Defining the impact of hemophilia: the Academic Achievement in Children with Hemophilia Study.

OBJECTIVES: We characterized a population-based cohort of school-aged children with severe hemophilia with respect to type of treatment, on-demand versus prophylaxis, and frequency of bleeding episodes in the year before enrollment. We also investigated the association between hemophilia-related morbidity, measured by number of bleeding episodes in the year before enrollment, and academic performance after adjustment for other factors known to have an effect on achievement. Finally, we explored the mechanisms for the association between bleeding episodes and academic achievement. STUDY DESIGN: This study was a multicenter investigation of boys 6 to 12 years old with severe factor VIII deficiency (clotting factor level <2%) receiving care in US hemophilia treatment centers. Children with a history of inhibitor, severe developmental disorder, significant psychiatric disorder, or insufficient fluency in English were excluded from the study. On-demand treatment was defined as administration of clotting factor on the occurrence of a bleeding episode. Prophylactic therapy was defined as a course of regular infusions for >2 months with a goal of preventing bleeding episodes. Academic achievement was measured by the Wechsler Individual Achievement Test. Quality of life was measured by the Child Health Questionnaire. Of particular interest was the Physical Summary (PhS) measure of the Child Health Questionnaire. The type of information captured by the PhS includes limitations in physical activity, limitations in the kind or amount of schoolwork or social activities the child engaged in, and presence of pain or discomfort. RESULTS: One hundred thirty-one children were enrolled, a median center recruitment rate of 77%. The mean age of the participants was 9.6 years, and approximately half of the participants had completed less than the fourth grade at the time of enrollment. Sixty-two percent of the children were on prophylaxis at enrollment, and 9% had previously been on prophylaxis but were currently on on-demand therapy. Two groups were defined: ever treated with prophylaxis and never treated with prophylaxis. For those ever treated, treatment duration ranged from 2.7 months to 7.7 years, with one half of the children treated with prophylaxis for >40% of their lifetimes; 29% had always been on on-demand therapy. Children in both treatment groups were similar with respect to age, clotting factor level, parents' education, and IQ. The median number of bleeding episodes experienced in the year before enrollment for the cohort as a whole was 12. The median number of bleeding episodes in children on prophylaxis at enrollment was significantly lower than in children on on-demand therapy (6 vs 25.5). The mean achievement scores were within the average range of academic performance: reading, 100.4; mathematics, 101.6; language, 108.1; writing, 95.4; and total achievement, 102.5. When children were categorized as above or below the study group median by number of bleeding episodes, those who had a low number of bleeding episodes (< or =11) had better total achievement (104.4 vs 100.6) and mathematics (103.6 vs 99.6) than children in the higher bleeding episode category (> or =12) after adjusting for child's IQ and parents' education. Treatment with prophylaxis per se was not associated with better test scores, but children who had been treated on a regimen of long-term prophylaxis (>40% of lifetime) and reported < or =11 bleeding episodes in the year before enrollment had significantly higher scores in total achievement (104.9 vs 100.6), mathematics (105.2 vs 99.6), and reading (104.0 vs 98.6) than all other children reporting > or =12 bleeding episodes in the same time period. Increased school absenteeism and hemophilia-related limitations in physical functioning among children with greater frequency of bleeding episodes were proposed as the mechanisms for lower scores. The number of bleeding episodes was positively correlated with school absenteeism (Spearman correlation = 0.23), and children with more school absences had lower scores in mathematics, reading, and total achievement, even after adjusting for the child's IQ and parents' education. Children with fewer bleeding episodes also had better PhS scores than children in the high bleeding episode category (48.4 vs 41.3). The mean PhS for children in the low bleeding episode group (48.4) was similar to that of the general US population (50), but the mean PhS for children in the higher bleeding episode group was almost a full standard deviation lower than the mean for the general US population. PhS scores were positively related to reading and total achievement scores after adjusting for IQ and parents' education. Of interest and concern was a group of children who were reportedly being treated with prophylaxis during the year before enrollment (N = 18) but whose bleeding events were not optimally suppressed. These children were 3 times as likely (33.3% vs 11.1%) to be receiving < or =2 infusions per week as children on prophylaxis who reported < or =11 bleeding episodes during the same period. A review of the sites of bleeding reported for the 18 children revealed that 12 (66.6%) experienced > or =25% of their bleeding episodes in the same joint. CONCLUSIONS: Each child should have the opportunity to achieve his or her potential. Control of a chronic disorder must include this important goal as well as the more commonly identified medical outcomes. This study has identified an important association between the number of bleeding episodes experienced and academic achievement in a cohort of school-aged children with severe hemophilia. The data support the assertion that therapeutic care programs in this population must not be evaluated only in terms of financial cost to achieve adequate musculoskeletal outcomes. Also significant are the individual and societal benefits of increased academic accomplishments if adequate suppression of hemorrhagic events can be attained. The number of bleeding episodes experienced, regardless of treatment regimen, should be followed to optimize the child's academic outcome.

HIV-associated changes in adaptive, emotional, and behavioral functioning in children and adolescents with hemophilia: results from the Hemophilia Growth and Development Study.

OBJECTIVE: To assess changes in adaptive, emotional, and behavioral functioning over four years in children and adolescents with hemophilia and with or without HIV infection and to evaluate the relationship of these changes to immune status. METHODS: Participants were 277 HIV-seropositive and 126 HIV-seronegative boys with hemophilia. Participants with HIV infection were divided into three groups based on trajectory of immune functioning (CD4+ cell counts) over the course of the study. Caregivers completed the Vineland Adaptive Behavior Scales and Pediatric Behavior Scale (PBS). RESULTS: Results showed declining Vineland Communication scores for participants with consistently poor immune functioning. These participants also started with more PBS Attention Deficit and Deviation symptoms, which then decreased more sharply than for other groups. Low CD4+ counts were consistently associated with more Health and Depression-Anxiety symptoms on the PBS. However, with few exceptions, group means remained within normal limits. CONCLUSIONS: According to their caregivers, boys with hemophilia and HIV infection showed considerable resilience with regard to adaptive behavior and emotional and behavioral problems. However, over time changes occurred in these areas that appear to be related to immune functioning.

Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation.

PURPOSE: To evaluate prospectively the effects on survival, relapse-free survival, and patterns of relapse of reduced-dose (23.4 Gy in 13 fractions) compared with standard-dose (36 Gy in 20 fractions) neuraxis irradiation in patients 3 to 21 years of age with low-stage medulloblastoma, minimal postoperative residual disease, and no evidence of neuraxis disease. PATIENTS AND METHODS: The Pediatric Oncology Group and Children's Cancer Group randomized 126 patients to the study. All patients received posterior fossa irradiation to a total dose of 54 Gy in addition to the neuraxis treatment. Patients were staged postoperatively with contrast-enhanced cranial computed tomography, myelography, and CSF cytology. Of the registered patients, 38 were ineligible. RESULTS: The planned interim analysis that resulted in closure of the protocol showed that patients randomized to the reduced neuraxis treatment had increased frequency of relapse. In the final analysis, eligible patients receiving standard-dose neuraxis irradiation had 67% event-free survival (EFS) at 5 years (SE = 7.4%), whereas eligible patients receiving reduced-dose neuraxis irradiation had 52% event-free survival at 5 years (SE = 7.7%) (P =.080). At 8 years, the respective EFS proportions were also 67% (SE = 8.8%) and 52% (SE = 11%) (P =.141). These data confirm the original one-sided conclusions but suggest that differences are less marked with time. CONCLUSION: Reduced-dose neuraxis irradiation (23.4 Gy) is associated with increased risk of early relapse, early isolated neuraxis relapse, and lower 5-year EFS and overall survival than standard irradiation (36 Gy). The 5-year EFS for patients receiving standard-dose irradiation is suboptimal, and improved techniques and/or therapies are needed to improve ultimate outcome. Chemotherapy may contribute to this improvement.

Attention in HIV-infected children: results from the Hemophilia Growth and Development Study.

Attentional functioning was examined in three groups of 7- to 19-year-old male participants with hemophilia: (1) HIV seronegative controls (HIV-, N = 66), (2) HIV seropositive participants with CD4+ lymphocyte counts greater than or equal to 200 (HIV+ CD4+ > or = 200, N = 79), and (3) severely immune suppressed HIV seropositive participants (HIV+ CD4+ < 200, N = 28). Two measures sensitive to attention deficits were used: the Continuous Performance Test (CPT) and the Span of Apprehension (Span). On the CPT, there was a decrement in attention in both HIV+ groups, as indexed by an increase in false alarm rate from Block 1 to Block 3, that was not present in the HIV- group. The longer the HIV+ children were required to sustain attention to the CPT, the more they responded to the incorrect stimulus. This effect decreased as age increased. Span percent correct and latency to correct were associated with the presence of a premorbid history of intracerebral hemorrhage, but were not sensitive to HIV status or degree of immune suppression in the HIV+ children, suggesting morbidity related to hemophilia. The remaining CPT and Span variables--hit rate, sensitivity, latency, percent correct, and latency to correct--showed the expected associations with age, but none showed conclusive associations with HIV status or immune suppression in the HIV+ participants.

Declining immune function in children and adolescents with hemophilia and HIV infection: effects on neuropsychological performance. Hemophilia Growth and Development Study.

OBJECTIVE: To determine whether declines in immune functioning are associated with changes in neuropsychological performance in children and adolescents with hemophilia who are infected with the human immunodeficiency virus (HIV). METHODS: Participants were 333 males with hemophilia, ages 6-19 years at entry. A baseline and four annual neuropsychological evaluations were given. A longitudinal growth curves analysis of data was performed to detect changes associated with declining immune function. The cohort was stratified into four groups: (1) HIV- (n = 126); (2) HIV+, average of first two and last two CD4 counts > or = 200, (n = 106; High CD4 group); (3) HIV+, average first two counts > or = 200, average last two counts < 200 (n = 41; CD4 Drop group); and (4) HIV+, average first two and last two counts < 200 (n = 60; Low CD4 group). RESULTS: There were significant differences among the four groups over time in nonverbal intelligence, perceptual/performance skills, nonverbal memory, academic achievement, and language. The Low CD4 group consistently showed the greatest decrement in performance. On measures showing a practice effect for repeated measurements, the Low CD4 group participants' scores remained stable over time, suggesting opposing effects of practice and HIV-related declines. Lowered academic performance relative to IQ was found in all groups. CONCLUSIONS: Declines in neuropsychological functioning are directly related to declines in immune functioning in HIV+ children, adolescents, and young adults with hemophilia. Hemophilia itself may be a risk factor for academic underachievement.

Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study.

PURPOSE: From 1986 to 1992, "eight-drugs-in-one-day" (8-in-1) chemotherapy both before and after radiation therapy (XRT) (54 Gy tumor/36 Gy neuraxis) was compared with vincristine, lomustine (CCNU), and prednisone (VCP) after XRT in children with untreated, high-stage medulloblastoma (MB). PATIENTS AND METHODS: Two hundred three eligible patients with an institutional diagnosis of MB were stratified by local invasion and metastatic stage (Chang T/M) and randomized to therapy. Median time at risk from study entry was 7.0 years. RESULTS: Survival and progression-free survival (PFS) +/- SE at 7 years were 55%+/-5% and 54%+/-5%, respectively. VCP was superior to 8-in-1 chemotherapy, with 5-year PFS rates of 63%+/-5% versus 45%+/-5%, respectively (P = .006). Upon central neuropathology review, 188 patients were confirmed as having MB and were the subjects for analyses of prognostic factors. Children aged 1.5 to younger than 3 years had inferior 5-year estimates of PFS, compared with children 3 years old or older (P = .0014; 32%+/-10% v 58%+/-4%, respectively). For MB patients 3 years of age or older, the prognostic effect of tumor spread (MO v M1 v M2+) on PFS was powerful (P = .0006); 5-year PFS rates were 70%+/-5%, 57%+/-10%, and 40%+/-8%, respectively. PFS distributions at 5 years for patients with M0 tumors with less than 1.5 cm2 of residual tumor, versus > or = 1.5 cm2 of residual tumor by scan, were significantly different (P = .023; 78%+/-6% v 54%+/-11%, respectively). CONCLUSION: VCP plus XRT is a superior adjuvant combination compared with 8-in-1 chemotherapy plus XRT. For patients with M0 tumors, residual tumor bulk (not extent of resection) is a predictor for PFS. Patients with M0 tumors, > or = 3 years with < or = 1.5 cm2 residual tumor, had a 78%+/-6% 5-year PFS rate. Children younger than 3 years old who received a reduced XRT dosage had the lowest survival rate.

Hemophilia growth and development study: relationships between neuropsychological, neurological, and MRI findings at baseline.

OBJECTIVE: To determine the effects of human immunodeficiency virus (HIV) infection on children's development by identifying neurological and environmental variables associated with neuropsychological measures of cognitive development in HIV-seronegative (HIV-) and HIV-seropositive (HIV+)children and adolescents with hemophilia. METHODS: Participants (N = 298; 60% HIV+) were males ages 7-19 years enrolled in the Hemophilia Growth and Development Study (HGDS). Least squares modeling was used to determine whether there was a difference at baseline in mean neuropsychological test scores by HIV status, age, and neurological baseline findings, adjusting for selected environmental and medical history variables. RESULTS: The participants were within age expectations for general intelligence. Variables associated with lowered neuropsychological performance included academic problems, coordination and/or gait abnormalities, parents' education, and previous head trauma. CONCLUSIONS: Hemophilia-related morbidity has a subtle adverse influence on cognitive performance. HIV infection was not associated with neuropsychological dysfunction in this group even when MRI abnormalities were present.

Behavioral adjustment and social functioning of long-term survivors of childhood leukemia: parent and teacher reports.

Obtained parent and teacher reports of behavior and social competence for children who were survivors of acute lymphoblastic leukemia (ALL). At follow-up, children were 5-18 years of age, 48 months postdiagnosis, in first continuous remission, and off chemotherapy. Each child had been randomized to receive either 1,800 cGy whole brain radiation therapy (WBRT) plus intrathecal methotrexate (IT MTX), or IT MTX alone as central nervous system prophylaxis, and one of four chemotherapy regimens that varied in treatment intensity. Scores on standardized measures (CBCL-P/T and PIC) were generally similar to instrument norms. Parents, but not teachers, reported heightened child somatic concerns. There was no effect of WBRT or chemotherapy regimen on ratings of behavioral adjustment. Results indicate minimal psychosocial morbidity among long-term survivors of ALL and suggest that the stressful life events associated with cancer and its treatment do not cause significant behavioral or emotional difficulties.

Results of a prospective randomized trial comparing standard dose neuraxis irradiation (3,600 cGy/20) with reduced neuraxis irradiation (2,340 cGy/13) in patients with low-stage medulloblastoma. A Combined Children's Cancer Group-Pediatric Oncology Group Study.

PURPOSE: To determine in a prospective randomized trial the effect on survival, progression-free survival, and patterns of relapse of a decrease in the neuraxis radiation dose from 3,600 cGy in 20 fractions to 2,340 cGy in 13 fractions in patients with newly diagnosed medulloblastoma between 3 and 21 years of age with low T stage (T1, T2 and T3A), minimal postoperative residual tumor, and no evidence of dissemination (M0). METHODS AND MATERIALS: Between June 1986 and November 1990, the Children's Cancer Group and the Pediatric Oncology Group randomized 126 patients in a two-arm study comparing the two different doses of neuraxis irradiation. In both arms, the posterior fossa received 5,400 cGy in 30 fractions. All patients were staged with myelography, postoperative lumbar cerebrospinal fluid cytology, and postoperative contrast-enhanced cranial computerized tomography to ensure no evidence of dissemination and no more than 1.5 cm3 residual tumor volume. Overall survival, progression-free survival, and patterns of recurrence were carefully monitored. Prospective endocrine and psychometric studies were performed to determine the benefit of decreasing the neuraxis radiation dose. RESULTS: Following an interim analysis at a median time on study of 16 months, the study was closed, since a statistically significant increase was observed in the number of all relapses as well as isolated neuraxis relapses in patients randomized to the lower dose of neuraxis radiation. CONCLUSIONS: In patients with newly diagnosed medulloblastoma considered to have a good prognosis on the basis of low T stage, minimal residual tumor after at least subtotal resection, and no evidence of dissemination after thorough evaluation, there is an increased risk of early relapse associated with lowering the dose of neuraxis radiation from 3,600 cGy in 20 fractions to 2,340 cGy in 13 fractions.

Neuropsychological effects of cranial irradiation in young children with acute lymphoblastic leukemia 9 months after diagnosis. The Children's Cancer Group.

STUDY OBJECTIVE: To determine the effects of cranial irradiation on neuropsychological test performance evident 9 months after diagnosis. DESIGN: A companion study to a randomized clinical trial (CCG-105). SETTING: Institutions participating in Childrens Cancer Group cooperative treatment trials. PATIENTS: Seventy-four children aged 3.0 to 6.5 years with average-risk acute lymphoblastic leukemia. Children with central nervous system leukemia at the time of diagnosis, preexisting mental retardation, or Down's syndrome or for whom English was not the primary language were not eligible for study. INTERVENTIONS: Children were randomized to receive treatment with one of four systemic chemotherapy regimens and either intrathecal methotrexate sodium during induction and consolidation plus 18 Gy of cranial irradiation or intrathecal methotrexate during induction, consolidation, and maintenance as central nervous system prophylaxis. MEASUREMENT AND RESULTS: The groups were comparable with regard to chronologic age, sex, and family socioeconomic status. Children who received cranial irradiation plus intrathecal methotrexate scored significantly lower on the McCarthy Motor Scale (P < .05) and the Token Test (P < .05) than children who received intrathecal methotrexate alone. The groups did not differ significantly on the McCarthy General Cognitive Index, Developmental Test of Visual Motor Integration, or Peabody Picture Vocabulary Test-Revised. CONCLUSIONS: Findings suggest that the combined effects of cranial irradiation and intrathecal methotrexate therapy on neuropsychological performance may be evident in young children as early as 9 months after diagnosis. Follow-up assessment of these children will reveal whether these effects remain constant, intensify, or resolve.

CNS prophylaxis of childhood leukemia: what are the long-term neurological, neuropsychological, and behavioral effects?

Current medical treatments for childhood acute lymphoblastic leukemia (ALL) have improved the outlook to where more than 50% can be expected to survive five years or more. The use of CNS prophylaxis has contributed in a significant way to these improved survival statistics by reducing the likelihood of CNS relapses. The literature relating to the potential adverse psychological consequences of CNS prophylaxis, which include cranial radiation therapy (CRT), is reviewed and analyzed. The majority of published papers of children in first remission report that CNS prophylaxis, which include both CRT and intrathecal methotrexate, results in a variety of learning problems in many children who were younger than age 5 when treated. The available literature on the social, emotional, and educational sequelae of childhood ALL is also reviewed.

"Mental imbalance" and the prediction of recurrent delinquent behavior.

Cognitive and personality patterns of 84 court-referred adolescents were examined to identify predictors of recurrent delinquent behavior. Continued behavioral problems at follow-up were more likely in adolescents with discrepancies between Verbal and Performance IQ or large differences between "neurotic" and "psychotic" scale elevations on the MMPI. Positive outcomes were most likely for adolescents who could be described as "mildly neurotic." Combining the discrepancy scores from the intelligence and personality tests with other background variables in a Bayesian conditional probability model resulted in accurate predictions of later behavior for 81% of the sample. These findings suggest that imbalances in cognitive and personality development may limit a delinquent adolescent's ability to interact appropriately with the environment.

Intelligence and achievement testing in childhood cancer: three years postdiagnosis.

Intellectual and educational testing, employing primarily the Wechsler Intelligence Scale for Children-Revised (WISC-R) and the Wide Range Achievement Test (WRAT), was administered to two groups of children, one with acute lymphoblastic leukemia (ALL), the other with a solid tumor (ST) which did not invade or involve the central nervous system (CNS). Initial testing was completed within 30 days following diagnosis and repeated one year and three years later. Separate ANOVA procedures on the ALL and ST patients were completed, with followup ANOVA procedures for two age groups. The ALL patients declined significantly on WISC-R vocabulary (p less than 0.05) and Full Scale IQ (p less than 0.05), but no significant changes were obtained from the ST patients. Separation of the ALL group into two age groups, less than 8 years and greater than or equal to 8 years revealed significant declines in the younger group on Verbal IQ, Performance IQ, Full Scale IQ, and WRAT arithmetic. However, no significant declines were observed in the older ALL group. The results suggest that declines in ability and achievement are limited to those ALL patients treated with CNS prophylaxis at relatively young ages.

MMPI profiles of rheumatic fever adolescents and adults.

MMPI elevations for adolescent and adult groups (N = 162) who had experienced rheumatic fever (RF) were generally lower than Mayo Clinic norms, particularly on scales K, 1, 2, 3, and 6. Significant age effects on Scales F, 3, 4, 8, and 9 confirm previous findings that adolescent groups score higher on the MMPI. Contrary to expectation, patients who had not experienced carditis as part of their RF scored significantly higher than carditis patients on scales 2, 3, and 4. The results are discussed from a chronic disease perspective.

Two studies of compliance with daily prophylaxis in rheumatic fever patients in Iowa.

We determined the penicillin compliance rates in school year 1974-75 for 235 children with rheumatic fever through analysis of urine specimens collected at school. Patients relatively low on compliance during the first year of sampling were divided into two equal size groups for a second year sampling study. One-half (N = 44) of these second year study patients and their parents were readvised regarding the need for penicillin prophylaxis and one-half (N = 44) served as controls. We related eductional data, behavioral ratings, and family information to compliance rates in both study years. The overall compliance for the children during the initial sampling year was 64.6 per cent. Factors found to be significantly related to compliance in year one were: 1) male sex, 2) large sibship, 3) increased number of behavior problems, 4) relatively poor academic progress, 5) lower maternal educational level, and 6) recurrence of rheumatic fever. Compliance rates for reinforced patients did not differ significantly from controls during the second year sampling.

Intrauterine fetal transfusion, 1965-1976, with an assessment of the surviving children.

The need for IUT in the management of Rh hemolytic disease is likely to continue in the foreseeable future. Recent reports have been skeptical about the success of this procedure and the quality of the surviving infants. Of 84 fetuses who received 134 IUT's, over all, 35.7 per cent survived; 48.3 per cent of the nonhydropic group survived. Fifteen of the 23 survivors between 3 and 11 years of age received intellectual, academic, behavioral, health, and developmental evaluations. When compared to sibling and high-risk control groups, the study children showed no significant differences in intelligence quotients, arithmetic achievements, or reading achievements; their school performance is acceptable and none is presenting significant behavioral problems. Except for an excessive number of umbilical and inguinal hernias, there were no physical abnormalities that could be directly related to IUT.

Outcome at ages 1, 3, and 5 years of children born to diabetic women.

A prospective study of infants born to women with diabetes mellitus is reported. The children were examined at birth and followed at 1, 3, and 5 years of age. Medical and psychological information was obtained through follow-up examinations. Intrauterine growth was atypical and there was an increase in neonatal problems and congenital malformations. There was an increased incidence of intellectual delay at 3 and 5 years of age. The presence of acetone in the urine during pregnancy had a significant, adverse effect on intellectual status of the offspring at 5 years of age. Birth weight was negatively related to intellectual status at both 3 and 5 years of age.