Anna W. Byars

Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis.

BACKGROUND Neurosurgical resection is the standard treatment for subependymal giant-cell astrocytomas in patients with the tuberous sclerosis complex. An alternative may be the use of everolimus, which inhibits the mammalian target of rapamycin, a protein regulated by gene products involved in the tuberous sclerosis complex. METHODS Patients 3 years of age or older with serial growth of subependymal giant-cell astrocytomas were eligible for this open-label study. The primary efficacy end point was the change in volume of subependymal giant-cell astrocytomas between baseline and 6 months. We gave everolimus orally, at a dose of 3.0 mg per square meter of body-surface area, to achieve a trough concentration of 5 to 15 ng per milliliter. RESULTS We enrolled 28 patients. Everolimus therapy was associated with a clinically meaningful reduction in volume of the primary subependymal giant-cell astrocytoma, as assessed on independent central review (P<0.001 for baseline vs. 6 months), with a reduction of at least 30% in 21 patients (75%) and at least 50% in 9 patients (32%). Marked reductions were seen within 3 months and were sustained. There were no new lesions, worsening hydrocephalus, evidence of increased intracranial pressure, or necessity for surgical resection or other therapy for subependymal giant-cell astrocytoma. Of the 16 patients for whom 24-hour video electroencephalography data were available, seizure frequency for the 6-month study period (vs. the previous 6-month period) decreased in 9, did not change in 6, and increased in 1 (median change, -1 seizure; P=0.02). The mean (±SD) score on the validated Quality-of-Life in Childhood Epilepsy questionnaire (on which scores can range from 0 to 100, with higher scores indicating a better quality of life) was improved at 3 months (63.4±12.4) and 6 months (62.1±14.2) over the baseline score (57.8±14.0). Single cases of grade 3 treatment-related sinusitis, pneumonia, viral bronchitis, tooth infection, stomatitis, and leukopenia were reported. CONCLUSIONS Everolimus therapy was associated with marked reduction in the volume of subependymal giant-cell astrocytomas and seizure frequency and may be a potential alternative to neurosurgical resection in some cases, though long-term studies are needed. (Funded by Novartis; ClinicalTrials.gov number, NCT00411619.).

Normal fMRI Brain Activation Patterns in Children Performing a Verb Generation Task

Although much is known concerning brain-language relations in adults, little is known about how these functions might be represented during the developmental period. We report results from 17 normal children, ages 7-18 years, who have successfully completed a word fluency paradigm during functional magnetic resonance imaging at 3 Tesla. Regions of activation replicate those reported for adult subjects. However, a statistically significant association between hemispheric lateralization of activation and age was found in the children. Specifically, although most subjects at all ages showed left hemisphere dominance for this task, the degree of lateralization increased with age. This study demonstrates that fMRI can reveal developmental shifts in the pattern of brain activation associated with semantic language function.

fMRI study of language lateralization in children and adults.

Language lateralization in the brain is dependent on family history of handedness, personal handedness, pathology, and other factors. The influence of age on language lateralization is not completely understood. Increasing left lateralization of language with age has been observed in children, while the reverse has been noted in healthy young adults. It is not known whether the trend of decreasing language lateralization with age continues in the late decades of life and at what age the inflection in language lateralization trend as a function of age occurs. In this study, we examined the effect of age on language lateralization in 170 healthy right‐handed children and adults ages 5–67 using functional MRI (fMRI) and a verb generation task. Our findings indicate that language lateralization to the dominant hemisphere increases between the ages 5 and 20 years, plateaus between 20 and 25 years, and slowly decreases between 25 and 70 years. Hum Brain Mapp, 2005.

A longitudinal functional magnetic resonance imaging study of language development in children 5 to 11 years old

Language skills continue to develop rapidly in children during the school‐age years, and the “snapshot” view of the neural substrates of language provided by current neuroimaging studies cannot capture the dynamic changes associated with brain development. The aim of this study was to conduct a 5‐year longitudinal investigation of language development using functional magnetic resonance imaging in healthy children.

Practical aspects of conducting large-scale functional magnetic resonance imaging studies in children

The potential benefits of functional magnetic resonance imaging (MRI) for the investigation of normal development have been limited by difficulties in its use with children. We describe the practical aspects, including failure rates, involved in conducting large-scale functional MRI studies with normal children. Two hundred and nine healthy children between the ages of 5 and 18 years participated in a functional MRI study of language development. Reliable activation maps were obtained across the age range. Younger children had significantly higher failure rates than older children and adolescents. It is concluded that it is feasible to conduct large-scale functional MRI studies of children as young as 5 years old. These findings can be used by other research groups to guide study design and plans for recruitment of young subjects. (J Child Neurol 2002;17:885—889).

Functional MRI of language lateralization during development in children.

Changes in the distribution of language function in the brain have been documented from infancy through adulthood. Even macroscopic measures of language lateralization reflect a dynamic process of language development. In this review, we summarize a series of functional MRI studies of language skills in children ages of five to 18 years, both typically-developing children and children with brain injuries or neurological disorders that occur at different developmental stages with different degrees of severity. These studies used a battery of fMRI-compatible language tasks designed to tap sentential and lexical language skills that develop early and later in childhood. In typically-developing children, lateralization changes with age are associated with language skills that have a protracted period of development, reflecting the developmental process of skill acquisition rather than general maturation of the brain. Normative data, across the developmental period, acts as a reference for disentangling developmental patterns in brain activation from changes due to developmental or acquired abnormalities. This review emphasizes the importance of considering age and child development in neuroimaging studies of language.

Bright spots: correlations of gray matter volume with IQ in a normal pediatric population

The localization of brain areas related to cognitive functions has yet to be thoroughly explored in children. We therefore set out to apply volumetric, voxel-based, and structural connectivity analyses to magnetic resonance images from a large sample of healthy children. We could confirm a strong correlation of whole-brain gray matter volume and the individual intelligence quotient; however, this correlation only developed with age in our sample, in that it was not present in the younger children. With the application of an optimized protocol for voxel-based morphometry, the anterior cingulate was shown to be directly correlated with a measure of human intelligence. Furthermore, an analysis of structural connectivity identified gray matter volume in several distinct brain areas to be related to cognitive functions. The implications of our findings for normal development, pathological processes, and our understanding of cognition are discussed and related to previous findings.

Neuropsychological status at seizure onset in children Risk factors for early cognitive deficits

Objective: This large, prospective, community-based study characterized neuropsychological functioning and academic achievement at the time of the first recognized seizure and identified risk factors for cognitive deficits. Methods: We compared 282 children (ages 6–14 years, IQ ≥70) with a first recognized seizure to 147 healthy siblings on a battery of well-standardized and widely used neuropsychological and academic achievement tests and examined relationships with demographic and clinical variables. Results: In this intellectually normal cohort, 27% with just one seizure and up to 40% of those with risk factors exhibited neuropsychological deficits at or near onset. Risk factors associated with neuropsychological deficits included multiple seizures (i.e., second unprovoked seizure; odds ratio [OR] = 1.96), use of antiepileptic drugs (OR = 2.27), symptomatic/cryptogenic etiology (OR = 2.15), and epileptiform activity on the initial EEG (OR = 1.90); a child with all 4 risks is 3.00 times more likely than healthy siblings to experience neuropsychological deficits by the first clinic visit. Absence epilepsy carried increased odds for neuropsychological impairment (OR = 2.00). Conclusions: A subgroup of intellectually normal children with seizures showed neuropsychological deficits at onset. Academic achievement was unaffected, suggesting that there is a window early in the disorder for intervention to ameliorate the impact on school performance. Therefore, the risk factors identified here (especially if multiple risks are present) warrant swift referral for neuropsychological evaluation early in the course of the condition.

fMRI Shows Atypical Language Lateralization in Pediatric Epilepsy Patients

Summary:  Purpose: The goal of this study was to compare language lateralization between pediatric epilepsy patients and healthy children.

Multimodality imaging in the surgical treatment of children with nonlesional epilepsy

Objectives: To evaluate the diagnostic value of individual noninvasive presurgical modalities and to study their role in surgical management of nonlesional pediatric epilepsy patients. Methods: We retrospectively studied 14 children (3–18 years) with nonlesional intractable focal epilepsy. Clinical characteristics, surgical outcome, localizing features on 3 presurgical diagnostic tests (subtraction peri-ictal SPECT coregistered to MRI [SISCOM], statistical parametric mapping [SPM] analysis of [18F] FDG-PET, magnetoencephalography [MEG]), and intracranial EEG (iEEG) were reviewed. The localization of each individual test was determined for lobar location by visual inspection. Concordance of localization between each test and iEEG was scored as follows: 2 = lobar concordance; 1 = hemispheric concordance; 0 = discordance or nonlocalization. Total concordance score in each patient was measured by the summation of concordance scores for all 3 tests. Results: Seven (50%) of 14 patients were seizure-free for at least 12 months after surgery. One (7%) had only rare seizures and 6 (43%) had persistent seizures. MEG (79%, 11/14) and SISCOM (79%, 11/14) showed greater lobar concordance with iEEG than SPM-PET (13%, 3/14) (p < 0.05). SPM-PET provided hemispheric lateralization (71%, 10/14) more often than lobar localization. Total concordance score tended to be greater for seizure-free patients (4.7) than for non–seizure-free patients (3.9). Conclusions: Our data suggest that MEG and SISCOM are better tools for lobar localization than SPM analysis of FDG-PET in children with nonlesional epilepsy. A multimodality approach may improve surgical outcome as well as selection of surgical candidates in patients without MRI abnormalities.