05). In a conclusion, for children with acute lymphoblastic leukemia and an isolated CNS relapse, with delayed definitive craniospinal irradiation allowing more intensive systemic and intrathecal chemotherapy results in better overall survival than has been previously reported.     

Cognitive deficits in long-term survivors of childhood brain tumors: Identification of predictive factors

BACKGROUND: To describe cognitive function and to evaluate the association between potentially predictive factors and cognitive outcome in an unselected population of survivors of childhood brain tumors. PROCEDURE: We studied a consecutive sample of 133 patients (76 had received radiotherapy (RT)) who had a brain tumor diagnosed before the age of 15 years and were treated during the period January 1970 through February 1997 in the Eastern part of Denmark. Biologic effective dose of irradiation (BED) was assessed in 71 patients. One hundred twenty-seven patients were able to cooperate to WISC-R and WAIS-R. Multiple regression models were constructed to evaluate relationships between possible risk factors and cognitive outcome. RESULTS AND CONCLUSIONS: The mean intelligence (IQ) scores were substantially lower than the expected means of the general population. Younger age at diagnosis, tumor site in cerebral hemisphere, hydrocephalus treated with shunt, and treatment with RT were found to be significant predictors of lower cognitive functions. RT was the most important risk factor for impaired intellectual outcome. The mean observed full scale IQ was 97.1 (SD = 14.3) for the non-irradiated patients and 78.8 (SD = 14.3) for the irradiated patients (adjusted P < 0.001). Verbal IQ, but not performance and full scale IQ, had a significant negative correlation to BED to the tumor site (P < 0.05). These results can be used to identify subgroups of children who are at increased risk for cognitive deficits allowing early and goal-directed intervention.     

Longitudinal follow-up of the intellectual and academic functioning of children receiving central nervous system-prophylactic chemotherapy for leukemia: a four-year final report.

This longitudinal investigation extends our prospective study of the intellectual and academic functioning of children treated for cancer to 4 years after diagnosis. In the longer term, the children who received central nervous system (CNS) chemotherapy experienced greater neurocognitive deficits, particularly in the area of academic achievement, than did the children who did not receive CNS chemotherapy. Specifically, the CNS chemotherapy-treated children scored lower on academic tests of reading at 3 and 4 years after diagnosis. The results suggest that CNS chemotherapy prophylaxis may adversely effect the development of higher-order mental abilities and cognitive skills during the late-effects period and may also impair academic achievement.     

Psychosocial status of young adult survivors of childhood cancer: a survey

The majority of childhood cancer patients now can expect to survive into early adulthood, cured of their cancer. Current adult survivors are a diverse group in terms of diagnosis, age at diagnosis, and types of treatment. It is estimated that by 1990, 1 in every 1,000 twenty-year-olds will have had cancer, making it important to describe the long-term psychosocial adjustment of this population. Patients who were diagnosed between 1948 and 1975 while less than 16 years of age, who were currently 18 years or older, had been off therapy for at least 5 years, and had no known brain damage were eligible for this survey and were identified through the tumor registry at the Children's Hospital of Philadelphia (CHP). Initially, the parents were contacted by letter. Ninety-five (57%) of the 167 eligible patients participated in a telephone interview, which covered educational achievement, occupational status, interpersonal relationships, marital status, pregnancies, employee benefits and insurance, and medical and health behaviors. Respondents were not different from nonrespondents in terms of sex, year of diagnosis, age at diagnosis, diagnoses, stage of illness, or type of treatments. There were no differences in terms of education, marital status, fertility issues, or occupational status by diagnosis group, age at diagnosis, or treatments. The patients were compared to siblings over 18 years of age in terms of education and marital status. No significant differences in sex distribution or years of education between patients and siblings were found. The siblings were, as a group, older than the patients and were more likely to be married. In general, these patients were functioning normally, but there are many unexplored areas of interpersonal relationships and productivity that need further study before conclusions regarding psychosocial adjustment of childhood cancer survivors can be drawn.     

Intellectual function in long-term survivors of childhood acute lymphoblastic leukemia: Protective effect of pre-irradiation methotrexate a childrens cancer study group study

Having demonstrated in a laboratory model that the neurotoxicity of CNS irradiation can be ameliorated with pre-irradiation methotrexate, we retrospectively compared two methods of CNS prophylaxis in childhood acute lymphoblastic leukemia which differed only in the timing of intrathecal methotrexate and radiotherapy. The results of standard IQ tests conducted 2–11 years after 24 Gy of cranial radiotherapy were obtained in 72 patients, of whom 27 had pre-irradiation methotrexate and 45 did not (control group). The two groups were otherwise comparable. In girls, the full-, performance-, and verbal-scale IQ scores were consistently higher in the pre-irradiation methotrexate group than in the corresponding control group (P<0.025). Among girls <5 years of age when irradiated, the mean IQ scores were 25–29 points higher after pre-irradiation methotrexate than after the control treatment (P<0.0007). These results suggest that pre-irradiation methotrexate may help prevent CNS radiotoxicity in children, and that the benefit is dependent on patient age and gender.