Bartlett D. Moore

Cognitive function and academic performance in neurofibromatosis. 1: consensus statement from the NF1 Cognitive Disorders Task Force.

Neurofibromatosis type 1 (NF1) is the most common single gene disorder to affect the human nervous system; it is inherited in an autosomal dominant manner with an estimated incidence of 1 in 3,500.l The physical features of NF1 are well characterized and include multiple cafe-au-lait spots, skinfold freckling, iris hamartomas (Lisch nodules), and benign and malignant neural tumors (e.g., neurofibromas, pheochromocytomas, and neurofibrosarcomas).’X2 CNS lesions include optic pathway gliomas, dural ectasia, and aqueduct stenosis. In addition to these specific pathologic lesions, cognitive impairment is common. Learning disabilities occur in at least 30 to 45% of children with NF1 and can be responsible for significant lifetime m~rb id i ty .~ ,~ The NF1 gene on human chromosome 17 has been ~ l o n e d ~ ~ and its protein product neurofibromin identified.*b9 The NF1 gene is usually classified as a tumor suppressor gene, as mutations in both NF1 alleles are detectable in malignant tumors associated with NF1lOJ1 and in benign tumors such as neurofibromas.12 The effects of the disorder on higher cortical function and the relationship between NF1 gene mutations, cognitive deficits, and intracranial pathology are less well understood. This consensus statement summarizes our current understanding of the frequency and nature of cognitive deficits and learning disability in children with NF1, provides recommendations for assessment and management, and examines the putative relationship between cognitive deficits and MRI signal abnormalities. We review possible pathogenetic mechanisms and future directions for research.

Neurocognitive Development of Children After a Cerebellar Tumor in Infancy: A Longitudinal Study

PURPOSE To assess the long-term neuropsychologic effects experienced by children who have tumors in the cerebellum that are diagnosed and treated during infancy. PATIENTS AND METHODS Twenty-seven children with posterior fossa tumors diagnosed at less than 36 months of age were assessed prospectively with a comprehensive set of age-appropriate tests. Group means and SDs are reported for assessments conducted at diagnosis (analysis 1) and at the most recent follow-up appointment (analysis 2). Cognitive developmental growth curves were derived from the prospective data (analysis 3) using mixed model regression analyses and controlling for age at diagnosis and socioeconomic status. RESULTS In the first analysis, eight of 11 infants at diagnosis scored within normal limits on all neuropsychologic domains, except for motor skills, which were impaired. In the second analysis, mean scores at the most recent follow-up of 21 of 27 patients were mostly in the normal range; however, group comparisons between those who had (n = 7) and had not (n = 14) been treated with cranial radiation therapy (CRT) showed that patients in the irradiated (CRT) group scored significantly lower than those in the nonirradiated (No-CRT) group on verbal intelligence quotient (IQ) and in the motor domain. In the third analysis (growth curves of CRT and No-CRT groups), statistically significant differences in slope were found on verbal IQ, performance IQ, perceptual-motor skills, language, and attention/executive skills. Slopes on the fine-motor domain were similar; both groups declined at approximately the same rate. CONCLUSION Neurocognitive development and outcome of children with cerebellar tumors diagnosed in infancy is very positive among those who were treated with surgery and chemotherapy. Declines in performance across time were minimal, and scores tended to remain within normal limits. By itself, a cerebellar tumor in infancy does not seem to have a significant impact on children. However, those who received CRT as part of their treatment are likely to have neurocognitive and psychosocial deficits that require remediational interventions.

Neuropsychologic effects of chemotherapy on children with cancer: a longitudinal study.

PURPOSE A prospective study was conducted to assess the effects of chemotherapy for cancer on childrens long-term neuropsychologic status. PATIENTS AND METHODS Ninety-nine children who received no cranial radiation therapy (CRT) completed four annual neuropsychologic assessments. Fifty-one patients received intrathecal (IT) chemotherapy (ITC); 48 received no CNS treatment. These two groups were compared using repeated-measures analysis of variance on IQ, memory, language, freedom from distractibility, academic achievement, executive functions, and fine-motor, perceptual-motor, and tactile-spatial skills. In addition, 51 of the sample of 99 patients had been examined 5 to 11 years after diagnosis. Their data were analyzed to evaluate the longer-term effects of chemotherapy. The predictability of demographic and medical variables on neuropsychologic outcome at 3-year and long-term follow-up study were assessed using multiple regression techniques. RESULTS Overall, the effects of chemotherapy in the absence of CRT appear to be slight. Patients who received ITC and intravenous (IV) methotrexate declined slightly on perceptual-motor skills, but were still well within the normal range. Both groups, regardless of treatment, declined on academic achievement tests, although not to a statistically significant degree. Age effects were found on performance IQ (PIQ) and perceptual-motor skills. Socioeconomic status (SES) correlated with a large number of variables. Sex effects were not significant. CONCLUSION The present results are largely consistent with previous findings for nonirradiated groups. Treatment effects from ITC are slightly more apparent 5 to 11 years after diagnosis than at 3-year follow-up evaluation but this does not constitute a clinically meaningful difference. More noticeable are academic declines among all groups, regardless of treatment.

Neuropsychological significance of areas of high signal intensity on brain MRIs of children with neurofibromatosis

Of children with neurofibromatosis (NF), 40% have a cognitive or learning impairment.Approximately 60% also have anomalous areas of high signal intensity on T2-weighted brain MRIs. The association of these hyperintensities and neuropsychological status is not fully understood. We administered a battery of neuropsychological tests and a standard clinical MRI to determine the impact of hyperintensity presence, number, and location on cognitive status in 84 children (8 to 16 years) with NF type 1. These children underwent standard clinical MRI using a GE 1.5-tesla scanner (except one child who was examined with a 1.0-tesla scanner). We conducted three types of analyses: Hyperintensity presence or absence.--Scores of children with (55%) and without hyperintensities (45%) were compared using t tests. No statistically significant differences between groups in intellectual functioning or any neuropsychological variable were found. Number of hyperintensities--The number of hyperintensity locations per child ranged from one to five (mean = 2.22). Pearson correlations revealed no significant association between the number of hyperintensities and neuropsychological performance. Location of hyperintensities--In four of the five locations studied, no statistically significant differences were found between scores of children with a hyperintensity in an area and those with one elsewhere. However, mean scores for IQ, Memory, Motor, Distractibility, and Attention domains for children with hyperintensities in the thalamus were significantly lower than scores for those with hyperintensities elsewhere. These results suggest that the simple presence or absence of hyperintensities, or their total number, is not as important as their anatomic location for detecting their relationship with neuropsychological status. Taking location into account, hyperintensities in the cerebral hemispheres, basal ganglia, brainstem, or cerebellum seem to have no impact on neuropsychological functioning, whereas hyperintensities in the thalamus do. NEUROLOGY 1996;46: 1660-1668

Brain volume in children with neurofibromatosis type 1: Relation to neuropsychological status

Objective: To determine characteristics of brain morphology in children and adolescents with neurofibromatosis type 1 and relate these characteristics to neuropsychological functioning. Background: Neurofibromatosis type 1 is associated with numerous CNS abnormalities and cognitive impairment. Abnormal high signal intensity visible on brain MRI, brain tumors, and macrocephaly are common. Research into links between neuroanatomic and cognitive features has been inconclusive. Methods: Fifty-two children and adolescents with neurofibromatosis type 1 were compared with 19 control subjects on several quantitative neuroanatomic and neuropsychological measures. Results: Total brain volume, especially gray matter, was significantly greater for neurofibromatosis type 1 subjects than the control subjects. Group differences in the ratio of gray matter to white matter were more prominent in younger than in older subjects. Volume of gray matter in the subjects with neurofibromatosis type 1 was related to their degree of learning disability. Corpus callosum size was significantly larger for subjects in the neurofibromatosis type 1 group, and diminished performance on measures of academic achievement and visual–spatial and motor skills were associated with greater regional corpus callosum size. Conclusions: Neuroanatomic morphology and the developmental pattern of gray matter and white matter in subjects with neurofibromatosis type 1 differed from in control subjects. Some of these differences are related to the neuropsychological status of the neurofibromatosis type 1 group. We propose that delayed developmental apoptosis results in macrocephaly and a delay in the development of appropriate neuronal connections in children with neurofibromatosis type 1. We further propose that these morphologic delays are related to the cognitive profile of neurofibromatosis type 1.

Behavioral phenotype of neurofibromatosis, type 1.

Neurofibromatosis, type 1 (NF1) is a very common inherited disorder that was first described in the late 19th century. NF1 is associated with a myriad of behavioral manifestations in addition to its frequent and often severe medical and physical complications. Learning disability, cognitive impairment, emotional and psychosocial difficulties have been reported so frequently in neurofibromatosis that these are often considered hallmarks. This report briefly introduces the medical and physical characteristics of NF1. We then detail the behavioral manifestations of NF1 with additional discussion of possible etiologies for the high incidence of these behavioral difficulties. MRDD Research Reviews 2000;6:117-124.

Social, emotional, and behavioral functioning of children with NF1

Children with neurofibromatosis type 1 (NF1) can have varying degrees of cognitive impairment, and are at risk for social, emotional, and behavioral dysfunction. We undertook an evaluation of social, emotional, and behavioral functioning of youth with NF1 and peers from multiple perspectives. We hypothesized that children with NF1 would have more psychosocial difficulties, which would be positively associated with neurological involvement. We compared 58 children with NF1, ages 7–15, with comparison classroom peers, classmates who were same race/gender and closest date of birth. Peer relationships, emotional well‐being, and behavior were evaluated from multiple perspectives in multiple settings. Results showed that teachers perceived children with NF1 as more prosocial (i.e., polite, helpful to others). Teachers and peers viewed children with NF1 as displaying less leadership behavior and as more socially sensitive‐isolated (i.e., often left out, trouble making friends). Children with NF1 had fewer friendships and were less well liked by peers. Mothers and fathers reported more problems with social functioning among children with NF1. Few group differences in emotional well‐being and behavior were identified according to child and father report. However, mothers perceived children with NF1 to have more emotional problems relative to comparison peers, predominantly among older children. Neurological involvement was significantly related to psychosocial problems. We conclude that children with NF1 are frequently socially isolated and rejected by peers; and that greater neurological involvement is associated with more emotional problems. Central nervous system involvement appears to play a key role in identifying children at risk for problems with friendships, social acceptance, and emotional functioning (i.e., depression).

Preventing Neurocognitive Late Effects in Childhood Cancer Survivors

Neurocognitive late effects are common sequelae of cancer in children, especially in those who have undergone treatment for brain tumors or in those receiving prophylactic cranial radiation therapy to treat leukemia. Neurocognitive morbidity in attention, executive functioning, processing speed, working memory, and memory frequently occurs and contributes to declines in intellectual and academic abilities. Oncologists are faced with the challenge of using the most effective, often the most intense, therapy to achieve the primary goal of medical success, balanced with the desire to prevent adverse late effects. Not all children with similar diagnoses and treatment have identical neurocognitive outcomes; some do very poorly and some do well. Attention now turns to the reliable prediction of risk for poor outcomes and then, using risk-adapted therapy, to preserve neurocognitive function. Prevention of late effects through rehabilitative strategies, continuation of school, and pharmacotherapy will be explored.

MOPP chemotherapy without irradiation as primary postsurgical therapy for brain tumors in infants and young children

Infants and young children who have brain tumors have a poor rateof survival and high treatment associated morbidity. A trial of mechlorethamine, vincristine (oncovin), procarbazine, and prednisone(MOPP) was performed to test the hypothesis that replacingradiotherapy with chemotherapy would improve survival and decreaselong term morbidity of infants who have brain tumors. Between 1976 and1988, 17 consecutive children less than 36 months old when diagnosed with medulloblastoma or ependymoma were treatedwith MOPP chemotherapy as primary therapy following surgical excision or biopsy of the tumor. Radiotherapy was reserved for recurrent disease. Ten of 17 children have survived without evidence of disease: medulloblastoma, eight of 12 with median survivaltime of 10.6 years (range, 6.2 to 15.2 yrs); and ependymoma, 2of 5 (at 13.0 and 16.0 yrs). Four of the 10 children with medulloblastomaand ependymoma who relapsed are now disease free at 7.5, 11.7, 12.2 and 13.5 yrs post relapse after receiving salvagetherapy with cisplatin (n = 1) or irradiation (n = 3). All relapsesoccurred within 26 months of diagnosis. Data on growth demonstrated heightless than the 5th percentile in all children who received cranial irradiation compared to 25 to 95th percentile for nonirradiated children. Intellectual ability for the groupwho did not require radiation was within normal range (mean IQ 100.1) and stable across annual assessments. Those who required radiation hadlower IQs which continued to decline over time (mean IQ 85 at mean age of 5.8 years, declining to 63 at 10 years).In young children with brain tumors, primary chemotherapy with MOPP, omitting radiotherapy, provides improved neurodevelopmental outcome and survival.

Caudate Nucleus Volume Asymmetry Predicts Attention-Deficit Hyperactivity Disorder (ADHD) Symptomatology in Children

Clinical diagnosis of attention-deficit hyperactivity disorder (ADHD) is based on evaluation of behavioral functioning in three domains: inattentiveness, hyperactivity, and impulsivity. Caudate and frontal lobe function figures prominently in several neuroanatomic models of attentional functioning. Studies comparing children with and without ADHD have found differences in the size and symmetry of the caudate nuclei. Using multiple regression, we tested the hypothesis that caudate volume symmetry (log left minus log right caudate volume) measured from serial sagittal magnetic resonance images in a sample of nonreferred children (12 girls/15 boys, 7.0 to 16.6 years, 81 to 129 IQ) would predict the cumulative severity of parent-reported ADHD diagnostic behaviors beyond variance predicted by age, sex, and level of internalizing problems as measured by the Child Behavior Checklist. No child had been previously diagnosed with ADHD, although one child was found to meet diagnostic criteria based on the rating scale used for the study. The degree of caudate asymmetry significantly predicted cumulative severity ratings of inattentive behaviors (P = .015), uniquely accounting for 17.1% of the variance in inattention symptomatology over demographic variables and internalizing problems, which collectively predicted 28.9% of the variance. Caudate asymmetry uniquely accounted for only 4.3% of the variance in cumulative severity ratings of hyperactive/impulsive symptomatology over demographic variables and internalizing problems that collectively predicted 21.2% of the variance. A greater degree of right to left caudate volume asymmetry predicted subclinical inattentive behaviors in a sample of nonreferred children. This finding is congruent with neuroanatomic models of attention emphasizing lateralized alteration in prefrontal/striatal systems. The results support the view that clinical ADHD is the extreme of a behavioral continuum that extends into the normal population. (J Child Neurol 2002;17:877—884).