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.

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.

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.

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.

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.

Short-term efficacy of methylphenidate: a randomized, double-blind, placebo-controlled trial among survivors of childhood cancer.

PURPOSE: Children surviving acute lymphoblastic leukemia (ALL) and malignant brain tumors (BTs) have a higher incidence of attention and learning problems in school than do their healthy peers. The present study tests the hypothesis that the psychostimulant methylphenidate (MPH) improves cognitive and social functioning among these patients. PATIENTS AND METHODS: We report on 83 long-term survivors of ALL and BT identified as having attentional deficits on behavioral testing and parent or teacher report, and problems with academic achievement. The 47 male and 36 female patients ranged from 0.6 to 14.3 years (median, 5.4 years) of age at diagnosis and 6.7 to 17.9 years (median, 11.9 years) of age at participation. The patients (40 ALL, 43 BT) participated in a randomized, double-blind, 3-week home cross-over trial of placebo (bid), low-dose MPH (0.3 mg/kg; maximum dose, 10 mg bid), and moderate-dose MPH (0.6 mg/kg; maximum dose, 20 mg bid). The primary end points were weekly teacher and parent reports on the Conners' Rating Scales and Social Skills Rating System. RESULTS: Compared to placebo, significant improvement with MPH was reported by teachers and parents on the Conners' Rating Scales and by teachers on the Social Skills Rating System. However, no consistent advantage of moderate dose over low dose was observed. Of those participating, 66 (79.5%) of the 83 patients continued on best clinical management. CONCLUSION: Treatment with MPH can at least temporarily reduce some attentional and social deficits among survivors of childhood ALL and BT. Long-term follow-up will reveal those subsets of patients who are more likely to benefit from MPH.

White matter lesions detected by magnetic resonance imaging after radiotherapy and high-dose chemotherapy in children with medulloblastoma or primitive neuroectodermal tumor.

PURPOSE: White matter lesions (WMLs) have been described as a delayed effect of cranial irradiation in children with brain tumors, or a transient subacute effect characterized by an intralesional or perilesional reaction. We report the occurrence of subacute WMLs detected by magnetic resonance imaging (MRI) in children treated for medulloblastoma or primitive neuroectodermal tumor (PNET) and document the associated clinical, radiologic, and neurocognitive findings. PATIENTS AND METHODS: Among 134 patients with medulloblastoma or supratentorial PNET treated prospectively with risk-adjusted craniospinal irradiation and conformal boost to the tumor bed, followed by four high-dose chemotherapy (HDC) cycles with stem-cell rescue, 22 developed WMLs on T1-weighted imaging with and without contrast and/or T2-weighted imaging on MRI. Patients had > or = 12 months of follow-up. Neurocognitive assessments included intelligence quotient (IQ) tests and tests of academic achievement. RESULTS: Twenty-two patients developed WMLs at a median of 7.8 months after starting therapy (range, 1.9 to 13.0 months). Lesions were predominantly in the pons (n = 8) and cerebellum (n = 6). Sixteen patients (73%) had WML resolution at a median of 6.2 months (range, 1.68 to 23.5 months) after onset; two patients developed necrosis and atrophy. Three developed persistent neurologic deficits. Cumulative incidence of WMLs at 1 year was 15% +/- 3%. Patients with WMLs had a significant decline in estimated IQ (-2.5 per year; P = .03) and math (-4.5 per year; P = .003) scores. CONCLUSION: WMLs in medulloblastoma or PNET patients treated with conformal radiotherapy and HDC are typically transient and asymptomatic, and may mimic early tumor recurrence. A minority of patients with WMLs develop permanent neurologic deficits and imaging changes. Overall, the presence of WMLs is associated with greater neurocognitive decline.

Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma.

PURPOSE: We conducted a phase II trial of conformal radiation therapy (CRT) for localized childhood ependymoma to determine whether the irradiated volume could be reduced to decrease CNS-related side effects without diminishing the rate of disease control. PATIENTS AND METHODS: Between July 1997 and January 2003, 88 pediatric patients (median age, 2.85 +/- 4.5 years) received CRT in which doses (59.4 Gy to 73 patients or 54.0 Gy after gross-total resection to 15 patients younger than 18 months) were administered to the gross tumor volume and a margin of 10 mm. Patients were categorized according to extent of resection (underwent gross total resection, n = 74; near-total resection, n = 6; subtotal resection, n = 8), prior chemotherapy (n = 16), tumor grade (anaplastic, n = 35), and tumor location (infratentorial, n = 68). An age-appropriate neurocognitive battery was administered before and serially after CRT. RESULTS: The median length of follow-up was 38.2 months (+/- 16.4 months); the 3-year progression-free survival estimate was 74.7% +/- 5.7%. Local failure occurred in eight patients, distant failure in eight patients, and both in four patients. The cumulative incidence of local failure as a component of failure at 3 years was 14.8% +/- 4.0%. Mean scores on all neurocognitive outcomes were stable and within normal limits, with more than half the cohort tested at or beyond 24 months. CONCLUSION: Limited-volume irradiation achieves high rates of disease control in pediatric patients with ependymoma and results in stable neurocognitive outcomes.

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.

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.

Acute effects of irradiation on cognition: changes in attention on a computerized continuous performance test during radiotherapy in pediatric patients with localized primary brain tumors.

PURPOSE: To assess sustained attention, impulsivity, and reaction time during radiotherapy (RT) for pediatric patients with localized primary brain tumors. METHODS AND MATERIALS: Thirty-nine patients (median age 12.3 years, range 5.9-22.9) with primary brain tumors were evaluated prospectively using the computerized Conners' continuous performance test (CPT) before and during conformal RT (CRT). The data were modeled to assess the longitudinal changes in the CPT scores and the effects of clinical variables on these changes during the first 50 days after the initiation of CRT. RESULTS: The CPT scores exhibited an increasing trend for errors of omission (inattentiveness), decreasing trend for errors of commission (impulsivity), and slower reaction times. However, none of the changes were statistically significant. The overall index, which is an algorithm-based weighted sum of the CPT scores, remained within the range of normal throughout treatment. Older patients (age >12 years) were more attentive (p < 0.0005), less impulsive (p < 0.07), and had faster reaction times (p < 0.001) at baseline than the younger patients. The reaction time was significantly reduced during treatment for the older patients and lengthened significantly for the younger patients (p < 0.04). Patients with a shunted hydrocephalus (p < 0.02), seizure history (p < 0.0006), and residual tumor (p < 0.02) were significantly more impulsive. Nonshunted patients (p < 0.0001), those with more extensive resection (p < 0.0001), and patients with ependymoma (p < 0.006) had slower initial reaction times. CONCLUSION: Children with brain tumors have problems with sustained attention and reaction time resulting from the tumor and therapeutic interventions before RT. The reaction time slowed during treatment for patients <12 years old. RT, as administered in the trial from which these data were derived, has limited acute effects on changes in the CPT scores measuring attention, impulsiveness, and reaction time.

Craniopharyngioma: the St. Jude Children's Research Hospital experience 1984-2001.

PURPOSE: To review our institution's experience in the treatment of craniopharyngioma and assess the merits of initial therapy with limited surgery and irradiation. METHODS AND MATERIALS: The data of 30 patients (median age 8.6 years) with a diagnosis of craniopharyngioma between April 1984 and September 1997 were reviewed. Their course of treatment, neurologic, endocrine, and cognitive function, and quality of life at last follow-up were compared. RESULTS: Fifteen patients were initially treated with surgery (8 required irradiation after relapse) and 15 with limited surgery and irradiation (2 required additional treatment for tumor progression). Only 1 patient died of tumor progression. The surgery group lost a mean of 9.8 points in full-scale IQ, and the combined-modality group lost only 1.25 points (p <0.063). Patients in the surgery group who had relapses (n = 9) lost a mean of 13.1 points (p <0.067). A loss of 10 points was considered clinically significant. The surgery group also had more frequent neurologic, ophthalmic, and endocrine complications. The mean Health Utility Index (a functional quality-of-life index) was higher for the combined-modality group (0.85) than for the surgery group (0.71; p <0.063, one-sided t test). CONCLUSIONS: The acute neurologic, cognitive, and endocrine effects of surgery often affect long-term function and quality of life. Our experience suggests that limited surgery and radiotherapy cause lesser or comparable sequelae. Diabetes insipidus was the only endocrine deficiency that differed substantially in frequency between the two groups. Newer radiation planning and delivery techniques may make a combined-modality approach a good initial option for most patients.

Predicting intellectual outcome among children treated with 35-40 Gy craniospinal irradiation for medulloblastoma.

Fifty children diagnosed with medulloblastoma completed 188 psychological evaluations using the Wechsler Intelligence Scales for Children (D. Wechsler, 1974, 1991) over a 7-year study period following 35-40 Gy postoperative craniospinal irradiation. Random coefficient models were used to predict the trend in the children's intellectual performance as a function of time since diagnosis, with both patient and treatment variables as parameters of this function. A quadratic model demonstrated a delay prior to decline in performance for older patients, whereas the younger patients showed an immediate loss of performance with a plateau at approximately 6 years postdiagnosis. A steeper decline was found for those with higher baseline performance. Clinicians may use the proposed predictive model to identify those patients who are at risk of significant intellectual decline.

Decline in corpus callosum volume among pediatric patients with medulloblastoma: longitudinal MR imaging study.

BACKGROUND AND PURPOSE: A decline in intrahemispheric cerebral white matter volume in children treated for brain tumors with cranial irradiation has been well documented. It was hypothesized that the development of the corpus callosum, the largest white matter commissure of the brain, would also be adversely affected after treatment with cranial irradiation in pediatric patients treated for medulloblastoma. METHODS: After diagnosis, 35 patients (22 male and 13 female patients) with histologically proved medulloblastoma were treated by maximal surgical resection, risk-adapted craniospinal irradiation, and chemotherapy. Using quantitative measurement techniques with MR imaging, corpus callosum volume was measured at multiple time points for each patient during a 4-year period. RESULTS: Quantitative MR imaging analyses of 239 examinations in 35 patients showed, in contrast to normal development, that the total midsagittal corpus callosum area decreased with time from craniospinal irradiation (-18.0 mm(2)/y; P <.0001). After examination of seven corpus callosum subregions, significant declines were also observed: genu (-2.2 mm(2)/y; P =.03), rostral body (-2.0 mm(2)/y; P =.04), anterior midbody (-1.4 mm(2)/y; P =.005), posterior midbody (-1.2 mm(2)/y; P =.004), isthmus (-2.4 mm(2)/y; P =.001), and splenium (-5.0 mm(2)/y; P =.007). CONCLUSION: The greatest deviation from normal development occurred in the most posterior subregions of the corpus callosum: the isthmus and the splenium. These corpus callosum subregions, associated with fibers traversing from the temporal, posterior parietal, and occipital lobes, are normally expected to have the highest rate of growth during childhood. However, these regions also received the highest total dose of irradiation, providing a possible explanation for atypical corpus callosum development observed in these 35 patients treated for medulloblastoma.

Cognitive impairment in children with hemoglobin SS sickle cell disease: relationship to MR imaging findings and hematocrit.

BACKGROUND AND PURPOSE: Children with hemoglobin SS sickle cell disease are known to suffer cognitive impairment if they have silent infarct, but recent evidence suggests that patients with hemoglobin SS sickle cell disease may be impaired even if they are free of infarction. We test a hypothesis that cognitive impairment in children with hemoglobin SS sickle cell disease is associated with low hematocrit and MR imaging abnormalities. METHODS: A cohort of 49 patients was examined, all of whom had hemoglobin SS sickle cell disease but no history of clinical stroke. The Wechsler scales, which are standardized and age-adjusted, were used to assess cognitive function. Patients also underwent MR imaging examination of the brain, and hematocrit was measured in a subset of 45 patients. MR images were evaluated by at least two readers, and abnormal imaging findings were evaluated by at least three readers. Any lesion was sufficient to be classified as abnormal, with lesions defined to include lacunar infarction, encephalomalacia, or leukoencephalopathy. Hematocrit data were used if obtained within 3 months of psychometric testing and if there were no confounding events in the patients' charts. Wechsler test scores were then evaluated in relation to imaging findings and hematocrit values. RESULTS: Patients with imaging abnormalities had more cognitive impairment than did patients with normal imaging findings in verbal intelligence quotient (P <.02) and verbal comprehension (P <.01). Patients with low hematocrit had cognitive impairment shown by many performance measures, including full-scale intelligence quotient (P <.006), verbal comprehension (P <.006), and freedom from distractibility (P <.02). Multivariate analysis showed that MR imaging and hematocrit were independent predictors of full-scale intelligence quotient. CONCLUSION: Focal brain injury, revealed by MR imaging, is associated with cognitive impairment, but our data suggest that diffuse brain injury may also contribute to impairment. These findings show that impairment is multifactorial and suggest that chronic brain hypoxia is part of the pathophysiology of sickle cell disease.