Disadvantage and neurocognitive comorbidities in childhood idiopathic epilepsies.

OBJECTIVE: This study was undertaken to characterize the relationship between neighborhood disadvantage and cognitive function as well as clinical, sociodemographic, and family factors in children with new onset idiopathic epilepsy and healthy controls. METHODS: Research participants were 288 children aged 8-18 years with recent onset epilepsy (CWE; n = 182; mean age = 12.2 ± 3.2 years), healthy first-degree cousin controls (HC; n = 106; mean age = 12.5 ± 3.0), and one biological or adopted parent per child (n = 279). All participants were administered a comprehensive neuropsychological battery (reasoning, language, memory, executive function, motor function, and academic achievement). Family residential addresses were entered into the Neighborhood Atlas to determine each family's Area Deprivation Index (ADI), a metric used to quantify income, education, employment, and housing quality. A combination of parametric and nonparametric (χ2 ) tests examined the effect of ADI by group (epilepsy and controls) across cognitive, academic, clinical, and family factors. RESULTS: Disadvantage (ADI) was equally distributed between groups (p = .63). For CWE, high disadvantage was associated with lower overall intellectual quotient (IQ; p = .04), visual naming/expressive language (p = .03), phonemic (letter) fluency (p < .01), passive inattention (omission errors; p = .03), delayed verbal recall (p = .04), and dominant fine motor dexterity and speed (p < .01). Cognitive status of the HC group did not differ by level of disadvantage (p = .40). CWE exhibited greater academic difficulties in comparison to HC (p < .001), which were exacerbated by disadvantage in CWE (p = .02) but not HC (p < .05). High disadvantage was associated with a threefold risk for academic challenges prior to epilepsy onset (odds ratio = 3.31, p = .024). SIGNIFICANCE: Socioeconomic hardship (increased neighborhood disadvantage) exerts a significant adverse impact on the cognitive and academic status of youth with new and recent onset epilepsies, an impact that needs to be incorporated into etiological models of the neurobehavioral comorbidities of epilepsy.

Neighborhood disadvantage and intellectual development in youth with epilepsy.

RATIONALE: Recent cross-sectional investigations have demonstrated an adverse impact of socioeconomic disadvantage on cognition and behavior in youth and adults with epilepsy. The goal of this study is to investigate the impact of disadvantage on prospective intellectual development in youth with epilepsy. METHOD: Participants were youth, aged 8-18 years, with recent onset epilepsy (n = 182) and healthy first-degree cousin controls (n = 106). The Wechsler Abbreviated Scale of Intelligence (WASI) was administered at baseline and 2 years later. The Neighborhood Atlas identified each family's Area Deprivation Index via state deciles and national percentiles. WASI data were analyzed by mixed group by time ANOVAs followed by regression analysis to identify other baseline predictors of time 2 outcomes. RESULTS: Youth with epilepsy demonstrated significant interactions between group and time for both verbal (F = 4.02, df = 1,215, p =.05) and nonverbal (F = 4.57, df = 1,215, p =.04) reasoning, demonstrating that disadvantage was associated with slower cognitive development compared to advantaged youth with epilepsy. Similar interactions were not observed for controls. CONCLUSIONS: In youth with new and recent onset epilepsies, neighborhood-level disadvantage is associated with a negative impact on the development of verbal and nonverbal reasoning skills.

Behavioral phenotypes of childhood idiopathic epilepsies.

OBJECTIVE: To characterize the presence and nature of discrete behavioral phenotypes and their correlates in a cohort of youth with new and recent onset focal and generalized epilepsies. METHODS: The parents of 290 youth (age = 8-18 years) with epilepsy (n = 183) and typically developing participants (n = 107) completed the Child Behavior Checklist for children aged 6-18 from the Achenbach System of Empirically Based Assessment. The eight behavior problem scales were subjected to hierarchical clustering analytics to identify behavioral subgroups. To characterize the external validity and co-occurring comorbidities of the identified subgroups, we examined demographic features (age, gender, handedness), cognition (language, perception, attention, executive function, speed), academic problems (present/absent), clinical epilepsy characteristics (epilepsy syndrome, medications), familial factors (parental intelligence quotient, education, employment), neuroimaging features (cortical thickness), parent-observed day-to-day executive function, and number of lifetime-to-date Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnoses. RESULTS: Hierarchical clustering identified three behavioral phenotypes, which included no behavioral complications (Cluster 1, 67% of epilepsy cohort [n = 122]), nonexternalizing problems (Cluster 2, 11% of cohort [n = 21]), and combined internalizing and externalizing problems (Cluster 3, 22% of cohort [n = 40]). These behavioral phenotypes were characterized by orderly differences in personal characteristics, neuropsychological status, history of academic problems, parental status, cortical thickness, daily executive function, and number of lifetime-to-date DSM-IV diagnoses. Cluster 1 was most similar to controls across most metrics, whereas Cluster 3 was the most abnormal compared to controls. Epilepsy syndrome was not a predictor of cluster membership. SIGNIFICANCE: Youth with new and recent onset epilepsy fall into three distinct behavioral phenotypes associated with a variety of co-occurring features and comorbidities. This approach identifies important phenotypes of behavior problem presentations and their accompanying factors that serve to advance clinical and theoretical understanding of the behavioral complications of children with epilepsy and the complex conditions with which they co-occur.

Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease.

In the PI(3,5)P2 biosynthetic complex, the lipid kinase PIKFYVE and the phosphatase FIG4 are bound to the dimeric scaffold protein VAC14, which is composed of multiple heat-repeat domains. Mutations of FIG4 result in the inherited disorders Charcot-Marie-Tooth disease type 4J, Yunis-Varón syndrome, and polymicrogyria with seizures. We here describe inherited variants of VAC14 in two unrelated children with sudden onset of a progressive neurological disorder and regression of developmental milestones. Both children developed impaired movement with dystonia, became nonambulatory and nonverbal, and exhibited striatal abnormalities on MRI. A diagnosis of Leigh syndrome was rejected due to normal lactate profiles. Exome sequencing identified biallelic variants of VAC14 that were inherited from unaffected heterozygous parents in both families. Proband 1 inherited a splice-site variant that results in skipping of exon 13, p.Ile459Profs(∗)4 (not reported in public databases), and the missense variant p.Trp424Leu (reported in the ExAC database in a single heterozygote). Proband 2 inherited two missense variants in the dimerization domain of VAC14, p.Ala582Ser and p.Ser583Leu, that have not been previously reported. Cultured skin fibroblasts exhibited the accumulation of vacuoles that is characteristic of PI(3,5)P2 deficiency. Vacuolization of fibroblasts was rescued by transfection of wild-type VAC14 cDNA. The similar age of onset and neurological decline in the two unrelated children define a recessive disorder resulting from compound heterozygosity for deleterious variants of VAC14.

Network analysis of prospective brain development in youth with benign epilepsy with centrotemporal spikes and its relationship to cognition.

OBJECTIVE: Benign epilepsy with centrotemporal spikes (BECTS) is the most common childhood idiopathic localization-related epilepsy syndrome. BECTS presents normal routine magnetic resonance imaging (MRI); however, quantitative analytic techniques have captured subtle cortical and subcortical magnetic resonance anomalies. Network science, including graph theory (GT) analyses, facilitates understanding of brain covariance patterns, potentially informing in important ways how this common self-limiting epilepsy syndrome may impact normal patterns of brain and cognitive development. METHODS: GT analyses examined the developmental covariance among cortical and subcortical regions in children with new/recent onset BECTS (n = 19) and typically developing healthy controls (n = 22) who underwent high-resolution MRI and cognitive assessment at baseline and 2 years later. Global (transitivity, global efficiency, and modularity index [Q]) and regional measures (local efficiency and hubs) were investigated to characterize network development in each group. Associations between baseline-based GT measures and cognition at both time points addressed the implications of GT analyses for cognition and prospective cognitive development. Furthermore, an individual contribution measure was investigated, reflecting how important for cognition it is for BECTS to resemble the correlation matrices of controls. RESULTS: Groups exhibited similar Q and overall network configuration, with BECTS presenting significantly higher transitivity and both global and local efficiency. Furthermore, both groups presented a similar number of hubs, with BECTS showing a higher number in temporal lobe regions compared to controls. The investigated measures were negatively associated with 2-year cognitive outcomes in BECTS. SIGNIFICANCE: Children with BECTS present a higher-than-normal global developmental configuration compared to controls, along with divergence from normality in terms of regional configuration. Baseline GT measures demonstrate potential as a cognitive biomarker to predict cognitive outcome in BECTS 2 years after diagnosis. Similarities and differences in developmental network configurations and their implications for cognition and behavior across common epilepsy syndromes are of theoretical interest and clinical relevance.

Progressive dissociation of cortical and subcortical network development in children with new-onset juvenile myoclonic epilepsy.

OBJECTIVE: Structural and functional magnetic resonance imaging (MRI) studies have consistently documented cortical and subcortical abnormalities in patients with juvenile myoclonic epilepsy (JME). However, little is known about how these structural abnormalities emerge from the time of epilepsy onset and how network interactions between and within cortical and subcortical regions may diverge in youth with JME compared to typically developing children. METHODS: We examined prospective covariations of volumetric differences derived from high-resolution structural MRI during the first 2 years of epilepsy diagnosis in a group of youth with JME (n = 21) compared to healthy controls (n = 22). We indexed developmental brain changes using graph theory by computing network metrics based on the correlation of the cortical and subcortical structural covariance near the time of epilepsy and 2 years later. RESULTS: Over 2 years, normally developing children showed modular cortical development and network integration between cortical and subcortical regions. In contrast, children with JME developed a highly correlated and less modular cortical network, which was atypically dissociated from subcortical structures. Furthermore, the JME group also presented higher clustering and lower modularity indices than controls, indicating weaker modules or communities. The local efficiency in JME was higher than controls across the majority of cortical nodes. Regarding network hubs, controls presented a higher number than youth with JME that were spread across the brain with ample representation from the different modules. In contrast, children with JME showed a lower number of hubs that were mainly from one module and comprised mostly subcortical structures. SIGNIFICANCE: Youth with JME prospectively developed a network of highly correlated cortical regions dissociated from subcortical structures during the first 2 years after epilepsy onset. The cortical-subcortical network dissociation provides converging insights into the disparate literature of cortical and subcortical abnormalities found in previous studies.

Contribution of Family Relatedness to Neurobehavioral Comorbidities in Idiopathic Childhood Epilepsies.

OBJECTIVES: Rates of cognitive, academic and behavioral comorbidities are elevated in children with epilepsy. The contribution of environmental and genetic influences to comorbidity risk is not fully understood. This study investigated children with epilepsy, their unaffected siblings, and controls to determine the presence and extent of risk associated with family relatedness across a range of epilepsy comorbidities. METHODS: Participants were 346 children (8-18 years), n=180 with recent-onset epilepsy, their unaffected siblings (n=67), and healthy first-degree cousin controls (n=99). Assessments included: (1) Child Behavior Checklist/6-18 (CBCL), (2) Behavior Rating Inventory of Executive Function (BRIEF), (3) history of education and academic services, and (4) lifetime attention deficit hyperactivity disorder (ADHD) diagnosis. Analyses consisted of linear mixed effect models for continuous variables, and logistic mixed models for binary variables. RESULTS: Differences were detected between the three groups of children across all measures (p<.001). For ADHD, academic problems, and executive dysfunction, children with epilepsy exhibited significantly more problems than unaffected siblings and controls; siblings and controls did not differ statistically significantly from each other. For social competence, children with epilepsy and their unaffected siblings displayed more abnormality compared with controls, with no statistically significant difference between children with epilepsy and unaffected siblings. For behavioral problems, children with epilepsy had more abnormality than siblings and controls, but unaffected siblings also exhibited more abnormalities than controls. CONCLUSIONS: The contribution of epilepsy and family relatedness varies across specific neurobehavioral comorbidities. Family relatedness was not significantly associated with rates of ADHD, academic problems and executive dysfunction, but was associated with competence and behavioral problems. (JINS, 2018, 24, 653-661).

Cognitive phenotypes in childhood idiopathic epilepsies.

OBJECTIVE: The objective of this study was to identify cognitive phenotypes in children with new-onset focal and generalized idiopathic epilepsies and determine their relationship with epilepsy syndrome, brain structure, neurodevelopmental history, and family characteristics. METHODS: One hundred thirty-eight children with new-onset epilepsy and 95 controls (age: 8-18) underwent neuropsychological, clinical, and quantitative MR evaluations. Control participants' neuropsychological data were subjected to confirmatory factor analysis and then resultant factor scores were applied to participants with epilepsy and subjected to latent class analysis. Identified cognitive phenotypes were examined in relation to epilepsy syndrome, quantitative neuroimaging, and familial and neurodevelopmental variables. RESULTS: Confirmatory factor analysis identified five cognitive factors (verbal, perceptual, speed, attention, executive), and latent class analysis identified three clusters of participants with epilepsy: 1) average and similar to controls, 2) mild impairment across multiple cognitive domains, and 3) impairment across all domains with severe attentional impairment, representing 44%, 44%, and 12% of the epilepsy sample, respectively. Cognitive phenotype membership was not associated with epilepsy syndrome but was associated with increasing abnormalities in brain structure, parental IQ, and features of early developmental history. SIGNIFICANCE: Cognitive phenotypes are present in idiopathic childhood epilepsies that are unassociated with traditional epilepsy syndromes but are associated with measures of brain structure, family history, and neurodevelopmental features.

Neurodevelopment in new-onset juvenile myoclonic epilepsy over the first 2 years.

OBJECTIVE: Adults with juvenile myoclonic epilepsy (JME) have subtle brain structural abnormalities in the frontothalamocortical network, poorer cognitive function, and worse long-term social outcomes, even when their seizures are controlled and/or remitted. The natural history of JME and development of abnormalities in brain structure and cognition from epilepsy onset has not been studied. METHODS: The maturational trajectories of cognitive and brain development were prospectively compared between 19 children with new-onset JME in the first 2 years after diagnosis and 57 healthy controls. RESULTS: Cognitive abilities of children with JME were similar to or worse than healthy controls at baseline but failed to reach the competence level of healthy controls at follow-up across most of the tested cognitive abilities. Abnormal patterns of brain development, as assessed by magnetic resonance imaging studies, were evident in children with JME and included attenuation of age-related decline in cortical volume, thickness, and surface area compared to typically developing children. The altered brain developmental trajectory in the JME group was evident in higher-association frontoparietotemporal brain regions (p < 0.05, corrected for multiple comparisons). INTERPRETATION: Children with JME have abnormal structural brain development and impaired cognitive development early in the course of their epilepsy.

Children with epilepsy and anxiety: Subcortical and cortical differences.

OBJECTIVE: Using a hypothesis-driven approach, subcortical and cortical regions implicated in anxiety disorders in the general population were examined in children with recent-onset epilepsy with versus without anxiety compared to controls. This study reports frequency of anxiety disorders while examining familial, clinical, and demographic variables associated with anxiety in children with epilepsy. METHOD: Participants included 88 children with epilepsy aged 8-18 years: 25 with a current anxiety disorder and 63 children with epilepsy and no current anxiety disorder. Forty-nine controls without anxiety disorders were included. T1 volumetric magnetic resonance imaging (MRI) scans were collected; subcortical volumes and cortical thickness were computed using the FreeSurfer image analysis suite. Analyses focused on adjusted measures of subcortical volumes and cortical thickness. RESULTS: Relative to controls, larger left amygdala volumes were found in the Epilepsy with Anxiety group compared to the Epilepsy without Anxiety group (p = 0.027). In the hippocampus, there were no significant differences between groups. Examination of cortical thickness demonstrated that the Epilepsy with Anxiety group showed thinning in left medial orbitofrontal (p = 0.001), right lateral orbitofrontal (p = 0.017), and right frontal pole (p = 0.009). There were no differences between groups in age, sex, IQ, age of onset, medications, or duration of epilepsy. There were more family members with a history of anxiety disorders in the Epilepsy with Anxiety group compared to the Epilepsy without Anxiety group (p = 0.005). SIGNIFICANCE: Anxiety is a common psychiatric comorbidity in children with recent-onset epilepsy with volumetric enlargement of the amygdala and thinner cortex in orbital and other regions of prefrontal cortex, suggesting structural abnormalities in brain regions that are part of the dysfunctional networks reported in individuals with anxiety disorders in the general population. These findings are evident early in the course of epilepsy, are not related to chronicity of seizures, and may be linked to a family history of anxiety and depressive disorders.

Cognition and brain development in children with benign epilepsy with centrotemporal spikes.

OBJECTIVE: Benign epilepsy with centrotemporal spikes (BECTS), the most common focal childhood epilepsy, is associated with subtle abnormalities in cognition and possible developmental alterations in brain structure when compared to healthy participants, as indicated by previous cross-sectional studies. To examine the natural history of BECTS, we investigated cognition, cortical thickness, and subcortical volumes in children with new/recent onset BECTS and healthy controls (HC). METHODS: Participants were 8-15 years of age, including 24 children with new-onset BECTS and 41 age- and gender-matched HC. At baseline and 2 years later, all participants completed a cognitive assessment, and a subset (13 BECTS, 24 HC) underwent T1 volumetric magnetic resonance imaging (MRI) scans focusing on cortical thickness and subcortical volumes. RESULTS: Baseline cognitive abnormalities associated with BECTS (object naming, verbal learning, arithmetic computation, and psychomotor speed/dexterity) persisted over 2 years, with the rate of cognitive development paralleling that of HC. Baseline neuroimaging revealed thinner cortex in BECTS compared to controls in frontal, temporal, and occipital regions. Longitudinally, HC showed widespread cortical thinning in both hemispheres, whereas BECTS participants showed sparse regions of both cortical thinning and thickening. Analyses of subcortical volumes showed larger left and right putamens persisting over 2 years in BECTS compared to HC. SIGNIFICANCE: Cognitive and structural brain abnormalities associated with BECTS are present at onset and persist (cognition) and/or evolve (brain structure) over time. Atypical maturation of cortical thickness antecedent to BECTS onset results in early identified abnormalities that continue to develop abnormally over time. However, compared to anatomic development, cognition appears more resistant to further change over time.

Brief clinical screening for academic underachievement in new-onset childhood epilepsy: utility and longitudinal results.

OBJECTIVE: This study was conducted to determine the lifetime rate and distribution of supportive academic and educational services provided to children with new- or recent-onset epilepsy and typically developing controls, the relationship of this history to objective academic test performance, and the course of performance over serial evaluations (baseline and 2 and 5years later). METHODS: Research participants were 91 children aged 8-18 at study entry, including 50 youth with recent-onset epilepsy (28 focal [FE] and 22 generalized [GE] epilepsy) and healthy first-degree cousin controls (n=41). The sample with epilepsy included children with uncomplicated epilepsy and normal imaging and development. Lifetime history of a diversity of supportive educational services was determined via a structured interview with parents at the baseline study visit. Associations were examined between these support services and participants' academic performance in reading, spelling, and arithmetic (Wide Range Achievement Test-Revision 3 [WRAT3] [12]) during three serial study visits including baseline and 2 and 5years later. RESULTS: Children with epilepsy had a higher lifetime rate of provision of diverse academic supportive services compared to controls at the baseline visit (52% vs. 18%). These services antedated epilepsy diagnosis in the majority (80.8%) of the children with epilepsy. Among children with epilepsy, children who presented with academic services had significantly lower WRAT3 reading, spelling, and arithmetic performance at baseline and at 2- and 5-year follow-ups. CONCLUSION: A brief structured clinical interview conducted with parents identifies children with epilepsy who are at academic risk at the time of diagnosis, with that risk persisting up to 5years later.

Longitudinal trajectories of behavior problems and social competence in children with new onset epilepsy.

AIM: To characterize the prospective trajectory of parent-reported behavior and social competence problems in children with new or recent onset epilepsy from diagnosis to 5 to 6 years after diagnosis compared to healthy control participants. METHOD: Thirty-five children (21 males, 14 females; mean age 14y 1mo [SD 3y 4mo] range 8-18y) with new/recent onset idiopathic generalized (IGE) and 34 children with localization-related epilepsies (LRE; 19 males, 15 females; mean age 10y 8mo [SD 2y 2mo] range 8-18y) underwent behavioral assessment (Child Behavior Checklist) at baseline, 2 years, and 5 to 6 years after diagnosis. The assessment comprised the summary scales Total Behavior Problems Internalizing Problems, Externalizing Problems, and Total Competence. Sixty-two children with normal development served as comparison participants. Analyses were based on random effects regression modeling comparing trajectories with respect to time since epilepsy diagnosis among groups. RESULTS: Differences in parent-reported behavioral problems between LRE and IGE syndrome groups and healthy comparison participants were detectable at or near the time of diagnosis and remained either stable (competence) or tended to abate (behavior problems) over the ensuing 5 to 6 years without evidence of progressive worsening. These trends were evident for both LRE and IGE groups, with no differences between them. INTERPRETATION: Behavior and competence problems in children with LRE and IGE are not characterized by progressive worsening over a 5- to 6-year period. Behavioral problems are present near the time of diagnosis and tend to abate over time, with competence problems being more persistent across serial assessments, and present in both LRE and IGE groups.

Neurodevelopmental alterations of large-scale structural networks in children with new-onset epilepsy.

Recent neuroimaging and behavioral studies have revealed that children with new onset epilepsy already exhibit brain structural abnormalities and cognitive impairment. How the organization of large-scale brain structural networks is altered near the time of seizure onset and whether network changes are related to cognitive performances remain unclear. Recent studies also suggest that regional brain volume covariance reflects synchronized brain developmental changes. Here, we test the hypothesis that epilepsy during early-life is associated with abnormalities in brain network organization and cognition. We used graph theory to study structural brain networks based on regional volume covariance in 39 children with new-onset seizures and 28 healthy controls. Children with new-onset epilepsy showed a suboptimal topological structural organization with enhanced network segregation and reduced global integration compared with controls. At the regional level, structural reorganization was evident with redistributed nodes from the posterior to more anterior head regions. The epileptic brain network was more vulnerable to targeted but not random attacks. Finally, a subgroup of children with epilepsy, namely those with lower IQ and poorer executive function, had a reduced balance between network segregation and integration. Taken together, the findings suggest that the neurodevelopmental impact of new onset childhood epilepsies alters large-scale brain networks, resulting in greater vulnerability to network failure and cognitive impairment.

Birth weight and cognition in children with epilepsy.

OBJECTIVE: Birth weight is an important indicator of prenatal environment, and subtle variations of birth weight within the normal range have been associated with differential risk for cognitive and behavioral problems. Therefore, we aimed to determine if there are differences in birth weight between full-term children with uncomplicated new/recent-onset epilepsies and typically developing healthy controls. We further examined the relationships between birth weight and childhood/adolescent cognition, behavior, and academic achievement. METHODS: One hundred eight children with new-onset/recent-onset epilepsy and 70 healthy controls underwent neuropsychological assessment. All participants were born full-term (>37 weeks) without birth complications. Parents were interviewed regarding their child's gestation, birth, and neurodevelopmental history. RESULTS: Birth weight of children with epilepsy was significantly lower than healthy controls (p = 0.023). Whereas birth weight (covaried with age, sex, handedness, and mother's education) was significantly associated with cognition in controls in multiple domains (intelligence, language, aspects of academic achievement), this relationship was absent in children with epilepsy. Birth weight was not associated with clinical epilepsy variables (age of onset, epilepsy syndrome) and was not predictive of a variety of other academic or psychiatric comorbidities of epilepsy. SIGNIFICANCE: Although the origin of lower birth weight in children with epilepsy is unknown, these findings raise the possibility that abnormal prenatal environment may affect childhood-onset epilepsy. Furthermore, the positive relationship between birth weight and cognition evident in healthy controls was disrupted in children with epilepsy. However, birth weight was not related to academic and psychiatric comorbidities of childhood epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Cognitive development in children with new onset epilepsy.

AIM: To characterize the prospective trajectory of cognitive development in children with new or recent onset epilepsy from baseline to 5 to 6 years after diagnosis. METHOD: Sixty-nine children (40 males, 29 females; age 8-18y), with new or recent onset epilepsies underwent neuropsychological assessment shortly after diagnosis (Wave 1), 2 years (Wave 2), and 5 to 6 years after diagnosis (Wave 3). Intelligence, academic achievement, language, executive function, and psychomotor speed were evaluated. Sixty-two children (28 males, 34 females; age 8-18) with typical development served as a comparison group at each time point. The cognitive data were examined by syndrome (localization-related epilepsy [LRE]; idiopathic generalized epilepsy [IGE]; comparison group). Mixed effect regression models compared trajectories among groups with respect to time since diagnosis. RESULTS: Cognitive abnormalities exhibited by children with epilepsy in arithmetic computation, response inhibition, attention, fine motor dexterity, and psychomotor speed (all p values <0.001), are detectable at or near the time of diagnosis and largely remain stable over the ensuing 5 to 6 years without evidence of progressive worsening or recovery. This course is evident across both LRE and IGE groups, with the LRE group performing better for some outcomes (arithmetic, response inhibition, psychomotor speed) and never worse than the IGE group. INTERPRETATION: Cognitive development in children with LRE and IGE is not characterized by progressive deterioration or lack of age-appropriate development; rather, development lags behind that of children with typical development. Cognitive abnormalities, when detected, are present near the time of diagnosis, persist over time, and require early intervention.

The neuropsychological and academic substrate of new/recent-onset epilepsies.

OBJECTIVE: To characterize neuropsychological and academic status in children, ages 8-18 years, with new-/recent-onset idiopathic generalized epilepsy (IGE) and idiopathic localization-related epilepsy (ILRE) compared with healthy controls. STUDY DESIGN: Participants underwent neuropsychological assessment, and parents were interviewed regarding their child's academic history. Cognitive scores for children with epilepsy were age- and sex-adjusted and compared with controls across both broad-band (IGE n = 41 and ILRE n = 53) and narrow-band (childhood/juvenile absence, juvenile myoclonic, benign epilepsy with centro-temporal spikes, and focal [temporal/frontal/not otherwise specified]) syndromes. Academic histories were examined, including problems antecedent to epilepsy onset and diagnosis. RESULTS: Children with new/recent-onset epilepsies exhibit considerable cognitive abnormality at baseline, including patterns of shared abnormalities across syndromes (eg, psychomotor slowing) as well as unique syndrome-specific cognitive effects (eg, executive function in IGE and language/verbal memory in ILRE) that are observed and sometimes exacerbated in specific IGE and ILRE syndromes. Academic difficulties are evident in approximately 50% of the children with epilepsy, affecting all syndrome groups to an equal degree. DISCUSSION: Patterns of shared and syndrome-specific cognitive abnormalities and academic problems are present early in the course of virtually all epilepsy syndromes examined here, including syndromes classically viewed as benign. This is the base upon which the effects of recurrent seizures, treatment, and psychosocial effects will be added over time.

Is lower IQ in children with epilepsy due to lower parental IQ? A controlled comparison study.

AIM: The aim of this study was to determine the relationship between parent and child Full-scale IQ (FSIQ) in children with epilepsy and in typically developing comparison children and to examine parent-child IQ differences by epilepsy characteristics. METHOD: The study participants were 97 children (50 males, 47 females; age range 8-18y; mean age 12y 3mo, SD 3y1mo) with recent-onset epilepsy including idiopathic generalized (n=43) and idiopathic localization-related epilepsies (n=54); 69 healthy comparison children (38 females, 31 males; age range 8-18y; mean age 12y 8mo, SD 3y 2mo), and one biological parent per child. All participants were administered the Wechsler Abbreviated Scale of Intelligence (WASI). FSIQ was compared in children with epilepsy and typically developing children; FSIQ was compared in the parents of typically developing children and the parents of participants with epilepsy; parent-child FSIQ differences were compared between the groups. RESULTS: FSIQ was lower in children with epilepsy than in comparison children (p<0.001). FSIQ of parents of children with epilepsy did not differ from the FSIQ of the parents of typically developing children. Children with epilepsy had significantly lower FSIQ than their parents (p<0.001), whereas comparison children did not. The parent-child IQ difference was significantly higher in the group with epilepsy than the comparison group (p=0.043). Epilepsy characteristics were not related to parent-child IQ difference. INTERPRETATION: Parent-child IQ difference appears to be a marker of epilepsy impact independent of familial IQ, epilepsy syndrome, and clinical seizure features. This marker is evident early in the course of idiopathic epilepsies and can be tracked over time.

Striatal hypertrophy and its cognitive effects in new-onset benign epilepsy with centrotemporal spikes.

PURPOSE: Benign epilepsy with centrotemporal spikes (BECTS), the most common childhood epilepsy syndrome, is a neurodevelopmental disorder with a genetic influence. Despite its signature electroencephalographic pattern and distinct focal motor seizure semiology, little is known about the underlying brain anatomic alteration and the corresponding cognitive consequences. Given the motor manifestations of seizures in BECTS, we hypothesize that anatomic networks in BECTS involve a distributed corticostriatal circuit. METHODS: We investigated volumetric differences and shape deformities of caudate, putamen, pallidum, and thalamus in a group of children with new- and recent-onset BECTS (N = 3) compared to healthy controls (N = 54). We correlated specific subcortical volumes in BECTS that were significantly different from those in healthy controls with performances in executive function. KEY FINDINGS: Children with BECTS demonstrated significantly hypertrophied putamen, which was selective among the subcortical regions examined. Shape analysis showed dorsoventral elongation of the left caudate and bilateral putamen, with subnuclei expansion in ventral and dorsal striatum. Larger putamen volumes were linked to better cognitive performances on two complementary executive function tests. SIGNIFICANCE: Children with BECTS showed aberrant volume and shape in subcortical regions that are critical for both motor processing and executive function. It is of importance to note that the hypertrophy appears to be cognitively adaptive, as enlargement was associated with improved cognitive performances. The anatomic abnormalities and their cognitive effects are evident in a group of children with new- and recent-onset epilepsy, suggesting that the structural brain anomalies occurred before the diagnosis of epilepsy.

Ventricular enlargement in new-onset pediatric epilepsies.

PURPOSE: To examine baseline and prospective (2-year) changes in third, fourth, and lateral ventricle volumes in children with new-onset idiopathic epilepsies and controls (age 8-18 years). METHODS: Structural magnetic resonance imaging (MRI) were collected from children with idiopathic generalized epilepsy (IGE, n = 29), idiopathic localization-related epilepsy (ILRE, n = 30), and healthy controls (HCs, n = 49). Volumes of the third, fourth, and lateral ventricles were derived and compared across groups, followed by shape analyses, to identify specific regions of ventricular abnormality. Of the initial cohort, a consecutive sample of 71 children returned 2 years later for reimaging and determination of progressive changes in the ventricular system. KEY FINDINGS: At baseline, children with new-onset IGE had significantly larger lateral and third ventricle volumes relative to the HC group. In addition, lateral ventricle enlargement in IGE was significantly greater compared to new-onset ILRE. Shape analysis of the lateral ventricles revealed that volume expansion in IGE was selective for the anterior horn, a region surrounded by the lateral and medial frontal lobes as well as basal ganglia. These abnormalities did not progress over a 2-year interval. SIGNIFICANCE: Abnormalities in brain development prior to onset and diagnosis of epilepsy are evident and reflected in expansion of the ventricular system, especially among children with IGE. These abnormalities appear to represent an antecedent and possibly static finding given the lack of progressive ventricular expansion over the 2-year interval following diagnosis and treatment.