Surgical outcomes in children with drug-resistant epilepsy and hippocampal sclerosis.

BACKGROUND: Hippocampal sclerosis (HS) is a common surgical substrate in adult epilepsy surgery cohorts but variably reported in various pediatric cohorts. OBJECTIVE: We aimed to study the epilepsy phenotype, radiological and pathological variability, seizure and neurocognitive outcomes in children with drug-resistant epilepsy and hippocampal sclerosis (HS) with or without additional subtle signal changes in anterior temporal lobe who underwent surgery. METHODS: This retrospective study enrolled children with drug-resistant focal epilepsy and hippocampal sclerosis with or without additional subtle T2-Fluid Attenuated Inversion Recovery (FLAR)/Proton Density (PD) signal changes in anterior temporal lobe who underwent anterior temporal lobectomy with amygdalohippocampectomy. Their clinical, EEG, neuropsychological, radiological and pathological data were reviewed and summarized. RESULTS: Thirty-six eligible patients were identified. The mean age at seizure onset was 3.7 years; 25% had daily seizures at time of surgery. Isolated HS was noted in 22 (61.1%) cases and additional subtle signal changes in ipsilateral temporal lobe in 14 (38.9%) cases. Compared to the normative population, the group mean performance in intellectual functioning and most auditory and visual memory tasks were significantly lower than the normative sample. The mean age at surgery was 12.3 years; 22 patients (61.1%) had left hemispheric surgeries. ILAE class 1 outcomes was seen in 28 (77.8%) patients after a mean follow up duration of 2.3 years. Hippocampal sclerosis was noted pathologically in 32 (88.9%) cases; type 2 (54.5%) was predominant subtype where further classification was possible. Additional pathological abnormalities were seen in 11 cases (30.6%); these had had similar rates of seizure freedom as compared to children with isolated hippocampal sclerosis/gliosis (63.6% vs 84%, p=0.21). Significant reliable changes were observed across auditory and visual memory tasks at an individual level post surgery. CONCLUSIONS: Favourable seizure outcomes were seen in most children with isolated radiological hippocampal sclerosis. Patients with additional pathological abnormalities had similar rates of seizure freedom as compared to children with isolated hippocampal sclerosis/gliosis.

Intraoperative changes in large-scale thalamic circuitry following laser ablation of hypothalamic hamartomas.

BACKGROUND AND OBJECTIVES: Gelastic seizures due to hypothalamic hamartomas (HH) are challenging to treat, in part due to an incomplete understanding of seizure propagation pathways. Although magnetic resonance imaging-guided laser interstitial thermal therapy (MRgLITT) is a promising intervention to disconnect HH from ictal propagation networks, the optimal site of ablation to achieve seizure freedom is not known. In this study, we investigated intraoperative post-ablation changes in resting-state functional connectivity to identify large-scale networks associated with successful disconnection of HH. METHODS: Children who underwent MRgLITT for HH at two institutions were consecutively recruited and followed for a minimum of one year. Seizure freedom was defined as Engel score of 1A at the last available follow-up. Immediate pre- and post- ablation resting-state functional MRI scans were acquired while maintaining a constant depth of general anesthetic. Multivariable generalized linear models were used to identify intraoperative changes in large-scale connectivity associated with seizure outcomes. RESULTS: Twelve patients underwent MRgLITT for HH, five of whom were seizure-free at their last follow-up. Intraprocedural changes in thalamocortical circuitry involving the anterior cingulate cortex were associated with seizure-freedom. Children who were seizure-free demonstrated an increase and decrease in connectivity to the pregenual and dorsal anterior cingulate cortices, respectively. In addition, children who became seizure-free demonstrated increased thalamic connectivity to the periaqueductal gray immediately following MRgLITT. DISCUSSION: Successful disconnection of HH is associated with intraoperative, large-scale changes in thalamocortical connectivity. These changes provide novel insights into the large-scale basis of gelastic seizures and may represent intraoperative biomarkers of treatment success.

Longitudinal point-of-care assessment of psychomotor vigilance in children in the epilepsy monitoring unit.

The epilepsy monitoring unit (EMU) is a complex and dynamic operational environment, where the cognitive and behavioural consequences of medical and environmental changes often go unnoticed. The psychomotor vigilance task (PVT) has been used to detect changes in cognition and behaviour in numerous contexts, including among astronauts on spaceflight missions, pilots, and commercial drivers. Here, we piloted serial point-of-care administration of the PVT in children undergoing invasive monitoring in the EMU. Seven children completed the PVT throughout their hospital admission and their performance was associated with daily seizure counts, interictal epileptiform discharges, number of antiseizure medications (ASMs) administered, and sleep quality metrics. Using mixed-effects models, we found that PVT reaction time and accuracy were adversely affected by greater number of ASMs and interictal epileptiform activity. We show that serial point-of-care PVT is simple and feasible in the EMU and may enable greater understanding of individual patient responses to medical and environmental alterations, inform clinical decision-making, and support quality-improvement and research initiatives.

Identification of brain cell types underlying genetic association with word reading and correlated traits.

Neuroimaging studies implicate multiple cortical regions in reading ability/disability. However, the neural cell types integral to the reading process are unknown. To contribute to this gap in knowledge, we integrated genetic results from genome-wide association studies for word reading (n = 5054) with gene expression datasets from adult/fetal human brain. Linkage disequilibrium score regression (LDSC) suggested that variants associated with word reading were enriched in genes expressed in adult excitatory neurons, specifically layer 5 and 6 FEZF2 expressing neurons and intratelencephalic (IT) neurons, which express the marker genes LINC00507, THEMIS, or RORB. Inhibitory neurons (VIP, SST, and PVALB) were also found. This finding was interesting as neurometabolite studies previously implicated excitatory-inhibitory imbalances in the etiology of reading disabilities (RD). We also tested traits that shared genetic etiology with word reading (previously determined by polygenic risk scores): attention-deficit/hyperactivity disorder (ADHD), educational attainment, and cognitive ability. For ADHD, we identified enrichment in L4 IT adult excitatory neurons. For educational attainment and cognitive ability, we confirmed previous studies identifying multiple subclasses of adult cortical excitatory and inhibitory neurons, as well as astrocytes and oligodendrocytes. For educational attainment and cognitive ability, we also identified enrichment in multiple fetal cortical excitatory and inhibitory neurons, intermediate progenitor cells, and radial glial cells. In summary, this study supports a role of excitatory and inhibitory neurons in reading and excitatory neurons in ADHD and contributes new information on fetal cell types enriched in educational attainment and cognitive ability, thereby improving our understanding of the neurobiological basis of reading/correlated traits.

Language and reading impairments are associated with increased prevalence of non-right-handedness.

Handedness has been studied for association with language-related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small samples, publication bias, and heterogeneous criteria across studies. Non-right-handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or language impairment and N = 4316 sex-matched controls identified from 10 distinct cohorts (age range 6-19 years old; European ethnicity) using a priori set criteria. A meta-analysis (Ncases  = 1994) showed elevated NRH % in individuals with language/reading impairment compared with controls (OR = 1.21, CI = 1.06-1.39, p = .01). The association between reading/language impairments and NRH could result from shared pathways underlying brain lateralization, handedness, and cognitive functions.

Which is more deleterious to cognitive performance? Interictal epileptiform discharges vs anti-seizure medication.

Children with epilepsy commonly have comorbid neurocognitive impairments that severely affect their psychosocial well-being, education, and future career prospects. Although the provenance of these deficits is multifactorial, the effects of interictal epileptiform discharges (IEDs) and anti-seizure medications (ASMs) are thought to be particularly severe. Although certain ASMs can be leveraged to inhibit IED occurrence, it remains unclear whether epileptiform discharges or the medications themselves are most deleterious to cognition. To examine this question, 25 children undergoing invasive monitoring for refractory focal epilepsy performed one or more sessions of a cognitive flexibility task. Electrophysiological data were recorded to detect IEDs. Between repeated sessions, prescribed ASMs were either continued or titrated to <50% of the baseline dose. Hierarchical mixed-effects modeling assessed the relationship between task reaction time (RT), IED occurrence, ASM type, and dose while controlling for seizure frequency. Both presence (ß ± SE = 49.91 ± 16.55 ms, p = .003) and number of IEDs (ß ± SE = 49.84 ± 12.51 ms, p < .001) were associated with slowed task RT. Higher dose oxcarbazepine significantly reduced IED frequency (p = .009) and improved task performance (ß ± SE = -107.43 ± 39.54 ms, p = .007). These results emphasize the neurocognitive consequences of IEDs independent of seizure effects. Furthermore, we demonstrate that inhibition of IEDs following treatment with select ASMs is associated with improved neurocognitive function.

Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities.

Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)-GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10-2, threshold = 2.5 × 10-2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10-2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10-4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people.

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.

Connectomic Profiles and Cognitive Trajectories After Epilepsy Surgery in Children.

BACKGROUND AND OBJECTIVES: Neurocognitive outcomes after surgery for temporal lobe epilepsy in childhood are variable. Postoperative changes are not directly predicted by seizure freedom, and associations between epilepsy, neuropsychological function, and developing neural networks are poorly understood. Here, we leveraged whole-brain connectomic profiling in magnetoencephalography (MEG) to retrospectively study associations between brain connectivity and neuropsychological function in children with temporal lobe epilepsy undergoing resective surgery. METHODS: Clinical and MEG data were retrospectively analyzed for children who underwent temporal lobe epilepsy surgery at the Hospital for Sick Children from 2000 to 2021. Resting-state connectomes were constructed from neuromagnetic oscillations via the weighted-phase lag index. Using a partial least-squares (PLS) approach, we assessed multidimensional associations between patient connectomes, neuropsychological scores, and clinical covariates. Bootstrap resampling statistics were performed to assess statistical significance. RESULTS: A total of 133 medical records were reviewed, and 5 PLS analyses were performed. Each PLS analysis probed a particular neuropsychological domain and the associations between its baseline and postoperative scores and the connectomic data. In each PLS analysis, a significant latent variable was identified, representing a specific percentage of the variance in the data and relating neural networks to clinical covariates, which included changes in rote verbal memory (n = 41, p = 0.01, σ2 = 0.38), narrative/verbal memory (n = 57, p = 0.00, σ2 = 0.52), visual memory (n = 51, p = 0.00, σ2 = 0.43), working memory (n = 44, p = 0.00, σ2 = 0.52), and overall intellectual function (n = 59, p = 0.00, σ2 = 0.55). Children with more diffuse, bilateral intrinsic connectivity across several frequency bands showed lower scores on all neuropsychological assessments but demonstrated a greater propensity for gains after resective surgery. DISCUSSION: Here, we report that connectomes characterized by diffuse connectivity, reminiscent of developmentally immature networks, are associated with lower preoperative cognition and postoperative cognitive improvement. These findings provide a potential means to understand neurocognitive function in children with temporal lobe epilepsy and expected changes postoperatively.

Language Difficulties in School-Age Children With Developmental Dyslexia.

Developmental dyslexia (DD) is a common reading disability, affecting 5% to 11% of children in North America. Children classified as having DD often have a history of early language delay (ELD) or language impairments. Nevertheless, studies have reported conflicting results as to the association between DD-ELD and the extent of current language difficulties in children with DD. To examine these relationships, we queried the parents of school-age children with reading difficulties on their child's early and current language ability. Siblings were also examined. Children were directly assessed using quantitative tests of language and reading skills. To compare this study with the literature, we divided the sample (N = 674) into three groups: DD, intermediate readers (IR), and skilled readers (SR). We found a significant association between DD and ELD, with parents of children in the DD/IR groups reporting their children put words together later than the SR group. We also found a significant association between DD and language difficulties, with children with low reading skills having low expressive/receptive language abilities. Finally, we identified early language predicted current language, which predicted reading skills. These data contribute to research indicating that children with DD experience language difficulties, suggesting early recognition may help identify reading problems.

Spectral changes following resective epilepsy surgery and neurocognitive function in children with epilepsy.

Decelerated resting cortical oscillations, high-frequency activity, and enhanced cross-frequency interactions are features of focal epilepsy. The association between electrophysiological signal properties and neurocognitive function, particularly following resective surgery, is, however, unclear. In the current report, we studied intraoperative recordings from intracranial electrodes implanted in seven children with focal epilepsy and analyzed the spectral dynamics both before and after surgical resection of the hypothesized seizure focus. The associations between electrophysiological spectral signatures and each child's neurocognitive profiles were characterized using a partial least squares analysis. We find that extent of spectral alteration at the periphery of surgical resection, as indexed by slowed resting frequency and its acceleration following surgery, is associated with baseline cognitive deficits in children. The current report provides evidence supporting the relationship between altered spectral properties in focal epilepsy and neuropsychological deficits in children. In particular, these findings suggest a critical role of disrupted thalamocortical rhythms, which are believed to underlie the spectral alterations we describe, in both epileptogenicity and neurocognitive function.NEW & NOTEWORTHY Spectral alterations marked by decelerated resting oscillations and ectopic high-frequency activity have been noted in focal epilepsy. We leveraged intraoperative recordings from chronically implanted electrodes pre- and postresection to understand the association between these electrophysiological phenomena and neuropsychological function. We find that the extent of spectral alteration, indexed by slowed resting frequency and its acceleration following resection, is associated with baseline cognitive deficits. These findings provide novel insights into neurocognitive impairments in focal epilepsy.

Brief video enhances teacher trainees' knowledge of epilepsy.

OBJECTIVE: Relative to the general population, children with epilepsy (CWE) demonstrate difficulties in aspects of cognition and mental health. Previous studies have found that teachers have poor knowledge about epilepsy, which may lead to inadequate management of CWE's comorbidities and seizures, potentially impacting CWE's school performance, social development, and safety. The current study aimed to evaluate whether a brief training program improves teachers' epilepsy knowledge. METHOD: Participants included pre-service teachers enrolled in the Faculty of Education at Western University (London, Ontario, Canada). There were no exclusion criteria. Pre-service teachers completed a questionnaire evaluating their experiences and knowledge of epilepsy prior to, and two weeks following, the training program. The training program consisted of a 10.5-min video and booklet that described the characteristics of seizures, seizure first aid, and the cognitive, psychological, and social consequences of epilepsy. RESULTS: Pre-service teachers' knowledge about epilepsy, seizure safety, and common comorbidities associated with epilepsy significantly improved after participating in the training program. Furthermore, pre-service teachers indicated greater self-reported knowledge about epilepsy and greater preparedness to handle a seizure in the classroom. CONCLUSION: The results of the current study demonstrated that a brief, cost-effective training program significantly enhances teachers' knowledge about epilepsy, seizure safety, and the comorbidities associated with epilepsy. Enhancing teachers' knowledge about epilepsy has the potential to improve children's academic and social success in school.

Memory outcomes following hemispherectomy in children.

OBJECTIVE: A vast proportion of children with epilepsy exhibit memory impairments. Although numerous studies have examined memory performance following pediatric resective epilepsy surgery, little is known about the memory outcomes following hemispherectomy. The few studies that report on memory performance typically include restricted measures, consist of case reports, or do not report on preoperative performance. Given the current limitations, the aim of this study was to delineate pre- and postoperative memory functioning in youth who underwent a hemispherectomy. METHOD: Participants included patients who had undergone a hemispherectomy at the Hospital for Sick Children, between 1999 and 2016. Standardized neuropsychological assessments of verbal (digit span, word list recall, word pair recall, stories) and visual (faces, dot locations) memory abilities prior to and after surgery were reviewed. A Wilcoxon signed rank test and effect sizes was completed to compare patients' memory performance to population norms and to assess pre- to postoperative difference scores. RESULTS: Thirteen participants were included in the study: five patients completed preoperative assessments only and eight patients completed pre- and postoperative assessments. Preoperatively, patients performed substantially worse relative to population norms as indicated by large effect sizes (r: 0.5-0.9). Postoperatively, effect sizes were large for the majority of the memory tests, demonstrating considerable differences in patients' memory scores over time. When clinically meaningful changes were examined, stable performance was evident on 63% of the memory tasks. CONCLUSION: Overall, the results highlight that youth who are eligible for hemispherectomy demonstrate profound memory deficits prior to surgery. In addition, undergoing hemispherectomy was not necessarily associated with declined memory performance, with the majority of patients showing stable scores.

Genome-wide association study of word reading: Overlap with risk genes for neurodevelopmental disorders.

Reading disabilities (RD) are the most common neurocognitive disorder, affecting 5% to 17% of children in North America. These children often have comorbid neurodevelopmental/psychiatric disorders, such as attention deficit/hyperactivity disorder (ADHD). The genetics of RD and their overlap with other disorders is incompletely understood. To contribute to this, we performed a genome-wide association study (GWAS) for word reading. Then, using summary statistics from neurodevelopmental/psychiatric disorders, we computed polygenic risk scores (PRS) and used them to predict reading ability in our samples. This enabled us to test the shared aetiology between RD and other disorders. The GWAS consisted of 5.3 million single nucleotide polymorphisms (SNPs) and two samples; a family-based sample recruited for reading difficulties in Toronto (n = 624) and a population-based sample recruited in Philadelphia [Philadelphia Neurodevelopmental Cohort (PNC)] (n = 4430). The Toronto sample SNP-based analysis identified suggestive SNPs (P ~ 5 × 10-7 ) in the ARHGAP23 gene, which is implicated in neuronal migration/axon pathfinding. The PNC gene-based analysis identified significant associations (P < 2.72 × 10-6 ) for LINC00935 and CCNT1, located in the region of the KANSL2/CCNT1/LINC00935/SNORA2B/SNORA34/MIR4701/ADCY6 genes on chromosome 12q, with near significant SNP-based analysis. PRS identified significant overlap between word reading and intelligence (R2 = 0.18, P = 7.25 × 10-181 ), word reading and educational attainment (R2 = 0.07, P = 4.91 × 10-48 ) and word reading and ADHD (R2 = 0.02, P = 8.70 × 10-6 ; threshold for significance = 7.14 × 10-3 ). Overlap was also found between RD and autism spectrum disorder (ASD) as top-ranked genes were previously implicated in autism by rare and copy number variant analyses. These findings support shared risk between word reading, cognitive measures, educational outcomes and neurodevelopmental disorders, including ASD.

Cognitive predictors of adaptive functioning in children with symptomatic epilepsy.

The current study sought to understand the contribution of the attention and working memory challenges experienced by children with active epilepsy without an intellectual disability to adaptive functioning (AF) while taking into account intellectual ability, co-occurring brain-based psychosocial diagnoses, and epilepsy-related variables. METHODS: The relationship of attention and working memory with AF was examined in 76 children with active epilepsy with intellectual ability above the 2nd percentile recruited from a tertiary care center. AF was measured using the Scales of Independent Behavior-Revised (SIB-R) and compared with norm-referenced data. Standardized clinical assessments of attention span, sustained attention, as well as basic and more complex working memory were administered to children. Commonality analysis was used to investigate the importance of the variables with respect to the prediction of AF and to construct parsimonious models to elucidate the factors most important in explaining AF. RESULTS: Seventy-one percent of parents reported that their child experienced mild to severe difficulties with overall AF. Similar proportions of children displayed limitations in domain-specific areas of AF (Motor, Social/Communication, Person Living, and Community Living). The reduced models for Broad and domain-specific AF produced a maximum of seven predictor variables, with little loss in overall explained variance compared to the full models. Intellectual ability was a powerful predictor of Broad and domain-specific AF. Complex working memory was the only other cognitive predictor retained in each of the parsimonious models of AF. Sustained attention and complex working memory explained a large amount of the total variance in Motor AF. Children with a previously diagnosed comorbidity displayed lower Social/Communication, Personal Living, and Broad AF than those without a diagnosis. At least one epilepsy-related variable appeared in each of the reduced models, with age of seizure onset and seizure type (generalized or partial) being the main predictors. CONCLUSION: Intellectual ability was the most powerful predictor of AF in children with epilepsy whose intellectual functioning was above the 2nd percentile. Co-occurring brain-based cognitive and psychosocial issues experienced by children with living epilepsy, particularly complex working memory and diagnosed comorbidities, contribute to AF and may be amenable to intervention.

Maintenance effects of working memory intervention (Cogmed) in children with symptomatic epilepsy.

PURPOSE: To extend previous research documenting the benefits of working memory (WM) intervention (Cogmed) immediately post-intervention in children with epilepsy by assessing the 3-month maintenance effects. METHODS: Participants involved in a previous randomized clinical trial (RCT) were invited to participate if they completed Cogmed within the last 3months (n=15) and additional participants (n=13) were prospectively recruited. Standardized assessments of near-transfer effects (i.e., visual and auditory attention and WM) were completed prior to and immediately after intervention and at 3-month follow-up. An additional measure assessing the far-transfer effect of fluid reasoning was administered prior to intervention and at 3-month follow-up. RESULTS: Participants exhibited gains in auditory and visual attention and WM immediately following intervention and gains were generally sustained at 3-month follow-up. Intervention did not improve visual-verbal WM or fluid reasoning. The clinical variables studied (i.e., age of seizure onset, seizure frequency, epilepsy duration, and overall intellectual functioning) did not elucidate reliable relationships with intervention. CONCLUSIONS: Working memory training is possibly efficacious in improving related skills which are maintained for 3months in children with active epilepsy. No transfer to fluid reasoning was documented. Further investigation by means of a large-scale RCT which includes a placebo and both objective and subjective measures of the impact of training on daily functioning is warranted.

Near-transfer effects following working memory intervention (Cogmed) in children with symptomatic epilepsy: An open randomized clinical trial.

OBJECTIVE: Limited research exists regarding the effectiveness of educational and psychological interventions for improving commonly presenting cognitive impairments experienced by children with epilepsy. We evaluated the efficacy of a commercially available, computerized, working memory (WM) program (Cogmed) using a well-defined population of children with epilepsy. METHODS: In this controlled trial, 77 children with symptomatic epilepsy (ages 6.5-15.5 years; 100% taking medication) with estimated intellectual ability greater than the 2nd percentile were randomly assigned to an intervention (n = 42) or waitlist-control (n = 35) group. Standardized assessments of attention and WM were administered pre- and posttraining or waitlist interval, 7 weeks apart. RESULTS: Without intervention, participants displayed significant weaknesses in intelligence, attention, and WM compared to normative samples. After controlling for preintervention scores and intelligence, we found that significant treatment effects for the intervention group were evident for visual attention span, auditory WM, and visual-verbal WM. Intention-to-treat analyses (all participants) and sensitivity analyses (n = 37 and n = 21 for the intervention and waitlist-control groups, respectively) were highly similar, providing confidence to the results. Effect sizes for significant outcomes were large (greater than or equal to two thirds of the standard deviation of the normative-data). The clinical/demographic and functional factors studied did not elucidate who most benefits from training. SIGNIFICANCE: This is the first study to evaluate the effectiveness of intervention to ameliorate WM deficits commonly experienced by children with symptomatic epilepsy. Results support group improvement on some untrained tasks immediately postintervention, demonstrating preliminary usefulness of Cogmed as a treatment option.

Academic achievement one year after resective epilepsy surgery in children.

PURPOSE: Few studies have examined the academic functioning of children following pediatric epilepsy surgery. Although intellectual functioning has been more thoroughly investigated, children with epilepsy may experience additional difficulties with academic skills. This study examined the academic outcomes of a cohort of children who underwent pediatric epilepsy surgery on an average 1.2 (standard deviation [SD]: 0.3) years prior. METHODS: Participants were 136 children (mean age: 14.3 years, [SD]: 3.7 years) who had undergone resective epilepsy surgery. Academic functioning was assessed presurgery and postsurgery using standardized tests of reading, reading comprehension, arithmetic, and spelling. RESULTS: At baseline, 65% of the children displayed low achievement (1 SD below test mean), and 28% had underachievement (1 SD below baseline IQ) in at least one academic domain. Examining change over time revealed that reading, numeral operations, and spelling significantly declined among all patients; seizure freedom at follow-up (attained in 64% of the patients) did not influence this relationship. Reading comprehension and IQ remained unchanged. Similar findings were found when examining patients with a baseline IQ of ≥ 70 and when controlling for IQ. Regression analyses revealed that after controlling for IQ, demographic and seizure-related variables were not significantly associated with academic achievement at follow-up. CONCLUSIONS: Results show baseline academic difficulties and deteriorations following surgery that go beyond IQ. Further investigations are required to determine whether the observed deteriorations result from the development of the child, the course of the disorder, or the epilepsy surgery itself. Long-term studies are warranted to identify the progression of academic achievement and whether the observed deteriorations represent a temporal disruption in function.

Executive functioning in children with intractable frontal lobe or temporal lobe epilepsy.

The aim of the present study was to shed light on the executive functioning deficits that might differentiate children with frontal lobe epilepsy (FLE) from children with temporal lobe epilepsy (TLE). Participants included 19 youth with intractable FLE and 47 youth with intractable TLE. Participants completed the Wisconsin Card Sorting Test (WCST), verbal fluency, Trail Making Test (Trails A and B), Digit Span Forward (DSF), and Digit Span Backward (DSB). When compared to the normative sample, the FLE group performed significantly worse on DSF, DSB, Trails B, and the WCST. Similarly, the TLE group performed significantly worse on DSF and DSB compared to the normative sample. Youth with FLE had significantly greater difficulty on the WCST compared to the TLE group. Overall, the results indicated that youth with FLE had significantly greater difficulty with concept formation compared to children with TLE. No differences between groups emerged on tasks assessing attention, working memory, mental flexibility, or rapid word retrieval. Both groups performed significantly below the normative sample levels on attention and working memory tasks. As a whole, it appears that some, although not all, executive dysfunction is specific to FLE.

Genetic variation in the KIAA0319 5' region as a possible contributor to dyslexia.

Reading disabilities (RD) have been linked and associated with markers on chromosome 6p with results from multiple independent samples pointing to KIAA0319 as a risk gene and specifically, the 5' region of this gene. Here we focus genetic studies on a 2.3 kb region spanning the predicted promoter, the first untranslated exon, and part of the first intron, a region we identified as a region of open chromatin. Using DNA from probands with RD, we screened for genetic variants and tested select variants for association. We identified 17 DNA variants in this sample of probands, 16 of which were previously reported in public databases and one previously identified in a screen of this region. Based on the allele frequencies in the probands compared to public databases, and on possible functional consequences of the variation, we selected seven variants to test for association in a sample of families with RD, in addition to four variants which had been tested previously. We also tested two markers 5' of this region that were previously reported as associated. The strongest evidence for association was observed with alleles of the microsatellite marker located in the first untranslated exon and haplotypes of that marker. These results support previous studies indicating the 5' region of the KIAA0319 gene as the location of risk alleles contributing to RD.