Faculty Bibliography

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by mutations in the TSC1 and TSC2 genes. Over 80% of TSC patients are affected by epilepsy, but the molecular events contributing to seizures in TSC are not well understood. Recent reports have demonstrated that the brain is enriched with microRNA activity, and they are critical in neural development and function. However, little is known about the role of microRNAs in TSC. Here, we report the characterization of aberrant microRNA activity in cortical tubers resected from 5 TSC patients surgically treated for medically intractable epilepsy. By comparing epileptogenic tubers with adjacent nontuber tissue, we identified a set of 4 coordinately overexpressed microRNAs (miRs 23a, 34a, 34b*, 532-5p). We used quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomic profiling to investigate the combined effect of the 4 microRNAs on target proteins. The proportion of repressed proteins among the predicted targets was significantly greater than in the overall proteome and was highly enriched for proteins involved in synaptic signal transmission. Among the combinatorial targets were TSC1, coding for the protein hamartin, and several epilepsy risk genes. We found decreased levels of hamartin in epileptogenic tubers and confirmed targeting of the TSC1 3' UTR by miRs-23a and 34a.

PURPOSE/OBJECTIVE:We evaluated if cortical thickness measures were associated with surgical outcome in patients with non-lesional neocortical epilepsy. METHODS:Twenty-one young patients (age: 2.4-19.7years) with epilepsy of neocortical origin and normal MRI underwent two-stage epilepsy surgery with subdural EEG monitoring. Cortical thickness was measured on presurgical volumetric MRI using the FreeSurfer software. The prognostic value of hemispheric and lobar/regional cortical thickness measures for 1-year and 2-year post-surgical seizure outcome has been analyzed. RESULTS:At one-year follow-up, 14 patients (67%) were seizure-free. Hemispheric and frontal lobe cortical thickness showed no/minimal asymmetry in seizure-free patients but thinner cortex ipsilateral to the seizure focus in those with recurrent seizures (p=0.02). More robust differences were found in patients≥6years of age (p=0.006 for frontal asymmetries), whose cortical thickness asymmetries remained prognostic for 2-year post-surgical outcome (p=0.007). By using an optimal cutoff threshold based on a receiver operating characteristic analysis, mean hemispheric asymmetry predicted one-year seizure freedom with 93% sensitivity and 71% specificity in the whole group, and with 100% sensitivity and 92% specificity in patients≥6years of age. CONCLUSION/CONCLUSIONS:In patients with neocortical epilepsy and normal MRI, neocortical thinning in the epileptic hemisphere, particularly in frontal cortex, is associated with poor surgical outcome. Although these results require validation in a larger cohort prospectively, these data suggest that presurgical evaluation of cortical thickness may assist in identification of patients at high risk for surgical failure.

BACKGROUND:Sturge-Weber syndrome is often accompanied by seizures and neurocognitive deterioration, although previous studies have suggested that early functional brain reorganization may diminish the cognitive sequelae in some children with unilateral Sturge-Weber syndrome. The "rules" governing these plasticity mechanisms are poorly understood. In this study, we evaluated longitudinal changes of cognitive functioning (intelligence quotient [IQ]) and assessed the performance of clinical, electroencephalography (EEG), and magnetic resonance imaging (MRI) variables for predicting IQ in children with Sturge-Weber syndrome. METHODS:Thirty-three young children (mean age: 3.3 years at baseline) with unilateral Sturge-Weber syndrome underwent MRI, scalp EEG, and neuropsychology evaluation twice, with a median follow-up of 2 years. None of the children had epilepsy surgery. Longitudinal IQ changes were calculated. Seizure variables, interictal EEG abnormalities, and extent and location of MRI brain involvement were correlated with IQ assessed at follow-up. RESULTS:Global IQ showed a highly variable course with both increases and decreases over time. Lower IQ at baseline was associated with interval IQ increase. In univariate analyses, lower outcome IQ was associated with baseline EEG abnormalities (P < 0.001), young age at seizure onset (P = 0.001), high seizure frequency (P = 0.02), and early frontal-lobe involvement on MRI (P = 0.01). In multivariate analysis, EEG abnormalities at baseline remained a robust, independent predictor of outcome IQ. CONCLUSIONS:The early trajectory of cognitive changes in children with unilateral Sturge-Weber syndrome is highly variable; children with improving IQ likely undergo effective unimpeded functional reorganization. Early onset, frequent seizures, and interictal epileptiform abnormalities on EEG likely interfere with this process resulting in poor cognitive functions. Future studies assessing interventions should target this high-risk subgroup to optimize cognitive outcome in Sturge-Weber syndrome.

BACKGROUND:The karyotype 49, XXXXY is one of the most severe forms of chromosome aneuploidy and is characterized clinically by developmental delay and profound language impairment, particularly involving expressive language functions. We describe the neurocognitive profile and structural anatomy of language pathway in a 2-year-old boy with 49, XXXXY syndrome with expressive aphasia. METHODS:Retrospective chart review of the patient was performed. We characterized the language deficits using neuropsychologic testing. We further studied the language pathways using diffusion tensor imaging analytical technique. RESULTS:The neurocognitive profile of the patient showed relative weakness of expressive language skills compared with other domains. Diffusion tensor imaging analysis demonstrated a poorly developed frontal aslant tract, a weak indirect segment of arcuate fasciculus, and normally developed direct segment of arcuate fasciculus. The frontal aslant tract is a novel pathway that connects the Broca's area with the anterior cingulate and presupplementary motor area and plays a role in the "motor stream" of language. CONCLUSION/CONCLUSIONS:A poorly developed frontal aslant tract may underlie the expressive language deficits and provide some insight into the role of X chromosome in modulating the development of language tracts.

Prevalence of autism spectrum disorders has increased over recent years, however, little is known about the identification and management of autism spectrum disorder in Africa. This report summarizes a workshop on autism spectrum disorder in Africa under the auspices of the International Child Neurology Association and the African Child Neurology Association through guided presentations and working group reports, focusing on identification, diagnosis, management, and community support. A total of 47 delegates participated from 14 African countries. Although there was a huge variability in services across the countries represented, numbers of specialists assessing and managing autism spectrum disorder was small relative to populations served. Strategies were proposed to improve identification, diagnosis, management and support delivery for individuals with autism spectrum disorder across Africa in these culturally diverse, low-resource settings. Emphasis on raising public awareness through community engagement and improving access to information and training in autism spectrum disorder. Special considerations for the cultural, linguistic, and socioeconomic factors within Africa are discussed.

OBJECTIVES: To determine safety and efficacy of the 5HT1A serotonin partial agonist buspirone on core autism and associated features in children with autism spectrum disorder (ASD). STUDY DESIGN: Children 2-6 years of age with ASD (N = 166) were randomized to receive placebo or 2.5 or 5.0 mg of buspirone twice daily. The primary objective was to evaluate the effects of 24 weeks of buspirone on the Autism Diagnostic Observation Schedule (ADOS) Composite Total Score. Secondary objectives included evaluating the effects of buspirone on social competence, repetitive behaviors, language, sensory dysfunction, and anxiety and to assess side effects. Positron emission tomography measures of tryptophan metabolism and blood serotonin concentrations were assessed as predictors of buspirone efficacy. RESULTS: There was no difference in the ADOS Composite Total Score between baseline and 24 weeks among the 3 treatment groups (P = .400); however, the ADOS Restricted and Repetitive Behavior score showed a time-by-treatment effect (P = .006); the 2.5-mg buspirone group showed significant improvement (P = .003), whereas placebo and 5.0-mg buspirone groups showed no change. Children in the 2.5-mg buspirone group were more likely to improve if they had fewer foci of increased brain tryptophan metabolism on positron emission tomography (P = .018) or if they showed normal levels of blood serotonin (P = .044). Adverse events did not differ significantly among treatment groups. CONCLUSIONS: Treatment with 2.5 mg of buspirone in young children with ASD might be a useful adjunct therapy to target restrictive and repetitive behaviors in conjunction with behavioral interventions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00873509.

OBJECTIVE:To examine whether diffusion-weighted imaging (DWI) tractography can detect multiple white matter pathways connected to language cortices, we employed a maximum a posteriori probability (MAP) classification method, which has been recently validated for the corticospinal tract. METHODS:DWI was performed in 12 normally developing children and 17 children with intractable focal epilepsy who underwent subsequent two-stage epilepsy surgery with intracranial functional mapping. First, whole-brain DWI tractography was performed to identify unique pathways originating from Broca's area, premotor area, and Wernicke's area on functional magnetic resonance imaging (fMRI) of normal children and intracranial electrical stimulation mapping (ESM) of children with epilepsy. Group averaging of these pathways based on fMRI was performed to construct the probability maps of language areas in standard MRI space. These maps were finally used to design a DWI-MAP classifier, which can automatically sort individual fibers originating from fMRI language areas as well as ESM language areas. RESULTS:In normally developing children, the DWI-MAP classifier predicted language-activation areas on fMRI with up to 77% accuracy. In children with focal epilepsy, the DWI-MAP classifier also showed high accuracy (up to 82%) for the fibers terminating in proximity to essential language areas determined by ESM. Decreased volumes in DWI-MAP-defined pathways after epilepsy surgery were associated with postoperative language deficits. SIGNIFICANCE/CONCLUSIONS:This study encourages further investigations to determine if DWI-MAP analysis can serve as a noninvasive diagnostic tool during pediatric presurgical planning by estimating not only the location of essential language cortices, but also the underlying fibers connecting these cortical areas.

We applied PET scanning with (11)C-[R]-PK11195 (PK) to evaluate neuroinflammatory changes in basal ganglia and thalamus in children with clinically diagnosed pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) and Tourette syndrome. Seventeen children with PANDAS (mean age: 11.4 ± 2.6 years; 13 males), 12 with Tourette syndrome (mean age: 11.0 ± 3.0 years; 10 males), and 15 normal adults (mean age: 28.7 ± 7.9 years; 8 males) underwent dynamic PK PET imaging and binding potential, a measure of ligand-TSPO receptor (expressed by activated microglia) binding, was calculated for basal ganglia and thalamus. Binding potential values, suggesting underlying activated microglia-mediated neuroinflammation, were found to be increased in bilateral caudate and bilateral lentiform nucleus in the PANDAS group and in bilateral caudate nuclei only in the Tourette syndrome group, compared to control group. These differences in the pattern and extent of neuroinflammation also signify a possible difference in pathophysiological etiology between PANDAS and Tourette syndrome patients.