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Background Sturge-Weber syndrome is a rare neurovascular disorder associated with capillary malformation, seizures, cognitive impairments, and stroke-like episodes (SLEs), arising from a somatic activating mutation in GNAQ. Studies suggest this mutation may cause hyperactivation of the mammalian target of rapamycin pathway. Sirolimus is an mammalian target of rapamycin inhibitor studied in other vascular anomalies and a potentially promising therapy in Sturge-Weber syndrome. Methods Ten patients with Sturge-Weber syndrome brain involvement and cognitive impairments were enrolled. Oral sirolimus was taken for six months (maximum dose: 2 mg/day, target trough level: 4-6 ng/mL). Neuropsychological testing, electroencephalography, and port-wine score were performed at baseline and after six months on sirolimus. Neuroquality of life, adverse events, and Sturge-Weber Syndrome Neurological Score (neuroscore) were recorded at each visit. Results Sirolimus was generally well tolerated; one subject withdrew early. Adverse events considered related to sirolimus were mostly (15/16) grade 1. A significant increase in processing speed was seen in the overall group (P = 0.031); five of nine patients with available data demonstrated statistically rare improvement in processing speed. Improvements were seen in the neuroquality of life subscales measuring anger (P = 0.011), cognitive function (P = 0.015), and depression (P = 0.046). Three subjects experiencing SLEs before and during the study reported shortened recovery times while on sirolimus. Conclusions Sirolimus was well tolerated in individuals with Sturge-Weber syndrome and may be beneficial for cognitive impairments, especially in patients with impaired processing speed or a history of SLE. A future, randomized, placebo-controlled trial of sirolimus in patients with Sturge-Weber syndrome is needed to further understand these potentially beneficial effects.

We evaluated stereo-EEG electrical stimulation mapping (ESM) for localization of anatomic sensorimotor parcels in pediatric patients with drug-resistant epilepsy. We also analyzed sensorimotor and after-discharge thresholds, and the somatotopy of sensorimotor responses.ESM was performed with 50 Hz, biphasic, 2-3 s trains, using 1-9 mA current. Pre- and post-implant neuroimaging was co-registered and intersected with Neurosynth reference, to classify each electrode contact as lying within/outside an anatomic sensorimotor parcel. Indices of diagnostic performance were computed. Sensorimotor and after-discharge thresholds were analyzed using multivariable linear mixed models.In 15 patients (6 females), aged 5.5-21.2 years, ESM showed high accuracy (0.80), high specificity (0.86), and diagnostic odds ratio (11.4, p 0.0001) for localization of sensorimotor parcels. Mean sensorimotor threshold (3.4 mA) was below mean after-discharge threshold (4.2 mA, p = 0.0004). Sensorimotor and after-discharge thresholds showed a significant decrease with increasing intelligence quotient. Somatotopy of sensorimotor responses was mapped to standardized brain parcels.We provide evidence for diagnostic validity and safety of stereo-EEG sensorimotor ESM.The somatotopy of sensorimotor responses elicited with electrical stimulation provide new insights into mechanisms of motor control and sensory perception.

Purpose We studied the association between electrical stimulation mapping (ESM) with a visual naming task and post-operative neuropsychological outcomes after pediatric epilepsy surgery. Methods Children who underwent epilepsy surgery, having pre- and 1-year post-surgery neuropsychological evaluation (NPE) available, were included. NPE scores were transformed using principal components (PC) analysis. The relationship between post-surgical PC scores, adjusted for pre-surgery PC scores, and ESM was analyzed. Clinical variables influencing this relationship were also sought. Results One hundred and four children (89 patients >5 years-old, and 15 patients 3−5 years-old) were included. Among children >5 years-of-age, a significant effect of language ESM was observed on all 3 post-surgery PC scores adjusted for respective pre-surgery PC scores. Specifically, only 30 % patients who underwent language ESM had a decrease in PC1 scores ≥1-year after epilepsy surgery, compared to 68 % those who did not undergo language ESM (p = 0.001). Seizure outcomes, age at the time of surgery, predominant seizure type, and family history of epilepsy were other significant determinants of post-surgical PC scores including a change in PC scores from pre-surgery baseline. Combinations of pre-surgical variables were able to predict post-surgical PC scores with high specificity. In children aged 3−5 years, no significant effect of language ESM was seen on post-surgery PC scores adjusted for respective pre-surgery PC scores. Conclusions Speech/language ESM should be performed more widely in patients >5 years-of-age undergoing epilepsy surgery. Also, more efficient brain mapping techniques and language paradigms are needed for younger children.

Aim This study aimed to define whether individuals with drug-resistant focal epilepsy also used regions related to cognitive control to facilitate reading. Methods We focused on patients with drug-resistant focal epilepsy in 2011-2014, who were aged 8-20 years and were being treated at the Cincinnati Children's Hospital, USA. They performed a verb generation functional magnetic resonance imaging task known to involve language and cognitive control, as well as a formal reading assessment. The reading scores were correlated with functional connectivity of the anterior cingulate cortex (ACC) using seed-to-voxel analysis. Results There were 81 potential patients and 13 (seven females) met the inclusion criteria. Their age at seizure onset was 0-13 years, and they had a mean age of 12.66 ± 3.17 years at the time of the study. Individuals with epilepsy demonstrated average intelligence and word reading ability. Their reading scores were positively correlated with functional connectivity between the ACC and regions related to emotional processing (right amygdala), learning and language processing (left cerebellum) and visual processing. Conclusion Our results support the role that the ACC plays in proficient reading among children with drug-resistant epilepsy, even in those with epileptogenic foci in areas related to language.

Objective To determine if routine electroencephalography (EEG) in seizure‐naive infants with tuberous sclerosis complex (TSC) can predict epilepsy and subsequent neurocognitive outcomes. Methods Forty infants 7 months of age or younger and meeting the genetic or clinical diagnostic criteria for tuberous sclerosis were enrolled. Exclusion criteria included prior history of seizures or treatment with antiseizure medications. At each visit, seizure history and 1‐hour awake and asleep video‐EEG, standardized across all sites, were obtained until 2 years of age. Developmental assessments (Mullen and Vineland‐II) were completed at 6, 12, and 24 months of age. Results Of 40 infants enrolled (mean age of 82.4 days), 32 completed the study. Two were lost to follow‐up and six were treated with antiepileptic drugs (AEDs) due to electrographic seizures and/or interictal epileptiform discharges (IEDs) on their EEG studies prior to the onset of clinical seizures. Seventeen of the 32 remaining children developed epilepsy at a mean age of 7.5 months (standard deviation [SD] = 4.4). Generalized/focal slowing, hypsarrhythmia, and generalized/focal attenuation were not predictive for the development of clinical seizures. Presence of IEDs had a 77.3% positive predictive value and absence a 70% negative predictive value for developing seizures by 2 years of age. IEDs preceded clinical seizure onset by 3.6 months (mean). Developmental testing showed significant decline, only in infants with ongoing seizures, but not infants who never developed seizures or whose seizures came under control. Significance IEDs identify impending epilepsy in the majority (77%) of seizure‐naive infants with TSC. The use of a 1‐hour awake and asleep EEG can be used as a biomarker for ongoing epileptogenesis in most, but not all, infants with TSC. Persistent seizures, but not history of interictal epileptiform activity or history of well‐controlled seizures, correlated with low scores on the Vineland and Mullen tests at 2 years of age.

Children with Benign Epilepsy with Centrotemporal Spikes (BECTS), despite high likelihood for seizure remission, are reported to have subtle difficulties in language and other cognitive skills. We used functional MRI and a story listening task to examine the effect of BECTS on patterns of activation and connectivity. Language and cognitive skills were assessed using standardized measures. Twenty-four children with recently diagnosed BECTS and 40 typically-developing children participated. In a functionally-defined region of interest in right inferior frontal gyrus, BECTS patients showed a lower level of activation. Across both groups combined, increased activation in superior/middle temporal regions of interest was associated with better language scores. Connectivity in the story processing network was similar between groups, but connectivity within left inferior frontal gyrus was decreased in children with BECTS. These results suggest that language networks are largely maintained in new-onset BECTS, but some subtle changes in activation and connectivity can be observed.

The Tuberous Sclerosis Complex Autism Center of Excellence Network (TACERN) is a 6-site collaborative conducting longitudinal research on infants with tuberous sclerosis complex (TSC), focused on identifying early biomarkers for autism spectrum disorder (ASD). A multidisciplinary research team that includes the specialties of psychology, neurology, pediatrics, medical genetics, and speech-language pathology, its members work together to conduct studies on neurological status, brain structure and function, neurodevelopmental phenotype, and behavioral challenges in this population. This article provides insights into the roles of the multidisciplinary multisite team and lessons learned from the collaboration, in terms of research as well as training of future researchers and clinicians. In addition, the authors detail the major findings to date, including those related to the identification and measurement of early symptoms of ASD, relationship between seizures and early development, and early biomarkers for epilepsy and developmental delay in infants and young children with TSC. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

This systematic review and meta-analysis evaluated the diagnostic validity of functional magnetic resonance imaging (fMRI) compared to electrical stimulation mapping (ESM) for pre-surgical language mapping.A structured literature search was performed and studies with electrode-level data comparing fMRI and ESM for language localization were analyzed. Outcome measures included pooled estimates of diagnostic odds ratio (DOR), sensitivity, and specificity. Sources of heterogeneity were explored with a meta-regression framework.Nine studies were included in the analysis having 5-40 patients with mean age 11.3-43.4 years. Verb generation and picture naming were the most common fMRI tasks, while picture naming was the most common ESM task. Sensitivity (0.37-0.95), specificity (0.36-0.97), and DOR (1.9-44.6) for fMRI compared to ESM varied widely across studies with statistically significant heterogeneities. Pooled estimates were: sensitivity 0.71 (95% confidence interval 0.54, 0.83), specificity 0.74 (0.58, 0.85), and DOR 7.0 (3.5, 13.8), from a valid meta-analysis (area under the summary receiver-operating-curve 0.78). fMRI was noted to have higher sensitivity in studies using higher maximal ESM currents. fMRI variables could not be included in the meta-regression because of substantial methodological differences among studies.fMRI is moderately sensitive and moderately specific for language localization compared to ESM in well-designed studies. However, because the confidence limits for sensitivity and DOR are close to the line of no effect, and there is high unmeasured heterogeneity, fMRI cannot perhaps be used as the only modality for language localization to inform neurosurgical decisions at present.

Objective Cerebral spatiotemporal dynamics of visual naming were investigated in epilepsy patients undergoing stereo-electroencephalography (SEEG) monitoring. Methods Brain networks were defined by Parcel-Activation-Resection-Symptom matching (PARS) approach by matching high-gamma (50-150 Hz) modulations (HGM) in neuroanatomic parcels during visual naming, with neuropsychological outcomes after resection/ablation of those parcels. Brain parcels with >50% electrode contacts simultaneously showing significant HGM were aligned, to delineate spatiotemporal course of naming-related HGM. Results In 41 epilepsy patients, neuroanatomic parcels showed sequential yet temporally overlapping HGM course during visual naming. From bilateral occipital lobes, HGM became increasingly left lateralized, coursing through limbic system. Bilateral superior temporal HGM was noted around response time, and right frontal HGM thereafter. Correlations between resected/ablated parcels, and post-surgical neuropsychological outcomes showed specific regional groupings. Conclusions Convergence of data from spatiotemporal course of HGM during visual naming, and functional role of specific parcels inferred from neuropsychological deficits after resection/ablation of those parcels, support a model with six cognitive subcomponents of visual naming having overlapping temporal profiles. Significance Cerebral substrates supporting visual naming are bilaterally distributed with relative hemispheric contribution dependent on cognitive demands at a specific time. PARS approach can be extended to study other cognitive and functional brain networks.

Background Language mapping with high-gamma modulation (HGM) has compared well with electrical cortical stimulation mapping (ESM). However, there is limited prospective data about its functional validity. We compared changes in neuropsychological evaluation (NPE) performed before and 1-year after epilepsy surgery, between patients with/without resection of cortical sites showing HGM during a visual naming task. Methods Pediatric drug-resistant epilepsy (DRE) patients underwent pre-surgical language localization with ESM and HGM using a visual naming task. Surgical decisions were based solely on ESM results. NPE difference scores were compared between patients with/without resection of HGM naming sites using principal component (PC) analysis. Follow-up NPE scores were modeled with resection group as main effect and respective pre-surgical score as a covariate, using analysis of covariance. Results Seventeen native English speakers (12 females), aged 6.5–20.2 years, were included. One year after epilepsy surgery, first PC score increased by (mean ± standard deviation) 14.4 ± 16.5 points in patients without resection, whereas it decreased by 7.6 ± 24.6 points in those with resection of HGM naming sites (p = 0.040). This PC score represented verbal comprehension, working memory, perceptual reasoning (Wechsler subscales); Woodcock-Johnson Tests of Achievement; and Peabody Picture Vocabulary Test. Subsequent analysis showed significant difference in working memory score between patients with/without resection of HGM naming sites (−15.2 points, 95% confidence limits −29.7 to −0.7, p = 0.041). Conclusion We highlight the functional consequences of resecting HGM language sites, and suggest that NPE of DRE patients should include comprehensive assessment of multiple linguistic and cognitive domains besides naming ability.

A novel analytic approach for task-related high-gamma modulation (HGM) in stereo-electroencephalography (SEEG) was developed and evaluated for language mapping.SEEG signals, acquired from drug-resistant epilepsy patients during a visual naming task, were analyzed to find clusters of 50-150 Hz power modulations in time-frequency domain. Classifier models to identify electrode contacts within the reference neuroanatomy and electrical stimulation mapping (ESM) speech/language sites were developed and validated.In 21 patients (9 females), aged 4.8-21.2 years, SEEG HGM model predicted electrode locations within Neurosynth language parcels with high diagnostic odds ratio (DOR 10.9, p 0.0001), high specificity (0.85), and fair sensitivity (0.66). Another SEEG HGM model classified ESM speech/language sites with significant DOR (5.0, p 0.0001), high specificity (0.74), but insufficient sensitivity. Time to largest power change reliably localized electrodes within Neurosynth language parcels, while, time to center-of-mass power change identified ESM sites.SEEG HGM mapping can accurately localize neuroanatomic and ESM language sites.Predictive modelling incorporating time, frequency, and magnitude of power change is a useful methodology for task-related HGM, which offers insights into discrepancies between HGM language maps and neuroanatomy or ESM.

Objective We studied age-related dynamics of information sharing among cortical language regions with electrocorticographic high-gamma modulation during picture-naming and story-listening tasks. Methods Seventeen epilepsy patients aged 4-19 years, undergoing extraoperative monitoring with left-hemispheric subdural electrodes, were included. Mutual information (MI), a nondirectional measure of shared information, between 16 pairs of cortical regions of interest, was computed from trial-averaged 70-150 Hz power modulations during language tasks. Impact of age on pairwise MI between language regions and their determinants were ascertained with regression analysis. Results During picture naming, significant increase in MI with age was seen between pairwise combinations of Broca's area, inferior precentral gyrus (iPreC), and frontal association cortex (FAC); Wernicke's area and posterior association cortex (PAC); and Broca's and Wernicke's areas. During story listening, significant age-related increase in MI was seen between Wernicke's area and either Broca's area, FAC, or PAC; and between Broca's area and FAC. Significant impact of baseline intelligence quotient was seen on the relationship between age and MI for all pairs, except between Broca's area and iPreC. The mean MI was higher during naming compared to listening for pairs including iPreC with Broca's area, FAC, or PAC and was lower for pairs of Wernicke's area or PAC with anterior language regions. Significance Information sharing matures with age "within" frontal and temporoparietal language cortices, and "between" Broca's and Wernicke's areas. This study provides evidence for distinct patterns of developmental plasticity within perisylvian language cortex and has implications for planning epilepsy surgery.

OBJECTIVE This prospective study compared the topography of high-gamma modulation (HGM) during a story-listening task requiring negligible patient cooperation, with the conventional electrical stimulation mapping (ESM) using a picture-naming task, for presurgical language localization in pediatric drug-resistant epilepsy. METHODS Patients undergoing extraoperative monitoring with subdural electrodes were included. Electrocorticographic signals were recorded during quiet baseline and a story-listening task. The likelihood of 70- to 150-Hz power modulation during the listening task relative to the baseline was estimated for each electrode and plotted on a cortical surface model. Sensitivity, specificity, accuracy, and diagnostic odds ratio (DOR) were estimated compared to ESM, using a meta-analytic framework. RESULTS Nineteen patients (10 with left hemisphere electrodes) aged 4-19 years were analyzed. HGM during story listening was observed in bilateral posterior superior temporal, angular, supramarginal, and inferior frontal gyri, along with anatomically defined language association areas. Compared to either cognitive or both cognitive and orofacial sensorimotor interference with naming during ESM, left hemisphere HGM showed high specificity (0.82-0.84), good accuracy (0.66-0.70), and DOR of 2.23 and 3.24, respectively. HGM was a better classifier of ESM language sites in the left temporoparietal cortex compared to the frontal lobe. Incorporating visual naming with the story-listening task substantially improved the accuracy (0.80) and DOR (13.61) of HGM mapping, while the high specificity (0.85) was retained. In the right hemisphere, no ESM sites for aphasia were seen, and the results of HGM and ESM comparisons were not significant. SIGNIFICANCE HGM associated with story listening is a specific determinant of left hemisphere ESM language sites. It can be used for presurgical language mapping in children who cannot cooperate with conventional language tasks requiring active engagement. Incorporation of additional language tasks, if feasible, can further improve the diagnostic accuracy of language localization with HGM.

Purpose We studied the effect of fosphenytoin (FOS) pre-medication on the incidence and thresholds of after-discharges (ADs), seizures, and functional responses during electrical stimulation mapping (ESM). Methods As individualized by the attending epileptologist, FOS was given intravenously at 2 mg-phenytoin-equivalents (PE)/kg/min or 150 mg-PE/min (whichever slower). Patients who received and did not receive FOS were compared for the incidence and thresholds of ADs, seizures, and functional responses. Results Before ESM, 40 and 82 patients respectively were pre-medicated/not pre-medicated with FOS. The incidence of ESM-induced seizures was significantly lower in FOS pre-medicated patients (22.5% vs. 42.7%, p = 0.044), whereas temporal language threshold was higher (9.2 vs. 6.5 mA, p = 0.032). FOS was more efficacious in preventing ESM-induced seizures in patients with symptomatogenic zone ipsilateral to the side of ESM. Although FOS dose had no significant effect on minimum language, minimum motor, or AD thresholds; seizure and temporal language thresholds showed trends approaching significance, intersecting at 12.2 mg-PE/kg. The incidence of ESM-induced seizures was significantly lower in those who received FOS at a dose of ≤12 mg/kg (9.1%) compared to those who did not receive any FOS (42.7%, p = 0.046), while the temporal language thresholds were not significantly different (6.3 vs. 6.5 mA, p = 0.897). Conclusions This study provides class III evidence that FOS pre-medication before ESM decreases the incidence of ESM-induced seizures, but increases temporal language threshold. FOS pre-medication may thus be considered before ESM. Future studies should prospectively verify these observations and characterize dose-response relationships.

Objective To evaluate if short‐term treatment with everolimus was safe and could improve neurocognition and behavior in children with TSC. Methods This was a prospective, double‐blind randomized, placebo‐controlled two‐center phase II study. Participants diagnosed with TSC and age 6–21 years were treated with 4.5 mg/m2 per day of oral everolimus (n = 32) or matching placebo (n = 15) taken once daily for 6 months. For efficacy, a comprehensive neurocognitive and behavioral evaluation battery was performed at baseline, 3 months, and 6 months. For safety, adverse events recorded continuously via patient diary were categorized and graded per NCI Common Toxicity Criteria for Adverse Events, version 3.0 (CTCAE 3.0). Analyses were performed on the intention‐to‐treat population (n = 47). Results Nearly all assessment measures failed to demonstrate significant differences between the two groups at the end of 6 months. Only one measure each of executive function (Cambridge Neuropsychological Test Automated Battery Stockings of Cambridge) favoring placebo (P = 0.025) and social cognition (Social Responsiveness Scale Social Cognition Subscale) favoring everolimus (P = 0.011) was observed. A total of 473 adverse events (AE) were reported. The average number of total AE per subject was similar for both placebo and everolimus. Most were mild or moderate in severity and serious AE were rare. Interpretation While safe, oral everolimus administered once daily for 6 months did not significantly improve neurocognitive functioning or behavior in children with TSC.

Objective This study examined the incidence, thresholds, and determinants of electrical cortical stimulation (ECS)-induced after-discharges (ADs) and seizures. Methods Electrocorticograph recordings were reviewed to determine incidence of ECS-induced ADs and seizures. Multivariable analyses for predictors of AD/seizure occurrence and their thresholds were performed. Results In 122 patients, the incidence of ADs and seizures was 77% (94/122) and 35% (43/122) respectively. Males (odds ratio [OR] 2.92, 95% CI 1.21–7.38, p = 0.02) and MRI-negative patients (OR 3.69, 95% CI 1.24–13.7, p = 0.03) were found to have higher odds of ECS-induced ADs. A significant trend for decreasing AD thresholds with age was seen (regression co-efficient −0.151, 95% CI −0.267 to −0.035, p = 0.011). ECS-induced seizures were more likely in patients with lateralized functional imaging (OR 6.62, 95% CI 1.36–55.56, p = 0.036, for positron emission tomography) and presence of ADs (OR 3.50, 95% CI 1.12–13.36, p = 0.043). Conclusions ECS is associated with a high incidence of ADs and seizures. With age, current thresholds decrease and the probability for AD/seizure occurrence increases. Significance ADs and seizures during ECS brain mapping are potentially hazardous and affect its functional validity. Thus, safer method(s) for brain mapping with improved neurophysiologic validity are desirable.

Background Epilepsy has previously been implicated in the development of autism spectrum disorder (ASD) in the setting of tuberous sclerosis complex (TSC). However, the role of language in this relationship is unclear, and the specific relationship between ASD, epilepsy, and language development in this population has not been well-studied. Objectives The objectives the study were to identify the role of early language in subsequent development of ASD, evaluate the impact of epilepsy as a covariate on language development, and evaluate the relationship between epilepsy, language development, and development of ASD. Methods This study included 154 children ages 3–36 months with TSC who were enrolled in the TSC Autism Center of Excellence Research Network (TACERN), a multicenter, prospective observational study to identify biomarkers of ASD. Developmental and autism-specific assessments were administered longitudinally. Appropriate variables from the Mullen Scales of Early Learning (MSEL), Vineland Adaptive Behavior Scales, 2nd Edition (VABS-II), and Preschool Language Scales, 5th Edition (PLS-5) were used to assess patients' language skills. At 36 months, clinical best estimate, which was based on clinical assessment and observation, was used to determine a diagnosis of ASD. Results By 12 months, all language variables on the MSEL, PLS-5, and VABS-II significantly predicted an ASD diagnosis at 36 months. Age at seizure onset was associated with language scores in that later seizure onset was associated with improved language scores on the MSEL, VABS-II, and PLS-5. Seizure onset prior to 6 months was associated with a diagnosis of ASD at 36 months. Higher seizure frequency negatively correlated with language scores at 12 months and beyond. Higher seizure frequency was also associated with an ASD diagnosis at 36 months. When looking at the relationship between epilepsy, language, and ASD diagnosis, by 18 months, language scores were more associated with a later ASD diagnosis at 36 months compared with age at seizure onset, which was a better predictor of later ASD diagnosis earlier in development. Conclusion Analysis of language variables and epilepsy characteristics from 6 to 36 months and ASD diagnosis at 36 months revealed significant relationships between all three variables. While the direction of these relationships needs further research, epilepsy, language, and the development of ASD are integrally related in young children with TSC.

Objective We studied spatiotemporal dynamics of electrocorticographic (ECoG) high-gamma modulation (HGM) during visual naming. Methods In 8 patients, aged 4–19 years, with left hemisphere subdural electrodes, propagation of ECoG HGM during overt visual naming was mapped with trial-averaged time-frequency analysis. Group-level synthesis was performed by transforming all electrodes to a standard space and assigning cortical parcels based on a reference atlas. Results After image display following cortical parcels were activated: inferior occipital, caudal angular, fusiform, and middle temporal gyri, and superior temporal sulcus [0–400 ms]; rostral pars triangularis (A45r), inferior frontal sulcus, caudal dorsolateral premotor cortex (A6cdl) [300–600 ms]; caudal ventrolateral premotor cortex (A6cvl), caudal pars triangularis (A45c), pars opercularis (A44) [400–800 ms]; primary sensorimotor cortex [600–1400 ms], with most prominent HGM in glossolaryngeal region (A4tl). Lastly, auditory cortex (A41/A42) and superior temporal gyrus (A22) were activated [900 ms–1.4 s]. After 1.5 s, HGM decreased globally, except in ventrolateral premotor cortex. Conclusions During visual naming, ECoG HGM shows a sequential but overlapping spatiotemporal course through cortical regions. We provide neurophysiologic validation for a model of visual naming incorporating both modular and distributed cortical processing. This may explain cognitive deficits seen in some patients after surgery involving HGM naming sites outside perisylvian language cortex.

Despite a positive prognosis for seizure remission, children with benign epilepsy with centrotemporal spikes (BECTS) have been reported to exhibit subtle neuropsychological difficulties. We examined the relationship between patterns of centrotemporal spikes (the typical electroencephalography [EEG] finding in BECTS) and neuropsychological and motor outcomes in children with new-onset BECTS. Thirty-four patients with new-onset BECTS (not taking antiepileptic medication) and 48 typically developing children participated in the study. In BECTS patients, centrotemporal spikes (CTS) were evaluated in the first hour awake and first 2 h of sleep in a 24-h EEG recording and left or right-sided origin was noted. General intellectual function, language, visuospatial skill, processing speed, and fine motor skill were assessed in all participants. We found no significant difference between BECTS patients and controls on measures of general intellectual function, or visuospatial or language testing. There were significant differences in processing speed index and nondominant hand fine motor scores between groups. Significant negative relationships were observed between rates of left-sided CTS and right hand fine motor scores. This suggests that psychomotor and fine motor speed are affected in BECTS, but the extent of affected domains may be more limited than previously suggested, especially in untreated patients early in the course of their epilepsy.

Objective: Pediatric stroke is a rare disease with potential for lifelong impact on cognition, social function, and financial productivity. Neuropsychological testing is critically important for understanding the impact of acquired brain injury on the component elements of cognition. Unfortunately patients cannot always access comprehensive testing resources due to a variety of barriers including limited behavioral health provider availability, cost, and insurance coverage. Physicians must be familiar with common neurocognitive difficulties after pediatric stroke to aide timely resource referral. In our study we review the neuropsychological profile of pediatric arterial ischemic stroke (AIS) patients. Methods: This is a single center retrospective case series of AIS patients evaluated from 2015-June 2018 by our multidisciplinary cerebrovascular center. Patients were referred for neuropsychology evaluation routinely after identification of stroke. The test battery was determined at the discretion of the evaluating psychologist and administered per standard protocol. Aggregate results are presented with mean ± standard deviation. Medical records have been abstracted and correlated to lesion laterality, time elapsed since injury, and neurologic comorbidities including ADHD and epilepsy. Results: The CV center cares for 120 children with AIS. 38 children have undergone neuropsychological testing in the study interval (23 females, 15 males). Median age at evaluation is 12 years. The mean full scale IQ for this cohort is 81±18 scoring in the low average range compared to the healthy population. The cohort showed lowest performance in visual spatial index (83±15) and working memory (84±16). Verbal comprehension (89±18), fluid reasoning (87±13), and processing speed indices (85±16) showed minimally higher scores. Conclusion Children with stroke are at risk for cognitive deficits with visual spatial and working memory difficulties most prominent in our cohort. Appropriate therapeutic and educational resources should be directed to address cognitive deficits when identified. Clinician recognition of support needs in this population will facilitate timely referral for intervention.

Objective Insomnia, especially maintenance insomnia, is widely prevalent in epilepsy. Although melatonin is commonly used, limited data address its efficacy. We performed a randomized, double-blind, placebo-controlled, crossover study to identify the effects of melatonin on sleep and seizure control in children with epilepsy. Methods Eleven prepubertal, developmentally normal children aged 6–11 years with epilepsy were randomized by a software algorithm to receive placebo or a 9-mg sustained release (SR) melatonin formulation for four weeks, followed by a one-week washout and a four-week crossover condition. The pharmacy performed blinding; patients, parents, and study staff other than a statistician were blinded. The primary outcomes were sleep onset latency and wakefulness after sleep onset (WASO) measured on polysomnography. The secondary outcomes included seizure frequency, epileptiform spike density per hour of sleep on electroencephalogram (EEG), and reaction time (RT) measures on psychomotor vigilance task (PVT). Statistical tests appropriate for crossover designs were used for the analysis. Results Data were analyzed from 10 subjects who completed the study. Melatonin decreased sleep latency (mean difference, MD, of 11.4 min and p = 0.02) and WASO (MD of 22 min and p = 0.04) as compared to placebo. No worsening of spike density or seizure frequency was seen. Additionally, slow-wave sleep duration and rapid eye movement (REM) latency were increased with melatonin and REM sleep duration was decreased. These changes were statistically significant. Worsening of headache was noted in one subject with migraine on melatonin. Conclusion SR melatonin resulted in statistically significant decreases in sleep latency and WASO. No clear effects on seizures were observed, but the study was too small to allow any conclusions to be drawn in this regard.

Objectives The aim of this study was to understand the relationship between cortical morphology, centrotemporal spike (CTS), and neuropsychological functioning in children with BECTS compared to their typically developing peers. Materials and methods To examine whole-brain differences in cortical thickness between groups, a general linear model approach was applied to T1-weighted structural magnetic resonance imaging (MRI) in children with BECTS and typically developing children. Further region-of-interest (ROI) analyses were performed to examine the effects of frequency and lateralization of CTS. In addition, the relationship between Processing Speed Index (PSI) and cortical thickness was investigated. Results Twenty-three patients with BECTS and thirty-two controls were included. There was no statistically significant difference in global cortical thickness between groups. With ROI analyses, we found significantly thinner cortex within right pars opercularis when comparing children with right predominant CTS, and with very frequent right CTS (>10/min) to the control group (P = 0.028 and P = 0.026, respectively). A statistically significant interaction of group (controls vs BECTS) and PSI was seen in bilateral frontal and right superior parietal cortices, indicating a positive relationship between cortical thickness and PSI in healthy controls but not BECTS. Conclusion A region of cortex where right CTS may originate was thinner in BECTS compared to children without BECTS. Typically developing children with faster processing speed had thicker cortices in regions supporting visuomotor integration, motor, and executive function, but this relationship was not observed in BECTS. These results suggest that BECTS is associated with atypical cortical morphology that may underlie poorer neuropsychological performance.

Summary Introduction This study describes development of a novel language mapping approach using high-γ modulation in electrocorticograph (ECoG) during spontaneous conversation, and its comparison with electrical cortical stimulation (ECS) in childhood-onset drug-resistant epilepsy. Methods Patients undergoing invasive pre-surgical monitoring and able to converse with the investigator were eligible. ECoG signals and synchronized audio were acquired during quiet baseline and during natural conversation between investigator and the patient. Using Signal Modeling for Real-time Identification and Event Detection (SIGFRIED) procedure, a statistical model for baseline high-γ (70–116 Hz) power, and a single score for each channel representing the probability that the power features in the experimental signal window belonged to the baseline model, were calculated. Electrodes with significant high-γ responses (HGS) were plotted on the 3D cortical model. Sensitivity, specificity, positive and negative predictive values (PPV, NPV), and classification accuracy were calculated compared to ECS. Results Seven patients were included (4 males, mean age 10.28 ± 4.07 years). Significant high-γ responses were observed in classic language areas in the left hemisphere plus in some homologous right hemispheric areas. Compared with clinical standard ECS mapping, the sensitivity and specificity of HGS mapping was 88.89% and 63.64%, respectively, and PPV and NPV were 35.29% and 96.25%, with an overall accuracy of 68.24%. HGS mapping was able to correctly determine all ECS+ sites in 6 of 7 patients and all false—sites (ECS+, HGS− for visual naming, n = 3) were attributable to only 1 patient. Conclusions This study supports the feasibility of language mapping with ECoG HGS during spontaneous conversation, and its accuracy compared to traditional ECS. Given long-standing concerns about ecological validity of ECS mapping of cued language tasks, and difficulties encountered with its use in children, ECoG mapping of spontaneous language may provide a valid alternative for clinical use.

Objective To examine current thresholds and their determinants for language and motor mapping with extra-operative electrical cortical stimulation (ECS). Methods ECS electrocorticograph recordings were reviewed to determine functional thresholds. Predictors of functional thresholds were found with multivariable analyses. Results In 122 patients (age 11.9 ± 5.4 years), average minimum, frontal, and temporal language thresholds were 7.4 (± 3.0), 7.8 (± 3.0), and 7.4 (± 3.1) mA respectively. Average minimum, face, upper and lower extremity motor thresholds were 5.4 (± 2.8), 6.1 (± 2.8), 4.9 (± 2.3), and 5.3 (± 3.3) mA respectively. Functional and after-discharge (AD)/seizure thresholds were significantly related. Minimum, frontal, and temporal language thresholds were higher than AD thresholds at all ages. Minimum motor threshold was higher than minimum AD threshold up to 8.0 years of age, face motor threshold was higher than frontal AD threshold up to 11.8 years age, and lower subsequently. UE motor thresholds remained below frontal AD thresholds throughout the age range. Conclusions Functional thresholds are frequently above AD thresholds in younger children. Significance These findings raise concerns about safety and neurophysiologic validity of ECS mapping. Functional and AD/seizure thresholds relationships suggest individual differences in cortical excitability which cannot be explained by clinical variables.

Tuberous sclerosis complex (TSC) is a genetic disorder with high prevalence of associated autism spectrum disorder (ASD). Our primary objectives were to determine early predictors of autism risk to identify children with TSC in most need of early interventions. The Autism Observation Scale for Infants (AOSI) was evaluated as a measure of ASD-associated behaviors in infants with TSC at age 12 months and its ability to predict ASD at 24 months.Children ages 0 to 36 months with TSC were enrolled in the TSC Autism Center of Excellence Research Network (TACERN), a multicenter, prospective observational study to identify biomarkers of ASD. The AOSI was administered at age 12 months and the Autism Diagnostic Observation Schedule-2 (ADOS-2) and Autism Diagnostic Interview-Revised (ADI-R) at 24 months. Developmental functioning was assessed using the Mullen Scales of Early Learning. Children were classified as ASD or non-ASD according to the ADOS-2.Analysis included 79 children who had been administered the AOSI at 12 months and ADOS-2 and ADI-R at 24 months. The ASD group had a mean AOSI total score at 12 months significantly higher than the non-ASD group (11.8 ± 7.4 vs 6.3 ± 4.7; P 0.001). An AOSI total score cutoff of 13 provided a specificity of 0.89 to detect ASD with the ADOS-2. AOSI total score at 12 months was similarly associated with exceeding cutoff scores on the ADI-R.The AOSI is a useful clinical tool in determining which infants with TSC are at increased risk for developing ASD.

A left-lateralized fronto-temporo-parietal language network has been well-characterized in adults; however, the neural basis of this fundamental network has hardly been explored in the preschool years, despite this being a time for rapid language development and vocabulary growth. We examined the functional imaging correlates associated with vocabulary ability and narrative comprehension in 30 preschool children ages 3 to 5. Bilateral auditory cortex and superior temporal activation as well as left angular and supramarginal gyrus activation were observed during a passive listening-to-stories task. Boys showed greater activation than girls in the right anterior cingulate and right superior frontal gyrus (SFG). Finally, children with higher vocabulary scores showed increased grey matter left-lateralization and greater activation in bilateral thalamus, hippocampus, and left angular gyrus. This study is novel in its approach to relate left-hemisphere language regions and vocabulary scores in preschool-aged children using fMRI.

We prospectively validated stereo-electroencephalography (EEG) electrical stimulation mapping (ESM) of language against a reference standard of meta-analytic functional magnetic resonance imaging (fMRI) framework (Neurosynth).Language ESM was performed using 50 Hz, biphasic, bipolar, stimulation at 1-8 mA, with a picture naming task. Electrode contacts (ECs) were scored as ESM+ if ESM interfered with speech/language function. For each patient, presurgical MRI was transformed to a standard space and coregistered with computed tomographic (CT) scan to obtain EC locations. After whole-brain parcellation, this fused image data were intersected with three-dimensional language fMRI (Neurosynth), and each EC was classified as lying within/outside the fMRI language parcel. Diagnostic odds ratio (DOR) and other indices were estimated. Current thresholds for language inhibition and after-discharges (ADs) were analyzed using multivariable linear mixed models.In 10 patients (5 females), aged 5.4-21.2 years, speech/language inhibition was noted with ESM on 87/304 (29%) ECs. Stereo-EEG language ESM was a valid classifier of fMRI (Neurosynth) language sites (DOR: 9.02, p 0.0001), with high specificity (0.87) but poor sensitivity (0.57). Similar diagnostic indices were seen for ECs in frontal or posterior regions, and gray or white matter. Language threshold (3.1 ± 1.5 mA) was lower than AD threshold (4.0 ± 2.0 mA, p = 0.0001). Language and AD thresholds decreased with age and intelligence quotient. Electrical stimulation mapping triggered seizures/auras represented patients' habitual semiology with 1 Hz stimulation.Stereo-EEG ESM can reliably identify cerebral parcels with/without language function but may under detect all language sites. We suggest a 50-Hz stimulation protocol for language ESM with stereo-EEG.

Background Previous studies have documented differences in neural activation during language processing in individuals with Down syndrome (DS) in comparison with typically developing individuals matched for chronological age. This study used functional magnetic resonance imaging (fMRI) to compare activation during language processing in young adults with DS to typically developing comparison groups matched for chronological age or mental age. We hypothesised that the pattern of neural activation in the DS cohort would differ when compared with both typically developing cohorts. Method Eleven persons with DS (mean chronological age = 18.3; developmental age range = 4–6 years) and two groups of typically developing individuals matched for chronological (n = 13; mean age = 18.3 years) and developmental (mental) age (n = 12; chronological age range = 4–6 years) completed fMRI scanning during a passive story listening paradigm. Random effects group comparisons were conducted on individual maps of the contrast between activation (story listening) and rest (tone presentation) conditions. Results Robust activation was seen in typically developing groups in regions associated with processing auditory information, including bilateral superior and middle temporal lobe gyri. In contrast, the DS cohort demonstrated atypical spatial distribution of activation in midline frontal and posterior cingulate regions when compared with both typically developing control groups. Random effects group analyses documented reduced magnitude of activation in the DS cohort when compared with both control groups. Conclusions Activation in the DS group differed significantly in magnitude and spatial extent when compared with chronological and mental age-matched typically developing control groups during a story listening task. Results provide additional support for an atypical pattern of functional organisation for language processing in this population.

SummaryObjective This prospective study compared presurgical language localization with visual naming–associated high-γ modulation (HGM) and conventional electrical cortical stimulation (ECS) in children with intracranial electrodes. Methods Patients with drug-resistant epilepsy who were undergoing intracranial monitoring were included if able to name pictures. Electrocorticography (ECoG) signals were recorded during picture naming (overt and covert) and quiet baseline. For each electrode the likelihood of high-γ (70–116 Hz) power modulation during naming task relative to the baseline was estimated. Electrodes with significant HGM were plotted on a three-dimensional (3D) cortical surface model. Sensitivity, specificity, and accuracy were calculated compared to clinical ECS. Results Seventeen patients with mean age of 11.3 years (range 4–19) were included. In patients with left hemisphere electrodes (n = 10), HGM during overt naming showed high specificity (0.81, 95% confidence interval [CI] 0.78–0.85), and accuracy (0.71, 95% CI 0.66–0.75, p

Objective Epilepsy is commonly seen in Tuberous Sclerosis Complex (TSC). The relationship between seizures and developmental outcomes has been reported, but few studies have examined this relationship in a prospective, longitudinal manner. The objective of the study was to evaluate the relationship between seizures and early development in TSC. Methods Analysis of 130 patients ages 0–36 months with TSC participating in the TSC Autism Center of Excellence Network, a large multicenter, prospective observational study evaluating biomarkers predictive of autism spectrum disorder (ASD), was performed. Infants were evaluated longitudinally with standardized evaluations, including cognitive, adaptive, and autism-specific measures. Seizure history was collected continuously throughout, including seizure type and frequency. Results Data were analyzed at 6, 12, 18, and 24 months of age. Patients without a history of seizures performed better on all developmental assessments at all time points compared to patients with a history of seizures and exhibited normal development at 24 months. Patients with a history of seizures not only performed worse, but developmental progress lagged behind the group without seizures. All patients with a history of infantile spasms performed worse on all developmental assessments at 12, 18, and 24 months. Higher seizure frequency correlated with poorer outcomes on developmental testing at all time points, but particularly at 12 months and beyond. Patients with higher seizure frequency during infancy continued to perform worse developmentally through 24 months. A logistic model looking at the individual impact of infantile spasms, seizure frequency, and age of seizure onset as predictors of developmental delay revealed that age of seizure onset was the most important factor in determining developmental outcome. Conclusions Results of this study further define the relationship between seizures and developmental outcomes in young children with TSC. Early seizure onset in infants with TSC negatively impacts very early neurodevelopment, which persists through 24 months of age.

Objective: To assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1). Methods: A multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8–15 years were screened for visuospatial learning or attention deficits (n = 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n = 74; 40 mg/d) or placebo (n = 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population. Results: Lovastatin had no significant effect on primary outcomes after 16 weeks of treatment: visuospatial learning (Cohen d = −0.15, 95% confidence interval −0.47 to 0.18) or sustained attention (Cohen d = 0.19, 95% confidence interval −0.14 to 0.53). Lovastatin was well tolerated, with no increase in reported adverse events compared to placebo. Conclusions: Lovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population. ClinicalTrials.gov identifier: This study was registered at ClinicalTrials.gov (NCT00853580) and Australian New Zealand Clinical Trials Registry (ACTRN12607000560493). Classification of evidence: This study provides Class I evidence that for children with NF1, lovastatin does not improve visuospatial learning or attention deficits.

In the study we describe adaptive functioning in children with epilepsy whose primary caregivers identified them as having learning problems. This was a cross-sectional study of 50 children with epilepsy and learning problems. Caregivers supplied information regarding the child’s adaptive functioning and behavior problems. Children rated their self-concept and completed a battery of neuropsychological tests. Mean estimated IQ (PPVT-III) in the participant children was 72.8 (SD = 18.3). On average, children scored 2 standard deviations below the norm on the Vineland Adaptive Behavior Scale–II and this was true even for children with epilepsy who had estimated IQ in the normal range. In conclusion, children with epilepsy and learning problems had relatively low adaptive functioning scores and substantial neuropsychological and mental health problems. In epilepsy, adaptive behavior screening can be very informative and guide further evaluation and intervention, even in those children whose IQ is in the normal range.

In children with benign childhood epilepsy with centrotemporal spikes, centrotemporal spikes may cause language dysfunction via disruption of underlying functional neuroanatomy. Fifteen patients with benign childhood epilepsy with centrotemporal spikes and 15 healthy controls completed 3 functional magnetic resonance imaging (MRI) language paradigms; standardized cognitive and language assessments were also performed. For all paradigms, children with benign childhood epilepsy with centrotemporal spikes showed specific regional differences in activation compared to controls. Children with benign childhood epilepsy with centrotemporal spikes also differed from controls on neuropsychological testing. They did not differ in general intelligence, but children with benign childhood epilepsy with centrotemporal spikes scored significantly lower than controls on tests of language, visuomotor integration, and processing speed. These results extend previous findings of lower language and cognitive skills in patients with benign childhood epilepsy with centrotemporal spikes, and suggest epilepsy-related remodeling of language networks that may underlie these observed differences.

This fMRI study investigated the development of language lateralization in left- and righthanded children between 5 and 18 years of age. Twenty-seven left-handed children (17 boys, 10 girls) and 54 age- and gender-matched right-handed children were included. We used functional MRI at 3T and a verb generation task to measure hemispheric language dominance based on either frontal or temporo-parietal regions of interest (ROIs) defined for the entire group and applied on an individual basis. Based on the frontal ROI, in the left-handed group, 23 participants (85%) demonstrated left-hemispheric language lateralization, 3 (11%) demonstrated symmetric activation, and 1 (4%) demonstrated right-hemispheric lateralization. In contrast, 50 (93%) of the right-handed children showed left-hemispheric lateralization and 3 (6%) demonstrated a symmetric activation pattern, while one (2%) demonstrated a right-hemispheric lateralization. The corresponding values for the temporo-parietal ROI for the left-handed children were 18 (67%) left-dominant, 6 (22%) symmetric, 3 (11%) right-dominant and for the right-handed children 49 (91%), 4 (7%), 1 (2%), respectively. Left-hemispheric language lateralization increased with age in both groups but somewhat different lateralization trajectories were observed in girls when compared to boys. The incidence of atypical language lateralization in left-handed children in this study was similar to that reported in adults. We also found similar rates of increase in left-hemispheric language lateralization with age between groups (i.e., independent of handedness) indicating the presence of similar mechanisms for language lateralization in left- and right-handed children.

BackgroundFunctional hemispherectomy is effective in carefully selected patients, resulting in a reduction of seizure burden up to complete resolution, improvement of intellectual development, and developmental benefit despite possible additional neurological deficit. Despite apparent hemispheric pathology on brain magnetic resonance imaging (MRI) or other imaging tests, scalp electroencephalography (EEG) could be suggestive of bilateral ictal onset or even ictal onset contralateral to the dominant imaging abnormality. We aimed to investigate the role of scalp EEG lateralization pre-operatively in predicting outcome.MethodsWe retrospectively reviewed 54 patients who underwent hemispherectomy between 1991 and 2009 at Medical College of Georgia (1991–2006) and Cincinnati Children's Hospital Medical Center (2006–2009) and had at least one year post-operative follow-up. All preoperative EEGs were reviewed, and classified as either lateralizing or nonlateralizing, for both ictal and interictal EEG recordings.ResultsOf 54 patients, 42 (78%) became seizure free. Twenty-four (44%) of 54 had a nonlateralizing ictal or interictal EEG. Further analysis was based on etiology of epilepsy, including malformation of cortical development (MCD), Rasmussen syndrome (RS), and stroke (CVA). EEG nonlateralization did not predict poor outcome in any of the etiology groups evaluated.ConclusionScalp EEG abnormalities in contralateral or bilateral hemispheres do not, in isolation, predict a poor outcome from hemispherectomy. Results of other non-invasive and invasive evaluations should be used to determine candidacy.

The authors used functional magnetic resonance imaging (fMRI) to investigate neural activation during a semantic-classification/object-recognition task in 13 persons with Down syndrome and 12 typically developing control participants (age range = 12–26 years). A comparison between groups suggested atypical patterns of brain activation for the individuals with Down syndrome. Correlation analyses between an index of visual spatial ability and brain activation depicted a positive relationship between (a) this index and brain activation in regions of the occipital and parietal lobes for the typically developing individuals and (b) the middle and dorsal frontal gyri in the individuals with Down syndrome. These findings supported the authors' hypothesis that persons with Down syndrome demonstrate atypical neural activation compared with typically developing individuals matched for chronological age.

Objectives The purposes of this 36-month study of children with first recognized seizures were: (1) to describe baseline differences in behavior problems between children with and without prior unrecognized seizures; (2) to identify differences over time in behavior problems between children with seizures and their healthy siblings; (3) to identify the proportions of children with seizures and healthy siblings who were consistently at risk for behavior problems for 36 months; and (4) to identify risk factors for behavior problems 36 months following the first recognized seizure. Risk factors explored included demographic (child age and gender, caregiver education), neuropsychological (IQ, processing speed), seizure (epileptic syndrome, use of antiepileptic drug, seizure recurrence), and family (family mastery, satisfaction with family relationships, parent response) variables. Methods Participants were 300 children aged 6 through 14 years with a first recognized seizure and 196 healthy siblings. Data were collected from medical records, structured interviews, self-report questionnaires, and neuropsychological testing. Behavior problems were measured using the Child Behavior Checklist and the Teacher's Report Form. Data analyses included descriptive statistics and linear mixed models. Results Children with prior unrecognized seizures were at higher risk for behavior problems at baseline. As a group, children with seizures showed a steady reduction in behavior problems over time. Children with seizures were found to have significantly more behavior problems than their siblings over time, and significantly more children with seizures (11.3%) than siblings (4.6%) had consistent behavior problems over time. Key risk factors for child behavior problems based on both caregivers and teachers were: less caregiver education, slower initial processing speed, slowing of processing speed over the first 36 months, and a number of family variables including lower levels of family mastery or child satisfaction with family relationships, lower parent support of the child's autonomy, and lower parent confidence in their ability to discipline their child. Conclusions Children with new-onset seizures who are otherwise developing normally have higher rates of behavior problems than their healthy siblings; however, behavior problems are not consistently in the at-risk range in most children during the first 3 years after seizure onset. When children show behavior problems, family variables that might be targeted include family mastery, parent support of child autonomy, and parents’ confidence in their ability to handle their children's behavior.

To evaluate the diagnostic value of individual noninvasive presurgical modalities and to study their role in surgical management of nonlesional pediatric epilepsy patients.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.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) (p0.05). 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).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.

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.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.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 (P0.001 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.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.).

Objectives Children with long-standing epilepsy have a significantly increased risk of academic underachievement compared with healthy controls. We prospectively followed children from seizure onset to assess the relationship between change in neuropsychological functioning and change in academic achievement and to explore the risk and protective moderating effects of demographic, seizure, and family variables. Methods As part of a larger study, neuropsychological and academic data were collected at both baseline and 36 months for 219 children 6–14 years of age with seizures. Prior factor analysis of results from a battery of well-standardized neuropsychological tests yielded four factors: language, processing speed, attention/executive/construction, and verbal memory/learning. Academic achievement was measured with the Woodcock–Johnson Revised Achievement Test Battery. Correlation coefficients and linear mixed models were used for analysis. Results The reading and math scores of children with seizures and siblings did not differ at baseline, but children with seizures had lower scores than siblings at 36 months. Writing scores were significantly lower for affected children than siblings at both times. Among children with seizures, there were positive correlations between neuropsychological functioning and academic achievement at baseline and 36 months. Changes in language and in verbal memory/learning were positively correlated with change in reading achievement ( r = 0.25 and r = 0.17, respectively). Age at onset moderated the association between change in neuropsychological functioning and change in reading and writing achievement ( P ≤ 0.006), with stronger relationships among younger children (β = 0.25–0.44). The association between change in language and change in writing achievement was moderated by caregiver anxiety ( P = 0.04; stronger for more anxious parents, β = 0.40), and the association between change in processing speed and change in math achievement was moderated by etiology ( P = 0.02; stronger for symptomatic/cryptogenic vs idiopathic, β = 0.29). Gender and other family variables did not have significant moderating effects. Conclusions Changes in neuropsychological function were associated with changes in academic achievement following onset of seizures, with risk factors being younger age at onset, lower caregiver education, high parental anxiety, and symptomatic/cryptogenic etiology. Academic performance should be closely monitored in children with early-onset seizures.

Summary Purpose: To test over time the relationships of neuropsychological functioning to mental health in children following a first recognized seizure and, of primary importance, to determine if the strength of these relationships differs based on risk and protective factors. Methods: In a larger prospective study, 135 children with a first seizure (ages 8–14 years) and 73 healthy sibling controls completed neuropsychological testing at baseline and 36 months. Structured telephone interviews were used to obtain data from children on mental health and family environment; major caregiving parents provided data on demographic and family variables. Data analyses included correlation coefficients and linear regression models. Results: Children with seizures showed an overall trend for improvement in mental health. More children with seizures than siblings had declines in processing speed. Declines in neuropsychological functioning were correlated with worse mental health. With regard to risk and protective factors, higher parent education protected against decline in self-esteem related to decline in processing speed. Better family functioning and greater parental support protected against decline in self-esteem related to decrease in verbal memory and learning. Older child age protected against increase in depressive symptoms related to decline in processing speed. Discussion: Seizure onset had a negative impact on mental health in children with declines in cognitive functioning except for older children and those with more family resources. Children should be assessed for declines in processing speed and, if found, those subgroups of children with less educated or more anxious parents and those in less supportive families should be targeted for interventions.

Purpose: Head motion during functional MRI scanning can lead to signal artifact, a problem often more severe with children. However, the documentation for the characteristics of head motion in children during various language functional tasks is very limited in the current literature. This report characterizes head motion in children during fMRI as a function of age, sex, and task. Methods: Head motion during four different fMRI language tasks was investigated in a group of 323 healthy children between the age of 5 and 18 years. A repeated measures ANOVA analysis was used to study the impact of age, sex, task, and the interaction of these factors on the motion. Results: Pediatric subjects demonstrated significantly different amounts of head motion during fMRI when different language tasks were used. Word-Picture Matching, the only task that involved visual engagement, suffered the least amount of motion, which was significantly less than in any of the other three tasks; the latter were not significantly different from each other. Further examination revealed that the main effect of language task on motion was significantly affected by age, sex, and their interaction. Conclusion: Our results suggest that age, sex, and task are all associated with the degree of head motion in children during fMRI experiments. Investigators working with pediatric patients may increase their success by using task components associated with less motion (e.g., visual stimuli), or by using this large scale dataset to estimate the effects of sex and age on motion for planning purposes. Hum Brain Mapp 2009. © 2008 Wiley-Liss, Inc.

Objective Functional MRI was used to determine differences in patterns of cortical activation between children who suffered perinatal left middle cerebral artery (MCA) stroke and healthy children performing a silent verb generation task. Methods Ten children with prior perinatal left MCA stroke (age 6–16 years) and ten healthy age matched controls completed an executive language activation task. fMRI scans were acquired on a 3 T scanner using T2 ∗ weighted gradient echo, echo-planar imaging (EPI) sequence. Random effects analysis and independent component analysis (ICA) were used to compute activation maps. Results Both analysis methods demonstrated alternative activation of cortical areas in children with perinatal stroke. Following perinatal stroke, typical left dominant productive language areas in the inferior frontal gyrus were displaced to anatomical identical areas in the right hemisphere ( p = .001). In addition, stroke patients showed more bilateral activation in superior temporal and anterior cingulate gyri and increased activation in primary visual cortex when compared to healthy controls. There was no relation between lesion size and the degree of right hemisphere activation. ICA showed that the healthy controls had a negative correlation with the time course in the right inferior frontal gyrus in the same region that was activated in stroke subjects. Interpretation This functional MRI study in children revealed novel patterns of cortical language reorganization following perinatal stroke. The addition of ICA is complementary to Random Effects Analysis, allowing for the exploration of potential subtle differences in pathways in functional MRI data obtained from both healthy and pathological groups.

Functional MRI was used to determine differences in patterns of cortical activation between children who suffered perinatal left middle cerebral artery (MCA) stroke and healthy children performing a silent verb generation task.Ten children with prior perinatal left MCA stroke (age 6-16 years) and ten healthy age matched controls completed an executive language activation task. fMRI scans were acquired on a 3T scanner using T2* weighted gradient echo, echo-planar imaging (EPI) sequence. Random effects analysis and independent component analysis (ICA) were used to compute activation maps.Both analysis methods demonstrated alternative activation of cortical areas in children with perinatal stroke. Following perinatal stroke, typical left dominant productive language areas in the inferior frontal gyrus were displaced to anatomical identical areas in the right hemisphere (p=.001). In addition, stroke patients showed more bilateral activation in superior temporal and anterior cingulate gyri and increased activation in primary visual cortex when compared to healthy controls. There was no relation between lesion size and the degree of right hemisphere activation. ICA showed that the healthy controls had a negative correlation with the time course in the right inferior frontal gyrus in the same region that was activated in stroke subjects.This functional MRI study in children revealed novel patterns of cortical language reorganization following perinatal stroke. The addition of ICA is complementary to Random Effects Analysis, allowing for the exploration of potential subtle differences in pathways in functional MRI data obtained from both healthy and pathological groups.