Evidence of change in brain activity among childhood cancer survivors participating in a cognitive remediation program.

Increased understanding of the underlying mechanisms of cognitive remediation is needed to facilitate development of intervention strategies for childhood cancer survivors experiencing cognitive late effects. Accordingly, a pilot functional magnetic resonance imaging (fMRI) study was conducted with 14 cancer survivors (12.02 ± 0.09 years old), who participated in a cognitive remediation clinical trial, and 28 healthy children (12.7 ± 0.6 years old). The ventral visual areas, cerebellum, supplementary motor area, and left inferior frontal cortex were significantly activated in the healthy participants during a continuous performance task. In survivors, brain activation in these regions was diminished at baseline, and increased upon completion of remediation and at a 6-month follow-up. The fMRI activation index for each region of interest was inversely associated with the Conners' Clinical Competence Index (p<.01). The pilot study suggests that fMRI is useful in evaluating neural responses to cognitive remediation.

Predicting methylphenidate response in long-term survivors of childhood cancer: a randomized, double-blind, placebo-controlled, crossover trial.

OBJECTIVE: To investigate the methylphenidate (MPH) response rate among childhood survivors of acute lymphoblastic leukemia (ALL) and brain tumors (BTs) and to identify predictors of positive MPH response. METHODS: Cancer survivors (N = 106; BT = 51 and ALL = 55) identified as having attention deficits and learning problems participated in a 3-week, double-blind, crossover trial consisting of placebo, low-dose MPH (0.3 mg/kg), and moderate-dose MPH (0.6 mg/kg). Weekly teacher and parent reports on the Conners' Rating Scales were gathered. RESULTS: Following moderate MPH dose, 45.28% of the sample was classified as responders. Findings revealed that more problems endorsed prior to the medication trial on parent and teacher ratings were predictive of positive medication response (p < .05). CONCLUSIONS: MPH significantly reduces attention problems in a subset of childhood cancer survivors. Parent and teacher ratings may assist in identifying children most likely to respond to MPH so prescribing may be optimally targeted.

Brain structural abnormalities in survivors of pediatric posterior fossa brain tumors: a voxel-based morphometry study using free-form deformation.

Voxel-based morphometry was used to compare brain structure of survivors of posterior fossa brain tumor (PFBT) with that of normal sibling controls to investigate disease- or cancer treatment-induced changes. Two different spatial normalization approaches that are available in public domain software (free-form deformation (FFD) and discrete cosine transform (DCT)) were compared for accuracy of normalization in the PFBT patients. Anatomical landmark matching demonstrated that spatial normalization was more accurate with FFD than with DCT. Voxel-based morphometry of the FFD-normalized magnetic resonance images from PFBT survivors and sibling controls detected reduced gray matter density in the thalamus and entorhinal cortex and reduced white matter density in the internal capsule, hypothalamus, corpus callosum, and cuneus of the occipital lobe in the PFBT survivors. Identification of these morphologic lesions may help localize the neural substrates of disease- or therapy-induced cognitive deficits in survivors of childhood cancer.

A multicenter, randomized clinical trial of a cognitive remediation program for childhood survivors of a pediatric malignancy.

Survivors of childhood cancer whose malignancy and/or treatment involved the central nervous system may demonstrate a consistent pattern of neurocognitive deficits. The present study evaluated a randomized clinical trial of the Cognitive Remediation Program (CRP). Participants were 6- to 17-year-old survivors of childhood cancer (N = 161; 35% female, 18% Hispanic, 10% African American, 64% Caucasian, 8% other) who were at least 1 year off treatment and who manifested an attentional deficit. They were enrolled at 7 sites nationwide. Two thirds of the participants were randomly assigned to cognitive remediation. All participants were assessed using a battery of academic achievement/neurocognitive tests and parent/teacher measures of attention. The CRP resulted in parent report of improved attention and statistically significant increases in academic achievement. Effect sizes were modest but were comparable with those for other clinical trials of brain injury rehabilitation and for psychological interventions in general. The CRP is presented as a potentially beneficial treatment for many survivors of pediatric cancer. Long-term clinical significance remains unproven. Further work is needed to improve effect sizes and treatment compliance and to address the needs of other populations with pediatric brain injury.

Neural correlates of a clinical continuous performance test.

Functional magnetic resonance imaging (fMRI) was performed in 30 healthy adults to identify the location, magnitude, and extent of activation in brain regions that are engaged during the performance of Conners' Continuous Performance Test (CPT). Performance on the task during fMRI was highly correlated with performance on the standard Conners' CPT in the behavioral testing laboratory. An extensive neural network was activated during the task that included the frontal, cingulate, parietal, temporal, and occipital cortices; the cerebellum and the basal ganglia. There was also a network of brain regions which were more active during fixation than task. The magnitude of activation in several regions was correlated with reaction time. Among regions that were more active during task, the overall volume of supratentorial activation and cerebellar activation was greater in the left hemisphere. Frontal activation was greater in dorsal than in ventral regions, and dorsal frontal activation was bilateral. Ventral frontal region and parietal lobe activation were greater in the right hemisphere. The volume of clusters of activation in the extrastriate ventral visual pathway was greater in the left hemisphere. This network is consistent with existing models of motor control, visual object processing and attentional control and may serve as a basis for hypothesis-driven fMRI studies in clinical populations with deficits in Conners' CPT performance.

Brief report: sluggish cognitive tempo among pediatric survivors of acute lymphoblastic leukemia.

OBJECTIVE: The purpose of the present study was to assess sluggish cognitive tempo (SCT) behavioral symptoms among pediatric survivors of acute lymphoblastic leukemia (ALL) and to determine the relationship of these behaviors with cognitive late effects. METHODS: ALL survivors (n = 80) and a sibling control group (n = 19) were administered intelligence (IQ) testing, achievement testing and SCT behavioral items. Group differences (patients vs. siblings) were examined on the SCT behaviors and partial correlations were conducted to explore the relationship of the SCT behaviors with IQ and achievement, while controlling for age at treatment and time since treatment. RESULTS: ALL survivors exhibited significantly more SCT symptoms than the sibling control group and increased SCT symptoms were associated with lower IQ and achievement scores. CONCLUSIONS: ALL survivors are vulnerable to SCT symptoms and these behaviors are associated with cognitive late effects. SCT symptoms may represent a behavioral component of cognitive late effects.

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.

Changes in attentional performance of children and young adults with localized primary brain tumors after conformal radiation therapy.

PURPOSE: To prospectively assess the impact of conformal radiation therapy (CRT) and demographic and clinical variables on four measures of attention in pediatric and young adult patients with localized primary brain tumors. PATIENTS AND METHODS: We prospectively evaluated 120 patients with primary brain tumors, ages 2 to 24.4 years (median, 9.2 years). Evaluations were done using the computerized Conners' Continuous Performance Test (CCPT). We analyzed errors of omission (inattentiveness), errors of commission (impulsivity), reaction time, and an overall index of performance before CRT, weekly during CRT, and serially up to 60 months after the start of CRT. RESULTS: Before CRT, patients exhibited mild inattentiveness. During CRT, impulsivity decreased significantly (P = .002). After CRT, inattentiveness increased significantly (P = .03), and global attention disorders were associated with craniopharyngioma (P < .0001), supratentorial tumors (P = .008), optic pathway and diencephalic tumors (P = .012), and subtotal resection of the tumor (P = .010). CONCLUSION: Brain tumors and their treatment impair sustained attention and reaction time. A decline in impulsivity and relative stability of the other CCPT scores over the course of CRT demonstrated the absence of early radiation-related cognitive sequelae. Local tumor effects, initial surgical intervention, and focal irradiation of central structures contribute to long-lasting attentional problems in pediatric and young adult patients.

Phase II trial of conformal radiation therapy for pediatric patients with craniopharyngioma and correlation of surgical factors and radiation dosimetry with change in cognitive function.

OBJECT: A Phase II trial of conformal radiation therapy (CRT) for craniopharyngioma was conducted to determine whether the irradiated volume could be safely reduced to decrease effects on cognitive function. METHODS: Between July 1997 and January 2003, 28 pediatric patients (median age 7.3 +/- 4.12 years) received CRT in whom doses (54-55.8 Gy) were administered to the gross tumor volume (solid and cystic components) surrounded by a 1-cm clinical target volume margin. Patients were evaluated serially with neuropsychometric testing. Statistical analyses were performed to determine the effect of clinical factors and radiation dosimetry on intelligence quotient (IQ). The median follow-up period was 36.6 months (range 24.4-80 months). The estimated 3-year progression-free survival rate was 90.3 +/- 7.3%. Three patients experienced local disease progression. Cognitive outcome for patients was adversely affected by the following factors: age younger than 7.4 years (p = 0.001), an interval between symptoms and diagnosis of more than 73 days (p = 0.06), more extensive surgery (p = 0.014), multiple surgical procedures (p = 0.002), diabetes insipidus (p = 0.02), hydrocephalus at diagnosis (p = 0.009), a cerebrospinal fluid shunt (p = 0.005), shunt revisions (p = 0.01), Ommaya reservoir laterality (p = 0.005), and cyst aspirations (p = 0.02). The percentage of total brain, supratentorial brain, or left temporal lobe volumes receiving a dose in excess of 45 Gy had a significant impact on longitudinal IQ. CONCLUSIONS: The use of CRT with a 1-cm margin for clinical target volume results in tumor control equivalent to that achieved using conventionally planned radiation therapy. Surgical morbidity and a volume-receiving dose more than 45 Gy are factors affecting longitudinal IQ after CRT in patients treated for craniopharyngioma.

Early patterns of verbal memory impairment in children treated for medulloblastoma.

Children treated for medulloblastoma demonstrate a variety of cognitive deficits in addition to white matter and hippocampal neuropathology. This study examined 40 children treated for medulloblastoma as compared with 40 demographically matched controls on the California Verbal Learning Test-Children's Version (D. C. Delis, J. H. Kramer, E. Kaplan, & B. A. Ober, 1994). Results revealed significantly poorer performance on indices of word recall in the patient group as compared with the controls in addition to milder but still significantly poorer recognition memory. These findings suggest that children treated for medulloblastoma demonstrate a mixed profile of memory impairment consisting of both retrieval and recognition deficits. Implications of these findings for understanding neurobehavioral sequelae within pediatric medulloblastoma populations and for designing educational and remediation strategies to be used with these children are discussed.

Factor analysis and validity of the Conners Parent and Teacher Rating Scales in childhood cancer survivors.

OBJECTIVE: To examine the factor structure of the Conners Parent Rating Scale-Revised: Short Form (CPRS-R:S) and the Conners Teacher Rating Scale-Revised: Short Form (CTRS-R:S) in children who are long-term survivors of acute lymphocytic leukemia (ALL) or brain tumors (BT)and who have received central nervous system directed treatment. METHOD: Parents and teachers of 150 long-term survivors completed the CPRS-R:S or CTRS-R:S as part of a screening battery. The data were submitted to a maximum likelihood confirmatory factor analysis to test the construct validity of the scales and the forms were compared. The CPRS-R:S was also compared to selected subscales of the Achenbach Child Behavior Checklist (CBCL) for further validation. RESULTS: The analyses demonstrated an adequate fit of the original three-factor structure of the CTRS-R:S [oppositional, cognitive problems/inattention, hyperactivity]. The analyses of the CPRS-R:S suggested a less adequate fit of the original three-factor structure but principal components factor analysis yielded a three-factor solution with factors similar to those of Conners' original factor structure. Significant correlations were found between the CPRS-R:S and the selected subscales of the CBCL. CONCLUSIONS: These findings support the similar construct validity of the original CTRS-R:S and CPRS-R:S. Although significantly correlated, the CPRS-R:S and CTRS-R:S are not interchangeable in the assessment of survivors of childhood cancer.

Modeling radiation dosimetry to predict cognitive outcomes in pediatric patients with CNS embryonal tumors including medulloblastoma.

PURPOSE: Model the effects of radiation dosimetry on IQ among pediatric patients with central nervous system (CNS) tumors. METHODS AND MATERIALS: Pediatric patients with CNS embryonal tumors (n = 39) were prospectively evaluated with serial cognitive testing, before and after treatment with postoperative, risk-adapted craniospinal irradiation (CSI) and conformal primary-site irradiation, followed by chemotherapy. Differential dose-volume data for 5 brain volumes (total brain, supratentorial brain, infratentorial brain, and left and right temporal lobes) were correlated with IQ after surgery and at follow-up by use of linear regression. RESULTS: When the dose distribution was partitioned into 2 levels, both had a significantly negative effect on longitudinal IQ across all 5 brain volumes. When the dose distribution was partitioned into 3 levels (low, medium, and high), exposure to the supratentorial brain appeared to have the most significant impact. For most models, each Gy of exposure had a similar effect on IQ decline, regardless of dose level. CONCLUSIONS: Our results suggest that radiation dosimetry data from 5 brain volumes can be used to predict decline in longitudinal IQ. Despite measures to reduce radiation dose and treatment volume, the volume that receives the highest dose continues to have the greatest effect, which supports current volume-reduction efforts.

Smaller white-matter volumes are associated with larger deficits in attention and learning among long-term survivors of acute lymphoblastic leukemia.

BACKGROUND: The primary objective of this study was to test the hypothesis that survivors of childhood acute lymphoblastic leukemia (ALL) have deficits in neurocognitive performance, and smaller white-matter volumes are associated with these deficits. METHODS: The patients studied included 112 ALL survivors (84 patients who had received chemotherapy only, 28 patients who had received chemotherapy and irradiation; 63 males, 49 females; mean age +/- standard deviation, 4.1 yrs +/- 2.6 yrs at diagnosis; mean +/- standard deviation yrs since diagnosis, 6.0 +/- 3.5 yrs), and 33 healthy siblings who participated as a control group. Neurocognitive tests of attention, intelligence, and academic achievement were performed; and magnetic resonance images were obtained and subsequently were segmented to yield tissue volume measurements. Comparisons of neurocognitive measures and tissue volumes between groups were performed, and the correlations between volumes and neurocognitive performance measures were assessed. RESULTS: Most performance measures demonstrated statistically significant differences from the normative test scores, but only attention measures exceeded 1.0 standard deviation from normal. Patients who had received chemotherapy alone had significantly larger volumes of white matter than patients who had received treatment that also included cranial irradiation, but their volumes remained significantly smaller than the volumes in the control group. Smaller white-matter volumes were associated significantly with larger deficits in attention, intelligence, and academic achievement. CONCLUSIONS: Survivors of childhood ALL had significant deficits in attention and smaller white-matter volumes that were associated directly with impaired neurocognitive performance. Cranial irradiation exacerbated these deficits.

Attention and memory functioning among pediatric patients with medulloblastoma.

OBJECTIVE: To test the hypotheses that memory and attention deficits are prevalent in survivors of childhood medulloblastoma (MB) and that these deficits are associated with problems with academic achievement. METHODS: The medical charts of 38 child survivors of MB, who were administered the California Verbal Learning Test, Child Version (CVLT-C), Conners' Continuous Performance Test (CPT), and the Wechsler Individual Achievement Test (WIAT) as part of a comprehensive neurocognitive test battery, were retrospectively reviewed. RESULTS: Although no significant verbal memory deficits were found, 8 of 11 CPT variables were significantly below the standardization mean (p < or = .01). Additionally, stepwise regression analyses found that increased omission errors were significantly associated with lower reading and math performance (p < or = .01). CONCLUSIONS: These findings confirm previous reports of attention deficits among survivors of MB and provide a better understanding of how the dysfunction of particular attentional substrates (e.g., perceptual sensitivity, response bias) may result in learning problems in this population.

Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma.

PURPOSE: This prospective, longitudinal study examined the effects of risk-adapted craniospinal irradiation (CSI) dose and the interactions of dose with age and time from diagnosis on intelligence quotient (IQ) and academic achievement (reading, spelling, and math) among patients treated for medulloblastoma (MB). PATIENTS AND METHODS: Patients received serial neurocognitive testing spanning from 0 to 6.03 years after diagnosis (median, 3.14 years). The multi-institutional study included 111 patients, who were 3 to 20 years of age at diagnosis (median age, 7.4 years), treated for MB with risk-adapted CSI followed by four cycles of high-dose chemotherapy (cyclophosphamide, cisplatin, and vincristine) with stem-cell support. High-risk patients (HR; n = 37) received CSI to 36 to 39.6 Gy and conformal boost treatment of the primary site to 55.8 to 59.4 Gy. Average-risk patients (AR; n = 74) received CSI to 23.4 Gy and conformal boost treatment of the posterior fossa to 36.0 Gy and primary site to 55.8 Gy. RESULTS: Multivariate modeling revealed statistically significant declines in mean IQ (-1.59 points/yr; P = .006), reading (-2.95 points/yr; P < .0001), spelling (-2.94 points/yr; P < .0001), and math (-1.87 points/yr; P = .003) scores for the entire group. The effects of risk-adapted radiation therapy on IQ, reading, and spelling were moderated by age, with the greatest rates of decline observed for the HR patients who were younger (< 7 years old) at diagnosis. CONCLUSION: Young age at diagnosis was the most prominent risk factor for neurocognitive deficits among survivors of MB despite reductions in CSI dosing and efforts to limit the boost volume. Younger patients exhibited substantial problems with the development of reading skills.

Radiation dosimetry predicts IQ after conformal radiation therapy in pediatric patients with localized ependymoma.

PURPOSE: To assess the effects of radiation dose-volume distribution on the trajectory of IQ development after conformal radiation therapy (CRT) in pediatric patients with ependymoma. METHODS AND MATERIALS: The study included 88 patients (median age, 2.8 years +/- 4.5 years) with localized ependymoma who received CRT (54-59.4 Gy) that used a 1-cm margin on the postoperative tumor bed. Patients were evaluated with tests that included IQ measures at baseline (before CRT) and at 6, 12, 24, 36, 48, and 60 months. Differential dose-volume histograms (DVH) were derived for total-brain, supratentorial-brain, and right and left temporal-lobe volumes. The data were partitioned into three dose intervals and integrated to create variables that represent the fractional volume that received dose over the specified intervals (e.g., V(0-20 Gy), V(20-40 Gy), V(40-65 Gy)) and modeled with clinical variables to develop a regression equation to estimate IQ after CRT. RESULTS: A total of 327 IQ tests were performed in 66 patients with infratentorial tumors and 20 with supratentorial tumors. The median follow-up was 29.4 months. For all patients, IQ was best estimated by age (years) at CRT; percent volume of the supratentorial brain that received doses between 0 and 20 Gy, 20 and 40 Gy, and 40 and 65 Gy; and time (months) after CRT. Age contributed significantly to the intercept (p > 0.0001), and the dose-volume coefficients were statistically significant (V(0-20 Gy), p = 0.01; V(20-40 Gy), p < 0.001; V(40-65 Gy), p = 0.04). A similar model was developed exclusively for patients with infratentorial tumors but not supratentorial tumors. CONCLUSION: Radiation dosimetry can be used to predict IQ after CRT in patients with localized ependymoma. The specificity of models may be enhanced by grouping according to tumor location.

Using problem-solving skills training to reduce negative affectivity in mothers of children with newly diagnosed cancer: report of a multisite randomized trial.

Mothers of children with cancer experience significant distress associated with their children's diagnosis and treatment. The efficacy of problem-solving skills training (PSST), a cognitive-behavioral intervention based on problem-solving therapy, was assessed among 430 English- and Spanish-speaking mothers of recently diagnosed patients. Participants were randomized to usual psychosocial care (UPC; n=213) or UPC plus 8 sessions of PSST (PSST; n=217). Compared with UPC mothers, PSST mothers reported significantly enhanced problem-solving skills and significantly decreased negative affectivity. Although effects were largest immediately after PSST, several differences in problem-solving skills and distress levels persisted to the 3-month follow-up. In general, efficacy for Spanish-speaking mothers exceeded that for English-speaking mothers. Findings also suggest young, single mothers profit most from PSST.

Cognitive deficits in children with sickle cell disease.

We tested a hypothesis that children with sickle cell disease who are completely normal by magnetic resonance imaging can still be cognitively impaired, as predicted by a model of diffuse brain injury. Fifty-four patients with hemoglobin SS (average age 10.9 years +/- 2.9 years SD) were examined with the Wechsler Intelligence Scale for Children-III (WISC-III) and were randomly matched by age, race, and gender with healthy children from the Wechsler normative database. Patients were also imaged at 1.5 Tesla with standard imaging sequences. Among 30 patients who were normal by magnetic resonance imaging, there were substantial deficits in Wechsler Full-Scale IQ, Verbal IQ, and Performance IQ (all P < .01) compared with African-American controls. The patient Wechsler Full-Scale IQ was 12.9 points lower than that of controls and decreased as a function of age (probability = .014). The findings suggest that there is diffuse brain injury in patients and that patient deficits increase with age.

Atypical white matter volume development in children following craniospinal irradiation.

Most children with medulloblastoma (MB), the second most common pediatric brain tumor, have a 70% probability of survival. However, survivors who receive aggressive therapy are at significant risk of cognitive deficits that have been associated with lower volumes of normal-appearing white matter (NAWM). We hypothesized that cranial irradiation inhibited normal brain volume development in these survivors. We retrospectively analyzed 324 MRI studies of 52 patients with histologically proven MB treated with surgery and 35 to 40 Gy craniospinal irradiation, with or without chemotherapy. The volume of NAWM and that of cerebrospinal fluid were quantified from a single index section and compared with those of healthy, age-similar control subjects. A quadratic random coefficient model was used to identify trends in brain volume with increasing age. Patients treated for MB at younger ages demonstrated substantially less development of NAWM volume than did their healthy peers. Younger age at the time of irradiation and the need for a ventricular shunt were significantly associated with reduced NAWM volume. NAWM and craniospinal fluid volume differences between patients who had shunts and those without resolved over a period of four to five years. NAWM volume is known to be associated with neurocognitive test performance, which shows deficiencies after cranial irradiation early in life. Therefore, volumetric monitoring of brain development can be used to guide the care of survivors, assess the toxicity of previous and current clinical trials, and aid in the design of therapies that minimize toxicity.

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.