Deborah P. Waber

Assessing children's copy productions of the Rey-Osterrieth Complex Figure.

This report describes developmental changes in childrens copy productions of the Rey-Osterrieth Complex Figure as well as a new method for evaluating these productions that is sensitive to parameters relevant for neuropsychological diagnosis. Based on protocols from a standardization sample of 454 children between the ages of 5 and 14, a system was devised for evaluating objectively: organization; production style; and, accuracy. Normative findings are described and implications for the use of this instrument in the neuropsychological assessment of children discussed.

The NIH MRI study of normal brain development: Performance of a population based sample of healthy children aged 6 to 18 years on a neuropsychological battery

The National Institutes of Health (NIH) Magnetic Resonance Imaging (MRI) Study of Normal Brain Development is a landmark study in which structural and metabolic brain development and behavior are followed longitudinally from birth to young adulthood in a population-based sample of healthy children. The neuropsychological assessment protocol for children aged 6 to 18 years is described and normative data are presented for participants in that age range (N = 385). For many measures, raw score performance improved steeply from 6 to 10 years, decelerating during adolescence. Sex differences were documented for Block Design (male advantage), CVLT, Pegboard and Coding (female advantage). Household income predicted IQ and achievement, as well as externalizing problems and social competence, but not the other cognitive or behavioral measures. Performance of this healthy sample was generally better than published norms. This linked imaging-clinical/behavioral database will be an invaluable public resource for researchers for many years to come.

Nutritional supplementation, maternal education, and cognitive development of infants at risk of malnutrition.

Infants born to families at risk of malnutrition were studied prospectively from the beginning of the 3rd trimester of the mothers pregnancy until the child reached 3 yr of age to ascertain the effects of nutritional supplementation and/or a maternal education program on their cognitive development. Four hundred thirty-three families were assigned randomly to six groups: group A served as a control; group B received the supplement from the age of 6 months to 3 yr; group C received the supplement during the 3rd trimester of pregnancy and the first 6 months of the childs life; and group D received the supplement throughout the entire study period. In addition, group A1 was enrolled in a maternal education program but received no nutritional supplement and group B1 received both treatments. The Griffiths test of infant development was administered at 4, 6, 12, 18, 24, and 36 months of age, and the Corman-Escalona Einstein scale was administered at each age up to 18 months. Children who received food supplementation performed better than those who did not, especially on subtests that were primarily motoric. The effect of food supplementation on behavior appeared to be contemporaneous. In addition, the treatment effects were more pronounced for girls than for boys in this sample. Although these interventions reduced the gap in cognitive performance between lower and upper socioeconomic classes, a disparity nevertheless remained by the end of the study.

Neuropsychological Aspects of Turner's Syndrome

Eleven patients with Turners syndrome (ages 13 to 23 years) were compared on a battery of neuropsychological measures with a control group matched for age and subtests of the Verbal IQ Scale of the Wechsler tests. Patients performed less well than controls on word fluency, perception of left and right, visuo‐motor co‐ordination, visual memory and motor learning. They also showed a higher incidence of left‐ear advantage on a dichotic listening test for phonemic stimuli than did controls. There was no clear evidence for a specific deficit in spatial ability in the patients tested.

Cognitive sequelae in children treated for acute lymphoblastic leukemia with dexamethasone or prednisone

PURPOSE The cognitive sequelae of treatment for childhood acute lymphoblastic leukemia (ALL) were compared in a group of patients who received dexamethasone during the intensification and maintenance phases of therapy with those in a historical control group for whom antileukemia therapy was similar, except that the corticosteroid component of therapy was prednisone. METHODS Patients treated for ALL on Dana-Farber Cancer Institute protocols 87-01 (n = 44) and 91-01 (n = 23) were evaluated by standard cognitive and achievement tests. Corticosteroid therapy was delivered in 5-day pulses given every 3 weeks during intensification and continuation phases of therapy for a total of 2 years. RESULTS Children treated on protocol 87-01 received prednisone at a dose of 40 mg/m2/d (standard risk, SR) or 120 mg/ m2/d (high risk, HR); those treated on protocol 91-01 received dexamethasone at a dose of 6 mg/m2 per day (SR) or 18 mg/m2 per day (HR). Children treated on protocol 91-01 performed less well on cognitive testing. Subsample analysis indicated that cranial radiation therapy and methotrexate dose did not account for differences in cognitive outcomes. CONCLUSIONS The findings of this preliminary study are consistent with the hypothesis that dexamethasone therapy can increase risk for neurocognitive late effects in children treated for ALL and indicate that further investigation of this question is warranted.

Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: cranial radiation requires an accomplice.

PURPOSE We evaluated cognitive sequelae of treatment for childhood acute lymphoblastic leukemia (ALL). CNS therapy consisted of cranial irradiation (CRT) or no radiation. Children were also randomized to single intravenous high-dose methotrexate (HD-MTX) or conventional-dose methotrexate (CD-MTX) during induction, and all patients received intrathecal (IT) and systemic continuation chemotherapy. PATIENTS AND METHODS Sixty-six patients treated for ALL on Dana-Farber Cancer Institute protocol 87-01 were evaluated by standardized cognitive and achievement tests. These children had been assigned at diagnosis to a standard-risk (SR) or high-risk (HR) group and received no CRT or 18 Gy CRT, respectively. All patients were randomized to receive MTX during remission induction, either as CD-MTX (40 mg/m2) or HD-MTX (4 g/m2) with leucovorin rescue. RESULTS There was no difference in cognitive outcomes between radiated and unirradiated patients (P > .4). However, the HD-MTX/CRT combination was associated with decreased intelligence quotient (IQ estimate, 9.3 points) for girls only (P < .08). A specific deficit in verbal coding and memory was documented for all patients (P < .0001). CONCLUSION We conclude the following: (1) 18 Gy CRT per se was not an independent toxic agent for cognitive outcome; (2) HD-MTX during induction was associated with IQ decline in girls, but only when it was followed by CRT; and (3) impairment of verbal memory and coding was a consistent finding that was independent of CRT, which implicates some component of chemotherapy, possibly prednisone, as a CNS toxin.

The relationship of sex and treatment modality to neuropsychologic outcome in childhood acute lymphoblastic leukemia.

PURPOSE Long-term adverse neurobehavioral sequelae frequently are observed in pediatric patients treated for acute lymphoblastic leukemia (ALL). To clarify the relative contribution of cranial irradiation (CRT) therapy and drug therapy to these outcomes, we evaluated neuropsychologic outcomes associated with different doses of CRT and intravenous (IV) methotrexate (MTX) in long-term survivors. PATIENTS AND METHODS Fifty-one patients treated for ALL on Dana-Farber Cancer Institute protocol 81-01 were evaluated by standardized cognitive and academic achievement tests. These children had been assigned at diagnosis to a standard-risk (SR) or high-risk (HR) group and received 1,800 cGy or 2,800 cGy CRT, respectively. A subgroup of these patients was randomized to receive MTX during remission induction, either as a single low dose (LD; 40 mg/m2) or a single high dose (HD; 4 g/m2) with leucovorin rescue. RESULTS Sex and MTX randomization jointly predicted the intelligence quotient (IQ). Fifty percent of girls versus 14% of boys exhibited low IQ (less than 90; P = .01); 80% of girls who received HD MTX versus 25% of girls who received LD MTX exhibited low IQ (P = .03). In contrast, risk group better predicted performance on tasks sensitive to verbal memory and/or coding. CONCLUSIONS We conclude that (1) significant neurotoxicity occurred principally in girls; (2) increased dose intensity of IV MTX was associated with lower IQ, but only in girls; and (3) increased dose of CRT may have been associated with impairment of verbal memory and coding.

Cortical thickness correlates of specific cognitive performance accounted for by the general factor of intelligence in healthy children aged 6 to 18

Prevailing psychometric theories of intelligence posit that individual differences in cognitive performance are attributable to three main sources of variance: the general factor of intelligence (g), cognitive ability domains, and specific test requirements and idiosyncrasies. Cortical thickness has been previously associated with g. In the present study, we systematically analyzed associations between cortical thickness and cognitive performance with and without adjusting for the effects of g in a representative sample of children and adolescents (N=207, Mean age=11.8; SD=3.5; Range=6 to 18.3 years). Seven cognitive tests were included in a measurement model that identified three first-order factors (representing cognitive ability domains) and one second-order factor representing g. Residuals of the cognitive ability domain scores were computed to represent g-independent variance for the three domains and seven tests. Cognitive domain and individual test scores as well as residualized scores were regressed against cortical thickness, adjusting for age, gender and a proxy measure of brain volume. g and cognitive domain scores were positively correlated with cortical thickness in very similar areas across the brain. Adjusting for the effects of g eliminated associations of domain and test scores with cortical thickness. Within a psychometric framework, cortical thickness correlates of cognitive performance on complex tasks are well captured by g in this demographically representative sample.

Neuropsychological Outcomes From a Randomized Trial of Triple Intrathecal Chemotherapy Compared With 18 Gy Cranial Radiation As CNS Treatment in Acute Lymphoblastic Leukemia: Findings From Dana-Farber Cancer Institute ALL Consortium Protocol 95-01

PURPOSE We evaluated late neuropsychological toxicity in children treated for standard-risk acute lymphoblastic leukemia (ALL) who were randomly assigned to receive either cranial radiation therapy (CRT) with double intrathecal (IT) chemotherapy or intensive triple IT chemotherapy (no CRT) as CNS-directed therapy. PATIENTS AND METHODS Between 1996 and 2000, 164 children with standard-risk ALL treated on Dana-Farber Cancer Institute Consortium Protocol 95-01 were randomly assigned to receive either 18 Gy CRT delivered in twice daily fractions (0.9 [DOSAGE ERROR CORRECTED] Gy) with double IT therapy (methotrexate and cytarabine) or intensive triple IT drug (methotrexate, cytarabine and hydrocortisone) without CRT. Neuropsychological testing was completed at a median 6 years postdiagnosis for 79 children (CRT, n = 39; triple IT, n = 40), all of whom were in continuous complete remission. RESULTS Cognitive function for both groups was solidly in the average range, with no consistent group differences in basic cognitive skills. Children treated on the CRT plus double IT arm did, however, exhibit less fluent output and were less effective at modulating their behavior by parent report. CONCLUSION This randomized trial revealed only subtle differences 6 years after diagnosis between children who received CNS therapy as CRT plus double IT drug or as intensive triple IT drug. In most situations where comparable therapeutic efficacy can be achieved without CRT, it is preferable to do so. Where therapeutically necessary, however, CRT at lower doses may not add risk for significant neurotoxicity.

Processing Speed in Children With Attention Deficit/Hyperactivity Disorder, Inattentive Type

Attention Deficit/Hyperactivity Disorder (ADHD) is among the most common and most often reconceptualized neurobehavioral disorders of childhood. In the most recent DSM-IV, a primarily inattentive subtype of ADHD (AD) has again been identified. This study explores the neuropsychological profile of this group of children. Eighty-two children referred for school-related problems participated. Twenty-five met criteria for AD; 52 met criteria for reading disability (RD); 9 were comorbid for RD and AD. AD children performed poorly on measures of information processing speed. Children with comorbid AD/RD were distinguishable from those with RD on speed of processing measures only. Vulnerability to information processing load may be at the root of many of the behavioral manifestations of AD.